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.


METHODS
Observational long term follow-up of a randomized, double blinded trial combined with an independent unvaccinated population based cohort.


METHODS
Single center study in Costa Rica.


METHODS
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.


METHODS
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.


METHODS
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.
Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA orestis.panagiotou@nih.gov wacholds@mail.nih.gov.
Orestis A
OA
Panagiotou
Information Management Services, Calverton, MD, USA.
Brian L
BL
Befano
Proyecto Epidemiológico Guanacaste, Fundación INCIENSA, San José, Costa Rica Prevention and Implementation Group, International Agency for Research on Cancer, Lyon, France.
Paula
P
Gonzalez
Proyecto Epidemiológico Guanacaste, Fundación INCIENSA, San José, Costa Rica.
Ana Cecilia
AC
Rodríguez
Prevention and Implementation Group, International Agency for Research on Cancer, Lyon, France.
Rolando
R
Herrero
Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, USA.
John T
JT
Schiller
Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Aimée R
AR
Kreimer
Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Mark
M
Schiffman
Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Allan
A
Hildesheim
Epidemiology Branch, National Institute of Environmental Health Sciences, National Institutes of Health, Durham, NC, USA.
Allen J
AJ
Wilcox
Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA orestis.panagiotou@nih.gov wacholds@mail.nih.gov.
Sholom
S
Wacholder
D000293:Adolescent; D000328:Adult; D005260:Female; D006801:Humans; D011247:Pregnancy; D055815:Young Adult; D000022:Abortion, Spontaneous / Q000139:chemically induced / Q000453:epidemiology; D003364:Costa Rica / Q000453:epidemiology; D004311:Double-Blind Method; D005500:Follow-Up Studies; D005865:Gestational Age; D008423:Maternal Age; D053918:Papillomavirus Vaccines; D011256:Pregnancy Outcome / Q000453:epidemiology; D016032:Randomized Controlled Trials as Topic
C510352:human papillomavirus vaccine, L1 type 16, 18; D053918:Papillomavirus Vaccines