Influenza illness and influenza vaccination during pregnancy and risk of preterm birth and fetal death

Pregnant women are considered a high-risk group for serious influenza illness and influenza-related complications. The World Health Organization and many high-income countries currently advise vaccination of pregnant women with inactivated influenza vaccine in any trimester. Although the primary goal of influenza vaccine recommendations is to directly protect pregnant women from influenza disease, recent observational studies have suggested that maternal influenza immunization could additionally protect against adverse pregnancy outcomes such as preterm birth and fetal death. The biologic plausibility of such findings depends on there being an adverse effect of maternal influenza disease on fetal health, but high‐quality evidence for this association is lacking. The overall aim of my doctoral research was to explore the risk of preterm birth and fetal death in relation to maternal influenza illness and maternal influenza vaccination during pregnancy, with emphasis on the 2009 H1N1 influenza pandemic.The first objective of this thesis was to summarize, through a systematic evidence review, comparative studies evaluating fetal death or preterm birth associated with influenza vaccination during pregnancy. We were unable to perform meta-analyses due to high clinical and statistical heterogeneity, but found that while most studies reported no association between preterm birth or fetal death and influenza vaccination during pregnancy, several reported significant risk reductions. The second objective of this thesis was to assess the association between 2009 pandemic H1N1 (pH1N1) influenza illness during pregnancy and perinatal outcomes using a retrospective cohort study design which accounted for the time-dependent nature of influenza and changing incidence of perinatal outcomes. In the overall obstetrical population of Ontario, there was no association between clinically-diagnosed pH1N1 influenza and preterm birth or spontaneous preterm birth, but among women with pre-existing medical conditions such as asthma, a diagnosis of influenza was associated with increased risk of preterm birth (adjusted hazard ratio [aHR]=1.54, 95% confidence interval [CI]: 1.09–2.17) and spontaneous preterm birth (aHR=1.72, 95% CI: 1.12–2.65), compared with unexposed pregnancy time. Motivated by limitations in individual-level measures of influenza illness and by the distinct temporal features of influenza viral activity, the third objective was to assess the association between an ecologic measure of influenza virus circulation and short-term variation in population-level rates of adverse perinatal outcomes using a time-series study design. Across a ten-year period in Ontario, the rate of preterm birth was not associated with circulating influenza in the week preceding birth (adjusted rate ratio: 1.01, 95% CI: 1.00–1.02), nor with the level of circulating influenza during the first month of gestation. Collectively, the results from this thesis suggest that influenza disease is not a major contributor to preterm birth in the Ontario obstetrical population, including during the 2009 H1N1 pandemic, when the health of pregnant women was of unprecedented high concern. High-quality data on the relationship between maternal influenza disease and adverse perinatal outcomes are critical for clarifying expectations for improved perinatal outcomes following maternal influenza immunization. Although influenza immunization during pregnancy is efficacious in preventing influenza disease in mothers and their newborns, considering the multifactorial etiology of adverse outcomes such as preterm birth, low prevalence of influenza during pregnancy and lack of consistent evidence that fetal health is adversely affected by maternal influenza disease, immunization would not be expected to produce a large improvement in perinatal outcomes to the extent suggested by some studies.

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