new england

The
journal of medicine
established in 1812 february 6, 2014 vol. 370 no. 6

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.

A BS T R AC T

Background
International postlicensure studies have identified an increased risk of intussuscep- From the Department of Population
tion after vaccination with the second-generation rotavirus vaccines RotaTeq (RV5, Medicine, Harvard Medical School and
Harvard Pilgrim Health Care Institute
a pentavalent vaccine) and Rotarix (RV1, a monovalent vaccine). We studied this (W.K.Y., T.A.L., M.K., R.P., G.M.L.), and
association among infants in the United States. the Division of Infectious Diseases and
Department of Laboratory Medicine, Bos-
ton Childrens Hospital (G.M.L.) all in
Methods Boston; the Division of Research, Kaiser
The study included data from infants 5.0 to 36.9 weeks of age who were enrolled in Permanente Northern California, Oakland
three U.S. health plans that participate in the Mini-Sentinel program sponsored by (T.A.L.); the Center for Biologics Evalua-
tion and Research, Food and Drug Ad-
the Food and Drug Administration. Potential cases of intussusception and vaccine ministration, Rockville, MD (D.M., M.N.);
exposures from 2004 through mid-2011 were identified through procedural and Aetna, Blue Bell, PA (C.N.M.-W.); Govern-
diagnostic codes. Medical records were reviewed to confirm the occurrence of intus- ment and Academic Research, HealthCore,
Alexandria, VA (N.S.); and Comprehensive
susception and the status with respect to rotavirus vaccination. The primary analy- Health Insights, Humana, Louisville, KY
sis used a self-controlled risk-interval design that included only vaccinated children. (M.S.). Address reprint requests to Dr. Yih
The secondary analysis used a cohort design that included exposed and unexposed at the Department of Population Medicine,
Harvard Medical School and Harvard Pil-
person-time. grim Health Care Institute, 133 Brookline
Ave., 6th Fl., Boston, MA 02215, or at
Results katherine_yih@harvardpilgrim.org.
The analyses included 507,874 first doses and 1,277,556 total doses of RV5 and This article was published on January 14,
53,638 first doses and 103,098 total doses of RV1. The statistical power for the 2014, at NEJM.org.
analysis of RV1 was lower than that for the analysis of RV5. The number of excess
N Engl J Med 2014;370:503-12.
cases of intussusception per 100,000 recipients of the first dose of RV5 was signifi- DOI: 10.1056/NEJMoa1303164
cantly elevated, both in the primary analysis (attributable risk, 1.1 [95% confidence Copyright 2014 Massachusetts Medical Society.
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 in-
tussusception 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 vaccina-
tion. (Funded by the Food and Drug Administration.)

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 The n e w e ng l a n d j o u r na l of m e dic i n e

I
n 1999, a tetravalent rhesushuman mended ages for vaccination plus adequate fol-
reassortant rotavirus vaccine (RotaShield, low-up time) who were members of an Aetna,
Wyeth Lederle) was voluntarily withdrawn HealthCore, or Humana health plan between
from the U.S. market within a year after licen- January 2004 and September 2011. Using a dis-
sure owing to an association with intussuscep- tributed database system,19,20 each of these data
tion. The excess risk of intussusception was esti- partners provided at least 3 consecutive years of
mated at approximately 1 to 2 cases per 10,000 claims and other administrative data during this
recipients of the vaccine.1 In 2006 and 2008, re- period, resulting in approximately 613,000 in-
spectively, a pentavalent bovinehuman reassortant fant-years observed.
rotavirus vaccine (RV5; RotaTeq, Merck) and a
monovalent human rotavirus vaccine (RV1; Ro- Study Design
tarix, GlaxoSmithKline) were licensed after eval- We used both a self-controlled risk-interval (SCRI)
uation in clinical trials involving more than design21-24 and a cohort design. A major advan-
60,000 infants, which provided enough statisti- tage of the former, which was prespecified as the
cal power to allow detection of an intussuscep- primary design, is that it inherently controls for
tion risk of a magnitude similar to that after vac- all fixed potential confounders such as sex, race
cination with RotaShield. In countries adopting or ethnic group, and chronic predisposing condi-
these newer rotavirus vaccines, the burden of tions. Another advantage is that it uses data only
rotavirus gastroenteritis and severe childhood from exposed children, thus minimizing poten-
diarrhea has been substantially reduced.2-9 tial misclassification bias due to incomplete data
After licensure, studies conducted outside the on vaccine exposure. The cohort design has high-
United States began to point to an association of er statistical power than the SCRI design, owing
RV5 and RV1 with intussusception, although the to the relatively large amount of historical and
risks were much lower than those seen with concurrent unexposed person-time used in the
RotaShield.10-12 Until quite recently, U.S. post generation of expected case counts. However, the
licensure studies of the safety of RV5 had not ability to control for confounding is not as good
shown a significant increase in the risk of intus- with this design as with the SCRI design. The
susception.13-16 However, a small increase in risk cohort design may also be subject to bias toward
could not be ruled out.13,15 RV1 has been used the null owing to misclassification of exposure if
less commonly in the United States, and no ad- some vaccinations are missed. A major challenge
equately powered U.S. postlicensure studies of in studying rotavirus vaccines and intussuscep-
the safety of this vaccine have been published. tion is the strong confounding effect of age,
Owing to the emerging international evidence since both vaccination and the risk of intussus-
of an association with intussusception10-12 and ception are age-dependent. The recommended
concerns about the lack of statistical power in ages for vaccination are 2, 4, and 6 months for
the U.S.-based studies that had been conducted, RV5 and 2 and 4 months for RV1, and the inci-
the Center for Biologics Evaluation and Research dence of hospitalizations for intussusception in
of the Food and Drug Administration (FDA) ini- the United States steadily increases from 2 cases
tiated the current study of RV5 and RV1 in the per 100,000 person-years at birth to a peak of 62
Post-Licensure Rapid Immunization Safety Mon- cases per 100,000 person-years at 26 to 29 weeks
itoring (PRISM) program,17 a component of the of age, subsequently falling to 26 cases per
Mini-Sentinel pilot program that was developed 100,000 person-years by 52 weeks of age.25
to conduct active surveillance of the safety of
medical products.18 Vaccine Exposures
Vaccination with RV5 and with RV1 was initially
Me thods identified in administrative data on the basis of
Current Procedural Terminology (CPT) codes
Study Population 90680 and 90681, respectively. We sought medi-
The study population consisted of children 5.0 cal records to validate vaccine exposure for all
through 36.9 weeks of age (to include the recom- infants with cases of intussusception that were

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 Intussusception Risk after Rotavirus Vaccination
determined to be confirmed or possible (see
definitions below), regardless of whether a record
of prior rotavirus vaccination existed in the elec-
tronic data.
Outcomes
Potential cases of intussusception during all per-
son-time from 5.0 to 36.9 weeks of age, irrespec-
tive of immunization status, were identified in
administrative data on the basis of any of three
codes in either the inpatient or emergency depart-
ment setting: International Classification of Diseases,
Ninth Revision (ICD-9) code 560.0 (intussuscep-
tion) or 543.9 (other and unspecified diseases of
the appendix, including intussusception) or CPT
code 74283 (therapeutic enema, contrast or air).
Only first-ever diagnoses were included.
Case status was determined by adjudication
that was based on a review of deidentified full-
text medical records. Cases were excluded if no
intussusception had been seen or an alternative
diagnosis had been made after surgery or air or
liquid-contrast enema. Each remaining potential
case was independently reviewed by one or more
adjudicators; the two main adjudicators were
pediatricians, and the third was an internist.
Adjudicators were unaware of the infants vac-
cination history and were instructed to classify
intussusception cases with the use of Brighton
Collaboration criteria.26 Level 1 cases were cases
of intussusception confirmed on the basis of
surgical, radiologic, or autopsy criteria and were
used in the primary analyses. Classification
rules were refined for Brighton level 2 cases,
which are defined on the basis of criteria repre-
senting less direct evidence of intussusception,
with further differentiation into level 2A cases
(those considered to be possible intussusception
on the basis of positive, equivocal, or discordant
results on abdominal radiography [ultrasonogra-
phy, plain radiography, or computed tomography])
and level 2B cases (those that met level 2 criteria
but were clearly not intussusception as evidenced
by normal radiologic results). Level 2A cases
combined with inconclusive cases, for which
the record stated a diagnosis of intussusception
but contained insufficient evidence to allow case
classification, were classified as possible in
tussusception and were included in sensitivity
analyses. Level 3 is the lowest level of diagnostic
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certainty and is defined by the presence of at
least four fairly nonspecific clinical criteria.
Level 3 cases were not included in the analysis.
All discrepancies in classification were resolved
by consensus.
Statistical Analysis
In the SCRI design,21-24 we used two alternative
risk intervals, 1 to 7 days after vaccination and
1 to 21 days after vaccination, and a control in-
terval from day 22 to day 42. We compared the
number of cases of intussusception in the risk
intervals and the control interval after each dose
and after all doses combined. Only cases of in-
tussusception that occurred within 42 days after
vaccination were included. We used logistic re-
gression, with an offset term to adjust for the
differential risk of intussusception according to
age in the risk and control intervals. For the off-
set term, we used age-specific background rates
extracted by Tate et al. 25 from the U.S. hospital-
discharge data of the Healthcare Cost and Utili-
zation Project (HCUP) for 11 years during which
no rotavirus vaccine was used (with data provid-
ed by J. Tate, personal communication). These
estimates were based on 3463 cases and thus
were quite precise,25 making it preferable to use
these rates rather than a risk function estimated
from the study population in the cohort design
(described below).
In the cohort design, which was our second-
ary approach, exposed person-time was defined
as person-time in the 1 to 21 days after rotavirus
vaccination. Unexposed person-time included
time during 5.0 to 36.9 weeks of age among
unvaccinated infants and among vaccinated in-
fants, excluding the day of vaccination and the
21 days after any dose of any rotavirus vaccine.
We used a Poisson regression model that included
adjustment for age with the use of a quadratic
risk function. Data from the study population
itself were used for age adjustment in con-
trast to the method used in the SCRI design
with the uncertainty in the age-dependent rates
taken into account by the regression. Calendar
time, various age functions, and several interac-
tion terms were examined during the building of
the model. Age, sex, data partner, and exposure
status were retained as independent covariates
in the final model.
505
 The n e w e ng l a n d j o u r na l
Since the risk of intussusception varies great-
ly by age in weeks, the attributable risk may vary
according to the age of the child at the time of
vaccination. We present the average attributable
risk on the basis of the observed age distribution
of the vaccinated children. The attributable risk
was calculated as the number of excess cases of
intussusception per 100,000 doses administered,
according to the formula 100,000no. of cases
in the risk window[1(1relative risk)][no.
of vaccine dosesC], where C is the proportion of
potential cases for which we were able to conduct
a chart review. By including C in the equation,
we adjusted the attributable risk for the missing
charts. We calculated the 95% confidence in-
tervals using the methods of Krishnamoorthy
and Lee27 (see the Supplementary Appendix, avail-
able with the full text of this article at NEJM.org).
We emphasize attributable risk over relative-
risk estimates in the results, because attribut-
able risks are more relevant from clinical and
public health perspectives and are less sensitive
to differences in the lengths of risk intervals. In
comparing our risk estimates with those of
other studies, we sometimes use relative risks,
either because a study with which we are com-
paring our results reported only relative risks
or because comparing attributable risks across
countries with different background rates of in-
tussusception can be misleading.
To ensure that our findings were robust, we
used alternative methods for age adjustment in
post hoc analyses. For the SCRI design, we used
the quadratic risk function from the unexposed
cohort person-time as the alternative, and for
the cohort design, we used the rates from Tate
et al.25 In addition, we conducted a series of
sensitivity analyses, which are described in the
Supplementary Appendix.
To identify clusters of intussusception onsets
within the 1-to-42-day period after rotavirus vac-
cination, we used the temporal scan statistic,28
a self-controlled design, with only vaccinated
children who had intussusception 1 to 42 days
after exposure included in the analysis. We evalu-
ated all potential risk windows starting 1 to 14
days after vaccination and ending 1 to 21 days
after vaccination, with adjustment for the multi-
ple testing inherent in the 203 intervals consid-
ered. The test statistic is the maximum likelihood
obtained among these intervals. To adjust for
age, we used the HCUP rates from Tate et al.25
to randomize the day of age at the onset of in-
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of m e dic i n e
tussusception according to the age-dependent
incidence curve, in order to obtain the distribu-
tion of the test statistic under the null hypothe-
sis. For example, for a child receiving the vaccine
at 100 days of age, the random case was assigned
a day of age in the interval of 101 to 142 days in
proportion to the incidence curve in that inter-
val. Analyses were conducted with the use of the
SaTScan software.29
R e sult s
Vaccine Doses Administered
The analyses included 1,277,556 doses of RV5, of
which 507,874 were first doses, and 103,098 doses
of RV1, of which 53,638 were first doses. The
distribution of RV5 doses and RV1 doses admin-
istered was very similar across the data partners
in the study. The results of the chart review re-
garding the vaccination status of infants with
confirmed cases of intussusception are shown in
Figure S1 in the Supplementary Appendix.
Intussusception Cases
Within the targeted age range, 343 potential cases
of intussusception were identified in the elec-
tronic data. The medical records for 267 of these
cases (78%) were reviewed and classified at the
following Brighton or modified Brighton levels
of diagnostic certainty: level 1, 124 cases; level
2A, 10 cases; level 2B, 10 cases; level 3, 11 cases;
inconclusive, 2 cases; and ruled out, 110 cases.
The positive predictive value of the case-finding
algorithm was thus 46% (124 of 267 cases).
Charts for the children with the remaining 76
potential cases (22%) were unobtainable.
Risk Estimates
RV5
In the SCRI analysis, the attributable risk of intus-
susception after dose 1 was significantly elevated
for both risk windows (1.1 [95% confidence in-
terval {CI}, 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). No significant increase in risk was seen
after dose 2 or dose 3. In the cohort analysis
(with a 21-day risk interval), there was a signifi-
cant attributable risk after dose 1 (1.2 [95% CI,
0.2 to 3.2]) but not after the other doses (Table 1).
RV1
After dose 1, there was just one case of intussus-
ception in the risk interval, and there were no
 Intussusception Risk after Rotavirus Vaccination

Table 1. Case Counts and Risk Estimates for Confirmed Intussusception after RV5.*

Dose, Type Age- Days after No. of Cases No. of Cases Attributable Risk/ No. of Doses Resulting
of Analysis, Adjustment Vaccination in Risk in Control Relative Risk 100,000 Doses in One Excess Case
and Design Method in Risk Window Window Window (95% CI) (95% CI) (95% CI)
Dose 1
Prespecified
SCRI Tate 1 to 7 5 3 9.1 (2.2 to 38.6) 1.1 (0.3 to 2.7) 89,000 (37,000 to 307,000)
SCRI Tate 1 to 21 8 3 4.2 (1.1 to 16.0) 1.5 (0.2 to 3.2) 65,000 (31,000 to 519,000)
Cohort PRISM 1 to 21 8 97 2.6 (1.2 to 5.8) 1.2 (0.2 to 3.2) 80,000 (31,000 to 434,000)
Post hoc
SCRI PRISM 1 to 7 5 3 7.0 (1.7 to 29.2) 1.1 (0.3 to 2.6) 92,000 (38,000 to 376,000)
SCRI PRISM 1 to 21 8 3 3.4 (0.9 to 13.0) 1.4 (0.01 to 3.1) 70,000 (32,000 to )
Cohort Tate 1 to 21 8 97 2.9 (1.4 to 6.0) 1.3 (0.3 to 3.3) 75,000 (30,000 to 316,000)
Dose 2
Prespecified
SCRI Tate 1 to 7 3 6 1.8 (0.4 to 7.2) 0.4 (0.3 to 1.9) 256,000 (52,000 to )
SCRI Tate 1 to 21 5 6 1.0 (0.3 to 3.1) 0.1 (1.8 to 1.8) (57,000 to )
Cohort PRISM 1 to 21 5 97 0.9 (0.4 to 2.2) 0.2 (1.1 to 1.8) (57,000 to )
Post hoc
SCRI PRISM 1 to 7 3 6 1.8 (0.4 to 7.2) 0.4 (0.3 to 1.9) 258,000 (52,000 to )
SCRI PRISM 1 to 21 5 6 1.0 (0.3 to 3.1) 0.1 (1.8 to 1.8) (57,000 to )
Cohort Tate 1 to 21 5 97 0.8 (0.3 to 2.0) 0.3 (1.2 to 1.6) (62,000 to )
Dose 3
Prespecified
SCRI Tate 1 to 7 3 4 2.2 (0.5 to 9.7) 0.6 (0.4 to 2.6) 159,000 (38,000 to )
SCRI Tate 1 to 21 4 4 1.0 (0.2 to 3.9) 0.05 (2.3 to 2.1) (47,000 to )
Cohort PRISM 1 to 21 5 97 0.9 (0.3 to 2.2) 0.3 (1.5 to 2.3) (43,000 to )
Post hoc
SCRI PRISM 1 to 7 3 4 2.3 (0.5 to 10.2) 0.7 (0.3 to 2.7) 152,000 (38,000 to )
SCRI PRISM 1 to 21 4 4 1.0 (0.2 to 4.0) 0.01 (2.1 to 2.2) 10,402,000 (46,000 to )
Cohort Tate 1 to 21 5 97 0.9 (0.4 to 2.2) 0.2 (1.4 to 2.4) (42,000 to )
All doses**
Prespecified
SCRI Tate 1 to 7 11 13 3.3 (1.5 to 7.4) 0.8 (0.2 to 1.6) 131,000 (63,000 to 497,000)
SCRI Tate 1 to 21 17 13 1.6 (0.8 to 3.3) 0.6 (0.4 to 1.7) 154,000 (60,000 to )
Cohort PRISM 1 to 21 18 97 1.3 (0.8 to 2.1) 0.4 (0.4 to 1.4) 272,000 (70,000 to )
Post hoc
SCRI PRISM 1 to 7 11 13 3.0 (1.4 to 6.8) 0.7 (0.2 to 1.6) 135,000 (63,000 to 540,000)
SCRI PRISM 1 to 21 17 13 1.5 (0.7 to 3.1) 0.6 (0.4 to 1.6) 174,000 (62,000 to )
Cohort Tate 1 to 21 18 97 1.3 (0.8 to 2.1) 0.4 (0.4 to 1.4) 273,000 (70,000 to )

* Cases of intussusception were adjudicated with the use of Brighton Collaboration criteria,26 with level 1 cases considered as confirmed
cases. We used two study designs: a self-controlled risk-interval (SCRI) design and a cohort design.
In prespecified analyses, we adjusted for age in the SCRI design using age-specific background rates extracted by Tate et al.25 from the U.S.
hospital-discharge data of the Healthcare Cost and Utilization Project for 11 years during which no rotavirus vaccine was used, and we adjust-
ed for age in the cohort design using a quadratic risk function drawn from the unexposed person-time. In addition to the prespecified analy-
ses, we performed post hoc analyses in which we used alternative methods for age adjustment to ensure that the findings were robust; for
the SCRI design, we used the quadratic risk function as the alternative, and for the cohort design, we used the rates from Tate et al.25
The control window for the SCRI design was 22 to 42 days after vaccination; the control period for the cohort design was all person-time
except for 0 to 21 days after any rotavirus vaccination (194,520,053 person-days).
A correction factor was incorporated for cases for which medical charts were missing (which accounted for 22% of the total potential cas-
es ascertained). The number of doses resulting in one excess case (last column) is obtained by taking the reciprocal of the attributable
risk expressed in terms of excess cases per 100,000 doses (penultimate column). Dashes are substituted for negative numbers of doses,
since a negative number of doses resulting in an excess case would not be interpretable. In the confidence intervals for number of doses,
the first (lower) number represents the highest risk, and the second (higher or blank) number represents the lowest risk.
The numbers of exposed person-days were 10,931,848 for dose 1; 9,263,327 for dose 2; 6,889,428 for dose 3; and 27,094,157 for all doses.
One of these cases was excluded from SCRI analysis because the age at vaccination plus the required 42-day follow-up period exceeded
the cutoff age for chart review.
** Relative risk estimates for the analyses of all doses represent a blend of the risks of the component doses. Attributable risk estimates for
the analyses of all doses are per 100,000 doses, so the total attributable risk for 100,000 fully vaccinated infants is larger.

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 The n e w e ng l a n d j o u r na l of m e dic i n e

Table 2. Case Counts and Risk Estimates for Confirmed Intussusception after RV1.*

Dose, Type Age- Days after No. of Cases No. of Cases Attributable Risk/ No. of Doses Resulting
of Analysis, Adjustment Vaccination in Risk in Control Relative Risk 100,000 Doses in One Excess Case
and Design Method in Risk Window Window Window (95% CI) (95% CI) (95% CI)
Dose 1
Prespecified
SCRI Tate 1 to 7 1 0 2.4 42,000
SCRI Tate 1 to 21 1 0 2.4 42,000
Cohort PRISM 1 to 21 1 97 2.9 (0.4 to 21.8) 1.6 (0.6 to 10.4) 63,000 (10,000 to )
Post hoc
SCRI PRISM 1 to 7 1 0 2.4 42,000
SCRI PRISM 1 to 21 1 0 2.4 42,000
Cohort Tate 1 to 21 1 97 3.2 (0.4 to 22.9) 1.6 (0.5 to 10.4) 61,000 (6000 to )
Dose 2
Prespecified
SCRI Tate 1 to 7 2 2 3.5 (0.5 to 25.1) 4.3 (1.8 to 17.8) 23,000 (6000 to )
SCRI Tate 1 to 21 3 2 1.7 (0.3 to 10.1) 3.7 (10.0 to 19.4) 27,000 (5000 to )
Cohort PRISM 1 to 21 3 97 5.1 (1.6 to 16.4) 7.3 (0.8 to 22.5) 14,000 (4000 to 131,000)
Post hoc
SCRI PRISM 1 to 7 2 2 3.6 (0.5 to 25.3) 4.4 (1.7 to 17.8) 23,000 (6000 to )
SCRI PRISM 1 to 21 3 2 1.7 (0.3 to 10.2) 3.7 (9.8 to 19.5) 27,000 (5000 to )
Cohort Tate 1 to 21 3 97 4.6 (1.5 to 14.7) 7.1 (0.6 to 22.3) 14,000 (4000 to 170,000)
All doses
Prespecified
SCRI Tate 1 to 7 3 2 5.7 (0.9 to 34.2) 3.1 (0.01 to 9.3) 33,000 (11,000 to 13,810,000)
SCRI Tate 1 to 21 4 2 2.3 (0.4 to 12.8) 2.8 (2.9 to 9.9) 35,000 (10,000 to )
Cohort PRISM 1 to 21 4 97 3.8 (1.4 to 10.4) 3.7 (0.3 to 10.5) 27,000 (10,000 to 288,000)
Post hoc
SCRI PRISM 1 to 7 3 2 5.5 (0.9 to 33.0) 3.1 (0.02 to 9.3) 33,000 (11,000 to )
SCRI PRISM 1 to 21 4 2 2.3 (0.4 to 12.6) 2.8 (3.0 to 9.9) 35,000 (10,000 to )
Cohort Tate 1 to 21 4 97 3.7 (1.4 to 10.1) 3.6 (0.3 to 10.5) 28,000 (10,000 to 313,000)

* The criteria for adjudication of cases, the methods of adjustment for age, and the control windows for the SCRI design and the cohort de-
sign were the same as for RV5.
A correction factor was incorporated for cases for which medical charts were missing (which accounted for 22% of the total potential cases
ascertained). The number of doses resulting in one excess case (last column) is obtained by taking the reciprocal of the attributable risk ex-
pressed in terms of excess cases per 100,000 doses (penultimate column). Dashes are substituted for negative numbers of doses, since a
negative number of doses resulting in an excess case would not be interpretable. In the confidence intervals for number of doses, the first
(lower) number represents the highest risk, and the second (higher or blank) number represents the lowest risk.
The numbers of exposed person-days were 1,178,772 for dose 1; 917,754 for dose 2; and 2,242,833 for all doses.
Relative risk estimates for the analyses of all doses represent a blend of the risks of the component doses. Attributable risk estimates for the
analyses of all doses are per 100,000 doses, so the total attributable risk for 100,000 fully vaccinated infants is larger.

cases in the control interval. The attributable risk

RV5 are also shown in Figure 1. In both the SCRI
in the SCRI analysis was not significant for either
and cohort analyses, when the quadratic risk
dose. However, the cohort (secondary) analysis function from the study population was used
instead of the rates from Tate et al.,25 the dose 1
showed a significant attributable risk after dose 2
(7.3 [95% CI, 0.8 to 22.5]) (Table 2). risk estimates were somewhat lower. However,
the attributable risk estimates were quite robust,
Alternative Age Adjustment with the attributable risk point estimates after
Results after alternative adjustment for age are dose 1 of RV5 ranging from 1.1 to 1.5 excess
shown in Tables 1 and 2; results after dose 1 of cases per 100,000 recipients of the first dose of

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 Intussusception Risk after Rotavirus Vaccination

3.5
No. of Excess Cases of Intussusception
per 100,000 First-Dose Recipients 3.0

2.5

2.0

1.5

1.0

0.5

0.0
SCRI, SCRI, SCRI, SCRI, Cohort, Cohort,
original age age adjustment original age age adjustment original age age adjustment
adjustment using study adjustment using study adjustment using Tate et al.
using Tate et al. population using Tate et al. population using study risk curve
risk curve risk function risk curve risk function population
Days 17 Risk Window Days 121 Risk Window

Figure 1. Attributable Risk of Intussusception after the First Dose of RotaTeq (RV5) Rotavirus Vaccine.
The attributable risk of intussusception after dose 1 of the RV5 vaccine, shown as the number of excess cases of in-
tussusception per 100,000 recipients, was calculated for two study designs a self-controlled risk-interval (SCRI)
design and a cohort design with the original age-adjustment method (based on the rates from Tate et al.25 in the
SCRI design and the quadratic risk function from the unexposed person-time in the cohort design) and an alterna-
tive age-adjustment method (based on the quadratic risk function from the unexposed cohort person-time in the
SCRI design and the rates from Tate et al.25 in the cohort design). For dose 1 of RV5, age adjustment with the use of
the quadratic risk function obtained from the study population results in only slightly lower attributable risks than
age adjustment with the use of hospital-discharge data from Tate et al.25

vaccine, regardless of study design, risk window, vaccinees. Subsequent doses of RV5 were not as-
or age-adjustment method. sociated with a significant increase in the risk of
intussusception. However, an increased risk as-
Clusters of Intussusception Onset sociated with those doses cannot be ruled out,
In the analyses of dose 1 and of all doses of RV5, given the overlapping confidence intervals of the
the temporal scan statistic showed a significant risk estimates for doses 1, 2, and 3. These risks
cluster of onset of intussusception 3 to 7 days must be considered in the context of the benefits
after vaccination (P=0.008 for dose 1; P=0.004 of vaccination, which include the prevention of a
for all doses). There was only a single case of in- projected 53,444 hospitalizations (95% CI, 37,622
tussusception after dose 1 of RV1; therefore, to 72,882) in a U.S. birth cohort of 4.3 million
there were insufficient data for the analysis of children.30
clusters of onset after dose 1. For all doses of Our results with respect to RV5 are similar to
RV1, there was a significant cluster on day 4 after those of the Vaccine Adverse Event Reporting
vaccination (P<0.001) (Fig. 2). System (VAERS), which used an SCRI design to
compare the numbers of spontaneously reported
Discussion cases in the 3-to-6-day period after vaccination
with those in the 0-to-2-day period after vaccina-
After the first dose of RV5, with a risk window of tion. That study showed an attributable risk of
21 days after vaccination, we found a significant 0.74 excess cases (95% CI, 0.24 to 1.71) per
increase in the risk of intussusception, with ap- 100,000 recipients of the first dose of vaccine
proximately 1.5 excess cases per 100,000 recipi- and no significant results for the other doses.31
ents of the vaccine, which was approximately one In contrast, the population-based Vaccine Safety
tenth the risk with Rotashield.1 The lower bound- Datalink (VSD) has not shown a significant in-
ary of the 95% confidence interval (representing crease in the risk of intussusception after
the higher-risk boundary) was 1 case per 31,000 RV5.14,15 The VSD, which used a cohort design

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 The n e w e ng l a n d j o u r na l of m e dic i n e

with a similar number of doses administered,

A RV5, Dose 1
the PRISM program reported a relative risk of
3
Dose 1 9.1 (95% CI, 2.2 to 38.6) for that dose and risk
5/11 cases
No. of Intussusception Cases

Relative risk, 9.7 window (Table 1). These results are not neces-
P=0.008
sarily inconsistent, because the confidence inter-
2
vals overlap. Recently published results from
Australia confirm earlier findings there10 of an
association between rotavirus vaccines and intus-
1 susception. Using a self-controlled case-series
design, investigators found a relative incidence
of intussusception of 9.9 (95% CI, 3.7 to 26.4)
0 with a 7-day risk window after dose 1 of RV5 (a
1 3 5 7 9 11 13 15 17 19 21 23 25 27 29 31 33 35 37 39 41
finding similar to the relative risk in the PRISM
Days after Vaccination
program), with smaller but also significantly
B RV5, All Doses increased risks for the 8-to-21-day risk window
3
after dose 1 and for the 7-day risk window after
Dose 3
10/30 cases dose 2.33
Dose 2
No. of Intussusception Cases

Relative risk, 4.5 The number of RV1 doses administered was

P=0.004 Dose 1
an order of magnitude lower than the number of
2
RV5 doses. As a result, the confidence intervals
around the risk estimates for RV1 were wider
than those for RV5. None of the attributable
1
risks from the SCRI (primary) analyses were
significant for RV1. However, the significant at-
tributable risk from the cohort (secondary) anal-
0 ysis of the incidence of intussusception after
1 3 5 7 9 11 13 15 17 19 21 23 25 27 29 31 33 35 37 39 41
dose 2 suggests some increase in risk, an obser-
Days after Vaccination
vation that is consistent with findings in Mexico
C RV1, All Doses and Brazil,11 Australia,33 and the United States.32
3 The relatively small number of children who re-
Dose 2
3/6 cases ceived RV1 makes for imprecise risk estimates
Dose 1
No. of Intussusception Cases

Relative risk, 48 and precludes accurate comparisons of the safe-

P<0.001
2
1
0 designs or populations; or to some combination
1 3 5 7 9 11 13 15 17 19 21 23 25 27 29 31 33 35 37 39 41
Days after Vaccination
Figure 2. Distribution of Intussusception Cases According to Day of Symp-
tom Onset after Vaccination.
The age-adjusted temporal scan statistic showed significant clustering on
days 3 to 7 after the first dose (Panel A) and after all doses (Panel B) of
RV5 and on day 4 after all doses of Rotarix (RV1) (Panel C).
and ICD-9coded visits without chart confirma-
tion, recently reported a relative risk of 2.63
(95% CI, 0.72 to 6.74) for intussusception after
dose 1, for a 7-day risk window32; in contrast,
ty of RV5 and RV1.
Table S6 in the Supplementary Appendix
summarizes risk estimates from the literature,
for approximately a 7-day risk interval after RV5
and RV1. Variation in point estimates could be
due to chance, especially because of the small
samples in some studies; to differences in study
of these factors.
There are several limitations of our study.
First, we were unable to obtain medical records
to validate the diagnosis for 22% of the potential
cases initially ascertained. However, our finding
of a significant increase in risk in the 7 days
after dose 1 of RV5 was quite robust when sub-
jected to various assumptions about which cases
would have been confirmed if the medical
records had been available (see the Supplemen-
tary Appendix). Also, all estimates of attributable
risk were adjusted for the unobtainable charts.

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 Intussusception Risk after Rotavirus Vaccination

Second, the statistical power was low for the
analysis of RV1 and was also an issue with re-
spect to the analysis of RV5. The missing charts
reduced the power and precision of the study,
affecting especially the self-controlled effect es-
timates and confidence intervals. A strength of
the study is the generally consistent results ob-
tained from two complementary designs and
from sensitivity analyses. In particular, the esti-
mates of attributable risk with respect to both
vaccines were robust with respect to alternative
age adjustments.
In conclusion, using two complementary ana-
lytic designs, we found evidence of an associa-
tion between RV5 and intussusception. The risk
was highest in the 3-to-7-day period after the
first dose. The estimated risk associated with
dose 1 of RV5 was about 1.5 excess cases per
100,000 recipients of the first dose of the
vaccine, which was roughly one tenth the risk
associated with the first-generation vaccine,
Rotashield. The risks of intussusception must be
considered in light of the demonstrated benefits
of rotavirus vaccination.
Supported by funding from the Food and Drug Administra-
tion, 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.
We thank Jacqueline Tate for supplying her data for the main
age adjustment; Ed Belongia for early guidance and adjudica-
tion; Michael Silverman for adjudication; Ruihua Yin for pro-
gramming the statistical analyses; and the following people
from the Mini-Sentinel program and the participating health
plans: Carolyn Balsbaugh, David Cole, Claudia Coronel-Moreno,
Lingling Li, Linda Pointon, Megan Reidy, Robert Rosofsky, and
Diana Santiago (Mini-Sentinel Operations Center); Carolyn Jevit,
Carolyn Neff, and Yihai Liu (Aetna); Chunfu Liu, Tosmai Puen-
patom, Marcus Wilson, and Amanda Rodriguez (HealthCore);
and Vinit Nair, Tom Stacey, and Qianli Ma (Humana).

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