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Expert Reviews ajog.


Sexually transmitted diseases and infertility

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

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

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pathogens, co-infections, and interactions C trachomatis and N gonorrhoeae associated with a signicantly increased
with host characteristics, including their C trachomatis and N gonorrhoeae have risk of tubal infertility in women,
individual vaginal microbiome, may all been extensively shown to be associated regardless of the infection invoking
affect a womans subsequent ability to with infertility, particularly by causing clinical symptoms.20,25,29-32 Extensive
conceive. While screening and treatment tubal inammation. In fact, early spec- research has also shown that C tracho-
efforts for C trachomatis and N gonor- ulation regarding the effect of N gonor- matis infection can cause PID, which
rhoeae have been developed to reduce the rhoeae on female fertility dates back to often precedes infertility. Today, C tra-
incidence of PID and subsequent TFI, the 1870s, when the German-born gy- chomatis accounts for approximately
additional data are needed to determine necologist Emil Noeggerath published 50% of cases of acute PID in developed
the role of other potential pathogens and his revolutionary claims about gonor- countries.33 Among PID patients, those
whether early detection can prevent tubal rhea as a clinical condition in his book with prior C trachomatis infection have
damage. In this article, we discuss the Latent Gonorrhoea Especially with Regard been shown to be more likely to expe-
pathogens C trachomatis, N gonorrhoeae, to its Inuence on Fertility in Women.14 rience subsequent infertility than those
Mycoplasma genitalium, T vaginalis, and Although he may have widely over- without a history of C trachomatis
other potential organisms that may affect estimated its repercussions (postulating infection.32-35
female fertility, and we address the clinical that gonorrhea causes 90% of female While C trachomatis seropositivity
importance of screening and preventing infertility), his theories eventually has long been shown to inuence fal-
the spread of those infections. sparked the initiation of further in- lopian tube patency,36 the use of a
vestigations.15 When the bacterium N newer, more sensitive and specic anti-
Methodology gonorrhoeae was nally isolated, Noeg- chlamydial assay by Geisler and co-
We conducted a comprehensive litera- geraths controversial claims regarding workers37 has only recently been shown
ture search to identify articles by using the persistence of this venereal poison to hold promise as a measure of tubal
the electronic databases MEDLINE, in the reproductive organs and its path- function.38 In a cohort study of 1250
Embase, Web of Science, and CINAHL, ologic consequences were reexamined.16 infertile women with documented tubal
in addition to scrutinizing references of Studies conducted more than a century patency undergoing fertility treatment,
identied articles. Within each database, later have since demonstrated the impact C trachomatis seropositivity using the
we combined the term female infer- of C trachomatis and N gonorrhoeae on antibody subclasses IgG1 and IgG3 was
tility with 4 different infection terms: subsequent infertility. tested.39 Results showed that of these 2
Chlamydia trachomatis, Neisseria C trachomatis, the most common antibody subclasses tested, seroposi-
gonorrhoeae, Mycoplasma genitalium, reportable disease in the United States, tivity to C trachomatis based on IgG3
and Trichomonas vaginalis. Within the affects nearly 1.5 million people in the detection was a strong predictor of both
MEDLINE database, we rened the US annually.17 Unfortunately, however, failure to conceive and ectopic preg-
search by excluding the Medical Subject because C trachomatis infections are nancy outcomes. Because IgG3 has
Headings unrelated to female infertility asymptomatic in most women,18,19 in- been shown to be involved in early in-
and at least 1 of the 4 organisms. Within fections are often unnoticed, untreated, ammatory response to infection,40 the
the Embase search, we used Emtree to and underreported. For almost 40 detection of IgG3 in these women may
identify terms, and used both female years, evidence has shown that un- reect a recently cleared or persistent C
infertility and uterine tube occlusion treated ascending C trachomatis infec- trachomatis infection, contributing to
as focused search terms to combine with tion can lead to irrevocable damage in fallopian tube damage while perhaps
each infection. We ltered results to only the fallopian tubes including proximal not yet leading to blockage of the fal-
include articles published in English and distal tubal occlusions leading to lopian tubes.39
between 1975 and April 2016. Additional infertility.9 The increased amount of In another study of subfertile women
relevant articles were identied from heat shock protein synthesized by C with no visible tubal pathology, positive
bibliographies and by the recommen- trachomatis induces a proinammatory chlamydial antibody testing was associ-
dation of medical experts. The inclusion immune response in the human fallo- ated with a 33% lower spontaneous
of the articles used in the analysis was pian tube epithelia, resulting in scarring pregnancy rate than those without
based on quality of the study and rele- and tubal occlusion.9,20,21 A number of chlamydial antibodies.28,39 Coppus and
vance to this review: studies were seroepidemiological studies have colleagues28 suggest that these low
excluded if they were conducted with examined the prevalence of antibodies pregnancy rates may not only be caused
few participants, had no comparison to C trachomatis and chlamydial heat by the known mechanism of chronic
group, or constituted case reports. shock protein in women with lapa- inammatory response causing fallopian
Studies that did not report sufcient data roscopically or hysterosalpingo- tube damage; persistent C trachomatis
to determine the association with female graphically conrmed fallopian tube infections have also been shown to elicit
infertility or reproductive morbidities damage and ectopic pregnancies.22-28 an autoimmune response to human heat
were excluded for lack of relevance to the The results of these studies indicate shock proteins, which may elevate the
topic of review. that history of C trachomatis infection is risk for impaired embryo development

2 American Journal of Obstetrics & Gynecology JANUARY 2017 Expert Reviews

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

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Svenstrup and colleagues24 that exam- women undergoing partial salpingec- antibodies. Still, results are conicting,
ined the relationship between Myco- tomy for sterilization or at the time of as Lind and Kristensen71 assessed the
plasma genitalium seropositivity and hysterectomy.66 They found a 6-fold signicance of antibodies to Myco-
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 conrm 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- tion.71-75 In an analysis of 586 women
directly addressing fertility rates, have ciations were not statistically signicant. 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 inam- 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
leads to infertility has been studied tubal damage.66 PID, 42% had chronic pelvic pain, and
through several in vitro models. McGo- Animal studies have also been per- 22% were infertile.72 However, a large
win and colleagues62,63 demonstrated formed to investigate the potential role prospective trial of 2378 young women in
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 inammation. Female gri- between Mycoplasma genitalium and
cellular immune responses that result in vet monkeys and marmosets inoculated acute PID. Among women with Myco-
inammation. 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-
tion, causing swelling of the cilia and similar to changes induced by chla- ence was not statistically signicant.63
detachment of cilia from the epithe- mydial infection.67 Additionally, female Oakeshott and colleagues76 concluded
lium.64 Svenstrup and colleagues65 also Swiss Webster mice developed upper that because the population attributable
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 inammation. 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 inam- talium infection, where, if conrmed,
epithelia. mation and occlusion.68 this 2-fold increased risk of PID due to
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 lem.72 Still, while evidence shows that
tube, the damage caused by Mycoplasma clinical PID and salpingitis. In an Mycoplasma genitalium is often present in
genitalium tends to be moderate.62 analysis of 193 patients with clinically or associated with PID cases,77 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 signi- 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 ence of antibodies to C trachomatis.69 investigated its effects on pregnancy
may cause even more severe tubal pa- An older study by Mller and col- outcomes such as ectopic pregnancy,
thology. One study conducted in Saudi leagues70 also showed an association; in recurrent pregnancy loss, and preterm
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

4 American Journal of Obstetrics & Gynecology JANUARY 2017 Expert Reviews

case-control study by Jurstrand and presence or history of other reproduc- the reproductive tract. Both Myco-
coworkers69 showed no signicant cor- tive tract infections. plasma hominis and U urealyticum, 2
relation between Mycoplasma genitalium Upon investigation of endometrial common species of genital myco-
antibodies and ectopic pregnancy. inammatory changes elicited by in- plasma, have been investigated as
According to a recent meta-analysis, fections, immunohistochemical evidence possible causative agents for infertility
Mycoplasma genitalium infection has shows that T vaginalis may contribute to and pelvic inammation. Mycoplasma
been shown to be signicantly associated upper genital tract inammation.85 hominis is commonly found in the
with increased risk of both spontaneous Pathologically, T vaginalis has been upper genital tract. The adverse inu-
abortion and preterm birth in some shown to be capable of ascending the ence of Mycoplasma hominis on the
studies, although evidence is inconsis- upper genital tract and has been associ- female reproductive tract was identi-
tent.77 While data are emerging on the ated with up to 30% of acute salpingitis ed in 1976 by Mrdh and colleagues,95
impact of Mycoplasma genitalium on the cases, although within the same study, as they demonstrated with in vitro organ
reproductive health of women, further trichomonads were not demonstrated in cultures the swelling of the ciliated tubal
research is necessary to solidify any con- tubal cultures from cases of salpingitis.86 epithelial cells due to Mycoplasma hominis
clusions regarding Mycoplasma genitalium T vaginalis has been shown to be infection. The organism has been isolated
and adverse pregnancy outcomes. associated clinically with endometritis, from the fallopian tubes of women with a
salpingitis, and atypical PID,87-90 history of infertility and laparoscopically
T vaginalis demonstrating that it may be an impor- conrmed salpingitis, although recent
Like that of Mycoplasma genitalium, the tant pathogen in upper genital tract data have not necessarily reproduced
role of T vaginalis infection in repro- damage. Other potential mechanisms these ndings.60,86,96,97
ductive tract pathology has been under- linking T vaginalis infection to infertility Ureaplasmas, including U ure-
studied, but investigators have shown include disruption of sperm motility,89 alyticum, have also been investigated as
that it may be associated with female phagocytosis of sperm, and trans- potential culprits of female infertility.
infertility. T vaginalis is the most com- portation of other infectious agents to the Like Mycoplasma hominis, ureaplasmas
mon nonviral sexually transmitted upper genital tract by motile trichomo- have been isolated from the fallopian
pathogen in the United States. According nads,82,83 although these mechanisms do tubes of patients with PID, yet their
to the World Health Organization, the not directly affect the female reproductive presence in patients with PID is rare.86,98
protozoan T vaginalis accounts for more tract. Some studies suggest a causal relation-
than half of all curable STDs world- Co-infection of T vaginalis and C ship between U urealyticum and infer-
wide.78 An estimated 7.4 million new trachomatis may increase the risk of up- tility, but most controlled studies do not
infections occur annually in the United per genital tract infection more than the conrm such a pathogenic role. Evi-
States79 and approximately 3.1% of risk of C trachomatis infection alone, and dence supporting both Mycoplasma
reproductive-age women are infected.80 women with both T vaginalis and HIV-1 hominis and U urealyticum as agents
Given the high prevalence of T vagi- have been shown to have a signicantly involved in infertility is not nearly as
nalis in the population, any potential higher risk of PID than women without conclusive as existing evidence for
impact of the organism on the upper T vaginalis.83,90 Because trichomonads pathogens such as C trachomatis and N
reproductive tract could constitute a are capable of phagocytizing bacteria, gonorrhoeae; while some investigators
serious public health concern. yeast, vaginal epithelial cells, myco- have been able to detect each of the or-
Data associating T vaginalis with TFI plasmas, and herpesviruses in vitro,91-94 ganisms in infertile patients and in pa-
and pelvic inammation in the litera- investigators speculate that T vaginalis tients with upper genital tract disorders,
ture are relatively weak. Few retrospec- infection may be capable of spreading several have not shown any correla-
tive studies have found that women other pathogens throughout the upper tion.98-101 As with T vaginalis, the exist-
with self-reported infertility were 2-3 genital tract, thereby indirectly eliciting ing evidence for Mycoplasma hominis
times more likely to have a current T tubal damage and infertility. Moreover, and ureaplasmas as pathogens causing
vaginalis infection, and women with a despite some of these weak associations, infertility is therefore not sufciently
self-reported history of a T vaginalis proposed mechanisms, and possible co- denitive.
infection have approximately a 2-fold infection risks, there is currently no While the focus of this review was to
risk of tubal infertility.44,80-84 Addi- strong conclusive evidence regarding the identify sexually transmitted pathogens
tionally, a trend exists between causative effects of T vaginalis on PID or that affect fertility, other infectious dis-
increasing number of episodes of T infertility. eases are important to consider in dis-
vaginalis infection and increasing risk of cussing infertility. In the developing
infertility.44 However, many of the Vaginal microbiome and other world where exposure to Mycobacterium
epidemiologic studies analyzing the potential pathogens tuberculosis is common, genital tuber-
association between trichomoniasis and N gonorrhoeae, C trachomatis, and culosis (GTB) is a signicant cause of
infertility failed to control for impor- Mycoplasma genitalium may not be the infertility. Although its incidence is <1%
tant confounding variables such as only organisms capable of damaging in industrialized 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 conrmed PID and acute recent study in Washington observed a
concern.102 In almost all cases of GTB, salpingitis.117 potential association between disease
Mycobacterium tuberculosis spreads However, the role of BV in infertility management trends and reduction
hematogenously from a primary source, and in upper genital tract morbidity is of reproductive morbidities.57 While
most commonly the lungs, to the fallo- still not completely clear, as other studies further investigations are necessary to
pian tubes, producing irreversible tubal refute any signicant correlation.118 establish a tangible benet, it is none-
damage and ultimately leading to TFI in Likewise, the studies that do show cor- theless well understood that women
up to 40% of cases.102 In addition relations between BV and tubal pathol- who delay seeking care for what is often
to infertility, GTB has also been shown to ogy do not necessarily help distinguish an asymptomatic infection have a
be an important risk factor for ectopic whether this nding is secondary to higher risk for infertility and other
pregnancy in developing coun- previous tubal damage caused by in- reproductive morbidities. The US Pre-
tries.103,104 The silent nature of GTB, fections such as C trachomatis and N ventive Services Task Force has issued
which often persists without any clinical gonorrhoeae, or whether BV infection chlamydia and gonorrhea screening
manifestations, allows development of may help spread these infections to the recommendations since 2000 to reduce
fulminating infection without detec- upper genital tract.111 It is uncertain associated morbidities,119 but such
tion.105 Early detection and treatment of whether or not BV itself is the direct guidelines regarding other nontradi-
GTB is vital to improve reproductive cause of damage on the fallopian tubes, tional pathogens have not been estab-
outcomes, but unfortunately provides but given its high prevalence among lished. Future research to evaluate the
no benet to reverse tubal damage once women with TFI, alongside the high impact of screening and treatment
the disease is advanced.106 percentage of women with BV that programs for nontraditional pathogens
Rather than a single organism remain undiagnosed and untreated, such as Mycoplasma genitalium and
impairing female fertility, variations in further investigations elucidating the other organisms in the microbiome
the overall vaginal microbiome, such as role of anaerobic overgrowth, biolms, should be considered to help guide
in bacterial vaginosis (BV), may also and the vaginal microbiome are clinical practice and health policy to
have a role in infertility.107 A recent needed.112 more effectively reduce the global
meta-analysis exploring the role of BVon burden of infertility. -
infertility has shown that BV is signi- Conclusions
cantly more prevalent in infertile women In summary, the totality of the evidence
than in pregnant women of the same linking N gonorrhoeae and C trachomatis REFERENCES
population.108 According to this sys- to infertility is compelling. However, the 1. Boivin J, Bunting L, Collins JA, Nygren KG.
tematic review of 12 studies reporting associations found among Mycoplasma International estimates of infertility prevalence
the prevalence of BV in patients with genitalium, T vaginalis, and other po- and treatment-seeking: potential need and de-
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