Risk for Congenital Malformation With H1N1 Influenza Vaccine: A Cohort Study With Sibling Analysis.

Background Earlier studies reporting varying risk estimates for congenital malformation in offspring of mothers undergoing vaccination against H1N1 influenza during pregnancy did not consider the potential role of confounding by familial (genetic and shared environmental) factors. Objective To evaluate an association between maternal H1N1 vaccination during pregnancy and offspring malformation, with familial factors taken into account. Design Population-based prospective study. Setting Sweden. Participants Liveborn offspring born between 1 October 2009 and 1 October 2011 to mothers receiving monovalent AS03-adjuvanted H1N1 influenza vaccine (Pandemrix [GlaxoSmithKline]) during pregnancy. A total of 40 983 offspring were prenatally exposed to the vaccine, 14 385 were exposed within the first trimester (14 weeks), and 7502 were exposed during the first 8 weeks of pregnancy. Exposed offspring were compared with 197 588 unexposed offspring. Corresponding risks in exposed versus unexposed siblings were also estimated. Measurements Congenital malformation, with subanalyses for congenital heart disease, oral cleft, and limb deficiency. Results Congenital malformation was observed in 2037 (4.97%) exposed offspring and 9443 (4.78%) unexposed offspring. Adjusted risk for congenital malformation was 4.98% in exposed offspring versus 4.96% in unexposed offspring (risk difference, 0.02% [95% CI, -0.26% to 0.30%]). The corresponding risk differences were 0.16% (CI, -0.23% to 0.56%) for vaccination during the first trimester and 0.10% (CI, -0.41% to 0.62%) for vaccination in the first 8 weeks. Using siblings as comparators yielded no statistically significant risk differences. Limitations The study was based on live births, and the possibility that data on miscarriage or induced abortion could have influenced the findings cannot be ruled out. Study power was limited in analyses of specific malformations. Conclusion When intrafamilial factors were taken into consideration, H1N1 vaccination during pregnancy did not seem to be linked to overall congenital malformation in offspring, although risk increases for specific malformations could not be ruled out completely. Primary Funding Source Swedish Research Council and Swedish Council for Working Life and Social Research.