Study Prompts Call To Examine Flu Vaccine And Miscarriage

A study published today in Vaccine suggests a strong association between receiving repeated doses of the seasonal influenza vaccine and miscarriage. The authors said the study is an unexpected signal that calls for deeper investigation and highlights the challenges of monitoring the safety of annual vaccines.

"We are not saying this is a causal relationship," said James Donahue, DVM, PhD, MPH, a senior epidemiologist at the Marshfield Clinic and the lead author of the study, meaning the data don't necessarily show that the flu vaccine causes miscarriages. "There's no biological basis for this phenomenon, so the study represents something that wasn't expected."

Researchers studying the flu vaccine in pregnancy have found a hint of a possible link between miscarriage early in pregnancy and the flu vaccine in women who received a certain version of the vaccine two years in a row.

It’s the first study to identify a potential link between miscarriage and the flu vaccine and the first to assess the effect of repeat influenza vaccination and risk of miscarriage. The findings suggest an association, not a causal link, and the research is too weak and preliminary, experts said, to change the advice, which is based on a multitude of previous studies, that pregnant women should get a flu vaccine to protect them from influenza, a deadly disease that may cause serious birth defects. But the study is likely to raise questions about the safety of the vaccine as flu season gets underway.

“I think it’s really important for women to understand that this is a possible link, and it is a possible link that needs to be studied and needs to be looked at over more [flu] seasons,” said Amanda Cohn, senior adviser for vaccines at the Centers for Disease Control and Prevention, which funded the study.

“We need to understand if it’s the flu vaccine, or is this a group of women [who received flu vaccines] who were also more likely to have miscarriages,” she said.

Health officials say they understand that the information may be of concern to pregnant women. They advised pregnant women to talk to their health-care providers for the most accurate information and to determine the best timing for a flu shot.

The CDC, the American Congress of Obstetricians and Gynecologists and the study authors continue to recommend that pregnant women get a flu vaccine during any stage of pregnancy because of the danger influenza poses to women and their developing babies. Vaccination during pregnancy is also the most effective strategy to protect newborns, experts say, because the flu vaccine is not approved for use in infants younger than six months.

Many previous studies have shown that flu vaccines can be given safely during pregnancy, including numerous studies that found no link between flu vaccination and miscarriage.

The new findings were part of an observational study published Wednesday in the journal Vaccine. The researchers who conducted the study emphasize that it is not a reason to avoid the flu vaccine, even for pregnant women.

“Science is an incremental process, and a lot of people don’t understand that very seldom does a single study provide a definitive answer that can lead to changes in recommendations,” said Edward Belongia, a senior epidemiologist at the Marshfield Clinic Research Institute in Wisconsin and one of the study authors.

Scientists at Marshfield compared 485 pregnant women, ages 18 to 44, who had a miscarriage to 485 pregnant women of similar ages who had normal deliveries during the flu seasons of 2010-2011 and 2011-2012. Of the women who miscarried, 17 had received flu vaccine in the 28 days before the miscarriage, and had also been immunized the prior flu season. Most miscarriages occurred in the first trimester, but several occurred during the second trimester. The median age of the fetus at time of miscarriage was 7 weeks.

By comparison, of the women who had normal deliveries, four who had received the flu vaccine in the preceding 28 days had also been vaccinated during the previous flu season.

“We only saw the link between vaccination and miscarriage if they had been vaccinated in the season before,” said James Donahue, an epidemiologist and lead author.

Marshfield researchers conducted a similar study among pregnant women during the 2005-2006 and 2006-2007 flu seasons, and found no association between the flu vaccine and miscarriage.

The Marshfield study had several limitations, including the small number of women who had miscarriages and who received vaccinations two years in a row.

The authors also said the results could be biased if women who sought care for their miscarriages were also more likely to have received flu vaccinations. Miscarriages, which are among the most challenging birth outcomes to study, often occur early in pregnancy and don't necessarily come to the attention of health-care providers — or the women themselves if they miscarry before they realize they are pregnant. If women who routinely get flu vaccines are also more likely to be aware of pregnancies earlier than other women or more likely to seek care before or after a miscarriage, that could explain the study findings.

If the flu vaccine did somehow make miscarriage more likely during the years in the study, a possible explanation could lie in the makeup of flu vaccine. As a result of the 2009 H1N1 swine flu pandemic that killed hundreds of thousands of people around the world, including more than 12,000 in the United States, vaccine manufacturers developed vaccines to protect against the new H1N1 strain, which was different from viruses that circulated before 2009.

Flu vaccinations of pregnant women increased substantially during and after the pandemic. The authors speculate that the association they observed — if it is real — may be related to an immunological response to having been vaccinated in two consecutive influenza seasons with the same vaccines. The composition of the vaccines to protect against H1N1 was identical in 2010-2011 and 2011-2012.

“Scientifically, it is unclear why this would occur,” said Haywood Brown, president of ACOG, noting that there was no such association with miscarriage more than 28 days after vaccination. He said multiple published studies and clinical experience support the advice that the flu vaccine is safe and effective during pregnancy.

“Additional studies are needed to address the concern raised by this study,” he said. “In evaluating all of the available scientific information, there is insufficient information to support changing the current recommendation, which is to offer and encourage routine flu vaccinations during pregnancy regardless of the trimester of pregnancy.”

The CDC is participating in an ongoing study investigating pregnant women who received the flu vaccine during three more recent flu seasons, starting in 2012-2013. Results are expected late next year or 2019.

“This is exactly why we study these things to make sure vaccines are safe and effective,” said the CDC's Cohn.

Since 2004, the CDC and other organizations have recommended routine flu vaccination for pregnant women regardless of their stage of pregnancy...