Effect of bivalent human papillomavirus vaccination on pregnancy outcomes: long term observational follow-up in the Costa Rica HPV Vaccine Trial

Abstract

Objective: To examine the effect 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, defined 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 after 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% confidence interval 0.78 to 1.34, one sided P=0.436) in unadjusted analyses. Results were similar after 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 stratified 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% confidence interval 1.02 to 1.77, one sided P=0.017).

Conclusions: There is no evidence that bivalent HPV vaccination affects 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 after 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.

Conflict of interest statement

Competing interests: All authors have completed the ICMJE uniform disclosure form at http://www.icmje.org/coi_disclosure.pdf (available on request from the corresponding authors). JTS and DRL are named inventor on US government owned HPV vaccine patents that are licensed to GlaxoSmithKline and Merck and for which the National Cancer Institute (NCI) receives licensing fees. They are entitled to limited royalties as specified by federal law. The other authors and investigators declare that they have no conflicts of interest. The researchers are completely independent from the non-government funders and sponsors. The NCI, National Institute of Environmental Health Sciences, and Costa Rica investigators are responsible for the design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation of the manuscript. The findings and conclusions in this report are those of the authors and do not necessarily represent the official views of the US Department of Health and Human Services, the National Institutes of Health, the NCI, the National Institute of Environmental Health Sciences, or any other funding agency. BLB is employed by a contractor company (Information Management Services) to the NCI; nevertheless, there is no conflict of interest in the authors’ submission, nor does this alter adherence to BMJ policies on sharing data.

© Panagiotou et al 2015.

Figures

Fig 1 Exposed and unexposed pregnancies in Costa Rica HPV Vaccine Trial (CVT) and long term follow-up study. Shown are relative risks of miscarriage for pregnancies conceived any time since vaccination with bivalent human papillomavirus (HPV) vaccine in the previously published pooled analysis of CVT and parallel PApilloma TRIal against Cancer In young Adults (PATRICIA) and in update of CVT, including data acquired after our previous report as well as corresponding fixed effect summary relative risks. Data are shown overall and by gestational age of miscarriage. *Long term follow-up study was implemented for all women enrolled in trial (except those living in Puntarenas)

Fig 2 Meta-analysis on risk of miscarriage for pregnancies conceived any time since vaccination with bivalent HPV overall and by gestational age in Costa Rica HPV Trial (CVT) and parallel PATRICIA trial