Original Article
Risk of Intussusception after Monovalent Rotavirus Vaccination
N Engl J Med 2014; 370:513-519February 6, 2014DOI: 10.1056/NEJMoa1311738
- Abstract
Background
Although current rotavirus vaccines were not associated with an increased risk of intussusception in large trials before licensure, recent postlicensure data from international settings suggest the possibility of a small increase in risk of intussusception after monovalent rotavirus vaccination. We examined this risk in a population in the United States.
Methods
Participants were infants between the ages of 4 and 34 weeks who were enrolled in six integrated health care organizations in the Vaccine Safety Datalink (VSD) project. We reviewed medical records and visits for intussusception within 7 days after monovalent rotavirus vaccination from April 2008 through March 2013. Using sequential analyses, we then compared the risk of intussusception among children receiving monovalent rotavirus vaccine with historical background rates. We further compared the risk after monovalent rotavirus vaccination with the risk in a concurrent cohort of infants who received the pentavalent rotavirus vaccine.
Results
During the study period, 207,955 doses of monovalent rotavirus vaccine (including 115,908 first doses and 92,047 second doses) were administered in the VSD population. We identified 6 cases of intussusception within 7 days after the administration of either dose of vaccine. For the two doses combined, the expected number of intussusception cases was 0.72, resulting in a significant relative risk of 8.4. For the pentavalent rotavirus vaccine, 1,301,810 doses were administered during the study period, with 8 observed intussusception cases (7.11 expected), for a nonsignificant relative risk of 1.1. The relative risk of chart-confirmed intussusception within 7 days after monovalent rotavirus vaccination, as compared with the risk after pentavalent rotavirus vaccination, was 9.4 (95% confidence interval, 1.4 to 103.8). The attributable risk of intussusception after the administration of two doses of monovalent rotavirus vaccine was estimated to be 5.3 per 100,000 infants vaccinated.
Conclusions
In this prospective postlicensure study of more than 200,000 doses of monovalent rotavirus vaccine, we observed a significant increase in the rate of intussusception after vaccination, a risk that must be weighed against the benefits of preventing rotavirus-associated illness. (Funded by the Centers for Disease Control and Prevention.)
Media in This Article
Figure 1
Assessment of Clustering of Cases of Intussusception after Monovalent or Pentavalent Rotavirus Vaccination, According to the Onset Interval and Dose.In the 30 days after rotavirus vaccination, 10 cases of intussusception occurred after the administration of 207,955 doses of the monovalent rotavirus vaccine (Panel A) and 38 cases after the administration of 1,301,810 doses of the pentavalent rotavirus vaccine (Panel B). The only significant clustering of cases (P=0.02) occurred between days 3 and 6 among children receiving the monovalent vaccine (Panel A, shaded).
Table 1
Risk of Intussusception within 7 Days after Monovalent Rotavirus Vaccination, as Compared with the Historical Background Rate in the Vaccine Safety Datalink, April 2008 to March 2013.Article Activity
- Article
The first licensed rotavirus vaccine (RotaShield) was withdrawn from the U.S. market in 1999 because of an increased risk of intussusception.1 Subsequently, two rotavirus vaccines have been licensed in the United States: RotaTeq (a pentavalent rotavirus vaccine) in 2006 and Rotarix (a monovalent rotavirus vaccine) in 2008.2,3 The two vaccines underwent prelicensure clinical trials involving 60,000 to 70,000 infants each, in which no increased risk of intussusception was identified.4,5
Postlicensure monitoring in the Vaccine Safety Datalink (VSD) project has not found an increase in the risk of intussusception after pentavalent rotavirus vaccination.6,7 At the time of the study of the pentavalent rotavirus vaccine, too few doses of the monovalent rotavirus vaccine had been administered to assess the risk of intussusception. Uptake of the monovalent rotavirus vaccine subsequently increased, allowing us to evaluate the association between receipt of the vaccine and intussusception in a U.S. population.
Methods
Study Design
The VSD project is a collaborative effort between the Centers for Disease Control and Prevention (CDC) and several integrated health care organizations, six of which participated in this study: Group Health Cooperative, Seattle; Kaiser Permanente Northwest, Portland, OR; Kaiser Permanente Northern California, Oakland; Kaiser Permanente Southern California, Pasadena; Kaiser Permanente Colorado, Aurora; and Marshfield Clinic Research Foundation, Marshfield, WI.8 Electronic data regarding vaccinations and health care utilization — including the diagnosis codes based on the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) from hospitals, emergency departments, and outpatient clinics — are updated weekly to conduct surveillance of adverse events after vaccination.
Study Oversight
The study was funded by the CDC. The protocol was approved by the institutional review board at each site and was determined to be public health surveillance by the CDC.
Study Participants
Our study included infants between the ages of 4 and 34 weeks who had received at least one dose of childhood vaccine. For the monovalent rotavirus vaccine, doses were limited to those administered between the ages of 4 and 20 weeks for dose 1 and between the ages of 10 and 34 weeks for dose 2. We identified all hospital and emergency department visits for intussusception occurring 1 to 30 days after monovalent rotavirus vaccination using ICD-9-CM codes (“543.9, other and unspecified disease of the appendix including intussusception” and “560.0, intussusception”), which were restricted to the first code given in the lifetime of the child. We reviewed medical records using the Brighton Collaboration definition9 for all suspected intussusception events that occurred within 7 days after any vaccination, excluding day 0 (the day of vaccination). The physician reviewers were aware of the type of vaccine that had been administered.
Monitoring of Intussusception
For sequential monitoring of intussusception after monovalent rotavirus vaccination, we determined background rates using ICD-9-CM–coded, computerized data regarding emergency department and hospital visits without medical-record review.7 We stratified the rates according to the week of age and site and restricted the analyses to the years from 2001 through 2005 to minimize bias from possible secular trends and to exclude the dates when the monovalent and pentavalent vaccines were both in use. We conducted weekly analyses from April 2008 through March 2013, using sequential monitoring methods.6,10-14 We stratified aggregated weekly data from all participating sites according to VSD site, age, sex, calendar week of monovalent rotavirus vaccination, number of doses, and other vaccines that were administered on the same day.
Statistical Analysis
We compared the observed rate of intussusception with the background rate and computed the relative risk by dividing the number of observed cases by the number of expected cases. We calculated the expected number of incident cases of intussusception using the age and site distribution of the population that received the monovalent vaccine multiplied by the corresponding background rates of intussusception.
We used the Poisson version of the maximized sequential probability ratio test (maxSPRT).15 The test statistic for maxSPRT is the log-likelihood ratio, which is calculated from the observed and expected numbers of cases of intussusception. We specified that a minimum of 3 observed cases must be identified to denote an elevated risk or signal. We further specified an alpha error of 0.05 and an upper limit for sequential monitoring of approximately 300,000 doses. For total doses administered, the upper limit was set at 3 intussusception cases, which provided a power of 73% to detect a relative risk of 3, a power of 90% to detect a relative risk of 4, and a power of more than 99% to detect a relative risk of 10. For calculating the risk separately for dose 1 and dose 2, the upper limit was set at 1.5 intussusception cases, corresponding to 175,000 and 125,000 doses, respectively. We used the upper limit and alpha-error level to determine the critical value of the log-likelihood ratio. If the log-likelihood ratio exceeded the critical value in the weekly analysis, the null hypothesis was rejected.
Once the log-likelihood ratio exceeded the critical value, we conducted further analyses, including an analysis of temporal clustering and a comparison with concurrent pentavalent rotavirus vaccination. Before conducting the concurrent analyses of monovalent and pentavalent vaccines, we updated our previous analyses of intussusception associated with pentavalent rotavirus vaccination. Our previous analysis covered the period from May 2006 through February 2010.7 For the current analysis, we extended the period to March 2013.
The comparison of monovalent and pentavalent vaccines was restricted to the time when the two vaccines were in use, April 2008 through March 2013. We reviewed medical records of all cases after the administration of either vaccine, regardless of setting (i.e., outpatient clinic, emergency department, or hospital). Two physicians independently reviewed abstracted charts; a third physician reviewed the case when there was disagreement between the first two reviewers. We used exact logistic regression to estimate relative risks of intussusception in children receiving the monovalent vaccine, as compared with the pentavalent vaccine, after adjustment for site, age (in weeks), dose, and sex. All analyses were conducted with the use of SAS software, version 9.3 (SAS Institute).
Results
Risk of Intussusception for Monovalent Vaccine
In the sequential analysis, the log-likelihood ratio first surpassed the critical value for all doses of monovalent rotavirus vaccine after the identification of the third case of intussusception, when 156,660 total doses had been administered. We continued surveillance through March 2013. At that time, 207,955 doses of monovalent rotavirus vaccine had been administered, including 115,908 first doses and 92,047 second doses. Six cases of intussusception occurred within 7 days after monovalent rotavirus vaccination. Four of these cases occurred in female infants (at ages 16, 16, 17, and 19 weeks) and two in male infants (at ages 9 and 17 weeks). Two cases occurred after dose 1, and 4 cases occurred after dose 2.
The 6 observed intussusception cases were significantly more than the 0.72 cases that were expected on the basis of historical data (Table 1Table 1
Risk of Intussusception within 7 Days after Monovalent Rotavirus Vaccination, as Compared with the Historical Background Rate in the Vaccine Safety Datalink, April 2008 to March 2013.). Similarly, the observed number of cases (4) after dose 2 was significantly greater than the expected number of 0.49. The 2 cases that were observed after dose 1 were less than the minimum number of required cases (3), so the log-likelihood ratio was not calculated. As compared with the historical rate of intussusception in the VSD population, the attributable risk of intussusception for infants receiving the monovalent rotavirus vaccine was 5.3 cases per 100,000 infants receiving the two doses of vaccine.We performed a cluster analysis of all intussusception cases (on the basis of ICD-9-CM codes) in the emergency department or hospital setting within 30 days after monovalent rotavirus vaccination. We identified a significant (P=0.02) cluster in the interval 3 to 6 days after such vaccination (Figure 1AFigure 1
Assessment of Clustering of Cases of Intussusception after Monovalent or Pentavalent Rotavirus Vaccination, According to the Onset Interval and Dose.In the 30 days after rotavirus vaccination, 10 cases of intussusception occurred after the administration of 207,955 doses of the monovalent rotavirus vaccine (Panel A) and 38 cases after the administration of 1,301,810 doses of the pentavalent rotavirus vaccine (Panel B). The only significant clustering of cases (P=0.02) occurred between days 3 and 6 among children receiving the monovalent vaccine (Panel A, shaded).
).Comparison with Pentavalent Rotavirus Vaccine
Our updated analysis of data regarding pentavalent rotavirus vaccination from May 2006 through March 2013 showed no significant increased risk of intussusception (Table 2Table 2
Risk of Intussusception within 7 Days after Pentavalent Rotavirus Vaccination, as Compared with the Historical Background Rate in the Vaccine Safety Datalink, May 2006 to March 2013.). Similarly, no temporal clustering was observed after pentavalent rotavirus vaccination (Figure 1B).The concurrent comparison of data regarding the monovalent and pentavalent vaccines was restricted to cases meeting Brighton Collaboration level 1 criteria (documented during surgery, on radiography, or on autopsy) that were diagnosed within 7 days after rotavirus vaccination in an outpatient clinic, emergency department, or hospital. The inclusion of possible cases that were first seen in a clinic resulted in a total of 7 possible cases after monovalent rotavirus vaccination and 9 after pentavalent rotavirus vaccination. Of these 16 possible cases that underwent medical record review, 5 of 7 cases (71%) after monovalent rotavirus vaccination were confirmed according to Brighton Collaboration level 1 criteria, and 1 case (14%) was categorized as Brighton Collaboration level 2. Six of the 9 cases (67%) after pentavalent rotavirus vaccination were confirmed as Brighton Collaboration level 1; the other 3 were determined not to be cases of intussusception.
The 6 cases of intussusception after pentavalent rotavirus vaccination occurred after the administration of 999,123 doses, and the 5 cases after monovalent rotavirus vaccination occurred after the administration of 207,995 doses (Table 3Table 3
Comparison of the Risk of Intussusception within 7 Days after the Receipt of Monovalent or Pentavalent Rotavirus Vaccination, as Restricted to Chart-Confirmed Cases in the Vaccine Safety Datalink, April 2008 to March 2013.). Because of the small number of cases, we could not precisely estimate dose-specific relative risks. In an analysis of a combination of all doses after adjustment for site, age (in weeks), and dose, the relative risk of intussusception associated with monovalent rotavirus vaccination was 9.1 (95% confidence interval [CI], 1.4 to 98.9). Since the monovalent rotavirus vaccine is only a two-dose series and since no increased risk of intussusception has been shown after the third dose of the pentavalent rotavirus vaccine, we performed an additional analysis restricted to doses 1 and 2; the relative risk after adjustment for age and site was 9.4 (95% CI, 1.4 to 103.8) (data not shown). The risk difference was 4.4 per 100,000 infants receiving the two doses of the monovalent rotavirus vaccine as compared with the first 2 doses of the pentavalent rotavirus vaccine.Discussion
In the sequential monitoring analyses, we observed an increased risk of intussusception within 7 days after the administration of any dose of monovalent rotavirus vaccine. We used the same sequential monitoring methods that we used in previous VSD studies that did not find an increased risk of intussusception after the administration of the pentavalent rotavirus vaccine.6,7 We also conducted a cluster analysis and a concurrent analysis comparing the risk after monovalent rotavirus vaccination with that after pentavalent rotavirus vaccination. All three analyses identified an increased risk of intussusception within the first week after monovalent rotavirus vaccination.
Our study had several strengths. The VSD vaccination data have previously been shown to be accurate,16 and the background rates that we used to calculate expected values in the sequential analysis were calculated from the same data source as was used in our study population. Our findings are not prone to selection bias as a result of physicians' reporting practices, since the VSD captures most vaccinations and we had 100% access to all medical records.
A potential limitation of the study is the use of unconfirmed cases of intussusception in the sequential analyses. However, both the background rates used to calculate the expected number of cases and the observed cases were restricted to inpatient and emergency department settings. When limited to such settings, cases based on these ICD-9-CM codes had previously been shown to have a positive predictive value of approximately 75% in the VSD data7 and in the current study. Moreover, our analysis comparing the monovalent vaccine with the pentavalent vaccine included only cases that were confirmed on medical-record review.
Another potential concern with our sequential analysis is the possible influence of temporal trends. We do not believe this is likely because no increased rate was seen after pentavalent rotavirus vaccination, as compared with historical rates. In addition, the concurrent comparison with pentavalent rotavirus vaccination also showed an increased risk associated with the monovalent vaccine.
Our updated analysis of pentavalent rotavirus vaccination included nearly 1.3 million doses and continued to find no significant increased risk of intussusception. The relative risk after the first dose of the pentavalent rotavirus vaccine was 2.63 (95% CI, 0.72 to 6.74). This analysis included all electronically recorded diagnoses without chart confirmation of cases; after medical-record review, only two of the four cases that occurred after the receipt of dose 1 were confirmed. Thus, in the VSD population, there was not sufficient evidence to conclude that the pentavalent rotavirus vaccine was associated with an increased risk of intussusception, so the pentavalent rotavirus vaccine served as an appropriate comparator for assessing risks after monovalent rotavirus vaccination.
Our finding of an increased risk of intussusception associated with monovalent rotavirus vaccination is consistent with findings from other studies.17,18 In Mexico, investigators found an increase by a factor of 5 in the risk of intussusception within 7 days after the administration of the first dose of monovalent rotavirus vaccine.18 An evaluation in Brazil observed a doubling of the risk within 7 days after the administration of the second dose of monovalent rotavirus vaccine but no increase after the first dose.18 Another study in Mexico showed a significant increase, by a factor of 6, in the risk within 7 days after the first dose of the monovalent vaccine.19
In addition, contrary to our findings of no increased risk associated with pentavalent rotavirus vaccination, other studies have suggested an increased risk. An Australian study showed that both the monovalent and pentavalent vaccines carried a significant increase, by a factor of 7 to 10, in the risk within 7 days after the administration of the first dose and a tripling in the risk after the second dose.20 Passive surveillance in the United States has also suggested the possibility of a small increased risk of intussusception after the first dose of the pentavalent vaccine.21 Finally, a recent analysis of databases of U.S. health insurance claims showed a significant increase, by a factor of 9, in the risk of intussusception within 7 days after the first dose of the pentavalent vaccine.17 The various findings in various studies may be due to several factors, including differences in the background rates of intussusception,22,23 uncontrolled confounding, and methodological differences.16,17
Given the small number of cases of intussusception, the increased risk after monovalent rotavirus vaccination in our study may also be the result of chance. The confidence intervals around our estimates, although significant, are wide. One less case of intussusception associated with the monovalent vaccine or one more case associated with the pentavalent vaccine could have made this comparison nonsignificant, but the relative risk would have remained elevated and still approached statistical significance. Continued surveillance in VSD data or confirmation in other U.S. populations could be helpful in confirming the level of increased risk after rotavirus vaccination.
Although we observed an increased risk of intussusception associated with monovalent rotavirus vaccination in the VSD population, the well-documented benefits of rotavirus vaccination need to be considered.24-27 Since the start of the U.S. rotavirus vaccination program, large declines in rotavirus disease and associated hospitalizations have occurred among U.S. infants.28-31 Thus, the benefits of rotavirus vaccination in infants have been found to outweigh possible small risks of intussusception.24-27
Supported by the CDC.
The views expressed in this article are those of the authors and do not necessarily represent the official position of the CDC.
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.
We thank the participating integrated health care organizations and their staff for their dedication, helpful insights, and participation in this project.
Source Information
From the Centers for Disease Control and Prevention, Immunization Safety Office, Atlanta (E.S.W., J.B., J.D., C.V., F.D.); Marshfield Clinic Research Foundation, Marshfield, WI (E.A.B.); Center for Health Research, Kaiser Permanente Northwest, Portland, OR (S.I., A.N.); Vaccine Study Center, Kaiser Permanente Northern California, Oakland (N.P.K.); Kaiser Permanente Colorado, Aurora (J.M.G.); Kaiser Permanente Southern California, Pasadena (S.J.J.); and Group Health Research Institute, Seattle (L.A.J.).
Address reprint requests to Mr. Weintraub at the Immunization Safety Office, Centers for Disease Control and Prevention, 1600 Clifton Rd. NE, MS D26, Atlanta, GA 30333, or at eiw8@cdc.gov.
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