Detectable Risks in Studies of the Fetal Benefits of Maternal Influenza Vaccination

Abstract

Maternal influenza vaccination prevents influenza illness in both mothers and newborns. Results from some recent studies have suggested that influenza vaccination might also prevent adverse pregnancy outcomes, such as preterm birth. However, it is challenging to conduct epidemiologic studies to evaluate the benefits to the fetus of maternal influenza vaccination because the causal benefit of vaccination is likely only experienced by the small fraction of the cohort in whom influenza illness is prevented by vaccination. The plausibility of detecting true differences in risks between groups under such conditions is rarely discussed. We aimed to inform the interpretation of studies in which the fetal benefits of maternal influenza vaccination are evaluated by estimating detectable risk ratios and necessary sample sizes for different study scenarios. Estimates of rates of influenza illness, vaccine effectiveness, vaccine uptake, and preterm birth and of the association of influenza illness with preterm birth were identified from the published literature. We calculated detectable risk ratios for preterm birth in vaccinated versus unvaccinated women and the associated sample size requirements. Our results demonstrated that under most scenarios, plausible differences between groups will be extremely challenging to detect (risk ratios for preterm birth of 0.9 to 1.0) and will require sample sizes infeasible for prospective epidemiologic research. This suggests that the large fetal benefits from influenza vaccination observed in epidemiologic studies are unlikely to be causal.

Keywords: immunization; influenza illness; influenza vaccine; pregnancy; pregnancy complication; preterm birth; sample size; statistical power.

Figure 1.

Schematic of influenza illness in women who were and were not vaccinated against influenza. Because the baseline seasonal attack rate for influenza illness is typically 5%–20% (16), most women will not contract influenza illness, irrespective of vaccination status. This fraction of the cohort is denoted as the “never influenza illness” group. Among those who receive the influenza vaccine, not all cases of influenza illness will be averted because the effectiveness of the influenza vaccine is not 100%. This fraction of the cohort is denoted as the “always influenza illness” group. The causal effect of vaccination will only be observed in the fraction of vaccinated women who did not contract influenza illness as a result of the vaccine (but who would have contracted influenza illness if they had not been vaccinated), denoted as the “causal effect of vaccine” group. The fraction of the vaccinated cohort for whom maternal influenza illness was averted because of vaccination is 2.5%–12% of women, assuming the above parameters.

Figure 2.

Sample sizes needed to detect various risk ratios for preterm birth associated with influenza vaccination at 80% power and α of 0.05, assuming an 11.1% baseline risk of preterm birth among women without influenza illness in pregnancy. Vertical dashed lines illustrate examples of a plausible scenario of a 5% influenza illness attack rate, 50% vaccine effectiveness, and a 1.5-fold increased risk of preterm birth associated with influenza illness (expected risk ratio of 0.99; gray dashed line) and the detectable risk ratio (0.86) under the scenario of a fixed sample size of 10,000 women with 50% vaccine uptake (or equal allocation to immunization and control in a randomized trial; black dashed line).