If you don't remember your password, you can reset it by entering your email address and clicking the Reset Password button. You will then receive an email that contains a secure link for resetting your password
If the address matches a valid account an email will be sent to __email__ with instructions for resetting your password
Department of Gynecology and Obstetrics, West China Second University Hospital, Sichuan University, Chengdu Sichuan Province, ChinaKey Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu Sichuan Province, China
Department of Gynecology and Obstetrics, West China Second University Hospital, Sichuan University, Chengdu Sichuan Province, ChinaKey Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu Sichuan Province, China
Department of Gynecology and Obstetrics, West China Second University Hospital, Sichuan University, Chengdu Sichuan Province, ChinaKey Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu Sichuan Province, China
Department of Gynecology and Obstetrics, West China Second University Hospital, Sichuan University, Chengdu Sichuan Province, ChinaKey Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu Sichuan Province, China
There is increasing evidence that human papillomavirus (HPV) infection affects reproductive health and fertility, although its impact on female fertility has not been thoroughly studied. MEDLINE, Embase, CENTRAL, Web of Science, CNKI, Wanfang, VIP and ClinicalTrials.gov databases were systematically searched for relevant articles. A meta-analysis was conducted of 11 studies including 15,450 female subjects that compared HPV prevalence between the infertile and general population, and evaluated the association between HPV positivity and female infertility. Seven case–control studies on 3581 participants reported indiscriminate genotype infections (high-risk/low-risk [HR/LR]-HPV), but the random effects model revealed no association between HPV infection and female infertility (odds ratio [OR] 2.13, 95% confidence interval [CI] 0.97–4.65, P = 0.06). Six studies with a total of 11,869 participants reported HR-HPV infections alone, and the pooled data showed a significant association between HR-HPV infection and female infertility (OR 2.33, 95% CI 1.42–3.83, P = 0.0008). It was concluded that HR-HPV infection is a potential risk factor of female infertility, but not an independent cause. Further prospective studies are needed to assess the exact role of HPV in female infertility.
Infertility, defined as the inability to conceive after a year of regular sexual intercourse without using contraceptives, affects 8–12% of reproductive-aged couples worldwide (
). It is three times more prevalent in South Asia, Africa, the Middle East, Central and Eastern Europe and Central Asia compared with the global average (
), most likely due to high unsafe abortion rates and poor maternal care that increases the risk of post-abortion and post-partum infections, as well as secondary infertility (
). Nevertheless, infertility rates are increasing worldwide year on year, which apart from affecting the quality of life and psychological status of patients, is contributing to significant economic burden (
Lifestyle and fertility: The influence of stress and quality of life on female fertility 11 Medical and Health Sciences 1114 Paediatrics and Reproductive Medicine Rosario Pivonello.
). However, any disease that disrupts the hypothalamus–pituitary–ovary axis and affects the sex hormone levels can lead to ovulatory dysfunction. Furthermore, pathological changes in the fallopian tubes can affect fertilization and embryo transportation, and endometrial lesions may also damage sperm capacitation and embryo implantation (
). In fact, 20–60% of female infertility cases are caused by sexually transmitted infections, which can eventually lead to pelvic inflammation and tubal obstruction (
). The most common pathogens associated with female genital tract infections include Mycoplasmas, Chlamydia trachomatis and Neisseria gonorrhoeae, in addition to some viruses (
The human papillomavirus (HPV) is one of the most common sexually transmitted viruses. During the HPV life cycle in host cells, the clonal transformation or the infectious virion production pathway can be induced, which respectively lead to tumours and infertility or early abortion (
). HPV is classified into low-risk (LR) and high-risk (HR) types according to their ability to induce tumours. HR-HPV infections are linked to several genital or oropharyngeal cancers, whereas LR-HPV infections generally produce benign lesions of the skin and mucosa, such as genital warts (
). Recent evidence suggests that HPV infections may cause male infertility by decreasing sperm motility, and adversely affect the outcomes of natural pregnancy or treatment with assisted reproductive technology (ART) (
). Presence of HPV in the spermatozoa has been correlated with a cumulative decrease in the rates of natural and assisted pregnancies, and an increase in abortion rates (
The risk of human papillomavirus infection for spontaneous abortion, spontaneous preterm birth, and pregnancy rate of assisted reproductive technologies: A systematic review and meta-analysis.
found that infection with the indiscriminate HPV genotype increased the risk of spontaneous abortion, and HR-HPV infection was a risk factor for spontaneous preterm birth. However, there is not enough evidence to indicate an association between HPV infections and the pregnancy or spontaneous abortion rates of ART (
To this end, a meta-analysis was conducted to evaluate the association between HPV infections and female infertility, in order to provide a theoretical basis for managing HPV in reproduction health care.
Materials and methods
Literature search
The MEDLINE (via PubMed), Embase (via OvidSP), CENTRAL (via Cochrane Library), Web of Science, CNKI, Wanfang, VIP and ClinicalTrials.gov databases were systematically searched for articles published up to 1 April 2019 using the following search words: ‘human papillomavirus’, ‘HPV’, ‘infertility’ and ‘female’. In addition, the reference lists of the selected articles were manually searched to identify additional studies. The systematic review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines (
Mendeley (version 1.19.4) was used to manage citations and extract data. Two authors independently evaluated all retrieved articles by title, abstract and full text, and selected studies based on the following inclusion criteria: (i) comparison of HPV prevalence between infertile and general populations, (ii) cohort study or case–control study design, (iii) detection of HPV DNA in the cervix by polymerase chain reaction (PCR) or Hybrid Capture® 2 (HC2) method. Studies were excluded if (i) they were review articles, editorials, opinions or case reports, or (ii) cervical cytology was used as a substitute to detect HPV infections. The following data were extracted from each study: first author, publication year, country, study design, HPV detection method, HPV genotype, HPV detection tissue, average age, number of HPV-infected patients with or without infertility and infertility classification. Any disagreement was resolved by discussion. The quality of case–control and cohort studies was assessed by the Newcastle–Ottawa Scale (NOS) (
Wells G.A., Shea B., O'Connell D., Peterson J., Welch V., Losos M., et al. 2010. The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses.www.ohri.ca/programs/clinical_epidemiology/nos_manual.pdf.
), and scored in three categories – selection of subjects, comparability of study groups and assessment of results/exposures – up to a maximum score of 9.
Statistical analysis
All statistical analyses were conducted using RevMan 5.3 (Copenhagen, The Cochrane Collaboration) on homogeneous case–control studies. The relationship between HPV infections and female infertility was estimated by odds ratio (OR) with 95% confidence intervals (CI). The heterogeneity was estimated by Cochrane's chi-squared-based Q-test. The random effects model based on the generic inverse variance method was applied when heterogeneity was significant (I2 > 50%). Subgroup analysis was performed according to infertility classification and HPV detection method. In addition, sensitivity analysis was used to assess whether a single study dominated the results of the meta-analysis. Finally, the publication bias was evaluated by visual inspection of the funnel plots. All statistical tests were two-sided, and statistical significance was defined as a P-value less than 0.05.
Results
Association between HPV infection and infertility
The systematic literature search initially identified 4236 relevant studies, of which 3209 were excluded based on their title or abstract; 237 studies were case reports, while 229 studies were reviews. A total of 148 studies were publications not in English or Chinese; 57 studies were excluded for no control groups; 102 studies were excluded for not reporting cervical HPV prevalence in infertile women; 78 studies were excluded for reporting the relationship between and male infertility; 165 studies were excluded for reporting other pathogens infection in infertile women. The selection process is shown in Figure 1. Eleven case–control studies (
studied the effect of HPV infections on infertility. From all women, samples were taken from the upper genital tract (UGT) (including fallopian tube flushing fluid, Douglas fossa effusion, endometrial curettage, ovarian biopsy) and lower genital tract (LGT) (including cervix, lower third of the vagina). It was found that the HR-HPV infection rate of UGT sites in the infertile group was higher when compared with that in the control group (OR 3.78, 95% CI 1.1–12.3, P = 0.027). Due to the limited number of studies, only the relationship between cervical HPV infection rate and the incidence of female infertility was analysed.
Figure 1PRISMA flow diagram showing the search for studies.
Seven of these case–control studies with a total of 3581 participants reported the incidence of indiscriminate genotype infection (HR/LR-HPV). However, the random effects model revealed no association between HPV infection and female infertility, indicating similar prevalence in the infertile and general population (OR 2.13, 95% CI 0.97–4.65, P = 0.06, I2 = 92%). Six studies reported the prevalence of HR-HPV infections among 11,869 participants, and the random effects model revealed a significant association between HR-HPV infection and female infertility (OR 2.33, 95% CI 1.42–3.83, P = 0.0008, I2 = 92%), suggesting higher prevalence among infertile women (Figure 2).
Figure 2Meta-analysis of human papilloma virus (HPV) prevalence in infertile women versus women in the general population for studies reporting the incidence of indiscriminate genotype infection (high-risk [HR]/low-risk [LR]-HPV) and studies reporting HR-HPV infections.
Subgroup analysis by infertility classes indicated that indiscriminate HPV infection was associated with secondary infertility (two studies, OR 3.12, 95% CI 1.44–6.78, P = 0.004, I2 = 36%), whereas it was not associated with primary infertility (two studies, OR 0.83, 95% CI 0.47–1.47, P = 0.53, I2 = 0%) and unknown infertility (four studies, OR 2.74, 95% CI 0.78–9.64, P = 0.12, I2 = 96%) (Figure 3). However, four of the six case–control studies that analysed the prevalence of HR-HPV infections did not clarify the type of infertility, which could result in heterogeneity. The pooled data indicated that HR-HPV infection was associated with unknown infertility (four studies, OR 2.96, 95% CI 1.74–5.05, P < 0.0001, I2 = 94%) and not with primary infertility (two studies, OR 1.16, 95% CI 0.43–3.10, P = 0.77, I2 = 60%) (Figure 4). Subgroup analysis based on the HPV detection method showed that HR-HPV prevalence detected by PCR was not related to infertility risk (four studies, OR 2.31, 95% CI 0.85–6.29, P = 0.10, I2 = 91%), whereas that detected by HC2 was associated with a high risk of female infertility (two studies, OR 2.19, 95% CI 1.34–3.56, P = 0.002, I2 = 89%) (Figure 4).
Figure 3Meta-analysis of indiscriminate HPV infection in infertile women versus women in the general population in subgroups based on infertility classification (primary, secondary or unknown).
Figure 4Meta-analysis of HR-HPV infection in infertile women versus women in the general population in subgroups based on infertility classifications (primary or unknown) and HPV detection method (polymerase chain reaction [PCR] or Hybrid Capture® 2 [HC2]).
A sensitivity analysis was conducted by sequentially removing individual studies to assess whether any one of these studies affected the results of the meta-analysis. No individual study affected the overall significance of OR.
Publication bias
The funnel plots for publication bias were symmetrical and Egger's test indicated no significant asymmetry in any of the analyses.
Discussion
Although previous meta-analyses have established an association between HPV infection and both male infertility (
The risk of human papillomavirus infection for spontaneous abortion, spontaneous preterm birth, and pregnancy rate of assisted reproductive technologies: A systematic review and meta-analysis.
), little is known regarding its role in female infertility. This is thought to be the first meta-analysis of studies comparing the prevalence of HPV infection in the infertile and general female population. However, due to the uneven quality of the included studies, no definite conclusion can be drawn regarding the relationship between indiscriminate HPV infection and female infertility, which needs to be confirmed by future high-quality studies. In contrast, HR-HPV infection showed a significant association with female infertility, but a similar impact of LR-HPV remains to be elucidated.
Because case–control studies do not provide sufficient aetiological evidence, it is essential to determine the mechanisms influencing HPV prevalence in a population. Therefore,
conducted a prospective cohort study on 11,088 women randomly selected for cervical HPV testing between 1991 and 1993, and followed up the HPV+ subjects for 20 years to identify those with persistent HPV infections. The diagnosis of infertility was obtained by linkage to the Danish Infertility Cohort. After adjusting for maternal age, marriage/cohabitation status, smoking, education level, previous pelvic inflammation and Chlamydia infection at the time of initial registration, they found no association between HR-HPV positivity (hazard ratio 0.88, 95% CI 0.75–1.02) or homotypic persistence (hazard ratio 0.97, 95% CI 0.66–1.44) and the risk of future infertility. However, there were several limitations in their study. For example, the cohort included women with unknown fertility status (lack of infertility diagnosis and pregnancy during follow-up), which may have underestimated the true proportion of infertile women, especially those with unrecognized fertility problems. Furthermore, although the authors excluded women with infertile male partners, they could not rule out the possibility that the fertility state of the women was influenced by their HPV+ fertile male partners. Based on the above results and this meta-analysis, it can be surmised that although HR-HPV infection is a high-risk factor for female infertility, it may not be an independent factor. The possible mechanisms by which HR-HPV can trigger female infertility are as follows.
reported that of infertile women who are Mycoplasma positive, Chlamydia positive, or Mycoplasma/Chlamydia double-positive, the infection rate with HR-HPV (31.44%, 61.77% and 78.95%, respectively) was significantly higher compared with that of Mycoplasma/Chlamydia double-negative patients (6.92%). It has been suggested that multiple transmitted infections often occur in infertile patients. We speculate that HPV may cause pelvic inflammation and salpingitis by co-infection with other pathogens, resulting in infertility.
showed that the abnormal rate of cervical cytology in infertile women was significantly higher compared with that in healthy women of childbearing age.
found that the incidence of cervical intraepithelial neoplasia (CIN) lesions in infertile populations with a HR-HPV infection was higher compared with that in the general population (8.30% versus 4.52%). These observations suggested that women seeking treatment for infertility problems have a higher probability of CIN lesions compared with fertile women of similar age and demographic background, resulting in cervical infertility.
demonstrated that the HR-HPV infection rate in ovarian tissues of endometriosis patients was higher compared with non-endometriosis patients. These findings suggested that a HR-HPV infection of the UGT may be associated with endometriosis, thereby leading to infertility. Therefore, further studies are needed to establish the pathological role of HR-HPV infections in female infertility.
The types and prevalence of HR-HPV infection differ between the infertile and general population.
reported an indiscriminate HPV prevalence of 17.9% in 391 infertile women, and 82.86% of the indiscriminate HPV-positive women were positive for HR-HPV. HPV52 is the most infectious genotype in the infertile population, followed by HPV58 and 16, whereas HPV6 is the most infectious genotype in the general population, followed by HPV52 and 16 (
). A recent systematic review and meta-analysis on the fertility and early pregnancy outcomes in women with CIN showed a higher overall pregnancy rate among the treated as opposed to untreated patients (43% versus 38%) (
studied 144 infertile patients with primary HR-HPV (HPV16, 18, 45, 31) and secondary HR-HPV (HPV33, 52, 58, 67) infections, of which some were treated with a loop electrosurgical excision procedure (LEEP), drug therapy or a combination of the two. The overall pregnancy rate in the treated group was significantly higher compared with that in the untreated group (31.67% versus 4.00%). Furthermore, the pregnancy rate after LEEP + drug treatment in the primary HR-HPV+ patients was higher than that in the drug-treated group (41.18% versus 6.67%). Therefore, the combination therapy is the optimal strategy for primary HR-HPV infections accompanied by cervical lesions (CIN I, II, III). However, the pregnancy rate among the untreated secondary HR-HPV+ patients was significantly higher than that in the treated patients in the same group (50.00% versus 13.33%). Therefore, secondary HR-HPV infection cases with chronic cervical inflammation or mild cervical lesion (CIN I) should be kept under observation.
Since 2006, HPV vaccination has been implemented in several countries to reduce viral transmission and the incidence of related diseases. At present, the approved HPV prophylactics include bivalent vaccines against the high-risk serotypes 16 and 18, and the tetravalent vaccine against the low-risk serotypes 6 and 11 in addition to 16 and 18, and are mainly used to prevent genital warts, cervical dysplasia and cervical cancer. In addition, the recently developed nine-valent vaccine against HPV6, 11, 16, 18, 31, 33, 45, 52 and 58 subtypes can prevent 90% of cervical cancer cases (
evaluated the effect of HPV vaccination on the fertility of males with HPV+ semen, and observed increased sperm motility and circulating anti-HPV antibodies. Furthermore, the pregnancy rate among the female partners of the vaccinated men was significantly higher compared with that of the control group (38.9% versus 15.0%) (
). Thus, anti-HPV vaccination can restore sperm health and increase the rate of natural pregnancies and live births.
There are several limitations in the present study that should be considered when interpreting the results. Firstly, only studies published in English and Chinese were included, which probably resulted in potential selection bias. Secondly, there was potential heterogeneity between the studies based on study design, sample size, ethnicity and the number of detected HPV types, but the grouping analysis provided little additional insight into the possible sources of heterogeneity. Some studies detected HR-HPV genotypes, while others reported indiscriminate HPV infections. Because the effects of the latter on infertility have not been clarified, the different HPV genotypes may have affected the pooled data. Furthermore, some studies used the HC2 DNA test to detect HR-HPV infections while others used PCR to detect HPV genotypes, which is another source of bias. Thirdly, most studies did not classify the infertile population in the primary, secondary, male factor, bilateral factors and idiopathic aetiological groups, which limits our understanding of the relationship between HPV and types of infertility.
HR-HPV infection is a potential risk but not an independent factor for female infertility, and probably causes secondary infertility along with other sexually transmitted pathogens. Thus, cervical HPV screening and treatment is recommended for women with fertility issues, along with its detection in the semen of their male partners. HPV vaccination should also be rigorously implemented. Further prospective studies are needed to assess the role of HPV infection in female infertility and the underlying mechanisms.
Acknowledgements
This work was supported by the Chengdu Science and Technology Huimin Technology Research and Development Project (grant number 2015-HMO1-00414-SF).
References
AbdullGaffar Badr
Kamal Mohamed O.
Hasoub Ahmed
The Prevalence of Abnormal Cervical Cytology in Women With Infertility.
Lifestyle and fertility: The influence of stress and quality of life on female fertility 11 Medical and Health Sciences 1114 Paediatrics and Reproductive Medicine Rosario Pivonello.
Wells G.A., Shea B., O'Connell D., Peterson J., Welch V., Losos M., et al. 2010. The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses.www.ohri.ca/programs/clinical_epidemiology/nos_manual.pdf.
The risk of human papillomavirus infection for spontaneous abortion, spontaneous preterm birth, and pregnancy rate of assisted reproductive technologies: A systematic review and meta-analysis.
Wang Hongjing gained her PhD from West China University of Chengdu, Sichuan Province. She is an Obstetrics and Gynecology Professor at West China Second University Hospital, and one of the academic and technological leaders of Sichuan Province. Her main fields are gynaecology, gynaecological oncology and women’s health care.
Key message
The relationship between indiscriminate HPV infection and female infertility needs to be confirmed by future high-quality studies. HR-HPV infection showed a significant association with female infertility, but a similar impact of LR-HPV remains to be elucidated. Thus, cervical HPV screening and treatment is recommended for women with fertility issues.
Article info
Publication history
Published online: November 15, 2019
Accepted:
October 30,
2019
Received in revised form:
October 21,
2019
Received:
October 8,
2019
Declaration: The authors report no financial or commercial conflicts of interest.
Score for quality assessment in case–control studies: maximum 9, minimum 0.
30799-0&id=gr1.jpg){kind=link}
30799-0&id=gr2.jpg){kind=link}
30799-0&id=gr3.jpg){kind=link}
30799-0&id=gr4.jpg){kind=link}