Although the increased morbidity and mortality of influenza during pregnancy provide a compelling reason to vaccinate pregnant women, pregnancy is associated with a decreased hemagglutination inhibition (HAI) response to influenza vaccine. We hypothesized that in addition to this quantitative reduction, pregnancy-associated increases in IL-4, IL-10 and IL-13 secretion might promote production of IgG4 over the better complement- and Fc receptor-activating isotypes, IgG1 and IgG3; such a change might decrease antibody-dependent killing of virus. To begin to evaluate this hypothesis, we compared IgG1, IgG3 and IgG4 anti-H1N1 titers by ELISA in sera obtained from 50 pregnant and non-pregnant 18-39 year old women 24-31 days after vaccination. The IgG1:IgG4 ratio was significantly decreased in pregnant vs. non-pregnant women (29.0±35.0 vs. 69.3±94.1 (mean ± SD), p=0.04). Both HAI (p=0.017) and IgG1 (p=0.047) titers were decreased in trimesters 2 and 3 vs. trimester 1. These changes could be quite marked: 28% of women immunized during trimesters 2 and 3 had a combination of high IgG4/low IgG1 titers that was not seen in any non-pregnant or first trimester vaccinated women. Our results suggest that cytokine-mediated qualitative and quantitative changes in the anti-influenza antibody response may decrease protection in a considerable percentage of women vaccinated during the last 2/3 of pregnancy, which, in turn, suggests a need to consider changes in vaccination for this population.