Study adds evidence on neonatal benefits of maternal flu shots

Researchers reported yesterday that pregnant women in Nova Scotia lowered their risk of having a preterm or low-birth-weight baby if they received an influenza vaccine while pregnant—a question on which past studies have not all agreed.

The authors found that in the 2010-11 and 2011-12 flu seasons, vaccinated women had a 25% reduction in risk of preterm birth and a 29% lower risk of having a low-birth-weight baby, compared with women who didn't get the vaccine, according to their report in the Canadian Medical Association Journal.

On the negative side, only 16% of pregnant women in the province received a flu shot in those two seasons, a fraction of the estimated 64% who were vaccinated during the 2009 pandemic, the report says. And a US expert who was not involved in the study noted some possible unmeasured confounders.

The study was conducted by a team from Dalhousie University and the Canadian Centre for Vaccinology in Halifax, N.S., with Alexandra Legge, BSc, as lead author.

Significant differences

In a retrospective cohort design, the authors used the Nova Scotia Atlee Perinatal Database to look at neonatal outcomes in all pregnant women who gave birth in the province between Nov 1, 2010, and Mar 31, 2012.

The database stores information gathered from clinical forms and hospital records after hospital discharge. Collection of information on maternal flu vaccination began in 2009, and the system also includes data on risk factors for flu complications.

The records revealed that of 12,223 women who gave birth during the study period, 1,958 (16.0%) received a seasonal flu vaccine while pregnant. Vaccination rates were higher in those who lived in rural areas and those who had medical conditions that increased their risk for serious flu, while vaccination was less likely in single women, those with more than one child, and those who smoked during pregnancy.

Compared with unvaccinated women, vaccinated women were found to have a significantly lower risk of having a preterm birth, with an odds ratio (OR) of 0.75 and a 95% confidence interval (CI) of 0.60 to 0.93.

The reduction in risk of having a low-birth-weight baby was also significantly lower in the vaccinated women: OR, 0.71; 95% CI, 0.54 to 0.92.

The maternal characteristics that were found to be associated with higher or lower vaccination rates, such as rural residence or single status, were seen as potential confounders. When the authors adjusted for these factors, they found no change in their results concerning preterm births and low birth weight.

The analysis found no effect of maternal vaccination on three other neonatal outcomes: low birth weight at term, smallness for gestational age, and composite neonatal morbidity. The latter variable included death within the first 28 days and various other conditions, such as low Apgar score, sepsis, asphyxia, and intraventricular hemorrhage.

Previous conflicting findings

The authors observe that previous observational studies have produced conflicting findings on the association between maternal flu vaccination and preterm birth. US and Canadian studies conducted during the 2009 pandemic suggested that vaccination reduced the risk of preterm birth, they note. But they say most studies conducted during ordinary flu seasons have not found a link between vaccination and a lower risk.

It's not clear whether the inconsistent findings are due to a true lack of association or are the result of methodologic challenges or other factors, such as demographic differences between study populations, the report says.

The researchers also note a possible mechanism for a beneficial effect of vaccination, if it exists. Maternal infection has been identified as a risk factor for preterm birth, and it has been suggested that inflammatory responses to infection may play a role in initiating labor, a hypothesis that has found some support in animal studies.

"By averting maternal infection, the vaccine may exert a protective effect on the fetus by avoiding the associated inflammatory response that may trigger premature labour," the authors write.

"Our findings add to the existing body of evidence that seasonal influenza vaccination during pregnancy not only offers maternal benefits but may also provide both prenatal benefits to the fetus and postnatal protection to the infant through transplacental antibodies," they conclude.

Consistent with Bangladesh trial

Edward Belongia, MD, director of the Epidemiology Research Center at the Marshfield Clinic Research Foundation in Wisconsin, said the study has some methodologic shortcomings, but the findings agree with those in a randomized trial that was conducted in Bangladesh and reported in 2012.

In the Bangladesh study, conducted in 2004 and 2005, infants born to mothers who were vaccinated during periods when flu was circulating were significantly less likely to be small for gestational age and weighed significantly more than infants of mothers who were not vaccinated. This effect was not seen in babies of mothers who were vaccinated when flu was not circulating.

"In this [Nova Scotia] study there's definitely a potential for unmeasured confounding that could be influencing the results," Belongia said. "They appear to have taken a time period of November 2010 to March 2012 and looked at women who gave birth at any point. So that would include women who most of the time during pregnancy were not in flu season. So their likelihood of encountering flu was pretty low. . . . They didn't distinguish between the period of flu circulation and the period of no flu circulation, which would've been helpful."

In addition, he said the authors apparently didn't assess the level of prenatal care in the women, which could be another source of confounding.

Nonetheless, he welcomed the findings: "Despite its limitations in design and the potential for unmeasured confounding, the fact that they did find some of the same benefits as in the randomized controlled trial in Bangladesh does provide some additional evidence that there's a real benefit from flu vaccination in terms of neonatal outcome."

Legge A, Dodds L, MacDonald NE, et al. Rates and determinants of seasonal influenza vaccination in pregnancy and association with neonatal outcomes. Can Med Assoc J 2014 (online release Jan 6) [Full text] [Abstract]

See also:

April 2012 CMAJ report on Bangladesh study

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