Human papilloma virus vaccines and infertility
Mortality due to cervical cancer remains high in several countries in the European Region7 and human papillomavirus (HPV) vaccines have been introduced in 38 of 53 countries in the Region, comprising 94% high-income, 29% middle-income and 57% low–middle-income (Gavi-eligible) countries. HPV vaccine coverage of adolescent girls is, however, highly variable, ranging from 6% to 95% in these countries.8 The reasons for low HPV vaccine coverage include concern about the safety of the vaccine among parents and adolescent girls, including fear that it could cause infertility, and anxiety that discussions about sex might promote early onset of sexual activity among adolescent girls. School teachers and even some health care workers also have concerns and fear; health care workers are concerned about safety (e.g. infertility, stress-related responses), and many are insufficiently informed to understand and trust the safety of HPV vaccines. Some feel insecure when there is a serious AE after HPV vaccination. In some settings, it is difficult to distinguish between good- and poor-quality scientific information. WHO is working in several countries to support vaccine introduction, including formative research to understand the concerns of target groups, communications plans, crisis communications plans and education of health care workers.
To respond to the concern raised in some countries that have recently introduced HPV vaccine, the literature on HPV vaccination and infertility was reviewed. Since the first marketing authorization in 2006, post-licensure monitoring and research have been conducted for the 3 vaccines (bivalent by GlaxoSmithKline, quadrivalent and 9-valent by Merck and Co.), with over 160 studies completed in several countries. HPV vaccines were found to have a favourable safety profile, with no confirmed clinically serious signals about safety. Anaphylaxis and syncope are known AEs. Concern about safety has, however, reduced vaccination rates in some countries.
Since 2012, individual case reports have linked vaccination against HPV with primary ovarian insufficiency (POI), defined as dysfunction or depletion of ovarian follicles, menopausal symptoms and reduced fertility before the age of 40. A systematic review of the literature on HPV vaccines and infertility was conducted, in which 608 articles were identified. After exclusion of duplicates and irrelevant studies, 9 articles were retained for the review, of which 7 addressed HPV vaccination and POI and 2 assessed the association between HPV vaccination and the ability to conceive. The details of the studies were reported to the Committee, which reviewed the evidence in the 9 articles (case reports, passive surveillance and epidemiological studies) and concluded that, although the safety of HPV vaccine has received considerable media attention, the evidence does not suggest a causal relationship between HPV vaccination and infertility.
Three articles reported on cases of POI in 6 girls 8–24 months after they received the first dose of quadrivalent vaccine.9-11 A temporal association was found, but there was no evidence for a causal association nor for the involvement of a vaccine component in the pathogenic process or of autoimmune disease. The authors did not consistently evaluate patients for POI by the method recommended by the American College of Obstetricians and Gynecologists and other organizations. Publicly available reports of data on POI from passive surveillance were available from Australia,12 Europe13 and the USA.14 All were reassuring, and the Committee concluded that there was no evidence for a causal relation between HPV vaccination and POI and that the safety profiles for both quadrivalent15 and 9-valent vaccines16 were consistent with pre-licensure and post-marketing safety data.
The epidemiological studies were reviewed. The first was a prospective cohort study of women planning a pregnancy in Canada and the USA.17 No association was found between HPV vaccination and fecundability. The second was an ecological evaluation of the association of HPV vaccination with pregnancy based on data from the National Health Nutrition Examination Survey 2007–2017, which was the only study that suggested any association. While women who received HPV vaccine were less likely to report ever having been pregnant, the article was retracted by the journal because of serious flaws in both data analysis and interpretation.18 The third study was an evaluation of hospital discharges from the National Inpatient Sample database in the USA, which showed no increase in hospital discharges of 15–17-year-old girls before or after introduction of HPV vaccine.19 A limitation of this study is that POI is rarely evaluated in inpatients. In the fourth, rigorous epidemiological study at one site of the Vaccine Safety Datalink20 (a population-based vaccine safety network of health care organizations in the USA), no association was found between POI and HPV vaccination. It was noted that no effect of HPV vaccination on fertility was found in 3 studies in rodents.
GACVS concluded that the available data do not support an association between HPV vaccination and infertility or POI. The current safety profile continues to be extremely favourable, as discussed at 7 previous GACVS meetings, and consistent with the pre-licensure safety profile.21 HPV vaccine safety will continue to be monitored and will be reviewed by GACVS as appropriate. GACVS recommends that communications strategies about vaccine safety ensure appropriate understanding of the safety profile.
7Vaccination, vaccins et produits biologiques. Genève, Organisation mondiale de la Santé, 2019 (https://www.who.int/immunization/monitoring_surveillance/data/en/, accessed December 2019).
8Estimations OMS de la couverture vaccinale contre le papillomavirus humain 2010-2018. Genève, Organisation mondiale de la Santé, 2019 (http://www.who.int/immunization/monitoring_surveillance/data/HPV_estimates.xls, accessed December 2019).
9Colafrancesco S1, et al. Human papilloma virus vaccine and primary ovarian failure: another facet of the autoimmune/inflammatory syndrome induced by adjuvants. Am J Reprod Immunol. 2013;70(4):309–316.
10Little DT, Ward HR. Premature ovarian failure 3 years after menarche in a 16-year-old girl following human papillomavirus vaccination. BMJ Case Rep. 2012; pii: bcr2012006879.
11Little DT, Ward HR. Adolescent premature ovarian insufficiency following human papillomavirus vaccination: a case series seen in general practice. J Invest Med High Impact Case Rep. 201428;2(4):2324709614556129.
12Database of Adverse Event Notifications (DAEN). Canberra: Department of Health; 2019 (https://www.tga.gov.au/database-adverse-event-notifications-daen, accessed December 2019).
13Eudravigilance – Base de données européenne des rapports d’effets indésirables susceptibles d’être liés à l’utilisation de médicaments. Amsterdam: Agence européenne des médicaments, 2019 (http://www.adrreports.eu/fr/index.html, accessed December 2019).
14Vaccine Adverse Event Reporting System (VAERS). Atlanta (GA): Centers for Disease Control and Prevention; 2019 ((https://www.cdc.gov/vaccinesafety/ensuringsafety/monitoring/vaers/index.html, accessed December 2019).
15Arana JE, et al. Post-licensure safety monitoring of quadrivalent human papillomavirus vaccine in the Vaccine Adverse Event Reporting System (VAERS), 2009–2015. Vaccine. 2018;36(13):1781–1788.
16Shimabukuro TT, et al. Safety of the 9-valent human papillomavirus vaccine. Pediatrics. 2019;144(6):e20191791.
17McInerney KA, et al. The effect of vaccination against human papillomavirus on fecundability. Paediatr Perinat Epidemiol. 2017;31(6):531–536.
18Statement of retraction: [A lowered probability of pregnancy in females in the USA aged 25–29 who received a human papillomavirus vaccine injection.] J Toxicol Environ Health Part A. 2019;81(14):661–674.
19Pellegrino P, et al. On the association between human papillomavirus vaccine and primary ovarian failure. Am J Reprod Immunol. 2014;71:293–294.
20Naleway AL, et al. Primary ovarian insufficiency and adolescent vaccination. Pediatrics. 2018;142(3):e20180943.
21See No. 28, 2017, pp. 398–401