Intussusception Risk after Rotavirus Vaccination in U.S. Infants
W. Katherine Yih, Ph.D., M.P.H., Tracy A. Lieu, M.D., M.P.H., Martin Kulldorff, Ph.D., David Martin, M.D., M.P.H., Cheryl N. McMahill-Walraven, M.S.W., Ph.D., Richard Platt, M.D., Nandini Selvam, Ph.D., M.P.H., Mano Selvan, Ph.D., Grace M. Lee, M.D., M.P.H., and Michael Nguyen, M.D.
N Engl J Med 2014; 370:503-512February 6, 2014DOI: 10.1056/NEJMoa1303164
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BACKGROUND
International postlicensure studies have identified an increased risk of intussusception after vaccination with the second-generation rotavirus vaccines RotaTeq (RV5, a pentavalent vaccine) and Rotarix (RV1, a monovalent vaccine). We studied this association among infants in the United States.
METHODS
The study included data from infants 5.0 to 36.9 weeks of age who were enrolled in three U.S. health plans that participate in the Mini-Sentinel program sponsored by the Food and Drug Administration. Potential cases of intussusception and vaccine exposures from 2004 through mid-2011 were identified through procedural and diagnostic codes. Medical records were reviewed to confirm the occurrence of intussusception and the status with respect to rotavirus vaccination. The primary analysis used a self-controlled risk-interval design that included only vaccinated children. The secondary analysis used a cohort design that included exposed and unexposed person-time.
RESULTS
The analyses included 507,874 first doses and 1,277,556 total doses of RV5 and 53,638 first doses and 103,098 total doses of RV1. The statistical power for the analysis of RV1 was lower than that for the analysis of RV5. The number of excess cases of intussusception per 100,000 recipients of the first dose of RV5 was significantly elevated, both in the primary analysis (attributable risk, 1.1 [95% confidence interval, 0.3 to 2.7] for the 7-day risk window and 1.5 [95% CI, 0.2 to 3.2] for the 21-day risk window) and in the secondary analysis (attributable risk, 1.2 [95% CI, 0.2 to 3.2] for the 21-day risk window). No significant increase in risk was seen after dose 2 or 3. The results with respect to the primary analysis of RV1 were not significant, but the secondary analysis showed a significant risk after dose 2.
CONCLUSIONS
RV5 was associated with approximately 1.5 (95% CI, 0.2 to 3.2) excess cases of intussusception per 100,000 recipients of the first dose. The secondary analysis of RV1 suggested a potential risk, although the study of RV1 was underpowered. These risks must be considered in light of the demonstrated benefits of rotavirus vaccination. (Funded by the Food and Drug Administration.)
Supported by funding from the Food and Drug Administration, through the Department of Health and Human Services, for the Mini-Sentinel and PRISM programs (contract number HHSF223200910006I).
Dr. McMahill-Walraven reports being an employee of and holding stock in Aetna. No other potential conflict of interest relevant to this article was reported.
Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.
This article was published on January 14, 2014, at NEJM.org.