HPV and Female Infertility: 2 New Studies Probe Link

The link between HPV and infertility in women is a matter of ongoing debate. There is evidence to suggest that women with HPV who undergo assisted reproduction may have lower pregnancy rates and higher rates of pregnancy loss, pointing to adverse effects of HPV on fertility.^1-3 Other studies, however, have failed to confirm these findings.⁴

A significant question not yet addressed: What role is played by other factors associated with both HPV and infertility? HPV infection often co-occurs with other types of sexually transmitted infections (STIs), especially chlamydia-a well-known cause of pelvic inflammatory disease (PID) which can cause infertility.

Now, 2 studies-both representing firsts in this area of research-aim at clarifying the matter.

Next: Study No 1.

Study No 1.

Researchers led by Bugge NØhr, MD, PhD, of the Department of Obstetrics and Gynecology, University Hospital of Herlev and Gentofte, Copenhagen, Denmark recently published results of the first cohort study to evaluate the link between past HPV infection and infertility.⁵ The population-based cohort study, published online in Fertility and Sterility, included more than 10 000 women aged 20-29 years who were tested for HPV between 1991-1993 and received repeat testing 2 years after the first test. Follow-up continued for approximately 20 years.

Results

• 17.6% of women initially tested positive for high risk HPV; 4.3% of these tested positive for the same high-risk HPV type on the follow-up visit, suggesting persistent infection.
   

• Among women who initially tested positive for HPV, 11.7% were later diagnosed with infertility.
   

• Results adjusted for age, smoking, educational level, PID, and chlamydia infection showed no significant link between infertility and testing positive for high risk HPV infection on the initial visit and testing positive for the same high risk type on follow-up (HR = 0.88; 95% CI, 0.75–1.02, and HR=0.97; 95% CI, 0.66–1.44, respectively).

That suggests infection with HPV, even persistent infection with a high-risk HPV type, may not affect fertility.

Next: Study limitations, caveats

Two primary limitations raise questions about results.

1. Notably, information about chlamydia infection was collected only at enrollment. So the study cannot determine whether women acquired other STIs over the nearly 20-year course of the study.

2.  Also, many HPV infections spontaneously resolve within 1 to 2 years of initial infection. But the study could not determine whether women who initially tested negative for HPV had already been infected and cleared the infection before testing. Likewise, it is not known whether women who initially tested negative initially and on follow-up became infected later on.

Next: Study No 2.

Study No 2.

In contrast, the second study is the first to suggest that high-risk HPV may ascend from the lower genital tract to infect the upper genital tract in women, where it may give rise to endometriosis and affect fertility.

Endometriosis is a well-known cause of female infertility. While high estrogen levels have long been thought to contribute to the condition, its pathogenesis remains unclear. Some scientists are now looking to an infectious cause for endometriosis.

The thinking: HPV, because it is often asymptomatic, could silently infect and cause changes in the upper genital tract that lead to infertility.

To test this hypothesis, Rodrigo M. Rocha, MD (Reproductive Endocrinology and Infertility, Medicine School, State University of Western Paraná, Cascavel PR, Brazil) and colleagues conducted a small case control study of 60 women who received laparoscopic surgery at a single private medical center in Brazil. During surgery, researchers collected from participants tissue samples from 6 sites along the upper and lower genital tract.  They used polymerase chain reaction (PCR) on the tissue samples to detect HPV and 6 other STIs: Chlamydia trachomatis, Neisseria gonorrhoeae, Mycoplasma genitalium, Trichomonas vaginalis, herpes simplex virus (HSV)-1, HSV-2 and Treponema pallidum.

Results

• 60% of women tested positive for HPV, and high-risk HPV type 16 was most prevalent (47.2%).
   

• Infertile women had almost 4 times increased odds of having high-risk HPV in upper genital tissue samples compared to fertile women (OR 3.78, 95% CI 1.10–12.30; P = 0.027).
   

• Women with endometriosis had more than 6 times increased odds of having high risk HPV vs women without endometriosis (OR 6.5, 95% CI 2.08–20.30; P = 0.0007).
   

• Results suggest that only high-risk HPV infected upper genital sites, whereas low-risk HPV appeared to remain in the lower genital tract.

None of the other 6 STIs were linked to infertility or endometriosis.

The case control design means that the study cannot prove HPV infection causes endometriosis or infertility, only that the two conditions are associated.

While neither study ends the debate over HPV infection and infertility, and both have methodologic limitations, this duo of firsts provides fodder for future, larger scale studies to advance knowledge on the issue.

REFERENCES

1. Perino A, Giovannelli L, Schillaci R, et al. Human papillomavirus infection in couples undergoing in vitro fertilization procedures: impact on reproductive outcomes. Fertil Steril. 2011;95:1845-8. doi: 10.1016/j.fertnstert.2010.11.047.

2. Depuydt CE1, Verstraete L, Berth M, et al. Human papillomavirus positivity in women underoing intrauterine insemination has a negative effect on pregnancy rates. Gynecol Obstet Invest. 2016;81(1):41-6. doi: 10.1159/000434749.

3. Spandorfer SD, Bongiovanni AM, Fasioulotis S, et al. Prevalence of cervical human papillomavirus in women undergoing in vitro fertilization and association with outcome. Fertil Steril. 2006 Sep;86(3):765-7.

4. Wang Y, Wang C, Qiao J, Wang L, et al. Relationship of cytopathology and cervical infection to outcome of in-vitro fertilization and embryo transfer. Int J Gynaecol Obstet. 2008;101:21-6.

5. Nøhr B, Kjaer SK, Soylu L, et al. High-risk human papillomavirus infection in female and subsequent risk of infertility: a population-based cohort study. Fertil Steril. 2019 Mar 25. pii: S0015-0282(19)30079-2. doi: 10.1016/j.fertnstert.2019.02.001.

6. Rocha RM, Souza RP, Gimenes F, et al. The high-risk human papillomavirus continuum along the female reproductive tract and its relationship to infertility and endometriosis. Reprod Biomed Online. 2019 Jan 8. pii: S1472-6483(19)30012-4. doi: 10.1016/j.rbmo.2018.11.032.