LAUSR

Influenza Vaccination in the First Trimester of Pregnancy and Risk of Autism Spectrum Disorder To the Editor In the cohort study by Zerbo et al “Association Between Influenza Infection and Vaccination During Pregnancy and Risk of Autism Spectrum Disorder,”1 the authors found that “influenza vaccination anytime during pregnancy was not associated with ASD [autism spectrum disorder] risk,” although the adjusted hazard ratio was of borderline significance (1.10; 95% CI, 1.00-1.21). They conclude that “there was a suggestion of increased ASD risk among children whose mothers received an influenza vaccination in their first trimester” (adjusted hazard ratio, 1.20; 95% CI, 1.04-1.39), “but the association was not statistically significant after adjusting for multiple comparisons.”1 We doubt these reassuring conclusions. First, the multiplicity of the hypotheses tested (for which nominal P values for all comparisons made should be at disposal) corresponds, in the authors’ view, to 4 times of each exposure: overall pregnancy time and 3 trimesters for flu and the same for flu vaccination. Nevertheless, the authors used the Bonferroni correction, which only adjusts for independent comparisons: we doubt that overall pregnancy time can be independent from the 3 trimesters in the same individual. Second, Bonferroni correction is more stringent than other corrections, and other equally legitimate tests might maintain the hazard ratio significance. Third, it is biologically plausible that eventual effects on the nervous system occur in the first trimester during its embryogenesis. Therefore, it could be logical to perform the main analysis in the first trimester. However, the main problem is that the influenza vaccination induces an inflammatory response during pregnancy,2,3 which the authors point out. Magnitude and duration of this response is lower and shorter than that induced by the viral infection, but their rates are very different: a Cochrane review4 demonstrated that only 1 to 3 influenza illnesses for every 100 healthy adults vaccinated are prevented (depending by the annual matching between vaccine and circulating strains): number needed to vaccinate, 33 to 100. Therefore, at a population level, 100 vaccinated women will probably experience more inflammatory effects vs those caused by only 1 to 3 influenzas (focused only on 1 to 3 of these 100 women). Table 31 shows that the inflammatory effect of flu during the first trimester interested only 2 of 1000 women (443 of 196 929), while the vaccination flogosis was distributed among 297 of 1000 vaccinated women (13 477 of 45 231). The logical conclusion, pending properly designed trials for further clarification, should not be “do not change vaccine policy or practice” for pregnant women (without proven important benefits, except for patients with coronary heart disease5). Instead, given the possible risk of 4 additional autism spectrum disorder cases for every 1000 women vaccinated, it seems reasonable to apply the precautionary principle and refrain from vaccinating pregnant women or at least to avoid vaccination in the first trimester of pregnancy.