Link Between Flu Vaccine and Miscarriage? Experts Unconvinced

Janis C. Kelly

September 14, 2017

( UPDATED September 15, 2017 — Editor's note: This article has been updated to include additional interviews. ) Unexpected data suggesting an association between miscarriage and previous receipt of influenza vaccines containing the A/H1n1 pdm2009 (pH1N1) antigen support additional research into the effects of repeated influenza vaccination on pregnancy. The findings, however, should not be interpreted as a reason for pregnant women to avoid flu shots, experts say.

James G. Donahue, DVM, PhD, and colleagues report in Vaccine that spontaneous abortion (SAB) was associated with influenza vaccination in the preceding 28 days, but that the association was significant only among women who had also been vaccinated in the previous influenza season.

"The association we observed was restricted to those women who had been vaccinated in the 28 days before their miscarriage and who had been vaccinated in the previous influenza season with a vaccine that contained antigens of the pandemic H1N1 influenza virus," Dr. Donahue, from Marshfield Clinic Research Institute, Wisconsin, told Medscape Medical News. "Our study does not and cannot establish a causal association between the vaccine and miscarriage."

He continued, "The association we observed between influenza vaccine and miscarriage was unexpected, particularly since our earlier study found no association and there is a wealth of data supporting the safety of vaccine in pregnancy, especially later in pregnancy. With additional study, we hope to better understand the association between miscarriage and repeated influenza vaccinations."

Guidance from both the American College of Obstetrics and Gynecology and the Centers for Disease Control and Prevention (CDC) recommends pregnant women get yearly influenza shots, regardless of their stage of pregnancy. This advice rests on the greater risk that influenza will cause severe illness in pregnant than in nonpregnant women, the need to protect developing babies and newborns (who cannot receive their own influenza shots until they are 6 months old), and data from prior studies supporting safety of influenza vaccines for pregnant women and their babies.

In response to the article by Dr Donahue and colleagues, Haywood L. Brown, MD, president of the American College of Obstetricians and Gynecologists (ACOG) released the following statement: "ACOG continues to recommend that all women receive the influenza vaccine. This is particularly important during pregnancy. Influenza vaccination is an essential element of prenatal care because pregnant women are at an increased risk of serious illness and mortality due to influenza. In addition, maternal vaccination is the most effective strategy to protect newborns because the vaccine is not approved for use in infants younger than six months."

Dr. Brown added, "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."

Christopher M. Zahn, MD, ACOG vice president for practice activities, told Medscape Medical News, "Providers should make clear to patients that the benefits of vaccination far outweigh any potential risk of vaccination, and is a critically important intervention to decrease the risk of contracting the flu during pregnancy. Flu vaccines have been safely given to millions of pregnant women, and numerous studies have shown no serious adverse events from flu vaccination in pregnancy, including miscarriage. However, we do know that pregnant women are more susceptible than the general population to serious illness and even death related to influenza, underscoring the need for vaccination."

Similarly, in an interview with the Associated Press, Gregory Poland, MD, editor-in-chief of Vaccine, acknowledged that the study was well designed and should prompt further research, but that he does not think influenza vaccines cause SAB. Dr Poland is also director of vaccine research at the Mayo Clinic in Rochester, Minnesota.

Case-Control Study

For the case-control study, Dr Donahue and colleagues analyzed data from 2010-2011 and 2011-2012 in the Vaccine Safety Datalink. They matched 485 cases of SAB with women in a control group based on site, date of last menstrual period, and age. Women in the control group had either live births or stillbirths. Cases were older than controls and were more likely to be African-American, to have had two or more spontaneous abortions, and to have smoked during pregnancy.

The primary vaccine exposure window was the 1 to 28 days before the SAB. The study was designed with 80% power to detect an odds ratio (OR) of 2.2 for miscarriage during days 1 to 28 of exposure, which would have required 500 matched case-control pairs but enrolled only 485 pairs.

The researchers did not estimate the overall incidence or prevalence of SAB in women who had or had not received the pH1N1 vaccine, or the incidence or prevalence of SAB in women who contract seasonal influenza infections.

The authors write, "In the primary analysis of this observational investigation, we found a modest but statistically significant association between SAB and [inactivated influenza vaccine] in the 28 days before the reference date."

However, when the researchers stratified the women according to vaccination history for a post hoc analysis, they found that the significant association was only maintained "among women who had received pH1N1-containing vaccine in the previous influenza season."

That conclusion rested on 17 cases and 4 controls who had same-season vaccination on days 1 to 28 and who had also been vaccinated in the previous season.

There were no significant differences among women vaccinated 29 to 56 days or more than 56 days before the reference date, regardless of whether they had also been vaccinated the previous year.

The researchers calculated odds ratios, but warn, "[W]hile the odds ratio in a case-control study is generally considered an estimate of the risk ratio, this is only true if the outcome is rare or controls were chosen using incidence density sampling. Since neither was the case in this study, the [odds ratios] should not be interpreted as risk ratios."

The OR calculations showed that women with SAB were twice as likely as the control patients to have had vaccine exposure during days 1 to 28. The post hoc analysis showed that women who suffered SAB were 7.7 times more likely than control patients to have also received a pH1N1-containing vaccine in the previous influenza season.

The authors conclude that more research is needed on the immunologic effects of influenza vaccination during pregnancy and that a CDC-funded follow-up study currently underway will evaluate SAB risk after repeated influenza vaccinations during the 2012 to 2013, 2013 to 2014, and 2014 to 2015 influenza seasons.

Dr. Donahue added, "There is no well-established biological mechanism to explain our observations. As stated in the paper, 'One possible explanation for these findings is that a second or boosting dose of pH1N1-containing vaccine may confer risk in early pregnancy, but receipt of an initial or priming dose does not.' We do not fully understand all components of the immune response to the influenza vaccine and novel antigens (such as pH1N1), including the effects of repeated vaccination. There are other possible explanations for our observations including biases, misclassification errors, and chance."

Dr. Zahn explained that ACOG carefully tracks pregnancy-related vaccine safety information via involvement with the National Vaccine Advisory Committee at the US Department of Health and Human Services and the Advisory Committee on Immunizations Practices at the Centers for Disease Control and Prevention. He also emphasized that numerous studies have not shown a risk for miscarriage associated with influenza vaccination, and that the study by Dr Donahue and colleagues only points to an association, which does not imply a cause-and-effect relationship.

The study was supported by the CDC. Dr Donahue has disclosed no relevant financial relationships. Other coauthors reported research support from GlaxoSmithKline, Sanofi Pasteur, Pfizer, Merck, MedImmune, Novartis, Protein Science, and Novavax. Dr. Zahn has disclosed no relevant financial relationships.

Vaccine. 2017;35:5314-5322. Article

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