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Sexually transmitted diseases and infertility


Danielle G. Tsevat, BA; Harold C. Wiesenfeld, MD, CM; Caitlin Parks, MD; Jeffrey F. Peipert, MD, PhD

Overview
Infertility, which is defined as the Female infertility, including tubal factor infertility, is a major public health concern worldwide.
inability to conceive after 12 months of Most cases of tubal factor infertility are attributable to untreated sexually transmitted
regular unprotected sexual intercourse, diseases that ascend along the reproductive tract and are capable of causing tubal
is a common public health concern inflammation, damage, and scarring. Evidence has consistently demonstrated the effects of
worldwide. Globally, 9% of Chlamydia trachomatis and Neisseria gonorrhoeae as pathogenic bacteria involved in
reproductive-aged women, including reproductive tract morbidities including tubal factor infertility and pelvic in-flammatory
nearly 1.5 million women in the United disease. There is limited evidence in the medical literature that other sexually transmitted
1,2
States, are infertile. The burden of organisms, including Mycoplasma genitalium, Trichomonas vaginalis, and other
infertility is inordinately higher among microorganisms within the vaginal microbiome, may be important factors involved in the
women in developing countries; in pathology of infertility. Further investigation into the vaginal microbiome and other potential
some regions of south and central Asia, pathogens is necessary to identify preventable causes of tubal factor infertility. Improved
sub-Saharan and northern Africa, the clinical screening and prevention of ascending infection may provide a solution to the
Mid-dle East, and eastern Europe, persistent burden of infertility.
infertility rates can reach up to 30% in
3 Key words: chlamydia, gonorrhea, infertility, STD, STI
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 couples, involuntary infertility can lead to along mucosal surfaces from the cervix
major psychological stressor for millions stigmatization, economic deprivation, to the endometrium and ultimately to the
4 social isolation and loss of status, public fallopian tubes. This causal pathway
of couples. In many areas of the world,
especially in low- and middle-income shame and humiliation, and in some presents itself clinically as acute pelvic
5,6
countries where having biological chil- cases, violence. Female infertility may inflammatory disease (PID), which in
dren is highly valued and expected of be attributed to a number of factors, turn is strongly associated with subse-
typically divided into endocrine, vaginal, quent TFI. In fact, approximately 15% of
From the Division of Clinical Research, cervical, uterine, tubal, and pelvic- women with PID develop TFI, and the
Department of Obstetrics and Gynecology, peritoneal factors, and although esti- number of episodes of PID a woman
Washington University in St Louis School of mates vary, approximately 15-30% of experiences is directly proportional to
Medicine, St Louis, MO (Ms Tsevat and Dr 7 11,12
cases still remain unexplained. Further her risk of infertility. However, the
Parks); Division of Gynecologic Specialties,
Department of Obstetrics and Gynecology, insight into the causes of infertility is majority of women with TFI do not have
University of Pittsburgh School of Medicine, necessary to help alleviate this multifac- a history of clinically diagnosed acute
Pittsburgh, PA (Dr Wiesenfeld); and torial burden on society. PID, but rather develop asymptomatic or
Department of Obstetrics and Gynecology, Tubal factor infertility (TFI) ranks minimally symptomatic salpingitis as a
Indiana University School of Medicine, among the most common causes of 9,13
Indianapolis, IN (Dr Peipert).
result of upper genital tract infection.
infertility, accounting for 30% of female Examining the effect of those infections,
Received May 27, 2016; revised July 29, infertility in the United States, and is
2016; accepted Aug. 8, 2016. particularly those that occur in the
even more prevalent in certain commu- absence of clinically evident PID, is
Drs. Wiesenfeld and Peipert contributed to this 8
manuscript on behalf of the Infectious Disease nities. Paralleling the aforementioned critical to understanding TFI.
Society for Obstetrics & Gynecology (IDSOG), global infertility disparity, TFI is Several sexually transmitted diseases
and the Publications Committee of IDSOG has disproportionately common in women in (STDs), including Chlamydia trachomatis
approved the final version. developing countries; for example, it has and Neisseria gonorrhoeae, have been
Disclosure: Dr Peipert receives research been shown to account for >85% of widely studied to understand their role in
support from Bayer, Merck, and Teva, and female infertility cases in regions of sub- salpingitis and infertility. Additionally, several
serves on advisory boards for Teva and Saharan Africa, compared to 33% of other pathogens such as Myco-plasma
Perrigo. The other authors report no financial 3
conflicts of interest in the past 12 months. cases worldwide. Most cases of TFI are genitalium, Trichomonas vaginalis, and
Corresponding author: Jeffrey F. Peipert, due to salpingitis, an inflammation of the other microorganisms within the vaginal
MD, PhD. jpeipert@iu.edu epithelial surfaces of the fallopian tubes, microbiome, may also play roles in tubal
0002-9378/$36.00
and subsequent pelvic-peritoneal damage and other potential cau-ses of
ª 2016 Elsevier Inc. All rights reserved.
adhesions, both of which are most infertility. Still, data suggest that not all
http://dx.doi.org/10.1016/j.ajog.2016.08.008
commonly caused by previous or infections yield the same long-term sequelae.
9,10
persistent infections. Bacteria ascend The roles of different STD

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pathogens, co-infections, and interactions with C trachomatis and N gonorrhoeae associated with a significantly increased
host characteristics, including their individual C trachomatis and N gonorrhoeae have risk of tubal infertility in women,
vaginal microbiome, may all affect a woman’s been extensively shown to be associated regardless of the infection invoking
subsequent ability to conceive. While with infertility, particularly by causing tubal 20,25,29-32
clinical symptoms. Extensive
screening and treatment efforts for C inflammation. In fact, early spec-ulation research has also shown that C tracho-
trachomatis and N gonor-rhoeae have been regarding the effect of N gonor-rhoeae on matis infection can cause PID, which
developed to reduce the incidence of PID and female fertility dates back to the 1870s, often precedes infertility. Today, C tra-
subsequent TFI, additional data are needed to when the German-born gy-necologist Emil chomatis accounts for approximately
determine the role of other potential Noeggerath published his revolutionary 50% of cases of acute PID in developed
pathogens and whether early detection can claims about gonor-rhea as a clinical 33
countries. Among PID patients, those
prevent tubal damage. In this article, we condition in his book Latent Gonorrhoea with prior C trachomatis infection have
discuss the pathogens C trachomatis, N Especially with Regard to its Influence been shown to be more likely to expe-
gonorrhoeae, Mycoplasma genitalium, T on Fertility in Women.14 Although he may rience subsequent infertility than those
vaginalis, and other potential organisms that have widely over-estimated its without a history of C trachomatis
repercussions (postulating that gonorrhea 32-35
may affect female fertility, and we address the infection.
clinical importance of screening and causes 90% of female infertility), his While C trachomatis seropositivity
preventing the spread of those infections. theories eventually sparked the initiation of has long been shown to influence fal-
further in-vestigations.15 When the 36
lopian tube patency, the use of a newer,
bacterium N gonorrhoeae was finally more sensitive and specific anti-
Methodology isolated, Noeg-gerath’s controversial claims chlamydial assay by Geisler and co-
We conducted a comprehensive litera-ture regarding the persistence of this “venereal 37
workers has only recently been shown
search to identify articles by using the poison” in the reproductive organs and its to hold promise as a measure of tubal
electronic databases MEDLINE, Embase, path-ologic consequences were 38
function. In a cohort study of 1250
Web of Science, and CINAHL, in addition reexamined.16 Studies conducted more than infertile women with documented tubal
to scrutinizing references of identified a century later have since demonstrated the patency undergoing fertility treatment, C
articles. Within each database, we impact of C trachomatis and N trachomatis seropositivity using the
combined the term “female infer-tility” with gonorrhoeae on subsequent infertility. antibody subclasses IgG1 and IgG3 was
4 different infection terms: “Chlamydia 39
tested. Results showed that of these 2
trachomatis,” “Neisseria gonorrhoeae,” C trachomatis, the most common antibody subclasses tested, seroposi-
“Mycoplasma genitalium,” and reportable disease in the United States, tivity to C trachomatis based on IgG3
“Trichomonas vaginalis.” Within the affects nearly 1.5 million people in the detection was a strong predictor of both
MEDLINE database, we refined the search 17 failure to conceive and ectopic preg-
US annually. Unfortunately, however,
by excluding the Medical Subject Headings because C trachomatis infections are nancy outcomes. Because IgG3 has been
unrelated to female infertility and at least 1 18,19 shown to be involved in early in-
asymptomatic in most women, in- 40
of the 4 organisms. Within the Embase fections are often unnoticed, untreated, flammatory response to infection, the
search, we used Emtree to identify terms, and underreported. For almost 40 years, detection of IgG3 in these women may
and used both “female infertility” and evidence has shown that un-treated reflect a recently cleared or persistent C
“uterine tube occlusion” as focused search ascending C trachomatis infec-tion can trachomatis infection, contributing to
terms to combine with each infection. We lead to irrevocable damage in the fallopian tube damage while perhaps not
filtered results to only include articles fallopian tubes including proximal yet leading to blockage of the fal-lopian
39
published in English between 1975 and and distal tubal occlusions leading to tubes.
April 2016. Additional relevant articles 9 In another study of subfertile women
infertility. The increased amount of heat
were identified from bibliographies and by shock protein synthesized by C with no visible tubal pathology, positive
the recommen-dation of medical experts. trachomatis induces a proinflammatory chlamydial antibody testing was associ-
The inclusion of the articles used in the immune response in the human fallo- ated with a 33% lower spontaneous
analysis was based on quality of the study pian tube epithelia, resulting in scarring pregnancy rate than those without
9,20,21 28,39
and rele-vance to this review: studies were and tubal occlusion. A number of chlamydial antibodies. Coppus and
excluded if they were conducted with few seroepidemiological studies have colleagues
28
suggest that these low
participants, had no comparison group, or examined the prevalence of antibodies pregnancy rates may not only be caused
constituted case reports. Studies that did not to C trachomatis and chlamydial heat by the known mechanism of chronic
report sufficient data to determine the shock protein in women with lapa- inflammatory response causing fallopian
association with female infertility or roscopically or hysterosalpingo- tube damage; persistent C trachomatis
reproductive morbidities were excluded for graphically confirmed fallopian tube infections have also been shown to elicit
lack of relevance to the topic of review. 22-28 an autoimmune response to human heat
damage and ectopic pregnancies. The
results of these studies indicate that shock proteins, which may elevate the
history of C trachomatis infection is risk for impaired embryo development

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41,42
and implantation. Chlamydial anti- pathogens the most important known Two of those studies demonstrated a
body testing may therefore continue to preventable causes of infertility, and significant correlation between presence
become a valuable predictor of not only improving screening programs for these of antibodies against Mycoplasma geni-
tubal patency, but also of ectopic preg- prevalent and commonly asymptomatic talium and laparoscopically confirmed
nancy, intrauterine insemination failure, pathogens may therefore make a TFI, independent of C trachomatis
and embryo and pregnancy wastage, critical impact in the prevention of seropositivity.23,24 According to Svenstrup
independent of tubal damage. tubal pa-thology and infertility. and colleagues,24 among women with TFI,
Although less prevalent than C tra- 23% had antibodies to C trachomatis and
chomatis in the United States, gonorrhea Mycoplasma genitalium 17% to Mycoplasma genitalium; whereas
is still the second most common While N gonorrhoeae and C trachomatis 15% and 4% of infertile women with
17 are known to be pathogens in salpingitis
reportable disease in the United States. normal fallopian tubes had antibodies to
N gonorrhoeae infections are also often and tubal infertility, in many cases, neither each, respec-tively. Although not quite as
asymptomatic among women, but as organism is identified.50 Myco-plasma high as the prevalence of antibodies to C
14 genitalium, a member of the Mollicutes trachoma-tis, prior Mycoplasma
Noeggerath suspected in the 1870s, the
bacterium is capable of ascending to the class with the smallest known genome of genitalium infec-tion is thought to be an
upper genital tract and causing severe any free-living organism,52 was discovered independent risk factor for TFI. In a similar
reproductive morbidities. In particular, N in 1981 when it was first isolated from men study by Clausen and colleagues, 23
gonorrhoeae attacks the epithelial cells 53
with nongono-coccal urethritis. After the serological analyses of women with TFI
of the fallopian tube, both initially by develop-ment of nucleic acid amplification reinforced the finding that Mycoplasma
attaching to the nonciliated mucosal cells assays in the early 1990s facilitating its genitalium is independently associated
and by sloughing off ciliated mucosal detec-tion, Mycoplasma genitalium has with tubal inflammation leading to
9
cells. The resulting damage hinders the since been shown to be a common sexually infertility.23 A more recent study by Idahl
fallopian tubes’ ability to transport the 54
transmitted organism. In 2007, the United and col-leagues59 examined the association
ovum for fertilization within the tubes States prevalence of Mycoplasma be-tween Mycoplasma genitalium
and implantation in the uterus, thus genitalium in young adults was 1%, antibodies and infertility in 239 women
ultimately elevating the risk of infertility placing it between the prevalences of N diagnosed with infertility of various causes,
and ectopic pregnancy. gonorrhoeae (0.4%) and C trachomatis including laparoscopically and hyster-
Several seroepidemiological studies have (2.3%) infections, and it has been detected osalpingographically confirmed TFI,
demonstrated the pathogen’s effects on in 15-20% of high-risk, sexually active compared to 244 fertile controls. The
fallopian tube damage and subse-quent women in the United States.55-57 results indicate that Mycoplasma geni-
43-47
infertility. Throughout those studies, talium serum antibodies are more com-mon
women with laparoscopically and Since its discovery, numerous studies among women with all causes of infertility
hysterosalpingographically con-firmed TFI demonstrate that Mycoplasma geni- (5.4%) than in fertile controls (1.6%).
have consistently demon-strated a talium is strongly associated with male Among the infertile women in that sample
significantly higher prevalence of urethritis. In an analysis of 34 studies diagnosed specifically with TFI, 9.1% were
serologically confirmed N gonorrhoeae published from 1993 through 2011 seropositive for Myco-plasma genitalium
infection than women with normal fal- studying men with nongonococcal ure- compared with 4.6% of the fertile controls,
lopian tubes. Like chlamydial PID, thritis, 13% of 7123 men tested positive although the as-sociation between TFI and
gonococcal PID has been shown to be an for Mycoplasma genitalium, and Mycoplasma genitalium was not
important cause of fallopian tube dam-age, several studies have demonstrated that statistically signifi-cant after adjusting for
greatly increasing a woman’s risk of TFI. Myco-plasma genitalium can cause C trachomatis seropositivity.59
Between 10-19% of women with cervical N 58
persistent or recurrent urethritis. After
gonorrhoeae infections have clinical signs
the initial findings of Mycoplasma
of acute PID48 and in re-gions of the United genitalium demonstrating its effects in Supporting evidence has shown an
States that had high endemic rates of males, in-vestigators soon began to look association between infection with
gonorrhea during the 1970s and 1980s, at its ef-fects on the female reproductive Mycoplasma genitalium at the time of
gonorrhea was found in >40-50% of tract. While there are fewer studies in infertility evaluation and laparoscopi-
patients with PID.49 In recent studies, the women, Mycoplasma genitalium has cally confirmed tubal infertility, rather
bacteria were identi-fied in approximately been inves-tigated to evaluate its than serologically investigating infection
20% of women diagnosed with acute PID, association with several morbidities in history. In a study comparing infertile
suggesting that N gonorrhoeae is not as women, including cervicitis, urethritis, and fertile women by polymerase chain
frequent a 58 reaction testing of cervical samples,
PID, ectopic preg-nancy, and TFI.
cause of acute PID as it was in the Four serological studies have investi- Mycoplasma genitalium was detected
50,51 more frequently in infertile women
past. Still, the impact of both chla- gated the relationship between past
mydial and gonococcal infections on the Mycoplasma genitalium infection in (19.6%) compared to fertile women
23,24,59,60 61
fallopian tubes currently make these women and tubal infertility. (4.4%). However, in the study by

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24 women undergoing partial salpingec- antibodies. Still, results are conflicting,
Svenstrup and colleagues that exam-

71
ined the relationship between Myco- tomy for sterilization or at the time of as Lind and Kristensen assessed the
plasma genitalium seropositivity and 66 significance of antibodies to Myco-
hysterectomy. They found a 6-fold
TFI, none of the women had a cervical higher rate of infection with C tracho- plasma genitalium in patients with acute
swab specimen indicating current My- matis and Mycoplasma genitalium in salpingitis and failed to confirm any
coplasma genitalium infection, and only women with ectopic pregnancy association.
1 was positive for C trachomatis. There compared to the controls. There was also Recent studies have examined the
does not appear to be a role for screening a higher rate of other infections, relationship between current cervical or
for Mycoplasma genitalium infection at including Ureaplasma urealyticum/U endometrial Mycoplasma genitalium
the time of infertility evaluation. parvum, Gardnerella vaginalis, N gonor- infection and upper genital tract infec-
Several other studies, although not rhoeae, and T vaginalis, but these asso- 71-75
tion. In an analysis of 586 women
directly addressing fertility rates, have ciations were not statistically significant. who participated in the PID Evaluation
investigated the effects that Mycoplasma The investigators noted that co-infection and Clinical Health (PEACH) Study, a
genitalium may have on tubal inflam- with at least 2 organisms led to a 5-fold randomized multicenter clinical trial in
mation, damage, and occlusion. The increase in the risk of ectopic preg- the United States, 31% of women who
mechanism by which Mycoplasma geni- nancy, providing further evidence that tested positive for Mycoplasma genitalium
talium may cause the tubal scarring that multiple infections lead to greater risk of in the endometrium reported recurrent
66
leads to infertility has been studied tubal damage. PID, 42% had chronic pelvic pain, and
72
through several in vitro models. McGo- Animal studies have also been per- 22% were infertile. However, a large
62,63 formed to investigate the potential role prospective trial of 2378 young women in
win and colleagues demonstrated
that the organism can attach to repro- of Mycoplasma genitalium on tubal London failed to show an association
ductive tract epithelial cells and elicits scarring and inflammation. Female gri- between Mycoplasma genitalium and
cellular immune responses that result in vet monkeys and marmosets inoculated acute PID. Among women with Myco-
inflammation. In another in vitro organ with Mycoplasma genitalium developed plasma genitalium at baseline, 3.9%
culture model, Mycoplasma genitalium severe endosalpingitis, along with developed PID after 12 months
adhered to human fallopian tube luminal exudates and adhesions between compared with 1.7% of women without
epithelium after experimental inocula- mucosal folds in the fallopian tubes, baseline infection; however, this differ-
63
tion, causing swelling of the cilia and similar to changes induced by chla- ence was not statistically significant.
67 76
detachment of cilia from the epithe- mydial infection. Additionally, female Oakeshott and colleagues concluded
64 65 Swiss Webster mice developed upper that because the population attributable
lium. Svenstrup and colleagues also
investigated whether mobile sperm reproductive tract infection as early as 3 risk of PID due to Mycoplasma genitalium
could serve as a vector for transmitting days after being inoculated with Myco- was only 4%, Mycoplasma genitalium
Mycoplasma genitalium to the upper plasma genitalium, showing experimen- infection is not an important risk factor
genital tract of women, demonstrating tally that Mycoplasma genitalium is for pelvic inflammation. This particular
that the organism does adhere to human capable not only of ascending through European population may not be gener-
spermatozoa and could be transported the upper genital tract, but persistently alizable to populations with higher
by sperm to the uterus and fallopian colonizing reproductive tract tissues that prevalence rates of Mycoplasma geni-
tubes to colonize and destroy the ciliated could lead to long-term tubal inflam- talium infection, where, if confirmed,
epithelia. 68 this 2-fold increased risk of PID due to
mation and occlusion.
When compared with the more severe Both serological and epidemiological Mycoplasma genitalium infection could
damage that C trachomatis and N gon- studies have explored whether Myco- constitute a major public health prob-
orrhoeae infection create in the fallopian plasma genitalium is associated with 72
lem. Still, while evidence shows that
tube, the damage caused by Mycoplasma clinical PID and salpingitis. In an Mycoplasma genitalium is often present in
62 analysis of 193 patients with clinically 77
genitalium tends to be moderate. or associated with PID cases, more data
However, when left untreated, damage diagnosed PID and 246 healthy preg- are necessary to determine the role of this
may accumulate and yield serious long- nant controls, 17% were Mycoplasma microorganism in the pathogenesis of
term sequelae on fallopian tube genitalium seropositive, although the PID and subsequent TFI.
function. Additionally, simultaneous association was not statistically signifi- Mycoplasma genitalium may not only
infection with Mycoplasma genitalium cant after adjusting for age and pres- affect tubal patency; several studies have
and other sexually transmitted bacteria 69 investigated its effects on pregnancy
ence of antibodies to C trachomatis.
may cause even more severe tubal pa- An older study by Møller and col- outcomes such as ectopic pregnancy,
thology. One study conducted in Saudi 70 recurrent pregnancy loss, and preterm
leagues also showed an association; in
Arabia used polymerase chain reaction a group of patients with acute PID birth. However, unlike for C trachomatis,
performed on tubal samples from without C trachomatis antibodies, there is limited evidence that the path-
women with ectopic pregnancy and almost 40% had a 4-fold change in ogen is associated with these adverse
compared them to samples from fertile the titre of Mycoplasma genitalium pregnancy outcomes. A serological

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79
States

44,80-84

77
inconsis-tent. While data are emerging on
the impact of Mycoplasma genitalium on the
case-control study by Jurstrand and reproductive health of women, further
69 research is necessary to solidify any con-
coworkers showed no significant cor-
relation between Mycoplasma genitalium clusions regarding Mycoplasma genitalium
antibodies and ectopic pregnancy. According and adverse pregnancy outcomes.
to a recent meta-analysis, Mycoplasma
genitalium infection has been shown to be
significantly associated with increased risk of T vaginalis
both spontaneous abortion and preterm birth
in some studies, although evidence is
Like that of Mycoplasma genitalium, the role of T vaginalis infection in repro-ductive tract pathology has been under-studied, but investigators have shown that it may be associated with female
infertility. T vaginalis is the most com-mon 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 world-wide.78 An estimated 7.4 million new infections occur annually in the United and approximately 3.1% of

80
reproductive-age women are infected. presence or history of other reproduc- the reproductive tract. Both Myco-plasma
Given the high prevalence of T vagi- tive tract infections. hominis and U urealyticum, 2 common
nalis in the population, any potential Upon investigation of endometrial species of genital myco-plasma, have been
impact of the organism on the upper inflammatory changes elicited by in- investigated as possible causative agents
reproductive tract could constitute a fections, immunohistochemical evidence for infertility and pelvic inflammation.
serious public health concern. shows that T vaginalis may contribute to Mycoplasma hominis is commonly found
Data associating T vaginalis with TFI upper genital tract inflammation.
85 in the upper genital tract. The adverse influ-
and pelvic inflammation in the litera-ture Pathologically, T vaginalis has been ence of Mycoplasma hominis on the
are relatively weak. Few retrospec-tive shown to be capable of ascending the female reproductive tract was identi-fied in
studies have found that women with self- upper genital tract and has been associ- 1976 by Mårdh and colleagues, 95 as they
reported infertility were 2-3 times more ated with up to 30% of acute salpingitis demonstrated with in vitro organ cultures
likely to have a current T vaginalis cases, although within the same study, the swelling of the ciliated tubal epithelial
infection, and women with a self- trichomonads were not demonstrated in cells due to Mycoplasma hominis
reported history of a T vaginalis tubal cultures from cases of salpingitis.
86
infection. The organism has been isolated
infection have approximately a 2-fold T vaginalis has been shown to be from the fallopian tubes of women with a
risk of tubal infertility. Addi- associated clinically with endometritis, history of infertility and laparoscopically
tionally, a trend exists between salpingitis, and atypical PID,
87-90
confirmed salpingitis, although recent
increasing number of episodes of T demonstrating that it may be an impor-
vaginalis infection and increasing risk tant pathogen in upper genital tract data have not necessarily reproduced
44
of infertility. However, many of the damage. Other potential mechanisms these findings.
60,86,96,97
epidemiologic studies analyzing the linking T vaginalis infection to infertility Ureaplasmas, including U ure-alyticum,
association between trichomoniasis and include disruption of sperm motility,
89
have also been investigated as potential
infertility failed to control for impor- phagocytosis of sperm, and trans- culprits of female infertility. Like
tant confounding variables such as portation of other infectious agents to the Mycoplasma hominis, ureaplasmas have
upper genital tract by motile trichomo- been isolated from the fallopian
82,83
nads, although these mechanisms do tubes of patients with PID, yet their
86,98
not directly affect the female presence in patients with PID is rare.
reproductive tract. Some studies suggest a causal relation-
Co-infection of T vaginalis and C ship between U urealyticum and infer-
trachomatis may increase the risk of up- tility, but most controlled studies do not
per genital tract infection more than the risk confirm such a pathogenic role. Evi-
of C trachomatis infection alone, and dence supporting both Mycoplasma
women with both T vaginalis and HIV-1 hominis and U urealyticum as agents
have been shown to have a significantly involved in infertility is not nearly as
higher risk of PID than women without conclusive as existing evidence for
83,90 pathogens such as C trachomatis and N
T vaginalis. Because trichomonads
are capable of phagocytizing bacteria, gonorrhoeae; while some investigators
yeast, vaginal epithelial cells, myco- have been able to detect each of the or-
plasmas, and herpesviruses in vitro,
91-94 ganisms in infertile patients and in pa-
tients with upper genital tract disorders,
investigators speculate that T vaginalis
several have not shown any correla-
infection may be capable of spreading 98-101
other pathogens throughout the upper tion. As with T vaginalis, the exist-
genital tract, thereby indirectly eliciting ing evidence for Mycoplasma hominis
tubal damage and infertility. Moreover, and ureaplasmas as pathogens causing
despite some of these weak associations, infertility is therefore not sufficiently
proposed mechanisms, and possible co- definitive.
infection risks, there is currently no While the focus of this review was to
strong conclusive evidence regarding the identify sexually transmitted pathogens that
causative effects of T vaginalis on PID affect fertility, other infectious dis-eases are
or infertility. important to consider in dis-cussing
infertility. In the developing world where
Vaginal microbiome and exposure to Mycobacterium tuberculosis
other potential pathogens is common, genital tuber-culosis (GTB) is a
N gonorrhoeae, C trachomatis, and significant cause of infertility. Although its
Mycoplasma genitalium may not be the incidence is <1% in industrialized
only organisms capable of damaging countries, GTB rates

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can be as high as 13% in developing the fallopian tubes of women with lap- population level is sparse, although a
countries, eliciting a major public health aroscopically confirmed PID and acute recent study in Washington observed a
102 117
concern. In almost all cases of GTB, salpingitis. potential association between disease
Mycobacterium tuberculosis spreads However, the role of BV in infertility management trends and reduction of
and in upper genital tract morbidity is 57
hematogenously from a primary source, reproductive morbidities. While
most commonly the lungs, to the fallo- still not completely clear, as other further investigations are necessary to
pian tubes, producing irreversible tubal studies refute any significant establish a tangible benefit, it is none-
damage and ultimately leading to TFI 118
correlation. Likewise, the studies theless well understood that women
102
in up to 40% of cases. In addition that do show cor-relations between BV who delay seeking care for what is
to infertility, GTB has also been shown to and tubal pathol-ogy do not necessarily often an asymptomatic infection have a
be an important risk factor for ectopic help distinguish whether this finding is higher risk for infertility and other
pregnancy in developing coun- secondary to previous tubal damage reproductive morbidities. The US Pre-
103,104
tries. The silent nature of GTB, caused by in-fections such as C ventive Services Task Force has issued
which often persists without any clinical trachomatis and N gonorrhoeae, or chlamydia and gonorrhea screening
manifestations, allows development of whether BV infection may help spread recommendations since 2000 to reduce
fulminating infection without detec- these infections to the upper genital associated morbidities,
119
but such
105 111
tion. Early detection and treatment of tract. It is uncertain whether or not guidelines regarding other nontradi-
GTB is vital to improve reproductive BV itself is the direct cause of damage tional pathogens have not been estab-
outcomes, but unfortunately provides no on the fallopian tubes, but given its lished. Future research to evaluate the
benefit to reverse tubal damage once the high prevalence among women with impact of screening and treatment
106
disease is advanced. TFI, alongside the high percentage of programs for nontraditional pathogens
Rather than a single organism women with BV that remain such as Mycoplasma genitalium and
impairing female fertility, variations in undiagnosed and untreated, further other organisms in the microbiome
the overall vaginal microbiome, such as investigations elucidating the role of should be considered to help guide
in bacterial vaginosis (BV), may also anaerobic overgrowth, biofilms, and the clinical practice and health policy to
107 112
have a role in infertility. A recent vaginal microbiome are needed. more effectively reduce the global
meta-analysis exploring the role of BVon burden of infertility. -
infertility has shown that BV is signifi- Conclusions
cantly more prevalent in infertile women In summary, the totality of the evidence
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