One more time: HPV vaccination is not associated with primary ovarian insufficiency

Many have been the times when I’ve pointed out that, of all the vaccines out there, antivaxers seem to loathe and fear the vaccine against the human papilloma virus (HPV) more than any other. True, it might seem at times that it’s the MMR vaccine that they hate and fear the most, given that the MMR vaccine was the one targeted by Andrew Wakefield with his fraudulent case series in 1998, a study that sparked a fear of of the vaccine whose consequences reverberate even today in the form of measles outbreaks. However, if you pay attention, you’ll see an element of hate and fear directed against the HPV vaccine that you don’t see nearly as much with the MMR. For instance, you don’t often see antivaxers blaming MMR for sudden death nearly as often as you do for the HPV vaccines Gardasil and Cervarix. They also like to blame the vaccine for not-so-sudden death. But, most of all, antivaxers like to claim that these vaccines cause primary ovarian insufficiency (sometimes also called premature ovarian failure). They do not, as you will soon see.

Of course, I’ve always suspected that there was a moralistic angle to antivaxer fear of HPV vaccines. The reason, of course, is that HPV is primarily a sexually transmitted disease. Some strains of the virus can produce lesions that lead to cervical cancer. Vaccinating against HPV thus protects against cervical cancer. Not surprisingly, it’s not at all uncommon to hear antivaxers say that their daughters don’t need the vaccine because they aren’t promiscuous or that the vaccine will give their daughters a reason to be promiscuous, both of which are utter BS. Never mind, though. The HPV vaccine has been referred to as the “promiscuity vaccine.” Never mind that anyone who remembers their own adolescence clearly would know that fear of catching HPV and then developing cervical cancer 20 or 30 years down the road is not a major concern among teens as their hormones rage. None of this matters to the people making these claims, however. Never mind that there is not only no evidence that HPV vaccination is associated with promiscuity but evidence that it is not.

Over the years, though, the claim I’ve tackled more times than any other dating back several years is the claim that the HPV vaccine somehow causes premature ovarian failure or primary ovarian insufficiency. The other common claim is that the vaccines cause infertility. Sometimes antivaxers doing such studies are so desperate that their studies are so bad as to be risible. Fortunately, last week a study was published that pretty much demolishes the claim that HPV vaccination causes primary ovarian insufficiency.

First of all, what is primary ovarian insufficiency? Basically, it’s a condition in which a woman’s ovaries shut down before the age of 40. Sometimes, ovarian insufficiency can set in as early as during the teen years, when it is a particularly devastating condition. (Just imagine going through, in essence, menopause at age 15 and you’ll get an idea of how profoundly horrific POF can be.) Unfortunately, the linking of a vaccine viewed as promoting promiscuity to a punishment of losing fertility is simply too natural and irresistible to cranks, regardless of how wrong it is. As for the causes of this condition, they’re largely unknown, although known causes of some cases include chromosomal abnormalities, chemotherapy or radiation therapy, and Fragile X syndrome. Of course, it is the lack of understanding of how and why premature ovarian insufficiency occurs that allows antivaxers the opening to claim that it must be the vaccines.

That’s why this study, Primary Ovarian Insufficiency and Adolescent Vaccination, published last week in the journal Pediatrics, is so important. Oddly enough, despite its importance, it flew almost entirely under the radar, with basically almost no press coverage that I could find. That, of course, is frustrating. Crappy case series claiming to find an association between primary ovarian insufficiency get played up, and a study like this we hear little about. The study itself comes from investigators at the Center for Health Research, Kaiser Permanente Northwest in Portland, Oregon; the Institute for Health Research, Kaiser Permanente Colorado in Denver; the Department of Pediatrics at the University of Colorado; and the Immunization Safety Office at the CDC. You might recall the recent study out of Kaiser Permanente in California that showed that the maternal Tdap vaccine is not associated with an increased risk of autism in the child. Kaiser Permanente can do these sorts of studies because of its tightly integrated system and electronic medical record, as well as its involvement with the Vaccine Safety Datalink, a database that does this:

The Vaccine Safety Datalink (VSD) is a collaborative project between CDC’s Immunization Safety Office and eight health care organizations. The VSD started in 1990 and continues today in order to monitor safety of vaccines and conduct studies about rare and serious adverse events following immunization.

The VSD uses electronic health data from each participating site. This includes information on vaccines: the kind of vaccine given to each patient, date of vaccination, and other vaccinations given on the same day. The VSD also uses information on medical illnesses that have been diagnosed at doctors’ offices, urgent care visits, emergency department visits, and hospital stays. The VSD conducts vaccine safety studies based on questions or concerns raised from the medical literature and reports to the Vaccine Adverse Event Reporting System (VAERS). When there are new vaccines that have been recommended for use in the United States or if there are changes in how a vaccine is recommended, the VSD will monitor the safety of these vaccines.

So why do this study in the first place? The authors admit that it was because of case series published by antivaxers:

Concern about infertility after HPV vaccination developed after case series were published describing the onset of primary ovarian insufficiency (POI), also known as premature ovarian failure or premature menopause, within 12 months after vaccination in 6 young women from 13 to 21 years of age.9,10 POI is characterized by either the dysfunction or depletion of ovarian follicles, menopausal symptoms (eg, amenorrhea or hot flashes), or reduced fertility. In girls <20 years of age, POI is uncommon with an estimated prevalence of 1 case per 10 000.11 Chromosomal abnormalities, including Turner syndrome and Fragile X syndrome, as well as the gonadotoxic treatment of cancer (chemotherapy or radiation) are known etiologies for POI; however, most POI is idiopathic but may be associated with underlying autoimmune (eg, rheumatoid arthritis or systemic lupus erythematosus), metabolic (eg, galactosemia), or infectious disease (eg, mumps).11

Reports of POI after HPV vaccination have garnered national media attention and have circulated widely on social media and other Internet sites,12–15 but to our knowledge, no population-based studies of POI after HPV vaccination have been conducted to date. The published case series must be interpreted with caution because the authors of the series included small samples of young women presenting for care at selected clinical sites, relied on self-reported vaccine exposures, and lacked controls. We conducted a retrospective cohort study to (1) identify and describe characteristics of idiopathic POI diagnosed in female patients 11 to 34 years of age, (2) describe the prevalence and age-specific incidence of POI, and (3) estimate the risk of idiopathic POI in female patients after HPV vaccination or other recommended adolescent vaccinations (Tdap, MenACWY, and inactivated influenza [II]).

I’ve discussed the “case series” that provoked this study before. For instance, reference 9 is a case report by Deirdre Therese Little, an antivaxer who is also on the board of advisors for an Australian Catholic anti-abortion group called Family Life International, whose official patron laments the growth of promiscuity and the “redefining” of marriage and who buys into the “HPV equals promiscuity” narrative. It was a horrible study that didn’t even really show a correlation between HPV vaccination and primary ovarian insufficiency. The second “case series” (reference 10) is by antivaccine scientist Yehuda Shoenfeld and Lucija Tomljenovic, both of whom I’ve written about before. Yehuda Shoenfeld is the Israeli scientist who invented a syndrome he dubbed “ASIA” for “Autoimmune/Inflammatory Syndrome Induced by Adjuvants.” Not surprisingly, the adjuvant he blames the most is aluminum salts used in some vaccines, and the most common one of these he blames is the aluminum in Gardasil. Tomljenovic has been the subject of several posts on this blog, some for her work with Canadian antivaccine scientist Christopher Shaw, others for her own antivaccine idiocy. Let’s just say that the tiny case series was not at all convincing for a link between HPV vaccination and primary ovarian insufficiency.

Such is the power of bad studies by antivaxers. They force scientists to respond with good science. This can be a good thing if there isn’t much evidence, but it’s often not because such bad science ends up causing the same questions (e.g., whether the MMR vaccine causes autism) to be studied over and over and over and over again, long past the point where the question has, for all intents and purposes, answered.

So let’s get to this study. The authors identified a cohort of all female patients 11 to 34 years of age with at least 30 days of health plan involvement at Kaiser Permanente Northwest from August 1, 2006 to December 31, 2014. The period was chosen to maximize the potential number of primary ovarian insufficiency (POI) cases in the initial period after HPV vaccine licensure and recommendation. Presumptive cases of POI were identified by searching the electronic health record databases. Each presumptive case was checked by at least one study investigator to rule out cases that were clearly miscoded or cases for which there were not adequate records, and then the cases were abstracted again by a second investigator. The authors excluded cases of POI with a known cause, including those with surgical menopause, those with a genetic condition, or those who had received chemotherapy or radiation therapy for cancer. This left the idiopathic cases, the cases without a clear cause, which is the largest number of cases.

Overall, the authors identified 199,078 females 11 to 34 years of age, of which . In this cohort there were 120 patients with an outpatient diagnosis of premature menopause, ovarian failure, or ovarian dysfunction. After the two rounds of chart review, the authors were left with 46 confirmed idiopathic cases of POI. The prevalence of idiopathic POI in the study period was 2.31/10,000 female patients, an incidence that increased with age, from a low of 0.87/1,000,000 person-months in 11- to 14-year-olds to a peak of 12.85/1,000,000 person-months in 30- to 34-year-olds. To estimate risk, hazard ratios, along with 95% confidence intervals associated with vaccination were calculated using time-dependent Cox proportional hazards modeling. The authors looked at not just HPV vaccination, but also Tdap, meningococcal conjugate (MenACWY), and inactivated influenza (II). Not surprisingly, the authors found no increased risk of POI after HPV vaccination, nor did they find increased risk after Tdap, II, or MenACWY vaccination.

Of course, this study was not without shortcomings. One such shortcoming, of course, is that there were relatively few cases to examine. (Fortunately, POI is not common, particularly in teenagers.) Also, it’s hard to apply the American Colleg of Obstetrics and Gynecology’s diagnostic criteria to a retrospective study relying on electronic health records because patients often did not undergo all of the diagnostic testing required to meet the definition. Similarly, There were also potential shortcomings associated with the use of a long exposure window between vaccination and POI diagnosis. Because the authors had no way of knowing what the optimal time window between vaccination and diagnosis to use in their modeling might be, the authors used any exposure to the vaccines under study before symptom onset. The authors noted that using this long an exposure window has the potential to mask a true acute risk of POI after vaccination, but that limiting their study to shorter windows might miss an association that requires a longer latent period. Still, despite these shortcomings, this is a resoundingly negative study.

It’s yet another indications that there was no link between HPV vaccination and premature ovarian failure in this population, of whom 58,871 were vaccinated for HPV. Indeed, if you look at the hazard ratios in Table 4, with the exception of II, they’re all below 1.0. Indeed, for HPV vaccination, the hazard ratio is 0.3, which implies a lower risk of POI associated with HPV vaccination. Of course, we can’t say that because the 95% confidence intervals overlap 1.0 for all four vaccines, meaning that there is no statistically significant increase or decrease in risk associated with these vaccinations.

In other words, this study failed to find any evidence that HPV vaccination, or any of the other three vaccines studied, were associated with an increased risk of POI. I’d say that this study also trumps the crappy, tiny case series touted by antivaxers as evidence that the HPV vaccine cause POI. Antivaxers publish small, poorly done studies that claim to find a danger from vaccines, and when real scientists do real studies those dangers are not confirmed.

Same as it ever was when it comes to vaccine safety.