A study by investigators from Costa Rica and the National Cancer Institute provides reassurance about the safety of human papillomavirus (HPV) vaccination for women who may become pregnant soon after receiving the vaccine. The findings, published in BMJ, show no increased risk of miscarriage for pregnancies conceived <90 days after vaccination, adding to results of an earlier study that found a similar trend for pregnancies conceived ≥90 days after vaccination.
Conducted in Costa Rica, the observational single-center study represented long-term follow up of a randomized double-blind trial combined with an independent, unvaccinated population-based cohort. The participants were 7466 women in the trial and 2836 women in the unvaccinated cohort who enrolled at the end of the randomized trial and in parallel with the observational trial component.
Women in the trial were randomized to 3 doses of either the experimental bivalent HPV L1 virus-like particle AS04 vaccine (n=3727) or the control hepatitis A vaccine (n=3739). Crossover bivalent HPV vaccination occurred in the hepatitis A vaccine arm at the end of the trial. Women in the unvaccinated cohort (n=2836) received no vaccination and were enrolled to allow continued evaluation of efficacy and safety of the vaccine despite loss of the original controls because of the crossover vaccination.
Of the 3394 pregnancies that occurred at any time after HPV vaccination, 318 were conceived <90 days after vaccination. Unexposed pregnancies comprised 2507 pregnancies conceived after hepatitis A vaccination and 720 conceived in the women who had not been vaccinated.
Miscarriages occurred in 451 (13.3%) of the exposed pregnancies, 50 (13.1%) of the pregnancies conceived <90 days after HPV vaccination, and 414 (12.8%) of the unexposed pregnancies. Of the latter pregnancies, 316 (12.6%) were in the hepatitis A vaccine group and 98 (13.6%) in the unvaccinated cohort. The relative risk (RR) for miscarriage of pregnancies conceived <90 days after vaccination versus all unexposed pregnancies was 1.02 (95% confidence interval [CI] 0.78 to 1.34, one sided P=0.436) in unadjusted analyses. Results were similar after adjustment for age at vaccination, age at conception, and calendar year, and in stratified analyses.
For pregnancies conceived at any time after HPV vaccination, exposure to the vaccine was not associated with an increased risk of miscarriage overall or in subgroups, except for miscarriages at weeks 13 to 20 of gestation (RR 1.35, 95% CI 1.02 to 1.77, one sided P=0.017). The outcome in this subgroup, the authors said, is compatible with chance and may be an artifact of a thorough set of sensitivity analyses. However, because they could not totally rule out a genuine association, the investigators recommend further exploration in ongoing and future studies. Curiously, the rate of miscarriages at 13 to 20 weeks in the women exposed to hepatitis A vaccine was lower than that in both the HPV-vaccinated group and the women who had no vaccination.