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Human papillomavirus infection and female infertility: a systematic review and meta-analysis
HPV infection and female Infertility
Conflict of interest: The authors declare that they have no conflict of interest.
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HPV infection and female Infertility: A systematic Review and meta-Analysis Shuang Yuan , Yichao Qiu , Yuanyuan Xu , Hongjing Wang PII: DOI: Reference:
S1472-6483(19)30799-0 https://doi.org/10.1016/j.rbmo.2019.10.019 RBMO 2291
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Reproductive BioMedicine Online
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8 October 2019 21 October 2019 30 October 2019
Please cite this article as: Shuang Yuan , Yichao Qiu , Yuanyuan Xu , Hongjing Wang , HPV infection and female Infertility: A systematic Review and meta-Analysis, Reproductive BioMedicine Online (2019), doi: https://doi.org/10.1016/j.rbmo.2019.10.019
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Title: HPV infection and female Infertility: a systematic Review and meta-Analysis Short title: HPV infection and female Infertility Authors Shuang Yuan1，2, Yichao Qiu1，2, Yuanyuan Xu1，2, Hongjing Wang1，2*. Affiliations 1. Department of Gynecology and Obstetrics, West China Second University Hospital, Sichuan University, Chengdu, Sichuan Province, China. 2. Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu, Sichuan Province, China. Funding: This work was supported by Chengdu Science and Technology Huimin Technology Research and Development Project [grant numbers 2015-HMO1-00414-SF] Conflict of interest: The authors declare that they have no conflict of interest. *Corresponding Author: Hongjing Wang Department of Gynecology and Obstetrics, West China Second University Hospital, Sichuan University, Chengdu, Sichuan Province, China.610041 Tel: 02885501211 E-mail: [email protected]
Abstract Increasing evidence shows that HPV infection affects reproductive health and fertility, although its impact on female fertility has not been thoroughly studied. We conducted a meta-analysis of 12 studies including 15450 female subjects that compared HPV prevalence between the infertile and general population, and evaluated the association between HPV positivity and female infertility. Seven case-controlled studies on 3581 participants reported indiscriminate genotype infections (HR/LR-HPV), but the random effects model revealed no association between HPV infection and female infertility (OR=2.13, 95%CI [0.97-4.65], P = 0.06). Six studies with a total of 11869 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). We 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. Keywords: Human papillomavirus; female Infertility; meta-analysis; systematic review
Introduction Infertility, defined as the inability to conceive even after a year of regular sexual intercourse without using contraceptives, affects 8%-12% of reproductive-aged couples worldwide(Ombelet et al., 2008; Vander Borght and Wyns, 2018a). It is three times more prevalent in South Asia, Africa, the Middle East, Central and Eastern Europe and Central Asia compared to the global average(Mascarenhas et al. 2012a), most likely due to high unsafe abortion rates and poor maternal care that increases the risk of post-abortion and postpartum infections, as well as secondary infertility (Inhorn and Patrizio, 2014). Nevertheless, infertility rates are increasing worldwide year after year, which apart from affecting the quality of life and psychological status of the patients, is contributing to significant economic burden(Mascarenhas et al. 2012b). Therefore, it is essential to analyze the etiology of infertility in order to devise effective preventive measures. Infertility is largely seen as a psychosomatic disease that is influenced by psychological and lifestyle factors(Palomba et al., 2018). However, any disease that disrupts the hypothalamus-pituitary-ovary axis and affects the sex hormones 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 (Vander Borght and Wyns, 2018b). In fact, 20% to 60% of female infertility cases is caused by sexually transmitted infections, which can eventually lead to pelvic inflammation and tubal obstruction (Pellati et al., 2008). The most common pathogens associated with female genital tract infections include Mycoplasmas, Chlamydia trachomatis, and Neisseria gonorrhoeae, in addition to some viruses (Guihong, 2016). 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 tumors and infertility or early abortion (Depuydt et al., 2016). HPV is classified into the low-risk (LR) and high-risk (HR) types according to their ability to induce tumors. 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 (Gravitt and Winer, 2017). Recent evidence suggests that HPV infections may cause male infertility by decreasing sperm motility, and adversely affect the outcomes of natural pregnancy or assisted reproductive techniques (Foresta et al., 2015; Marco et al., 2014). Presence of HPV in the sperm has been correlated to a cumulative decrease in the rates of natural and assisted pregnancies, and an increase in abortion rates (Garolla et al., 2016). Several meta-analyses have also demonstrated an association between HPV infection and IVF/ICSI outcome. Xiong et al. 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 (Xiong et al., 2018a). However, there is not enough evidence to indicate an association between HPV infections and the pregnancy or spontaneous abortion rates of ART (Siristatidis et al., 2018a). To this end, we conducted a meta-analysis 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 till April 1, 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-analysis (PRISMA) guidelines 6. Data Selection and Extraction Mendeley (version 1.19.4) was used to manage citations and extract data. Two reviewers independently evaluated all retrieved articles by title, abstract and full text, and selected studies based on the following inclusion criteria: (1) comparison of HPV prevalence between infertile and general populations, (2) cohort study or case-controlled study design, (3) detection of HPV DNA in the cervix by polymerase chain reaction (PCR) or Hybrid Capture 2 (HC2) method. Studies were excluded if (1) they were review articles, editorials, opinions or case reports, or (2) cervical cytology was used as a substitute to detect HPV infections. The following data was extracted from each study: first author, publication year, country of region, 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 were assessed by Newcastle-Ottawa Scale (NOS), and scored in three categories – selection of subjects, comparability of study groups and assessment of results/exposures – to a maximum score of 9. Statistical Analysis All statistical analyses were conducted using Revman (version 5.3; Cochrane
Collaboration Network) on homogeneous case-controlled studies. The relationship between HPV infections and female infertility was estimated by odds ratio (OR) with 95% CIs. The heterogeneity was estimated by Cochran's Chi-square-based Q-test. The random effect model based on 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 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. The selection process is shown in Figure 1. Twelve studies, including 11 case-controlled studies and 1 prospective cohort study, were included for the meta-analysis, and their main characteristics and NOS scores are summarized in Table 1 (Hongli et al., 2016; Jinhua et al., 2013; Jun et al., 2017; Lundqvist et al., 2002; Moragianni et al., 2019; Na et al., 2016; Nøhr et al., 2019a; Rocha et al., 2019a; Shaofang et al., 2012; Ying et al., 2010; Yinghui and Xiangkun, 2013; Zhu et al., 2016). All included studies, except one, only described HPV infections at the cervix. Rocha et al. 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 1/3 of the vagina). It was found that the HR-HPV infection rate of UGT sites in the infertile group was higher when compared to that in the control group (OR=3.78, 95% CI [1.1-12.3], P=0.027)(Rocha et al., 2019b). Due to the limited number of studies, we only analyzed the relationship between cervical HPV infection rate and the incidence of female infertility. Seven of these case-controlled 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). Six studies reported the prevalence of HR-HPV infections among 11869 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), suggesting higher prevalence among infertile women (Figure 2). Nøhr et al. conducted a prospective cohort study on 11088
women randomly selected for cervical HPV testing between 1991-1993, 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. They found no association between HR-HPV positivity (HR=0.88,95%CI [0.75–1.02]) or homotypic persistence (HR=0.97,95%CI [0.66–1.44]) and the risk of future infertility(Nøhr et al., 2019b). Heterogeneity analysis Subgroup analysis by infertility classes indicated that indiscriminate HPV infection was associated with secondary and not with primary infertility. However, 4 of the 6 studies that analyzed the prevalence of HR-HPV infections did not clarify the type of infertility, which could result in heterogeneity (Figure 3). Subgroup analysis based on the HPV detection method showed that HR-HPV prevalence detected by PCR was not related to infertility risk, whereas that detected by HC2 was associated with a high risk of female infertility (Figure 4). Sensitivity analysis We conducted a sensitivity analysis 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 ORs. 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 (Lyu et al., 2017) and the outcomes of natural or IVF/ICSI pregnancies (Siristatidis et al., 2018b; Xiong et al., 2018b), little is known regarding its role in female infertility. To the best of our knowledge, this is the first meta-analysis of studies comparing the prevalence of HPV infection in the infertile and general female population. However, due to the low-accuracy and uneven quality of the included studies, we cannot draw a definite conclusion 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. Since case-controlled studies do not provide sufficient etiological evidence, it is
essential to determine the mechanisms influencing HPV prevalence in a population. Therefore, Nøhr et al. conducted an observational prospective study on 1861 female patients with HR-HPV infection and 794 patients with persistent HR-HPV infection over a period of 20 years (Nøhr et al., 2019c). After adjusting for maternal age, marriage/cohabitation status, smoking, education level, previous pelvic inflammation and Chlamydia infection at the time of initial registration, they detected no association between HR-HPV positivity or homotypic persistence and future risk of 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 our meta-analysis, we surmise 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: (1) Co-infection: Wang et al. reported that infertile women who are mycoplasma positive, chlamydia positive, and mycoplasma chlamydia double-positive, the infection rate of HR-HPV (31.44%, 61.77%, 78.95%) was significantly higher compared to that of mycoplasma and chlamydia double-negative patients (6.92%) (Xiaochang et al., 2014). It has been suggested that multiple transmitted infections often occur in infertile patients. We speculated that HPV may cause pelvic inflammation and salpingitis by co-infection with other pathogens, resulting in infertility. (2) Cervical lesion ： AbdullGaffar et al. showed that the abnormal rate of cervical cytology in infertile women was significantly higher compared to that in healthy women of childbearing age (AbdullGaffar et al., 2010). Li et al. found that the incidence of CIN lesions in infertile populations with a HR-HPV infection was higher compared to that in the general population (8.30% vs 4.52%) (Qinyan et al., 2014). These observations suggested that women seeking treatment for infertility problems have a higher probability of CIN lesions compared to reproductive women of similar age and demographic background, resulting in cervical infertility. (3) Endometriosis: Heidarpour et al. demonstrated that the HR-HPV infection rate in ovarian tissues of endometriosis patients was higher compared to the control group(Heidarpour et al., 2017). These findings suggested that a HR-HPV infection of the upper genital tract may 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 differ between the infertile and general
population. Wu et al. detected 5.4%, 36.8%, 40.3% and 17.5% prevalence of HPV in infertile women under 25, 25-29, 30-34 and above 35 years of age respectively (Jinhua et al., 2013a). Zhou et al. reported an indiscriminate HPV prevalence of 17.9% in 391 infertile women, and 82.86% were positive for HR-HPV (Zhou and Wei, 2015). HPV52 is the most infectious genotype in the infertile population, followed by HPV58 and 16. In contrast, HPV 6 is the most infectious genotype in the general population, followed by HPV52 and 16 (Jinhua et al., 2013b). A recent systematic review and meta-analysis on the fertility and early pregnancy outcomes in women with cervical intraepithelial neoplasia (CIN) showed a higher overall pregnancy rate among the treated as opposed to untreated patients (43% vs 38%) (Conner et al., 2014), indicating that clearing HPV particles from the cervix improves fertility. Zhang et al. (Zhang et al., 2010) studied 144 infertile patients with primary HR-HPV (HPVl6, 18, 45, 31) and secondary HR-HPV (HPV33, 52, 58, 67) infections, of which some were treated with loop electrosurgical excision procedure (LEEP), drug therapy or their combination. The overall pregnancy rate in the treated group was significantly higher compared to that in the untreated group (31.67% vs 4%). 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% vs 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% vs 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, cervical cancer etc. 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(Bonde et al., 2014). With global implementation of HPV vaccination, the incidence of cervical cancer and HPV-related adverse pregnancy outcomes may decrease in future. Foresta et al. 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 to that of the control group (38.9% vs 15%)(Foresta et al., 2015). 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 language were included, which likely 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 insights into the possible sources of heterogeneity. Some studies detected only types 16 and 18, or 13 HR-HPV genotypes, while others reported HR-HPV and LR-HPV infections. Since 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 etiological groups, which limits our understanding of the relationship between HPV and types of infertility.
Conclusions HR-HPV infection is a potential high-risk but not an independent factor for female infertility, and likely 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.
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Wang Hongjing has a PhD in West China University of Chengdu, Sichuan Province. She is an obstetrics & gynecology professor at West China Second University Hospital. She is one of the academic and technological leaders of Sichuan Province. Her main fields are Gynaecology, Gynecological Oncology and Women's Health Care.
Key message: We cannot draw a definite conclusion 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. Thus, cervical HPV screening and treatment is recommended for women with fertility issues, along with its detection in the semen of their male partners.
Table 1. Characteristics of included studies
aut co stu hor nu dy ,ye ntr des ar y ign
H P V de te cti on m et ho d
Na et al. 20 16
ch in a
cas e-c onr tol
P C R
Unk own
Jin hua et al. 20 13
ch in a
cas e-c onr tol
P C R
52、 58、 16
Mo rag ian ni et al. 20 19 Yin gh ui et al. 20
gr ee ce
ch in a
cas e-c onr tol
cas e-c onr tol
P C R
P C R
HPV geno type
Unk own
Unk own
HPV detection tissue
av er ag e ag e
infe rtile pati ents indi scri min ate HP V infe ctio n
ferti le pati ents indi scri min ate HP V infe ctio n
inf ert ile pa tie nts H RH P V inf ect io n
fer tile pat N ien infe O ts rtile S H clas s R- sifi c HP cati o V on r inf e ect ion
cervix
2 5- 25/3 5/15 4 00 0 2
Un ko wn
7
cervix
1 9- 77/7 36/4 4 78 28 3
Un ko wn
7
2 24 5
19/1 22/1 11 04
Pri mar y infe rtili ty
7
2 5- 40/7 29/8 3 5 9 9
Sec ond ary infe rtili ty
6
cervix
cervix
13
Sh aof ang ch et in al. a 20 12 Jun et al. 20 17
ch in a
cas e-c onr tol
cas e-c onr tol
P C R
Unk own
P C R
the most com mon: HPV 58,5 2,16
cervix
2 4- 19/3 5/31 4 7 4
cervix
1 7- 432/ 185/ 8 648 770 2
6
38 1/ 64 8
14 8/7 70
Un ko wn
7
2 8- 15/2 21/3 4 5 5 7
13 /2 5
Pri mar 12/ y 35 infe rtili ty
8
cervix
2 34 3
34 7/ 11 00
10 88/ 76 00
Un ko wn
7
cervix
2 34 0
33 /1 30
17/ 15 0
Un ko wn
7
cervix
2 14 2
14 5/ 50 0
98/ 50 0
Un ko wn
7
Ro cha et al. 20 19
br az il
cas e-c onr tol
P C R
the most vaginal,cervix,en com dometrium,tubes mon: ,ovarium,periton HPV uem 16,8 2,6
Lip ing et al. 20 15
ch in a
cas e-c onr tol
H C 2
Unk own
Lid on g et al. 20 07
ch in a
cas e-c onr tol
P C R
Unk own
Ho ngl i et al. 20 16
ch in a
cas e-c onr tol
H C 2
Unk own
Sec ond ary infe rtili ty
Lu nd qvi st et al. 20 02
cas sw e-c ed onr en tol
Bu gge Nø hr et al 20 19
pro de spe n ctiv m e ar coh k ort
P C R
H C 2
HPV 16,1 8,31, 33
Unk own
cervix
cervix
2 04 0
2 02 9
15 /2 14
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Figure 1. PRISMA flow diagram showing the search for studies
Figure 2. Meta-analysis on HPV prevalence in infertile versus general women
Figure 3. Subgroup analysis based on infertility classes of indiscriminate HPV infection.
Figure 4. Subgroup analysis based on infertility classes and HPV detection method of HR HPV infection.
Conflict of interest: The authors declare that they have no conflict of interest.
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HPV infection and female Infertility: A systematic Review and meta-Analysis Shuang Yuan , Yichao Qiu , Yuanyuan Xu , Hongjing Wang PII: DOI: Reference:
S1472-6483(19)30799-0 https://doi.org/10.1016/j.rbmo.2019.10.019 RBMO 2291
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Reproductive BioMedicine Online
Received date: Revised date: Accepted date:
8 October 2019 21 October 2019 30 October 2019
Please cite this article as: Shuang Yuan , Yichao Qiu , Yuanyuan Xu , Hongjing Wang , HPV infection and female Infertility: A systematic Review and meta-Analysis, Reproductive BioMedicine Online (2019), doi: https://doi.org/10.1016/j.rbmo.2019.10.019
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Title: HPV infection and female Infertility: a systematic Review and meta-Analysis Short title: HPV infection and female Infertility Authors Shuang Yuan1，2, Yichao Qiu1，2, Yuanyuan Xu1，2, Hongjing Wang1，2*. Affiliations 1. Department of Gynecology and Obstetrics, West China Second University Hospital, Sichuan University, Chengdu, Sichuan Province, China. 2. Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu, Sichuan Province, China. Funding: This work was supported by Chengdu Science and Technology Huimin Technology Research and Development Project [grant numbers 2015-HMO1-00414-SF] Conflict of interest: The authors declare that they have no conflict of interest. *Corresponding Author: Hongjing Wang Department of Gynecology and Obstetrics, West China Second University Hospital, Sichuan University, Chengdu, Sichuan Province, China.610041 Tel: 02885501211 E-mail: [email protected]
Abstract Increasing evidence shows that HPV infection affects reproductive health and fertility, although its impact on female fertility has not been thoroughly studied. We conducted a meta-analysis of 12 studies including 15450 female subjects that compared HPV prevalence between the infertile and general population, and evaluated the association between HPV positivity and female infertility. Seven case-controlled studies on 3581 participants reported indiscriminate genotype infections (HR/LR-HPV), but the random effects model revealed no association between HPV infection and female infertility (OR=2.13, 95%CI [0.97-4.65], P = 0.06). Six studies with a total of 11869 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). We 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. Keywords: Human papillomavirus; female Infertility; meta-analysis; systematic review
Introduction Infertility, defined as the inability to conceive even after a year of regular sexual intercourse without using contraceptives, affects 8%-12% of reproductive-aged couples worldwide(Ombelet et al., 2008; Vander Borght and Wyns, 2018a). It is three times more prevalent in South Asia, Africa, the Middle East, Central and Eastern Europe and Central Asia compared to the global average(Mascarenhas et al. 2012a), most likely due to high unsafe abortion rates and poor maternal care that increases the risk of post-abortion and postpartum infections, as well as secondary infertility (Inhorn and Patrizio, 2014). Nevertheless, infertility rates are increasing worldwide year after year, which apart from affecting the quality of life and psychological status of the patients, is contributing to significant economic burden(Mascarenhas et al. 2012b). Therefore, it is essential to analyze the etiology of infertility in order to devise effective preventive measures. Infertility is largely seen as a psychosomatic disease that is influenced by psychological and lifestyle factors(Palomba et al., 2018). However, any disease that disrupts the hypothalamus-pituitary-ovary axis and affects the sex hormones 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 (Vander Borght and Wyns, 2018b). In fact, 20% to 60% of female infertility cases is caused by sexually transmitted infections, which can eventually lead to pelvic inflammation and tubal obstruction (Pellati et al., 2008). The most common pathogens associated with female genital tract infections include Mycoplasmas, Chlamydia trachomatis, and Neisseria gonorrhoeae, in addition to some viruses (Guihong, 2016). 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 tumors and infertility or early abortion (Depuydt et al., 2016). HPV is classified into the low-risk (LR) and high-risk (HR) types according to their ability to induce tumors. 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 (Gravitt and Winer, 2017). Recent evidence suggests that HPV infections may cause male infertility by decreasing sperm motility, and adversely affect the outcomes of natural pregnancy or assisted reproductive techniques (Foresta et al., 2015; Marco et al., 2014). Presence of HPV in the sperm has been correlated to a cumulative decrease in the rates of natural and assisted pregnancies, and an increase in abortion rates (Garolla et al., 2016). Several meta-analyses have also demonstrated an association between HPV infection and IVF/ICSI outcome. Xiong et al. 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 (Xiong et al., 2018a). However, there is not enough evidence to indicate an association between HPV infections and the pregnancy or spontaneous abortion rates of ART (Siristatidis et al., 2018a). To this end, we conducted a meta-analysis 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 till April 1, 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-analysis (PRISMA) guidelines 6. Data Selection and Extraction Mendeley (version 1.19.4) was used to manage citations and extract data. Two reviewers independently evaluated all retrieved articles by title, abstract and full text, and selected studies based on the following inclusion criteria: (1) comparison of HPV prevalence between infertile and general populations, (2) cohort study or case-controlled study design, (3) detection of HPV DNA in the cervix by polymerase chain reaction (PCR) or Hybrid Capture 2 (HC2) method. Studies were excluded if (1) they were review articles, editorials, opinions or case reports, or (2) cervical cytology was used as a substitute to detect HPV infections. The following data was extracted from each study: first author, publication year, country of region, 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 were assessed by Newcastle-Ottawa Scale (NOS), and scored in three categories – selection of subjects, comparability of study groups and assessment of results/exposures – to a maximum score of 9. Statistical Analysis All statistical analyses were conducted using Revman (version 5.3; Cochrane
Collaboration Network) on homogeneous case-controlled studies. The relationship between HPV infections and female infertility was estimated by odds ratio (OR) with 95% CIs. The heterogeneity was estimated by Cochran's Chi-square-based Q-test. The random effect model based on 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 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. The selection process is shown in Figure 1. Twelve studies, including 11 case-controlled studies and 1 prospective cohort study, were included for the meta-analysis, and their main characteristics and NOS scores are summarized in Table 1 (Hongli et al., 2016; Jinhua et al., 2013; Jun et al., 2017; Lundqvist et al., 2002; Moragianni et al., 2019; Na et al., 2016; Nøhr et al., 2019a; Rocha et al., 2019a; Shaofang et al., 2012; Ying et al., 2010; Yinghui and Xiangkun, 2013; Zhu et al., 2016). All included studies, except one, only described HPV infections at the cervix. Rocha et al. 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 1/3 of the vagina). It was found that the HR-HPV infection rate of UGT sites in the infertile group was higher when compared to that in the control group (OR=3.78, 95% CI [1.1-12.3], P=0.027)(Rocha et al., 2019b). Due to the limited number of studies, we only analyzed the relationship between cervical HPV infection rate and the incidence of female infertility. Seven of these case-controlled 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). Six studies reported the prevalence of HR-HPV infections among 11869 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), suggesting higher prevalence among infertile women (Figure 2). Nøhr et al. conducted a prospective cohort study on 11088
women randomly selected for cervical HPV testing between 1991-1993, 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. They found no association between HR-HPV positivity (HR=0.88,95%CI [0.75–1.02]) or homotypic persistence (HR=0.97,95%CI [0.66–1.44]) and the risk of future infertility(Nøhr et al., 2019b). Heterogeneity analysis Subgroup analysis by infertility classes indicated that indiscriminate HPV infection was associated with secondary and not with primary infertility. However, 4 of the 6 studies that analyzed the prevalence of HR-HPV infections did not clarify the type of infertility, which could result in heterogeneity (Figure 3). Subgroup analysis based on the HPV detection method showed that HR-HPV prevalence detected by PCR was not related to infertility risk, whereas that detected by HC2 was associated with a high risk of female infertility (Figure 4). Sensitivity analysis We conducted a sensitivity analysis 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 ORs. 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 (Lyu et al., 2017) and the outcomes of natural or IVF/ICSI pregnancies (Siristatidis et al., 2018b; Xiong et al., 2018b), little is known regarding its role in female infertility. To the best of our knowledge, this is the first meta-analysis of studies comparing the prevalence of HPV infection in the infertile and general female population. However, due to the low-accuracy and uneven quality of the included studies, we cannot draw a definite conclusion 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. Since case-controlled studies do not provide sufficient etiological evidence, it is
essential to determine the mechanisms influencing HPV prevalence in a population. Therefore, Nøhr et al. conducted an observational prospective study on 1861 female patients with HR-HPV infection and 794 patients with persistent HR-HPV infection over a period of 20 years (Nøhr et al., 2019c). After adjusting for maternal age, marriage/cohabitation status, smoking, education level, previous pelvic inflammation and Chlamydia infection at the time of initial registration, they detected no association between HR-HPV positivity or homotypic persistence and future risk of 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 our meta-analysis, we surmise 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: (1) Co-infection: Wang et al. reported that infertile women who are mycoplasma positive, chlamydia positive, and mycoplasma chlamydia double-positive, the infection rate of HR-HPV (31.44%, 61.77%, 78.95%) was significantly higher compared to that of mycoplasma and chlamydia double-negative patients (6.92%) (Xiaochang et al., 2014). It has been suggested that multiple transmitted infections often occur in infertile patients. We speculated that HPV may cause pelvic inflammation and salpingitis by co-infection with other pathogens, resulting in infertility. (2) Cervical lesion ： AbdullGaffar et al. showed that the abnormal rate of cervical cytology in infertile women was significantly higher compared to that in healthy women of childbearing age (AbdullGaffar et al., 2010). Li et al. found that the incidence of CIN lesions in infertile populations with a HR-HPV infection was higher compared to that in the general population (8.30% vs 4.52%) (Qinyan et al., 2014). These observations suggested that women seeking treatment for infertility problems have a higher probability of CIN lesions compared to reproductive women of similar age and demographic background, resulting in cervical infertility. (3) Endometriosis: Heidarpour et al. demonstrated that the HR-HPV infection rate in ovarian tissues of endometriosis patients was higher compared to the control group(Heidarpour et al., 2017). These findings suggested that a HR-HPV infection of the upper genital tract may 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 differ between the infertile and general
population. Wu et al. detected 5.4%, 36.8%, 40.3% and 17.5% prevalence of HPV in infertile women under 25, 25-29, 30-34 and above 35 years of age respectively (Jinhua et al., 2013a). Zhou et al. reported an indiscriminate HPV prevalence of 17.9% in 391 infertile women, and 82.86% were positive for HR-HPV (Zhou and Wei, 2015). HPV52 is the most infectious genotype in the infertile population, followed by HPV58 and 16. In contrast, HPV 6 is the most infectious genotype in the general population, followed by HPV52 and 16 (Jinhua et al., 2013b). A recent systematic review and meta-analysis on the fertility and early pregnancy outcomes in women with cervical intraepithelial neoplasia (CIN) showed a higher overall pregnancy rate among the treated as opposed to untreated patients (43% vs 38%) (Conner et al., 2014), indicating that clearing HPV particles from the cervix improves fertility. Zhang et al. (Zhang et al., 2010) studied 144 infertile patients with primary HR-HPV (HPVl6, 18, 45, 31) and secondary HR-HPV (HPV33, 52, 58, 67) infections, of which some were treated with loop electrosurgical excision procedure (LEEP), drug therapy or their combination. The overall pregnancy rate in the treated group was significantly higher compared to that in the untreated group (31.67% vs 4%). 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% vs 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% vs 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, cervical cancer etc. 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(Bonde et al., 2014). With global implementation of HPV vaccination, the incidence of cervical cancer and HPV-related adverse pregnancy outcomes may decrease in future. Foresta et al. 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 to that of the control group (38.9% vs 15%)(Foresta et al., 2015). 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 language were included, which likely 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 insights into the possible sources of heterogeneity. Some studies detected only types 16 and 18, or 13 HR-HPV genotypes, while others reported HR-HPV and LR-HPV infections. Since 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 etiological groups, which limits our understanding of the relationship between HPV and types of infertility.
Conclusions HR-HPV infection is a potential high-risk but not an independent factor for female infertility, and likely 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.
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Wang Hongjing has a PhD in West China University of Chengdu, Sichuan Province. She is an obstetrics & gynecology professor at West China Second University Hospital. She is one of the academic and technological leaders of Sichuan Province. Her main fields are Gynaecology, Gynecological Oncology and Women's Health Care.
Key message: We cannot draw a definite conclusion 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. Thus, cervical HPV screening and treatment is recommended for women with fertility issues, along with its detection in the semen of their male partners.
Table 1. Characteristics of included studies
aut co stu hor nu dy ,ye ntr des ar y ign
H P V de te cti on m et ho d
Na et al. 20 16
ch in a
cas e-c onr tol
P C R
Unk own
Jin hua et al. 20 13
ch in a
cas e-c onr tol
P C R
52、 58、 16
Mo rag ian ni et al. 20 19 Yin gh ui et al. 20
gr ee ce
ch in a
cas e-c onr tol
cas e-c onr tol
P C R
P C R
HPV geno type
Unk own
Unk own
HPV detection tissue
av er ag e ag e
infe rtile pati ents indi scri min ate HP V infe ctio n
ferti le pati ents indi scri min ate HP V infe ctio n
inf ert ile pa tie nts H RH P V inf ect io n
fer tile pat N ien infe O ts rtile S H clas s R- sifi c HP cati o V on r inf e ect ion
cervix
2 5- 25/3 5/15 4 00 0 2
Un ko wn
7
cervix
1 9- 77/7 36/4 4 78 28 3
Un ko wn
7
2 24 5
19/1 22/1 11 04
Pri mar y infe rtili ty
7
2 5- 40/7 29/8 3 5 9 9
Sec ond ary infe rtili ty
6
cervix
cervix
13
Sh aof ang ch et in al. a 20 12 Jun et al. 20 17
ch in a
cas e-c onr tol
cas e-c onr tol
P C R
Unk own
P C R
the most com mon: HPV 58,5 2,16
cervix
2 4- 19/3 5/31 4 7 4
cervix
1 7- 432/ 185/ 8 648 770 2
6
38 1/ 64 8
14 8/7 70
Un ko wn
7
2 8- 15/2 21/3 4 5 5 7
13 /2 5
Pri mar 12/ y 35 infe rtili ty
8
cervix
2 34 3
34 7/ 11 00
10 88/ 76 00
Un ko wn
7
cervix
2 34 0
33 /1 30
17/ 15 0
Un ko wn
7
cervix
2 14 2
14 5/ 50 0
98/ 50 0
Un ko wn
7
Ro cha et al. 20 19
br az il
cas e-c onr tol
P C R
the most vaginal,cervix,en com dometrium,tubes mon: ,ovarium,periton HPV uem 16,8 2,6
Lip ing et al. 20 15
ch in a
cas e-c onr tol
H C 2
Unk own
Lid on g et al. 20 07
ch in a
cas e-c onr tol
P C R
Unk own
Ho ngl i et al. 20 16
ch in a
cas e-c onr tol
H C 2
Unk own
Sec ond ary infe rtili ty
Lu nd qvi st et al. 20 02
cas sw e-c ed onr en tol
Bu gge Nø hr et al 20 19
pro de spe n ctiv m e ar coh k ort
P C R
H C 2
HPV 16,1 8,31, 33
Unk own
cervix
cervix
2 04 0
2 02 9
15 /2 14
Pri mar 18/ y 19 infe 7 rtili ty
7
20 0/ 12 36
Pri 16 mar 61/ y 93 infe 59 rtili ty
8
Figure 1. PRISMA flow diagram showing the search for studies
Figure 2. Meta-analysis on HPV prevalence in infertile versus general women
Figure 3. Subgroup analysis based on infertility classes of indiscriminate HPV infection.
Figure 4. Subgroup analysis based on infertility classes and HPV detection method of HR HPV infection.