written by Tara Haelle

As one of the newest vaccines, the HPV (human papillomavirus) vaccine is one of those plagued with some of the worst misinformation out there. Horrible anecdotes tell of strange illnesses and death that have struck down girls after they received their first HPV shot, and I’ve even written about Katie Couric’s irresponsible spotlight on these stories when there is no evidence that such tragic incidents are actually related to the vaccine.

This is a shame since this vaccine is one of the very few which can actually prevent cancer, of the cervix for women but also of the throat, mouth, neck, penis and anus. Yet the anecdotes are frightening and powerful, and researchers continue to study safety concerns to make sure nothing has been missed. A large, very well-designed study in JAMA today continues that research by looking at the risk of blood clots with the quadrivalent HPV shot, Gardasil.

Although many concerns associated with HPV vaccine have been addressed by the CDC, those who prefer to see the primary research can review the existing excellent studies showing no link between the vaccine and autoimmune, neurological or blood clot problems. But good science requires an accumulation of evidence, including evidence of no harm.

And that’s exactly what this new study shows: no risk of blood clots from the vaccine.

The researchers started with a population data set: all the women in Denmark who were aged 10 to 44 between October 1, 2006, and July 31, 2013, which included more than 1.6 million females. (Scandinavian countries’ nationalized health care systems make it conveniently possible to use data from an entire population’s medical records.)

Among these 1.6 million girls and women, about a half million (31%) had received Gardasil. Also out of this 1.6 million, a total of 5,396 individuals had experienced a venous thromboembolism during that study period. (A venous thromboembolism is blood clot that breaks free in the veins and starts traveling up toward the lung, where it could become a pulmonary embolism).

Then the researchers excluded all the women who had been pregnant with the blood clot or who had had surgery in the past month or been diagnosed with cancer in the past year – pregnancy, cancer and surgery all increase the likelihood of a blood clot. These exclusions left 4,375 women, about one in five of whom had been vaccinated against HPV.

Those 889 women are the ones the researchers focused on.

Most case-control studies compare cases (those with the outcome, in this case a blood clot) with controls (people “matched” to the cases who did not experience the outcome). But this study used a clever design that was developed specifically to study vaccine safety: the self-controlled case series method.

People who choose to get vaccines often differ from those who choose not to in ways that can never be controlled for. (Their decisions about medical care can differ so much that it’s impossible to take into account all the possible factors that could lead to different outcomes.) So the self-controlled case series method compares people to themselves during and outside of a predefined “risk window.”

In this case, the risk window was the 42 days after receiving the HPV vaccine. The researchers looked at all the women who had blood clots and then looked at whether those clots occurred during the 42-day period after the vaccine or whether they occurred before or after that risk window. Using this method, people serve as their own controls, and their risk of a blood clot *specifically following* the vaccine can be accurately calculated.

And these calculations – before taking into account anything else – showed no increased risk of a blood clot in those 42 days after vaccination. (The calculation actually showed a 23% lower risk of a clot in those 42 days, but the result was not statistically significant, so this finding is almost certainly just a result of chance.) Considering this study used ALL the women who both had a blood clot and had gotten the vaccine out of 1.6 million people, the findings are very reliable.

But the researchers did additional analyses to make the conclusions even stronger, and these extra analyses offer even more assurance about the vaccine’s safety.

After doing that crude calculation to find no risk of blood clots after the shot, the researchers then did an analysis of ALL the women who had blood clots, even if they didn’t have the vaccine, to make adjustments for age (older women have a higher risk of blood clots than younger women). They found the same lack of an association, which means blood clots are occurring at about the same rate among women at various ages regardless of whether they received the HPV shot or not. That’s stronger evidence that the vaccine was irrelevant for these women’s blood clots.

Then, the researchers used the same data on the 889 women to make adjustments for age and for those who were taking birth control pills (which increases the risk of blood clots). They also made calculations only for the women who were taking blood thinners four weeks after the blood clot. (Since they were using medical records, a prescription for blood thinners confirms the blood clot diagnosis).

All these calculations showed the same thing: there was no increased risk of a blood clot after the quadrivalent HPV vaccine (Gardasil). That doesn’t mean a woman will never have a blood clot in the month and a half after getting an HPV shot – but her risk of a blood clot then is no different than any other time. Having a blood clot after the vaccine would just be a coincidence, NOT something caused by the vaccine.

Because an early study did find increased numbers of blood clots among those who had the HPV vaccine, this new study is more reassurance that the early findings were the result of “confounding variables,” not evidence of an actual risk of blood clots from the shot. (A confounding variable is a something which makes it difficult to tell whether a specific outcome was the result of a particular intervention, such as a vaccine, or the possible result of that variable.)

The confounding variable in past research was most likely oral contraceptives since blood clots are a known possible side effect of birth control pills. (In fact, I had one myself that nearly killed me 18 years ago.) If more of the girls getting the HPV shot were taking birth control than the girls not getting the vaccine, then we would expect to see more blood clots among the vaccine recipients (ie, the birth control takers) than among the others not getting the vaccine (with a lower uptake of birth control pills).

Another different past study that had found a link between blood clots and the HPV vaccine had too few vaccinated cases for the statistics to be very solid. This study, on the other hand, is about as solid as science gets. It’s a very well-designed study that uses an entire population and runs the numbers multiple ways and finds no blood clot risk from the vaccine. Yet, the vaccine itself protects against a sexually transmitted virus that can cause cancer… which can cause blood clots. So there ya go.