HPV Vaccine & Infertility: No Link

 In Fertility

Naturopathic Perspective

Max Cohen, ND

A research paper by Delong was recently published that has generated considerable attention, especially in online environments where vaccine misinformation tends to thrive. This research makes a bold claim, which is that a decline in fertility rates is due in part to vaccination against certain strains of the human papillomavirus (HPV).1 Delong’s claim was based on NHANES data for 2007-2014 revealing fewer pregnancies among vaccinated women compared to women not receiving the vaccine. Although these correlations can appear worrisome at first, they do not prove cause and effect. Nevertheless, this paper has led to increased concerns that the HPV vaccine is in some way dangerous. Before exploring why the data do not support this claim, let’s briefly review HPV and the HPV vaccine.

Human Papillomavirus

HPV is an extremely common infection, usually acquired from sexual activity. It is estimated that at least three-quarters of the US population will contract some form of HPV in their lifetime.2 This usually happens during adolescence, when many people first become sexually active. The symptoms of HPV infection can range from nothing, to genital warts, to genital/oral cancers. It’s impossible to tell if you will develop cancer from an HPV infection, and these cancers can take 10+ years to develop.3 Some strains of the virus are more likely to cause cancer than others, and these strains are the focus of vaccination efforts.

There are over 10 000 cases of HPV-associated cancers per year in the United States4 (and over 500 000 worldwide5), and that doesn’t count the roughly 300 000 pre-cancer diagnoses (abnormal cells found on a pap test, which require additional testing or surgical procedures to evaluate), or the nearly 30 000 non-cervical cancers caused by HPV each year.4 Eighty-eight percent of these cancers are preventable with vaccination.4 You cannot develop cancer from an infection you did not contract.

The HPV Vaccine

There have been several HPV vaccines, but all of them use selected naturally-occurring proteins from up to 9 different high-risk HPV strains.6 Like any vaccination, a small amount of antigen helps the body create an immunity against these versions of the virus. By introducing the immune system to these viral proteins, it is able to recognize and neutralize the virus if that person is ever exposed. This is only effective before an exposure, which is why the vaccine is recommended for ages 11-127; it was recently approved for adults up to age 45.8 The vaccine is extremely effective: nearly 100% of those vaccinated will become immune to high-risk strains of HPV and the cancers they cause.6

HPV Vaccine & Fertility

Strong claims require equally strong evidence. So do any data support the researcher’s claim that vaccination could lead to reduced fertility? The answer is no. Using population-level epidemiological data to evaluate this claim is reasonable. I will note that while I am not an epidemiologist, neither is the author of the paper in question, which should raise immediate concern about the validity of these findings.

Delong’s rationale for this study includes Vaccine Adverse Event Reporting System (VAERS) database entries for POI. There are significant problems with using VAERS data in this way, as I will discuss shortly. For the data analysis, Delong utilized 2 publicly available datasets from the Centers for Disease Control and Prevention (CDC). VAERS is neither designed nor able to show causal links between vaccines and adverse events, but rather serves as a collection of unverified reports provided by healthcare providers or patients. The events do not even need to be health related. As an example, “car accident 2 days after receiving vaccine” was reported to VAERS, and can be found in the system. VAERS is simply a database, without any ability to determine causality.

VAERS is valuable as a detector of potential safety signals. For example, if I administered a vaccine to a patient with chronic migraines, and the following day the patient developed a severe headache with concomitant light and sound sensitivity, this would be reported to VAERS. But did the vaccine cause the migraine? We don’t know. If the report of a headache existed in isolation, it is very unlikely that the vaccine in-and-of-itself caused the migraine. If other healthcare providers around the country all started reporting severe headaches after vaccination, the information would start to compile in the database and a potential safety signal would be detected and reported.

A real-world example of this was a previous version of the oral rotavirus vaccine. This vaccine, while effective at preventing dehydration from diarrhea caused by rotavirus, was also found to cause intussusception (telescoping of the intestines – a potentially deadly condition) at the same rate of actually contracting the rotavirus infection.9 This safety issue was detected by VAERS, and the CDC suspended use of the vaccine until further investigation could be completed. After case-control studies confirmed a correlation, the vaccine was quickly removed from the market.9

A Close Look at the Data

Back to the research question at hand. Delong’s study1 presumes that VAERS reports of premature ovarian insufficiency (POI) following vaccination are the reason for reduced birth rates in a population vaccinated against HPV. POI is a rare condition in which the ovaries fail before age 40, causing menopause at a much earlier age than normal. There is no known association between HPV vaccination and infertility/POI, and numerous high-quality studies looking at short- and long-term outcomes have supported this conclusion.10-12

Furthermore, like all vaccines, the HPV vaccination is comprised of naturally occurring HPV proteins. It thus follows that if POI were caused by the vaccine, one would assume that wild-type HPV infection must also be capable of causing POI at or above the rates seen in a vaccinated population. This is, of course, not the case: background levels of POI occur in up to 1% of the female population under 40 years of age13 regardless of vaccine status, and POI is not a known effect of HPV infection.

In fact, the HPV vaccine appears to improve fertility in women with a history of sexually transmitted infections (STI).12 STIs are a known risk factor for reduced female fertility, and HPV has also specifically been shown to reduce the quality of sperm.12 Preventing infection through vaccination would thus be expected to have either no effect on fertility or to improve it.

Additionally, individuals with higher socioeconomic status tend to have fewer children,14 and also have greater access to health care. As such, these individuals are more likely to have received HPV vaccinations and other preventive care. This is compounded by the well-recognized fact that the fertility rate has been dropping over the last 30 years due to a confluence of many factors,15 but did not see a sudden new decline with the introduction of the HPV vaccine. Delong’s study does not address whether the individuals in the analysis were using contraception. These confounders are not adequately accounted for, and depending on the covariate analysis, the researcher found only intermittent statistical significance. This strongly suggests that there is no correlation between HPV vaccination and POI/infertility. Further, the failure to account for so many confounding variables makes it highly unlikely that the study’s interpretation of these data is valid at all.

HPV infection is a well-documented risk factor for cervical and oropharyngeal cancers, and with the advent of the HPV vaccine, this risk is now modifiable. Primary prevention of these conditions via vaccination offers a significant reduction in morbidity/mortality and reduces the need for surgical interventions such as loop electrosurgical excision (LEEP) or cervical conization. Preventing cancer is always preferable to treating it!

The Bottom Line

Concerns that HPV vaccination can induce infertility or POI are unfounded and should not be a factor in vaccine counseling. There is ample evidence that the HPV vaccine is safe. Clinicians should encourage this vaccine for its robust efficacy at preventing infection from high-risk HPV subtypes and the cancers these viruses cause.

References:

  1. Delong G. A lowered probability of pregnancy in females in the USA aged 25-29 who received a human papillomavirus vaccine injection. J Toxicol Environ Health A. 2018;81(14):661-674.
  2. Cates W Jr. Estimates of the incidence and prevalence of sexually transmitted diseases in the United States. American Social Health Association Panel. Sex Transm Dis. 1999;26(4 Suppl):S2-S7.
  3. Centers for Disease Control and Prevention. Human Papillomavirus (HPV). Last updated November 16, 2017. CDC Web site. www.cdc.gov/std/hpv/stdfact-hpv.htm. Accessed October 25, 2018.
  4. Centers for Disease Control and Prevention. Cancers associated with human papillomavirus, United States—2010–2014. USCS Data Brief, No. 1. December 2017. CDC Web site. https://www.cdc.gov/cancer/hpv/pdf/USCS-DataBrief-No1-December2017-508.pdf. Accessed October 25, 2018.
  5. World Health Organization. Cervical cancer. WHO Web site. http://www.who.int/cancer/prevention/diagnosis-screening/cervical-cancer/en/. Accessed October 25, 2018.
  6. Joura EA, Giuliano AR, Iversen OE, et al. A 9-valent HPV vaccine against infection and intraepithelial neoplasia in women. N Engl J Med. 2015;372(8):711-723.
  7. Human Papillomavirus (HPV) Vaccination: What Everyone Should Know. Last updated November 22, 2016. CDC Web site. Accessed October 25, 2018.
  8. S. Food & Drug Administration. FDA approves expanded use of Gardasil 9 to include individuals 27 through 45 years old. October 5, 2018. FDA Web site. https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm622715.htm. Accessed October 26, 2018.
  9. Foster S. Rotavirus Vaccine and Intussusception. J Pediatr Pharmacol Ther. 2007;12(1):4-7.
  10. Naleway AL, Mittendorf KF, Irving SA, et al. Primary Ovarian Insufficiency and Adolescent Vaccination. Pediatrics. 2018;142(3). pii: e20180943.doi:10.1542/peds.2018-0943.
  11. Arnheim-Dahlström L, Pasternak B, Svanström H, et al. Autoimmune, neurological, and venous thromboembolic adverse events after immunisation of adolescent girls with quadrivalent human papillomavirus vaccine in Denmark and Sweden: cohort study. BMJ. 2013;347:f5906.
  12. Mcinerney KA, Hatch EE, Wesselink AK, et al. The Effect of Vaccination Against Human Papillomavirus on Fecundability. Paediatr Perinat Epidemiol. 2017;31(6):531-536.
  13. Beck-Peccoz P, Persani L. Premature ovarian failure. Orphanet J Rare Dis. 2006;1:9.
  14. The Statistics Portal. Birth rate in the United States in 2015, by household income. 2018. Available at: https://www.statista.com/statistics/241530/birth-rate-by-family-income-in-the-us/. Accessed October 26, 2018.
  15. Hamilton BE, Martin JA, Osterman MJK, et al. Births: Provisional data for 2017. Vital Statistics Rapid Release. Report No. 004. May 2018. CDC Web site. https://www.cdc.gov/nchs/data/vsrr/report004.pdf. Accessed October 26, 2018.

Max Cohen, ND, is a naturopathic physician working in urgent and primary care in Portland, OR, and a member of the OANP and NAPCP. Dr Cohen completed his medical training and residency at the National University of Natural Medicine (NUNM). Prior to medical school he worked as a microbiologist, assisting in a tuberculosis research laboratory. Dr Cohen is an evidence-based-medicine advocate and educator. When not seeing patients, he spends his time outdoors, hiking, biking, and backpacking.

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