Influenza Pandemics—Pregnancy, Pathogenesis, and Perinatal Outcomes

Abstract

SINCE THE 1918 INFLUENZA PANDEMIC, IT HAS BEEN clear that pandemic influenza is associated with increased morbidity and mortality in pregnancy, and more recent studies have shown that nonpandemic seasonal influenza strains also lead to morbidity for pregnant women and their infants. In the 2009 worldwide pandemic of influenza A(H1N1)pdm09, pregnant women were at high risk for severe complications, including death and intensive care unit admission. The adverse effects of antenatal influenza infection on pregnant women and their infants suggest a biological effect of influenza infection in the mother that compromises the fetus. These effects are rarely associated with direct infection of the fetus with influenza virus, although fetal infection has been reported infrequently during epidemics, pandemics, and with the H5N1 influenza strain. Instead, it appears that the normal pregnancy-associated immunologic changes may inhibit the inflammatory response to influenza virus infection in pregnancy, leading to increased risks to mother and infant. Because of these observations, pregnant women have been listed among high-risk groups for seasonal influenza vaccine in the United States since 1997, and safety data suggest these vaccines are safe in pregnancy. Pregnant women were prioritized for immunization during the 2009 influenza A(H1N1)pdm09 pandemic, despite limited data on the safety of pandemic influenza vaccines in pregnancy. In this issue of JAMA, Pasternak and colleagues report the results of an observational cohort study on the safety in pregnancy of the monovalent inactivated ASO3adjuvanted split virion influenza A(H1N1)pdm09 vaccine. The authors linked several Danish national registries to examine outcomes in infants born during the 2009 influenza A(H1N1)pdm09 pandemic. From a cohort of 53 432 infants, 6989 received the influenza vaccine during pregnancy. The authors included 330 infants whose mothers received the influenza A(H1N1)pdm09 vaccine in the first trimester and 6642 infants whose mothers received the vaccine in the second or third trimesters in propensity score analyses matched 1:1 with infants whose mothers were unvaccinated. No statistically significant relationships were found between receipt of vaccine and several perinatal outcomes, including major birth defects, preterm birth, and fetal growth restriction. The authors had sufficient sample size to exclude these adverse outcomes after vaccination in the second or third trimesters, but could only exclude moderate to large risks after vaccination in the first trimester. In addition, these authors recently reported on the risk of fetal death (spontaneous abortion and stillbirth) in the same cohort and found no increased risk after vaccination in pregnancy. These results suggest that this monovalent adjuvanted pandemic vaccine is safe when given during pregnancy. The authors did not address the question of vaccine effectiveness and did not discuss the issue of narcolepsy, which was observed with use of this adjuvanted vaccine in Scandinavian countries. However, the researchers have the opportunity to follow up this cohort of children to determine long-term vaccine safety, ie, assessment of early infant development. Recently, Fell et al reported a similar analysis of the use of H1N1 pdm09 adjuvanted vaccine in a cohort in Ontario, Canada, of 55 570 pregnant women, of whom 23 340 received the vaccine. This study demonstrated that mothers who were immunized were less likely than mothers who were not to have an infant with small for gestational age (relative risk [RR], 0.90; 95% CI, 0.85-0.96), preterm birth at less than 32 weeks gestation (RR, 0.73; 95% CI, 0.530.91), and fetal death (RR, 0.66; 95% CI, 0.47-0.91). Reports of maternal vaccination during seasonal influenza have also shown a reduction in the proportion of small for gestational age births and an increase in mean birth weight associated with immunization of the pregnant woman, or a decrease in birth weight related to influenza infection. The pandemic vaccine used in Denmark was an adjuvanted vaccine. In the United States, a nonadjuvanted vaccine was used during the 2009 pandemic with identical H1N1 viral antigens, which were also included in the seasonal trivalent vaccines for 2009-2012. Data from the United States