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Risk of Spontaneous Abortion After Inadvertent Human Papillomavirus Vaccination in Pregnancy

Kharbanda, Elyse O., MD, MPH; Vazquez-Benitez, Gabriela, PhD; Lipkind, Heather S., MD, MS; Sheth, Sangini S., MD, MPH; Zhu, Jingyi, PhD; Naleway, Allison L., PhD; Klein, Nicola P., MD, PhD; Hechter, Rulin, MD, PhD; Daley, Matthew F., MD; Donahue, James G., DVM, PhD; Jackson, Michael L., PhD; Kawai, Alison Tse, ScD; Sukumaran, Lakshmi, MD, MPH; Nordin, James D., MD, MPH

doi: 10.1097/AOG.0000000000002694
Contents: Cancer Prophylaxis/Sterilization: Original Research

OBJECTIVE: To evaluate the risk of spontaneous abortion after quadrivalent human papillomavirus (4vHPV) vaccination before and during pregnancy across seven integrated health systems within the Vaccine Safety Datalink.

METHODS: Within a retrospective observational cohort, we compared risks for spontaneous abortion after 4vHPV in three exposure windows: distal (16–22 weeks before the last menstrual period [LMP]), peripregnancy (within 6 weeks before the LMP), and during pregnancy (LMP through 19 weeks of gestation). Women 12–27 years of age with a pregnancy between 2008 and 2014, with continuous insurance enrollment 8 months before and through pregnancy end, and with a live birth, stillbirth, or spontaneous abortion were included. Pregnancies were identified through validated algorithms. Spontaneous abortions and stillbirths were verified by chart review with spontaneous abortions adjudicated by clinical experts. We excluded multiple gestations, spontaneous abortions before 6 weeks of gestation, and women using medications increasing risk of spontaneous abortion. Spontaneous abortion risk after 4vHPV during pregnancy was compared with distal vaccination using time-dependent covariate Cox models. Spontaneous abortion risk for peripregnancy compared with distal vaccination was evaluated with standard Cox models.

RESULTS: We identified 2,800 pregnancies with 4vHPV exposure in specified risk windows: 919 (33%) distal, 986 (35%) peripregnancy, and 895 (32%) during pregnancy. Mean age was 22.4 years in distal and peripregnancy groups compared with 21.4 years among women vaccinated during pregnancy. Among women with distal 4vHPV exposure, 96 (10.4%) experienced a spontaneous abortion. For peripregnancy and during pregnancy exposures, spontaneous abortions occurred in 110 (11.2%) and 77 (8.6%), respectively. The risk of spontaneous abortion was not increased among women who received 4vHPV during pregnancy (adjusted hazard ratio 1.10, 95% CI 0.81–1.51) or peripregnancy 1.07 (0.81–1.41).

CONCLUSION: Inadvertent 4vHPV exposure during or peripregnancy was not significantly associated with an increased risk of spontaneous abortion.

Quadrivalent human papillomavirus vaccination inadvertently administered during pregnancy or peripregnancy is not associated with increased risk of spontaneous abortion.

HealthPartners Institute, Minneapolis, Minnesota; the Department of Obstetrics, Gynecology, & Reproductive Sciences, Yale University School of Medicine, New Haven, Connecticut; the Center for Health Research, Kaiser Permanente Northwest, Portland, Oregon; the Vaccine Study Center, Kaiser Permanente Northern California, Oakland, and the Department of Research and Evaluation, Kaiser Permanente Southern California, Pasadena, California; the Institute for Health Research, Kaiser Permanente Colorado, Denver, Colorado; Marshfield Clinic Research Institute, Marshfield, Wisconsin; Kaiser Permanente Washington Health Research Institute, Seattle, Washington; Harvard Pilgrim Health Care Institute, Boston, Massachusetts; and the Centers for Disease Control and Prevention, Atlanta, Georgia.

Corresponding author: Elyse O. Kharbanda, MD, MPH, Department of Research, HealthPartners Institute, Mail Stop 23301A, PO Box 1524, Minneapolis, MN 55440; email:

Supported by the Centers for Disease Control and Prevention, Contract 200-2012-53526-0006. Dr. Sheth is supported, in part, by Clinical and Translational Science Awards Grant Number UL1 TR000142 from the National Center for Advancing Translational Science, components of the National Institutes of Health (NIH), and NIH roadmap for medical research. Findings and conclusions of this report are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention or of NIH.

Each author has indicated that he or she has met the journal's requirements for authorship.

Financial Disclosure Dr. Sheth has received research support from Merck. Dr. Naleway has received research support from Merck, Medimmune, and Pfizer. Dr. Klein has received research support from GlaxoSmithKline, Sanofi Pasteur, Merck & Co, Pfizer, Medimmune, Novartis (now GlaxoSmithKline), Dynavax, and Protein Science. Dr. Hechter has received research support from GlaxoSmithKline. Dr. Jackson has received research support from Sanofi Pasteur. The other authors did not report any potential conflicts of interest.

Presented at the Health Care Systems Research Network (HCSRN) Annual Meeting, April 11–13, 2018, Minneapolis, Minnesota.

The authors thank Zhiyuan Xu, MA, Leslie Kuckler, MPH, Lina Sy, MPH, Cheryl Carlson, MPH, Laurie VanArman, LPN, and Dianne Eggen, RN, for their assistance with data collection.

Received February 21, 2018. Received in revised form April 9, 2018. Accepted April 12, 2018.

© 2018 by the American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. All rights reserved.