OBJECTIVE: To examine the efect of the bivalent human papillomavirus (HPV) vaccine on miscarriage. DESIGN: Observational long term follow-up of a randomized, double blinded trial combined with an independent unvaccinated population based cohort. SETTING: Single center study in Costa Rica. PARTICIPANTS: 7466 women in the trial and 2836 women in the unvaccinated cohort enrolled at the end of the randomized trial and in parallel with the observational trial component. INTERVENTION: Women in the trial were assigned to receive three doses of bivalent HPV 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 received (n=2836) no vaccination. MAIN OUTCOME MEASURE: Risk of miscarriage, defned by the US Centers for Disease Control and Prevention as fetal loss within 20 weeks of gestation, in pregnancies exposed to bivalent HPV vaccination in less than 90 days and any time from vaccination compared with pregnancies exposed to hepatitis A vaccine and pregnancies in the unvaccinated cohort. RESULTS: Of 3394 pregnancies conceived at any time since bivalent HPV vaccination, 381 pregnancies were conceived less than 90 days from vaccination. Unexposed pregnancies comprised 2507 pregnancies conceived afer hepatitis A vaccination and 720 conceived in the unvaccinated cohort. Miscarriages occurred in 451 (13.3%) of all exposed pregnancies, in 50 (13.1%) of the pregnancies conceived less than 90 days from bivalent HPV vaccination, and in 414 (12.8%) of the unexposed pregnancies, of which 316 (12.6%) were in the hepatitis A vaccine group and 98 (13.6%) in the unvaccinated cohort. The relative risk of miscarriage for pregnancies conceived less than 90 days from vaccination compared with all unexposed pregnancies was 1.02 (95% confdence interval 0.78 to 1.34, one sided P=0.436) in unadjusted analyses. Results were similar afer adjusting for age at vaccination (relative risk 1.15, one sided P=0.17), age at conception (1.03, P=0.422), and calendar year (1.06, P=0.358), and in stratifed analyses. Among pregnancies conceived at any time from bivalent HPV vaccination, exposure was not associated with an increased risk of miscarriage overall or in subgroups, except for miscarriages at weeks 13-20 of gestation (relative risk 1.35, 95% confdence interval 1.02 to 1.77, one sided P=0.017). CONCLUSIONS: There is no evidence that bivalent HPV vaccination afects the risk of miscarriage for pregnancies conceived less than 90 days from vaccination. The increased risk estimate for miscarriages in a subgroup of pregnancies conceived any time afer vaccination may be an artifact of a thorough set of sensitivity analyses, but since a genuine association cannot totally be ruled out, this signal should nevertheless be explored further in existing and future studies. TRIAL REGISTRATION: Clinicaltrials.gov NCT00128661 and NCT01086709.
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