Study shows miscarriage risk may have increased after flu shots, puzzling researchers

Sometimes when scientists study things, they come up with results they didn’t expect, can’t explain, and may secretly wish they’d never sought. A new journal article looking at whether getting a flu shot during pregnancy increases a woman’s risk of miscarrying may be one such case.

The article reports that at least in the 2010-11 and 2011-12 influenza seasons, pregnant women who were vaccinated against flu may have been at a higher risk of suffering a miscarriage — but only if they had also received a flu shot in the previous year as well.

The results, published Wednesday in the journal Vaccine, are puzzling and contradict earlier research. A study conducted by the same scientists about a decade ago looked at this question and concluded there was no miscarriage risk from getting a flu shot.

The new finding raises a lot of questions and is sure to provoke concern among pregnant women, who may be tempted to forgo vaccinations. But experts and even the authors themselves caution that this result is far from conclusive.

In fact, they aren’t clear if the finding is actually real or the product of some unobserved statistical fluke. The researchers are already looking at data for subsequent years to try to determine if the association is real, and if it is, whether it is still ongoing.

But what you find, you have to publish — at least when the finding raises the kind of questions this research does.

“I understand it’s disconcerting. It’s not a message that we welcome or want. But it is what we found, and we have an obligation to let people know about that,” said senior author Dr. Edward Belongia, a longtime vaccine researcher who heads the Center for Clinical Epidemiology and Population Health at Wisconsin’s Marshfield Clinic.

Belongia is also a member of the Advisory Committee on Immunization Practices, an expert panel that makes vaccine policy recommendations to the Centers for Disease Control and Prevention.

ACIP has known about this work for a couple of years and to date has chosen not to change its recommendation that pregnant women at all stages of pregnancy get a flu shot. The researchers made a preliminary report to the panel in June of 2015.

ACIP next meets at the end of October and will discuss the finding further then, said Dr. Amanda Cohn, senior adviser for vaccines at the CDC and executive secretary of the ACIP. Cohn said she couldn’t predict at this point whether those deliberations will lead to a vote on a policy recommendation.

Dr. Laura Riley, an ACIP member, is not convinced the finding is real. Riley, who is vice chair of obstetrics at Massachusetts General Hospital, said she doesn’t think there’s a biologically plausible explanation for why repeated flu shots would increase the risk of miscarriage. “I remain skeptical,” she said, adding the question needs more study.

“It’s not going to change my practice, that’s for sure,” Riley told STAT. “I feel like women should be vaccinated when the vaccine becomes available and when they’re in my office. And if that’s in the first trimester, second trimester, third trimester, I’m vaccinating.”

She and other doctors will be doing a lot of that in the weeks to come. This is, after all, flu shot season in the Northern Hemisphere.

Belongia said while it’s not clear whether flu shots could increase the risk of miscarriage, it is known that contracting the flu during pregnancy can be dangerous for both a woman and her fetus.

But he and the CDC’s Cohn advised that pregnant women who are concerned should talk with their doctors. One option might be to time the flu shot for some point after the first trimester, if that’s possible, they suggested.

Riley chairs a committee on immunization for the American Congress of Obstetricians and Gynecologists. That organization is preparing fact sheets and talking points for its members, who will undoubtedly face a chorus of questions from concerned patients in coming weeks.

“The thing is, your average OB-GYN is not reading Vaccine. And so they’re not going to have the details,” Riley said.

“So that’s our job, to make sure that they’re adequately educated so that they can talk to their patients in an intelligent manner.”

Studies have been done that suggest flu vaccination during pregnancy is safe, though there is very limited data on which to gauge whether that is also true for the first trimester, which is critical time in fetal development. It is also the time when miscarriages are most likely to occur.

Starting in the late 1990s, the CDC recommended that pregnant women in their second or third trimester get vaccinated against influenza. In 2004 the ACIP voted to extend the recommendation to all pregnant women.

About a decade ago, Belongia and colleagues in a CDC-funded project called the Vaccine Safety Datalink looked at whether rates of miscarriage were higher among women who received a flu shot. They found they were not, based on data from the 2005-06 and 2006-07 flu seasons.

But in 2009, influenza underwent a seismic shift. A flu virus that had been infecting pigs started transmitting to and among people, triggering the first flu pandemic in 41 years.

One of the seasonal flu viruses that had circulated before 2009 disappeared — that happens after pandemics. So it was taken out of the flu vaccine and the new virus — which goes by the cumbersome name H1N1pdm09 — replaced it.

Given the change in the flu shot composition, the CDC reached out to Belongia and his colleagues to ask them to redo the miscarriage study.

“They wanted to make sure,” said James Donahue, who is the lead author of the new article.

The team looked at data from 485 women who miscarried, comparing them to similar women who had carried to term or who suffered a stillbirth — a late-term pregnancy loss.

They were surprised to see evidence of more miscarriages among women who had received a flu shot. So they started to look more closely at the data and saw that the apparent association seemed to be among women who got flu shots in the year before their pregnancy and the year in which they were pregnant.

But when they started to drill down into subsets of the 485 women who miscarried, the numbers started to get very small. That injects a lot of uncertainty into the analysis. A larger study might not have produced this result.

Dr. Gaston De Serres, an infectious diseases epidemiologist with the Quebec Public Health Institute, has written about flu vaccine safety in pregnancy. He thinks there isn’t enough evidence to say one way or another whether it’s safe to get a flu shot in the first trimester of pregnancy.

That said, he doesn’t believe this study answers the question; the numbers are just too small.

“I wouldn’t take these results at face value,” De Serres said. “This paper is not a game changer by itself.”

The design of the study also limits how much can be said about the increased risk of miscarriages, if there is one. The study calculated the odds that women would miscarry after influenza vaccination and seems to indicate there might be a risk. But the numbers it generated cannot be used to quantify how big the risk is.

It’s estimated that between 10 percent and 15 percent of pregnancies end in miscarriage. De Serres said that if that rate had gone up sharply, it would not have taken a retrospective study to identify that there was a problem. Obstetrical practices would have noticed the change and sounded an alarm.

Another important caveat: The researchers conducted an observational study, looking after the fact at the medical records of women who had miscarried.

Observational studies cannot prove that something, like a flu shot, caused something else, like a miscarriage. Causality can only be proved through clinical trials that randomly select people to get a drug or a treatment and select other people who are like them to get a placebo, and then monitor what happens. Because flu shots are recommended for all pregnant women, that kind of trial could not be conducted in the United States.

Donahue said the team is repeating the observational study, looking at data for the three years starting in 2012-13. But the work takes time; the findings aren’t expected until 2018 or early 2019.

“We’re really sort of at the beginning of this process with this study. I have no doubt that we will eventually sort this out,” Belongia said. In the meantime, he said, pregnant women should get flu shots.

“There’s a large amount of data and studies confirming the safety of flu vaccine in the second and third trimester. And the benefit is proven, and the safety is rock solid,” he said. “And we want to be really sure that people don’t get the mistaken message that this study is suggesting that getting a flu vaccine at any time in pregnancy might be risky.”



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