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

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.

Effect of bivalent human papillomavirus vaccination on pregnancy outcomes: long term observational follow-up in the Costa Rica HPV Vaccine Trial by Orestis A Panagiotou, et al. on behalf  of the Costa Rica HPV Vaccine Trial (CVT) Group
BMJ2015; 351 (Published 07 September 2015)

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