Keywords
chlamydia trachomatis - infertility - tubal factor infertility - sexually transmitted
diseases - human reproduction
Palavras-chave
clamídia trachomatis - infertilidade - infertilidade tubária - infecções sexualmente
transmissíveis - reprodução humana
Introduction
Chlamydia trachomatis (CT) infections represents, globally, the most prevalent sexually transmitted infection
(STI) caused by bacteria, with 131 million new cases per year.[1]
[2]
Chlamydia trachomatis, which is an obligate intracellular parasite, can have a specific infectious potential
to epithelial cells from male and female reproductive tracts. In symptomatic cases,
men can present with urethritis, or, less commonly, epididymitis, and women, besides
yellowish vaginal discharge, spontaneous bleeding, pain during sex or urination, and
pelvic pain, may be led to pelvic inflammatory disease (PID).[3]
[4] However, most women and 50% of men affected do not present many identifiable clinical
symptoms, having an unnoticed infection.[5] Therefore, the majority of infected individuals do not seek treatment, not only
risking their sexual partners' health, but also worsening their condition, as the
persistent presence of the pathogen evocates a chronic immune response, leading to
an enhanced production of genital immune mediators, like interleukin (IL)-, IL-6 and
gamma interferon, which increases the number of epithelial cells destroyed.[5]
[6] This process is very dangerous, especially among women, once the manifestations
and consequences are more damaging to their reproductive health than man's, a fact
elucidated by the evidence that approximately 20% of women with chlamydial lower genital
tract infection will develop PID, 4% develop chronic pelvic pain, 2% adverse pregnancy
outcomes (chromosomal abnormalities, miscarriages, congenital malformations and stillbirth)
and 3% infertility—probably due to scar formation and occlusion of the Fallopian tubes.[7] The last possible consequence mentioned is defined as a couple's ineptitude to conceive
after at least 12 months of regular unprotected intercourse and affects up to 15%
of the reproductive-aged population.[8] Even though this issue is widely recognized amidst the medical community as a secondary
effect of female CT infection, the level of evidence corroborating the association
is relatively weak.[7] Thus, by doing a systematic review, we aim to contribute to the consolidation of
this correlation.
Methods
The development of this study was based on the review writing methods of the Preferred
Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) statement.[9]
We included cohort studies, case-control studies, crosssectional studies, and a letter,
which were performed in the last 5 years and contained data about the correlation
between infertility among reproductive-aged women and previous CT infection. Additionally,
studies that compared the fertility rates between women with and without positive
immunoglobulin G (IgG) for CT were admitted in this systematic review. There was no
language restriction for the studies selection. Articles related to endocrine causes
or just male infertility were excluded, as well as studies focused on STI in general
or on different from CT. Additionally, we ruled out articles perceived as duplicates
and reviews about the subject.
The electronic database chosen to carry out the search was the Medline/PubMed, with
the last survey on May 11, 2021. The only filter used was the publication date, with
the previous 5 years having been selected.
The authors conducted research individually. Subsequently, the studies obtained were
carefully analyzed by them and, in case of disagreement, a consensus was used to decide
whether the article would be included in the review or not. As we retrieved the information
needed for our study through reading the texts, no contact has been made with the
authors of the ones selected.
The research on the PubMed/Medline database was conducted using the following describers:
(chlamydia [MeSH terms] OR chlamydia [all fields] OR chlamydiae [all fields] OR chlamydias [all fields]) AND (infertile> [all fields] OR infertilities [all fields] OR infertility [MeSH terms] OR infertility [all fields] OR infertile [all fields] OR infertility [all fields]) AND (y_5 [filter]); chlamydia [MeSH terms] OR chlamydia [all fields] OR chlamydiae [all fields] OR chlamydias [all fields]) AND (tubal [all Fields] AND (alter [all fields] OR altered [all fields] OR alteration [all fields] OR alterations [all fields] OR altered [all fields] OR altering [all fields] OR alters [all fields]) AND (infertile [all fields] OR infertilities [all fields] OR infertility [MeSH terms] OR infertility [all fields] OR infertile [all fields] OR infertility [all fields]); (chlamydia [MeSH terms] OR chlamydia [all fields] OR chlamydiae [all fields] OR chlamydias [all fields]) AND (low [all fields] AND (pregnancy [MeSH terms] OR pregnancy [all fields] OR pregnancies [all fields] OR pregnancy [all fields]) AND rates [all fields]) AND (y_5 [filter]).
Firstly, in the identification phase, we found 325 studies through the database research
and 2 by the references analyzed, leading us to 327 articles from which 5 were removed
for being duplicates. Therefore, we had to screen 322 studies and, then, exclude 293
that failed to meet our eligibility criteria. So, in the eligibility phase, we assessed
29 articles. Finally, we removed seven studies for not having the possible correlation
between CT infections and female infertility as the main focus, and three articles
for being about STI in general. Moreover, two studies designed as reviews were ruled
out too. Ergo, we included 17 studies in our qualitative synthesis.
Results
The flow diagram below ([Fig. 1]), which is in line with the PRSIMA methodology9, shows that we screened 322 publications from the existing literature in the Medline/Pubmed
database. Subsequently, 305 manuscripts had to be removed in view of the following
criteria: The data presented was not focused on the correlation between infertility
among reproductive-aged women and previous CT infection or on the comparison of fertility
rates of infected and not infected women; were related to endocrine or male causes
of infertility; were focused on STI in general or just in others different from CT
infection; were designed as reviews. Hence, 17 studies were included in our systematic
review.
Fig. 1 PRISMA flow diagram.
The findings of our research are summarized in [Chart 1]. As we can see, from the 17 manuscripts included, 8 were designed as cohort studies
(including the regular, the retrospective and the longitudinal kind), 5 as case-control
studies, 3 as cross-sectional studies and 1 as a letter- which was about a cross-sectional
hospital-based study. In relation to the screening of CT infection, the methods used
were very diversified- 4 used polymerase chain reaction (PCR), 2 enzyme linked immunosorbent
assay (ELISA), 2 CT serology, 1 nucleic acid amplification test (NAAT), 1 major outer
membrane protein (MOMP) and 1 automated DNA extraction method. Also, some works used
more than one strategy- 1 CT serology and PCR, 1 MOMP and ELISA, 1 CT serology and
NAATs and 1 CSI-PCR, CT serology and/or self-reported infection. In 2 articles, however,
the method of screening was not specified. The association between CT infection and
female infertility, which is our main focus, was considered positive in 13.
Chart 1
Results
|
Author (year)
|
Design
|
Journal
|
Methods of CT screening
|
Number of participants
|
Association between CT infection and female infertility
|
Main results
|
|
Menon et al. (2016)[10]
|
Cross-sectional study
|
Journal of Medical Microbiology
|
ELISA
|
239
|
Positive
|
Up to half of women who are subfertile in this population could have CT as a cause
or contributing factor.
|
|
Rawre et al. (2016)[11]
|
Retrospective cohort study
|
APMIS
|
PCR
|
628
|
Positive
|
Significant association between rates of chlamydial infection and type of infertility,
specially tubal factor infertility (74.7%; 56/75)
|
|
Davies et al. (2016)[12]
|
Retrospective cohort study
|
The Lancet Infectious Diseases
|
Not specified
|
516,720
|
Positive
|
A positive CT test increased the risk of pelvic inflammatory disease, ectopic pregnancy,
and tubal factor infertility by at least 30%.
|
|
Dehghan Marvast et al. (2017)[13]
|
Case-control study
|
Andrologia
|
CT serology and PCR
|
324
|
Negative
|
In contrast to other studies, this study did not support the relationship between
CT infection and TFI.
|
|
Ramadhani et al. (2017)[14]
|
Letter
|
Sexually Transmitted Infections
|
PCR
|
290
|
Positive
|
CT was more highly associated with primary infertility
|
|
Zhu et al. (2017)[15]
|
Case-control study
|
Reproductive Health
|
PCR
|
30,760
|
Positive
|
The prevalence of CT in subfertile couples in this study was 3.15% and increased yearly
from 2.45% in 2010 to 3.69% in 2014.
|
|
Begum et al. (2017)[16]
|
Cohort study
|
Mymensingh Medical Journal
|
ELISA
|
69
|
Positive
|
This study shows that by laparoscopy, significant number of cases of tubal and pelvic
pathology was diagnosed in the chlamydia trachomatis seropositive subfertile female
|
|
Joolayi et al. (2017)[17]
|
Case-control study
|
International Journal of Reproductive BioMedicine
|
MOMP and ELISA
|
225
|
Negative
|
6 (6%) infertile and 2 (1.6%) fertile women were positive for IgM (p = 0.21). Also, PCR was positive for CT infection in 5 infertile (5%) and 2 fertile
women (1.6%) (p = 0.35). We did not find any seropositive immunoglobulin G in both groups.
|
|
Rantsi et al. (2018)[18]
|
Cohort study
|
American Journal of Reproductive Immunology
|
MOMP
|
96
|
Negative
|
The overall pregnancy rate or live birth rate did not differ by the presence of antibodies
or CMI against CT. Time to spontaneous pregnancy was longer among CT positive women
|
|
Kayiira et al. (2019)[19]
|
Retrospective cohort study
|
Fertility Research and Practice
|
Are not specified
|
253
|
Positive
|
Exposure to current CT infection reduced chance of clinical pregnancy and a live birth
after tubal flushing. Women with current CT infection had an increased risk of adverse
events
|
|
Beyuo et al. (2019)[20]
|
Cross-sectional study
|
International Journal of Gynecology and Obstetrics
|
CT Serology
|
189
|
Positive
|
CT infection was present in 7.9% of women with suspected TFI, which was confirmed
in 35% of them.
|
|
Al-Farraj and Moubayed (2019)[21]
|
Case-control study
|
Saudi Journal of Biological Sciences
|
Automated DNA extraction method
|
200
|
Positive
|
The percentage positivity to infection was significantly more among the infertile
group com- pared to the control group.
|
|
Hoenderboom et al. (2019)[22]
|
Cohort study
|
Sexually Transmitted Infections
|
PCR, CT serology and/or self-reported infection
|
13,498
|
Positive
|
This study adds to the evidence that chlamydia increases the risk for PID and TFI
in women even if the infection was treated,29 but also showed that incidence rates
were small.
|
|
den Heijer et al. (2019)[23]
|
Retrospective cohort study
|
Clinical Infectious Diseases
|
CT serology and NAATs
|
857,324
|
Positive
|
Women who tested CT-positive had a substantially higher risk of experiencing female
infertility (approximately 70%) than CT-negative women
|
|
Sukatendel et al. (2019)[24]
|
Cross-sectional study
|
Open Access Macedonian Journal of Medical Science
|
PCR
|
50
|
Positive
|
The proportion of CT infection in tubal abnormality in this study was 66.7%, It was
obtained that there was a significant relationship between CT infection with tubal
abnormality (non-patency tubal) with p-value < 0.005 (p = 0.001)
|
|
Hoenderboom et al. (2020)[25]
|
Longitudinal cohort study
|
Sexually Transmitted Diseases
|
NAATs
|
5,704
|
Negative
|
Overall pregnancy rates were not lower in chlamydia-positive women compared with chlamydia-negative
women, but among women with a pregnancy intention, time to pregnancy was longer and
pregnancy rates were lower in chlamydia-positive women.
|
|
van Dooremalen et al. (2020)[26]
|
Case-control study
|
Microorganisms
|
CT serology
|
891
|
Positive
|
CT antibodies were present significantly more often in the TFI+ compared to the TFI − group,
respectively, 41.9% versus 9.6%
|
Abbreviations: CMI, cell-mediated immunity; CT, chlamydia trachomatis; DNA, deoxyribonucleic
acid; ELISA, enzyme-linked immunosorbent assay; NAAT, nucleic acid amplification test;
PCR, polymerase chain reaction; PID, pelvic inflammatory disease; TFI, tubal factor
infertility.
Discussion
This systematic review corroborates the hypothesis that CT infection potentiates female
infertility, as 76.47% of the included studies found a positive correlation between
them. The results of the study conducted by Menon et al.,[10] which included 239 women, indicate that up to half of subfertile women could have
CT as a cause or contributing factor. This is also expressed in den Heijer et al.[23] finding that CT-positive women had approximately 70% higher chance of experiencing
infertility. Davies et al.,[12] Ramadhani et al.,[14] and Kayiira et al.,[19] by presenting results that strengthen the discussed association, claim that policies
of routine screening and interventions focused on preventing both first and repeated
infections are extremely important in order to improve women's long-term reproductive
health.[12]
[14]
[19]
The type of female infertility more commonly associated with CT infection is tubal
factor infertility (TFI), which occurs due to tubal occlusion (Toye et al., 1993).[27] According to Hoenderboom et al.,[22] CT positivity represents a fourfold higher risk for TFI. In the study performed
by van Dooremalen et al.,[26] it is observed that CT antibodies were significantly more common among the group
with TFI compared to the group without it, respectively 41.9% and 9.6%.[26] Additionally, Rawre et al.[11] supported this correlation, once they observed that 56 out of the 75 women with
TFI had had CT infection. Nevertheless, the mechanism behind this interconnection
is still unclear.[27]
If we imagine PID with severe adherences and significant tubal damage, it is easy
to conclude that an anatomic cause harms fertility.[28]
[29] Howbeit, there are some situations that do not visually present any alteration,
which may suggest that there is also a molecular explanation. As CT is an intracellular
pathogen that impairs the endothelium and the tubal muscle, probably it leads to an
alteration in tubal motility and in endothelial cilia function.[30] This may explain the variations in intrauterine and tubal conformation, which presents
areas of constrictions, which are observed during laparoscopy procedure, when a saline
solution is inserted into the female reproductive tract. Even being fleeting there,
CT facilitates the installation of other microorganisms in the female reproductive
organs, causing a shift in its microbiota, with antigenic stimulus affecting the gametes
and their conjunction.[31]
[32]
[33] This immunological alteration can also explain the mild endometriosis in patients
that previously presented CT infection, once the immunological imbalance caused might
lead to the impossibility of an adequate action of the lymphocytes, allowing the maintenance
of viable endometrial cells in the pelvic environment.[34] Thus, the CT infection and its associated mechanical and biochemical damage, as
well as endometriosis, induce a modification in the female reproductive tract's environment,
which becomes hostile to the gametes.
Concerning the four articles that denied the association between CT infection and
female infertility, Rantsi et al.[18] and Hoenderboom et al.[25] do affirm, however, that a longer time to conceive spontaneously was observed in
women previously infected. This may indicate that past CT infection reduced the number
of ciliated mucosal cells, leading to functional tubal damage and impairing the potential
for pregnancy, even if it did not cause tubal occlusion. Joolayi et al.[17] point out some limitations of its study, such as the low number of the study population,
the low number of women with secondary infertility, the short time of study, and the
lack of real-time PCR.
We must mention that our review has two types of identified risks of bias—the publication
and the selection bias. The first one is due to the fact that studies with a positive
result have better chance of being published. Moreover, as we used only one database
to find the articles, we might not have had access to articles on the subject published
in other platforms, resulting in a selection bias. Also, there is a chance that we
have not used all the proper keywords or that we failed to include in the review a
useful study, which increases the last-mentioned type of bias.
Conclusion
Even though a consensus among doctors about the matter is not established yet, this
systematic review emphasizes that there is an important association between previous
CT infection and female infertility, once the majority of publications analyzed confirms
it. Evidence of tubal damage is highly suggestive of impaired fertility as a secondary
consequence of this parasite infection, but there is a need for further studies on
the possible molecular causes. Finally, we believe that making CT screening part of
the infertility investigation routine is extremely relevant and has a reasonable justification.
