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

Antivaxers claim that HPV vaccination causes primary ovarian insufficiency, also known as premature ovarian failure. A large epidemiological study has just shown them to be wrong. As usual.

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.

By Orac

Orac is the nom de blog of a humble surgeon/scientist who has an ego just big enough to delude himself that someone, somewhere might actually give a rodent's posterior about his copious verbal meanderings, but just barely small enough to admit to himself that few probably will. That surgeon is otherwise known as David Gorski.

That this particular surgeon has chosen his nom de blog based on a rather cranky and arrogant computer shaped like a clear box of blinking lights that he originally encountered when he became a fan of a 35 year old British SF television show whose special effects were renowned for their BBC/Doctor Who-style low budget look, but whose stories nonetheless resulted in some of the best, most innovative science fiction ever televised, should tell you nearly all that you need to know about Orac. (That, and the length of the preceding sentence.)

DISCLAIMER:: The various written meanderings here are the opinions of Orac and Orac alone, written on his own time. They should never be construed as representing the opinions of any other person or entity, especially Orac's cancer center, department of surgery, medical school, or university. Also note that Orac is nonpartisan; he is more than willing to criticize the statements of anyone, regardless of of political leanings, if that anyone advocates pseudoscience or quackery. Finally, medical commentary is not to be construed in any way as medical advice.

To contact Orac: [email protected]

26 replies on “One more time: HPV vaccination is not associated with primary ovarian insufficiency”

most POI is idiopathic but may be associated with … infectious disease (eg, mumps).

If only there were some way of preventing this!

“The warts caused by some strains of the virus can progress to cervical dysplasia, which can further progress into cervical cancer.”

This is now considered to be scientifically inaccurate. Low grade squamous intraepithelial lesion (LGSIL) by itself is now thought to have nothing to do with cervical cancer. LGSIL includes condyloma accuminatum (common genital wart) and flat warts formerly referred to as CIN I or mild dysplasia. High grade squamous intraepithelial lesion (HGSIL), formerly referred to as CIN II, CIN III, and moderate and severe dysplasia) is a premalignant condition associated with high risk HPV types. That’s why the vaccines target the high risk types.

Another way to think of this is that LGSIL involves productive infections, those that produce new, infectious viral particles, and that HGSIL involves non-productive infections, those that are integrated into host DNA.

LGSIL does not progress to HGSIL, although occasionally they can coexist in the same patient.

I changed the text to remove reference to warts, because (1) I want to be accurate, but also (2) I really, really don’t want readers to perseverate over this point, which is relatively minor when compared to the main message that certain strains of HPV can lead to cervical cancer and HPV vaccination prevents that.

I had several antivaccine activists try to reframe the discussion by calling the HPV vaccines the genital warts vaccines, so being cautious there makes sense. Cervarix doesn’t even include the genital warts strains.

It’s not completely unrelated though, because it would be comforting to see a decline in cervical cancer or in situ cancer in the 20-24 age group in the UK after the nationwide vaccination campaign of girls from 2008 to 2010.

Related or not, HPV scientific details are a distraction to the key messages in today’s post, which to me are:

Anti-vaccine advocates can create fear inexpensively with case reports or series (sometimes with fraudulent data e.g. Wakefield)
Responsible scientists consume significant resources to address the fears with data (e.g. the Kaiser study of POI)
The results, however compelling from a science perspective, are never enough for the anti-vaccine cult

In a few years Orac will be posting about postural orthostatic hypotension after HPV vaccination. Same as it ever was…

Shoenfeld was also an expert witness in NVICP on two out of the three cases in reference ten.

Certainly good to have this. The believers won’t change, but they’re not the target.

HPV-linked oral cancers are on the rise, too, in both men and women. I think I read they’re now the most common causes of oral cancers? And, such cancers have (this is from memory) approximately a 50% five-year survival rate. The surgery is often quite disfiguring. These cancers are not good.

Wouldn’t you think that would be serious enough to overcome vague fears of vaccines or worries about “promiscuity”? If that last one bothered you, you’d do it this way: get both your sons and daughters the full HPV vaccine series at the recommended ages, but don’t tell them what the shots are for. Make something up: they’re shots for (fill in the name of a disease). That, of course, will discourage promiscuity while also protecting them from oral cancer!:)

So, that “promiscuity” excuse is bogus (except as a source of extra animus): these people are just irrationally anti-vax, the end, to the point of preferring to watch their children suffer and die.

My sister is a science skeptic herself, and wanted to get my teenaged nephew vaccinated for HPV.

Once I explained to him what genital warts were, and showed him pictures, he was fully on board. He doesn’t want to get HPV.

He isn’t even dating. According to him, he can’t find a girl who fits his high standards (smart, pretty, and likes gaming).

According to him, he can’t find a girl who fits his high standards (smart, pretty, and likes gaming).
Perhaps he needs to broaden his definition of gaming.

Oh, he does! He’ll get there. He’s a late bloomer who skipped a grade in high school and is effectively taking all college classes.

I’m surprised you would advocate lying. In any case, it hardly ever helps in the long run.

Antivaxers have a new martyr.

Texas Children’s Hospital has fired a nurse who posted information about a child’s measles on an antivax Facebook page*. The toddler was a patient at the hospital and apparently the reason for the firing was disclosure of confidential patient information. Though lack of mental competence might have been another consideration.

“In screen shots viewed by Eyewitness News, the nurse stated, “.. for the first time in my career I saw Measles this week. Actually most of my coworkers and the ER docs saw measles for the first time as well. And honestly, it was rough. The kid was super sick. Sick enough to be admitted to the ICU and he looked miserable…By no means have I changed my vax stance, and I never will. But I just wanted to share my experience and how much worse it was than I expected.”

The postings included some comments by other group members, and at one point, the nurse commented, “I’m not kidding that I thought about swabbing his mouth and bringing it home to my 13 (year old).”

*”Proud Parents of Unvaccinated Children – Texas”

Stuff like this makes me weep.

Ugh. And I’m due to discuss vaccination with my nursing students soon. I’m sure this will come up.

I know I should never be surprised that anti-vaxxers think that the normal rules do not apply to them.

I don’t get this. You see what measles can be and still you’re against preventing it and to make matters worse, you even think about giving this illness to your son? I’m sorry, but that would be child-abuse in my book.

I’m always saddened when a parent says they want to “wait a little longer” for more data on HPV vaccination. In the next few years the research will clearly show prevention of cervical cancer by HPV vaccination. At that point it’s going to be hard not to reply “what else could you possibly be waiting for?”. Almost always it’s these piss poor “studies” and anecdotes flitting around the internet that have parents scared.

In the next few years the research will clearly show prevention of cervical cancer by HPV vaccination

You’re a bit behind the times. The proof has already come in.

Research gate is a joke. There’s no mechanism for moderating nonsense. It’s become a haven of woo. I have an account there, but I only use it to post my own publications when they are open access, so there is one more place where people can find them.

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