Postmarketing Monitoring of Intussusception After RotaTeq^™ Vaccination --- United States, February 1, 2006--February 15, 2007

Rotavirus is the leading cause of severe gastroenteritis in children aged <5 years worldwide. In February 2006, a new rotavirus vaccine, RotaTeq^™ (Merck and Co., West Point, Pennsylvania), was licensed in the United States, and the Advisory Committee on Immunization Practices (ACIP) recommended it for routine vaccination of U.S. infants with 3 doses, administered orally at ages 2, 4, and 6 months (1). Because a previous rotavirus vaccine, Rotashield^™ (Wyeth Laboratories, Marietta, Pennsylvania), was withdrawn from the U.S. market in 1999 after postmarketing surveillance identified an association* with intussusception (a rare type of bowel obstruction) (2), the safety of RotaTeq was evaluated in a prelicensure clinical trial involving 71,725 infants who received either vaccine or placebo (3). In this controlled trial, no statistically significant elevated risk for intussusception was observed within a 42-day period after RotaTeq vaccination. However, postmarketing monitoring for intussusception after RotaTeq vaccination is necessary because of possible differences in the characteristics of infants who received the vaccine in routine use compared with the infants in the clinical trials. Also, the large numbers of infants being vaccinated provides an opportunity to detect intussusception occurring at a low rate after vaccination. This report presents data from the first year of postmarketing monitoring for intussusception after RotaTeq vaccination in the United States, with particular focus on all intussusception reports received by the Vaccine Adverse Event Reporting System (VAERS) during February 1, 2006--February 15, 2007. As of February 15, 2007, postmarketing surveillance did not suggest association of RotaTeq vaccination with intussusception. CDC reaffirms vaccine policy recommendations to routinely vaccinate U.S. infants with RotaTeq at ages 2, 4, and 6 months.

In the United States, the postmarketing safety of RotaTeq is being monitored jointly by CDC and the Food and Drug Administration (FDA) through both evaluation of reports to VAERS and active surveillance using data from the Vaccine Safety Datalink (VSD) (4,5). Merck and Co. also is conducting a postmarketing observational study, which will monitor for occurrence of intussusception within 30 days of RotaTeq vaccination in 44,000 infants in the United States. VAERS is a passive national surveillance system that receives reports of adverse events after vaccination from various sources, including vaccine manufacturers, health-care providers, immunization programs, and vaccine recipients (4). VAERS reports of serious adverse events after RotaTeq vaccination are reviewed daily by staff physicians and epidemiologists at CDC and FDA. Health-care providers are contacted to verify diagnoses and obtain additional clinical information and vaccination history. VSD is a collaborative project between CDC and several large U.S. health maintenance organizations (HMOs) in which computerized vaccination data can be linked to medical outcomes (5). Because of the limited number of administered doses of RotaTeq vaccine reported in VSD to date, this analysis focused on VAERS data.

To assess a potential association between intussusception and RotaTeq vaccination, the number of intussusception reports to VAERS after RotaTeq vaccination was compared with the number of intussusception cases expected to occur by chance alone (i.e., the background cases of intussusception). Because the background rates of natural intussusception and number of vaccine doses administered vary substantially by age, the analysis was stratified into three age groups (6--14 weeks, 15--23 weeks, and 24--35 weeks). The observed reports of intussusception were compared with the expected number of cases of intussusception for the three age groups within 1--21 days and 1--7 days after RotaTeq vaccination. These periods were selected on the basis of the potential risk periods identified from experience with Rotashield and the hypothesis that any possible risk of intussusception requires replication of the vaccine virus in the intestinal tract, which might occur 1--15 days after vaccination, on the basis of the RotaTeq clinical trials (1--3).

The background rates of intussusception for the three age groups were determined from hospital discharges coded with the International Classification of Diseases, Ninth Revision code for intussusception (560.0) at the VSD study sites for 2000--2004, when no rotavirus vaccine was in use. The expected number of background cases for risk periods of 1--21 days and 1--7 days were calculated by multiplying the VSD background rates of intussusception for each age group by the estimated number of vaccine doses administered to that age group. For these calculations, the following was assumed: 1) administered doses of vaccine approximated the total number of doses of RotaTeq distributed by the manufacturer during February 1, 2006--January 31, 2007; and 2) the national distribution of vaccine doses to infants in these three age groups approximated the distribution of vaccine doses administered in each of the three age groups in VSD. Observed versus expected reporting rate ratios (RRs) with 95% confidence intervals (CIs) were calculated using the exact age-stratified Poisson test.

VAERS Reports

During February 1, 2006--February 15, 2007, VAERS received 567 reports of adverse events after RotaTeq vaccination, including 35 reports of intussusception (Figure 1) that were confirmed using the Brighton Collaboration case definition (6). Of these 35 reports, 17 (49%) occurred in infants within 1--21 days of vaccination, including 11 (31%) that occurred within 1--7 days of vaccination. Among the other 18 reports, onset of intussusception ranged from 22--73 days, with the exception of one report, with onset on the same day as vaccination (Figure 1).

All 17 intussusception reports occurring within 1--21 days of vaccination were radiographically confirmed (i.e., by barium enema or ultrasonogram). Of these 17 cases, nine (53%) occurred in vaccinees after dose 1, eight (47%) after dose 2, and none after dose 3 of vaccine (Figure 2). Ten (59%) infants required surgery (including five who needed intestinal resection); for seven (41%) infants, intussusception was resolved by enema reduction or resolved spontaneously (Table 1).

Observed Versus Expected Calculations

As of January 31, 2007, the manufacturer had distributed 3.6 million doses of RotaTeq (Merck, unpublished data, 2007). According to VSD data, an estimated 57%, 31%, and 12% of these doses had been distributed among infants aged 6--14, 15--23, and 24--35 weeks, respectively; an estimated 61% were dose 1, 30% were dose 2, and 9% were dose 3. Using VSD data for 2000--2004, the background rate of intussusception was 18.1 per 100,000 person years (PY) at ages 6--14 weeks, 32.5 per 100,000 PY at ages 15--23 weeks, and 42.5 per 100,000 PY at ages 24--35 weeks. By applying these background intussusception rates to the estimated distributed doses per age group, an expected number of 52 intussusception cases was calculated for the period 1--21 days after vaccination; 17 of these cases would be expected to occur at 1--7 days after vaccination. In contrast, 17 intussusception cases were reported to VAERS that occurred within 1--21 days after vaccination, including 11 that occurred 1--7 days after vaccination. Thus, the number of cases of intussusception reported through VAERS was not elevated above the age-adjusted background rates of intussusception for either 1--21 days (RR = 0.32; CI = 0.17--0.55) or 1--7 days (RR = 0.61; CI = 0.29--1.18) after RotaTeq vaccination (Table 2).

VSD Results

During February 1, 2006--February 15, 2007, a total of 28,377 doses of RotaTeq were administered to infants in VSD-monitored HMOs. No cases of intussusception within 30 days of vaccination were reported among these recipients. In contrast, during the same period, within 30 days of vaccination, eight cases of intussusception were reported among approximately 240,110 infants of the same age group who received vaccines other than RotaTeq.

Reported by: E Belongia, MD, Marshfield Clinic, Marshfield, Wisconsin. H Izurieta, MD, MM Braun, MD, R Ball, MD, Center for Biologics Evaluation and Research, Food and Drug Admin. P Haber, MPH, J Baggs, PhD, E Weintraub, MPH, P Gargiullo, PhD, C Vellozzi, MD, J Iskander, MD, Immunization Safety Office, Office of the Chief Science Officer; M Patel, MD, U Parashar, MBBS, M Cortese, MD, J Gentsch, PhD, G Wallace, MD, D Bartlett, MPH, National Center for Immunization and Respiratory Diseases (proposed), CDC.

Editorial Note:

Intussusception is the most common cause of acute intestinal obstruction in infants aged <1 year. Although many etiologies have been associated with intussusception (e.g., adenovirus infection or Meckel's diverticulum), the cause is often unknown. In the United States, approximately 1,200--1,400 cases of intussusception occur annually, even in the absence of rotavirus vaccination (7). Using surveillance data to ascertain whether RotaTeq is associated with intussusception requires careful assessment of the observed number of cases after vaccination compared with the number that would have been expected to occur based on the background rate of natural intussusception.

Postmarketing surveillance data available to date do not suggest that RotaTeq is associated with intussusception. The reported number of VAERS intussusception cases among infants vaccinated with RotaTeq does not exceed the number of expected background cases for either the 1--7 day period or the 1--21 day period after vaccination.Within each age group, which corresponds to the risk after each of the 3 doses of RotaTeq, the observed number of reports also is within the expected range (Table 2). In addition, no cases of intussusception were detected within 30 days of vaccination in more than 28,000 VSD infants reported to have received RotaTeq vaccination. However, because of possible underreporting to VAERS and the limited number of infants in VSD vaccinated with RotaTeq to date, the possibility cannot be excluded that an increased risk for intussusception (or any other adverse event) might be observed over time.

Although the 17 intussusception cases occurring in infants within 1--21 days of RotaTeq vaccination do not exceed the expected number for this risk period, a majority of these cases (11 [65%]) occurred within 1--7 days of vaccination. Of these 11 infants, five had onset in October 2006. The apparent clustering of reported intussusception cases in the week after vaccination might be explained by characteristics of VAERS reporting, which is generally more complete for severe adverse events that occur close to the time of vaccination (4). The reason for the large number of reports in the first 7 days after vaccination during the month of October is unclear. This temporal pattern is not consistent with the pattern of vaccine distribution data by month. As more data become available, the significance of the apparent clustering of intussusception cases in the week after RotaTeq vaccination will be examined further.

VAERS data merit cautious interpretation because of the inherent limitations of passive surveillance. Underreporting is a limitation of VAERS; however, the high level of awareness of the association of the previous Rotashield vaccine with intussusception among U.S. pediatricians and family practitioners (8) likely has improved reporting of RotaTeq-related adverse events to VAERS. This conclusion is supported by the response to a vaccine label change to RotaTeq issued by Merck (and an accompanying public health notification issued by FDA [available at http://www.fda.gov/cber/safety/phnrota021307.htm] that received extensive media coverage and was widely distributed among pediatricians) on February 13, 2007, adding intussusception as a reported adverse event after vaccination. Although the initial public health alert for Rotashield published on July 16, 1999, resulted in approximately 42 additional reports (i.e., historical cases that occurred prior to the label change) of intussusception to VAERS, the recent RotaTeq label change had generated reports of only five additional cases as of March 2, 2007. Only one of these reports occurred within 1--21 days of RotaTeq vaccination. Inclusion of this case in the analysis will not affect the conclusions of this report.

The findings in this report are subject to at least two additional limitations. First, the proportion of distributed doses of RotaTeq that had been administered could not be determined. If the number of doses administered was overestimated, the expected background number of cases would decrease and the potential for an association between vaccine and risk for intussusception would increase. Second, although the most robust data available were used to estimate background rates for intussusception hospitalizations, the accuracy and completeness of these data have not been verified. A preliminary study suggests that hospital discharge diagnoses might not include some intussusception cases, such as those managed in non-inpatient settings (e.g., emergency departments, short-stay units, or 23-hour observation units) (9); thus, the background incidence of intussusception might have been underestimated. In addition, electronically coded data on intussusception might not represent true cases (10). The likelihood of finding an association between vaccine and intussusception might increase or decrease depending on the effect of these factors.

The number of reports to VAERS of intussusception after administration of RotaTeq has not exceeded the number expected to occur based on background rates. RotaTeq vaccine is recommended for all infants at ages 2, 4, and 6 months. Health-care providers are reminded that the first dose should be administered to infants only between ages 6 and 12 weeks, and the full series should be completed before age 32 weeks (1). CDC and FDA will continue to monitor adverse events reported after RotaTeq vaccination. All persons are encouraged to report cases of intussusception or any adverse events after RotaTeq or any other vaccination to VAERS. Reports may be submitted securely online at http://www.vaers.hhs.gov or by fax at 877-721-0366. Reporting forms and additional information are available by telephone at 800-822-7967.

References

1. CDC. Prevention of rotavirus gastroenteritis among infants and children: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR 2006;55(No. RR-12).
2. Murphy TV, Gargiullo PM, Massoudi MS, et al. Intussusception among infants given an oral rotavirus vaccine. N Engl J Med 2001;344: 564--72.
3. Vesikari T, Matson DO, Dennehy P, et al. Safety and efficacy of a pentavalent human-bovine (WC3) reassortant rotavirus vaccine. N Engl J Med 2006;354:23--33.
4. Rosenthal S, Chen R. The reporting sensitivities of two passive surveillance systems for vaccine adverse events. Am J Public Health 1995;85:1706--9.
5. Mullooly J, Drew L, DeStefano F, et al. Quality of HMO vaccination databases used to monitor childhood vaccine safety. Vaccine Safety DataLink Team. Am J Epidemiol 1999;149:186--94.
6. Bines JE, Kohl KS, Forster J, et al. Acute intussusception in infants and children as an adverse event following immunization: case definition and guidelines of data collection, analysis, and presentation. Vaccine 2004;22:569--74.
7. Tai JH, Curns AT, Parashar UD, Bresee JS, Glass RI. Rotavirus vaccination and intussusception: can we decrease temporally associated background cases of intussusception by restricting the vaccination schedule? Pediatrics 2006;118:e258-64.
8. Kempe A, Daley MF, Parashar UD, et al. Will pediatricians adopt the new rotavirus vaccine? Pediatrics 2007;119:1--10.
9. Staat MA, Roberts N, Bernstein DI. Epidemiology and clinical features of intussusception in children <24 months of age in Hamilton County, Ohio [abstract]. Pediatr Res 2000;49:242A.
10. Kramarz P, France EK, Destefano F, et al. Population-based study of rotavirus vaccination and intussusception. Pediatr Infect Dis J 2001;20:410--6.

* The odds of intussusception were 37 times higher among vaccine recipients than among unvaccinated infants during the 3--7 days after dose 1 of Rotashield.

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Date last reviewed: 3/15/2007