new england

journal of medicine
The

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 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.

From the Department of Population

Medicine, Harvard Medical School and
Harvard Pilgrim Health Care Institute
(W.K.Y., T.A.L., M.K., R.P., G.M.L.), and
the Division of Infectious Diseases and
Department of Laboratory Medicine, Boston Childrens Hospital (G.M.L.) all in
Boston; the Division of Research, Kaiser
Permanente Northern California, Oakland
(T.A.L.); the Center for Biologics Evaluation and Research, Food and Drug Administration, Rockville, MD (D.M., M.N.);
Aetna, Blue Bell, PA (C.N.M.-W.); Government and Academic Research, HealthCore,
Alexandria, VA (N.S.); and Comprehensive
Health Insights, Humana, Louisville, KY
(M.S.). Address reprint requests to Dr. Yih
at the Department of Population Medicine,
Harvard Medical School and Harvard Pilgrim Health Care Institute, 133 Brookline
Ave., 6th Fl., Boston, MA 02215, or at
katherine_yih@harvardpilgrim.org.
This article was published on January 14,
2014, at NEJM.org.
N Engl J Med 2014;370:503-12.
DOI: 10.1056/NEJMoa1303164
Copyright 2014 Massachusetts Medical Society.

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.)

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n 1999, a tetravalent rhesushuman

reassortant rotavirus vaccine (RotaShield,
Wyeth Lederle) was voluntarily withdrawn
from the U.S. market within a year after licensure owing to an association with intussusception. The excess risk of intussusception was estimated at approximately 1 to 2 cases per 10,000
recipients of the vaccine.1 In 2006 and 2008, respectively, a pentavalent bovinehuman reassortant
rotavirus vaccine (RV5; RotaTeq, Merck) and a
monovalent human rotavirus vaccine (RV1; Rotarix, GlaxoSmithKline) were licensed after evaluation in clinical trials involving more than
60,000 infants, which provided enough statistical power to allow detection of an intussusception risk of a magnitude similar to that after vaccination with RotaShield. In countries adopting
these newer rotavirus vaccines, the burden of
rotavirus gastroenteritis and severe childhood
diarrhea has been substantially reduced.2-9
After licensure, studies conducted outside the
United States began to point to an association of
RV5 and RV1 with intussusception, although the
risks were much lower than those seen with
RotaShield.10-12 Until quite recently, U.S. post
licensure studies of the safety of RV5 had not
shown a significant increase in the risk of intussusception.13-16 However, a small increase in risk
could not be ruled out.13,15 RV1 has been used
less commonly in the United States, and no adequately powered U.S. postlicensure studies of
the safety of this vaccine have been published.
Owing to the emerging international evidence
of an association with intussusception10-12 and
concerns about the lack of statistical power in
the U.S.-based studies that had been conducted,
the Center for Biologics Evaluation and Research
of the Food and Drug Administration (FDA) initiated the current study of RV5 and RV1 in the
Post-Licensure Rapid Immunization Safety Monitoring (PRISM) program,17 a component of the
Mini-Sentinel pilot program that was developed
to conduct active surveillance of the safety of
medical products.18

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mended ages for vaccination plus adequate follow-up time) who were members of an Aetna,
HealthCore, or Humana health plan between
January 2004 and September 2011. Using a distributed database system,19,20 each of these data
partners provided at least 3 consecutive years of
claims and other administrative data during this
period, resulting in approximately 613,000 infant-years observed.
Study Design

We used both a self-controlled risk-interval (SCRI)

design21-24 and a cohort design. A major advantage of the former, which was prespecified as the
primary design, is that it inherently controls for
all fixed potential confounders such as sex, race
or ethnic group, and chronic predisposing conditions. Another advantage is that it uses data only
from exposed children, thus minimizing potential misclassification bias due to incomplete data
on vaccine exposure. The cohort design has higher statistical power than the SCRI design, owing
to the relatively large amount of historical and
concurrent unexposed person-time used in the
generation of expected case counts. However, the
ability to control for confounding is not as good
with this design as with the SCRI design. The
cohort design may also be subject to bias toward
the null owing to misclassification of exposure if
some vaccinations are missed. A major challenge
in studying rotavirus vaccines and intussusception is the strong confounding effect of age,
since both vaccination and the risk of intussusception are age-dependent. The recommended
ages for vaccination are 2, 4, and 6 months for
RV5 and 2 and 4 months for RV1, and the incidence of hospitalizations for intussusception in
the United States steadily increases from 2 cases
per 100,000 person-years at birth to a peak of 62
cases per 100,000 person-years at 26 to 29 weeks
of age, subsequently falling to 26 cases per
100,000 person-years by 52 weeks of age.25
Vaccine Exposures

Vaccination with RV5 and with RV1 was initially

identified in administrative data on the basis of
Me thods
Current Procedural Terminology (CPT) codes
Study Population
90680 and 90681, respectively. We sought mediThe 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

504

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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 electronic data.

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.

Outcomes

Potential cases of intussusception during all person-time from 5.0 to 36.9 weeks of age, irrespective of immunization status, were identified in
administrative data on the basis of any of three
codes in either the inpatient or emergency department setting: International Classification of Diseases,
Ninth Revision (ICD-9) code 560.0 (intussusception) 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 fulltext 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 vaccination 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 representing 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 [ultrasonography, 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

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 interval 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 intussusception that occurred within 42 days after
vaccination were included. We used logistic regression, with an offset term to adjust for the
differential risk of intussusception according to
age in the risk and control intervals. For the offset term, we used age-specific background rates
extracted by Tate et al. 25 from the U.S. hospitaldischarge data of the Healthcare Cost and Utilization Project (HCUP) for 11 years during which
no rotavirus vaccine was used (with data provided 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 secondary 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 infants, 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 contrast 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 interaction 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.

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Since the risk of intussusception varies greatly 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 intervals using the methods of Krishnamoorthy
and Lee27 (see the Supplementary Appendix, available with the full text of this article at NEJM.org).
We emphasize attributable risk over relativerisk estimates in the results, because attributable 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 comparing our results reported only relative risks
or because comparing attributable risks across
countries with different background rates of intussusception 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 vaccination, 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 evaluated all potential risk windows starting 1 to 14
days after vaccination and ending 1 to 21 days
after vaccination, with adjustment for the multiple testing inherent in the 203 intervals considered. 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 in506

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tussusception according to the age-dependent

incidence curve, in order to obtain the distribution of the test statistic under the null hypothesis. 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 interval. 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 administered was very similar across the data partners
in the study. The results of the chart review regarding 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 electronic 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 intussusception after dose 1 was significantly elevated
for both risk windows (1.1 [95% confidence interval {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 significant 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 intussusception in the risk interval, and there were no

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Intussusception Risk after Rotavirus Vaccination

Table 1. Case Counts and Risk Estimates for Confirmed Intussusception after RV5.*
Dose, Type
AgeDays after No. of Cases No. of Cases
of Analysis,
Adjustment Vaccination
in Risk
in Control
and Design
Method in Risk Window Window
Window
Dose 1
Prespecified
SCRI
Tate
1 to 7
5
3
SCRI
Tate
1 to 21
8
3
Cohort
PRISM
1 to 21
8
97
Post hoc
SCRI
PRISM
1 to 7
5
3
SCRI
PRISM
1 to 21
8
3
Cohort
Tate
1 to 21
8
97
Dose 2
Prespecified
SCRI
Tate
1 to 7
3
6
SCRI
Tate
1 to 21
5
6
Cohort
PRISM
1 to 21
5
97
Post hoc
SCRI
PRISM
1 to 7
3
6
SCRI
PRISM
1 to 21
5
6
Cohort
Tate
1 to 21
5
97
Dose 3
Prespecified
SCRI
Tate
1 to 7
3
4
SCRI
Tate
1 to 21
4
4
Cohort
PRISM
1 to 21
5
97
Post hoc
SCRI
PRISM
1 to 7
3
4
SCRI
PRISM
1 to 21
4
4
Cohort
Tate
1 to 21
5
97
All doses**
Prespecified
SCRI
Tate
1 to 7
11
13
SCRI
Tate
1 to 21
17
13
Cohort
PRISM
1 to 21
18
97
Post hoc
SCRI
PRISM
1 to 7
11
13
SCRI
PRISM
1 to 21
17
13
Cohort
Tate
1 to 21
18
97

Relative Risk
(95% CI)

Attributable Risk/
100,000 Doses
(95% CI)

No. of Doses Resulting

in One Excess Case
(95% CI)

9.1 (2.2 to 38.6)

4.2 (1.1 to 16.0)
2.6 (1.2 to 5.8)

1.1 (0.3 to 2.7)

1.5 (0.2 to 3.2)
1.2 (0.2 to 3.2)

89,000 (37,000 to 307,000)

65,000 (31,000 to 519,000)
80,000 (31,000 to 434,000)

7.0 (1.7 to 29.2)

3.4 (0.9 to 13.0)
2.9 (1.4 to 6.0)

1.1 (0.3 to 2.6)

92,000 (38,000 to 376,000)
1.4 (0.01 to 3.1)
70,000 (32,000 to )
1.3 (0.3 to 3.3)
75,000 (30,000 to 316,000)

1.8 (0.4 to 7.2)

1.0 (0.3 to 3.1)
0.9 (0.4 to 2.2)

0.4 (0.3 to 1.9)

0.1 (1.8 to 1.8)
0.2 (1.1 to 1.8)

256,000 (52,000 to )
(57,000 to )
(57,000 to )

1.8 (0.4 to 7.2)

1.0 (0.3 to 3.1)
0.8 (0.3 to 2.0)

0.4 (0.3 to 1.9)

0.1 (1.8 to 1.8)
0.3 (1.2 to 1.6)

258,000 (52,000 to )
(57,000 to )
(62,000 to )

2.2 (0.5 to 9.7)

0.6 (0.4 to 2.6)
1.0 (0.2 to 3.9) 0.05 (2.3 to 2.1)
0.9 (0.3 to 2.2) 0.3 (1.5 to 2.3)

159,000 (38,000 to )
(47,000 to )
(43,000 to )

2.3 (0.5 to 10.2) 0.7 (0.3 to 2.7)

1.0 (0.2 to 4.0) 0.01 (2.1 to 2.2)
0.9 (0.4 to 2.2) 0.2 (1.4 to 2.4)

152,000 (38,000 to )
10,402,000 (46,000 to )
(42,000 to )

3.3 (1.5 to 7.4)

1.6 (0.8 to 3.3)
1.3 (0.8 to 2.1)

0.8 (0.2 to 1.6) 131,000 (63,000 to 497,000)

0.6 (0.4 to 1.7)
154,000 (60,000 to )
0.4 (0.4 to 1.4)
272,000 (70,000 to )

3.0 (1.4 to 6.8)

1.5 (0.7 to 3.1)
1.3 (0.8 to 2.1)

0.7 (0.2 to 1.6) 135,000 (63,000 to 540,000)

0.6 (0.4 to 1.6)
174,000 (62,000 to )
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 adjusted for age in the cohort design using a quadratic risk function drawn from the unexposed person-time. In addition to the prespecified analyses, 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 cases 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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Table 2. Case Counts and Risk Estimates for Confirmed Intussusception after RV1.*
Dose, Type
of Analysis,
and Design

AgeDays after
No. of Cases No. of Cases
Adjustment Vaccination
in Risk
in Control
Method in Risk Window Window
Window

Relative Risk
(95% CI)

Attributable Risk/
100,000 Doses
(95% CI)

2.4

2.4

No. of Doses Resulting

in One Excess Case
(95% CI)

Dose 1
Prespecified
SCRI
SCRI
Cohort

Tate

1 to 7

Tate

1 to 21

PRISM

1 to 21

97

2.9 (0.4 to 21.8) 1.6 (0.6 to 10.4)

42,000
42,000
63,000 (10,000 to )

Post hoc
SCRI

PRISM

1 to 7

2.4

SCRI

PRISM

1 to 21

2.4

Tate

1 to 21

97

3.2 (0.4 to 22.9) 1.6 (0.5 to 10.4)

61,000 (6000 to )

Tate

1 to 7

3.5 (0.5 to 25.1) 4.3 (1.8 to 17.8)

23,000 (6000 to )

Tate

1 to 21

1.7 (0.3 to 10.1) 3.7 (10.0 to 19.4)

PRISM

1 to 21

97

5.1 (1.6 to 16.4) 7.3 (0.8 to 22.5)

14,000 (4000 to 131,000)

23,000 (6000 to )

Cohort

42,000
42,000

Dose 2
Prespecified
SCRI
SCRI
Cohort

27,000 (5000 to )

Post hoc
SCRI

PRISM

1 to 7

3.6 (0.5 to 25.3) 4.4 (1.7 to 17.8)

SCRI

PRISM

1 to 21

1.7 (0.3 to 10.2) 3.7 (9.8 to 19.5)

27,000 (5000 to )

Tate

1 to 21

97

4.6 (1.5 to 14.7) 7.1 (0.6 to 22.3)

14,000 (4000 to 170,000)

Tate

1 to 7

5.7 (0.9 to 34.2) 3.1 (0.01 to 9.3) 33,000 (11,000 to 13,810,000)

Tate

1 to 21

2.3 (0.4 to 12.8) 2.8 (2.9 to 9.9)

35,000 (10,000 to )

PRISM

1 to 21

97

3.8 (1.4 to 10.4) 3.7 (0.3 to 10.5)

27,000 (10,000 to 288,000)

33,000 (11,000 to )

Cohort
All doses
Prespecified
SCRI
SCRI
Cohort
Post hoc
SCRI

PRISM

1 to 7

5.5 (0.9 to 33.0) 3.1 (0.02 to 9.3)

SCRI

PRISM

1 to 21

2.3 (0.4 to 12.6) 2.8 (3.0 to 9.9)

35,000 (10,000 to )

Tate

1 to 21

97

3.7 (1.4 to 10.1) 3.6 (0.3 to 10.5)

28,000 (10,000 to 313,000)

Cohort

* The criteria for adjudication of cases, the methods of adjustment for age, and the control windows for the SCRI design and the cohort design 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 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 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

in the SCRI analysis was not significant for either
dose. However, the cohort (secondary) analysis
showed a significant attributable risk after dose 2
(7.3 [95% CI, 0.8 to 22.5]) (Table 2).

RV5 are also shown in Figure 1. In both the SCRI

and cohort analyses, when the quadratic risk
function from the study population was used
instead of the rates from Tate et al.,25 the dose 1
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
508

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Intussusception Risk after Rotavirus Vaccination

No. of Excess Cases of Intussusception

per 100,000 First-Dose Recipients

3.5
3.0
2.5
2.0
1.5
1.0
0.5
0.0

SCRI,
original age
adjustment
using Tate et al.
risk curve

SCRI,
age adjustment
using study
population
risk function

Days 17 Risk Window

SCRI,
original age
adjustment
using Tate et al.
risk curve

SCRI,
age adjustment
using study
population
risk function

Cohort,
original age
adjustment
using study
population

Cohort,
age adjustment
using Tate et al.
risk curve

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 intussusception 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 alternative 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 associated with a significant increase in the risk of
or age-adjustment method.
intussusception. However, an increased risk associated with those doses cannot be ruled out,
Clusters of Intussusception Onset
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
Our results with respect to RV5 are similar to
clusters of onset after dose 1. For all doses of
RV1, there was a significant cluster on day 4 after those of the Vaccine Adverse Event Reporting
System (VAERS), which used an SCRI design to
vaccination (P<0.001) (Fig. 2).
compare the numbers of spontaneously reported
cases in the 3-to-6-day period after vaccination
Discussion
with those in the 0-to-2-day period after vaccinaAfter 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 inary 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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509

The

n e w e ng l a n d j o u r na l

A RV5, Dose 1
No. of Intussusception Cases

Dose 1

5/11 cases
Relative risk, 9.7
P=0.008
2

1 3 5 7 9 11 13 15 17 19 21 23 25 27 29 31 33 35 37 39 41

Days after Vaccination

B RV5, All Doses

No. of Intussusception Cases

Dose 3

10/30 cases
Relative risk, 4.5
P=0.004

Dose 2
Dose 1

1 3 5 7 9 11 13 15 17 19 21 23 25 27 29 31 33 35 37 39 41

Days after Vaccination

C RV1, All Doses

No. of Intussusception Cases

Dose 2

3/6 cases
Relative risk, 48
P<0.001

Dose 1

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 Symptom 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 confirmation, 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,
510

of

m e dic i n e

with a similar number of doses administered,

the PRISM program reported a relative risk of
9.1 (95% CI, 2.2 to 38.6) for that dose and risk
window (Table 1). These results are not necessarily inconsistent, because the confidence intervals overlap. Recently published results from
Australia confirm earlier findings there10 of an
association between rotavirus vaccines and intussusception. Using a self-controlled case-series
design, investigators found a relative incidence
of intussusception of 9.9 (95% CI, 3.7 to 26.4)
with a 7-day risk window after dose 1 of RV5 (a
finding similar to the relative risk in the PRISM
program), with smaller but also significantly
increased risks for the 8-to-21-day risk window
after dose 1 and for the 7-day risk window after
dose 2.33
The number of RV1 doses administered was
an order of magnitude lower than the number of
RV5 doses. As a result, the confidence intervals
around the risk estimates for RV1 were wider
than those for RV5. None of the attributable
risks from the SCRI (primary) analyses were
significant for RV1. However, the significant attributable risk from the cohort (secondary) analysis of the incidence of intussusception after
dose 2 suggests some increase in risk, an observation that is consistent with findings in Mexico
and Brazil,11 Australia,33 and the United States.32
The relatively small number of children who received RV1 makes for imprecise risk estimates
and precludes accurate comparisons of the safety 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
designs or populations; or to some combination
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 subjected to various assumptions about which cases
would have been confirmed if the medical
records had been available (see the Supplementary 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 respect to the analysis of RV5. The missing charts
reduced the power and precision of the study,
affecting especially the self-controlled effect estimates and confidence intervals. A strength of
the study is the generally consistent results obtained from two complementary designs and
from sensitivity analyses. In particular, the estimates of attributable risk with respect to both
vaccines were robust with respect to alternative
age adjustments.
In conclusion, using two complementary analytic designs, we found evidence of an association 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
References
1. Murphy TV, Gargiullo PM, Massoudi
MS, et al. Intussusception among infants
given an oral rotavirus vaccine. N Engl J
Med 2001;344:564-72.
2. Patel MM, Steele D, Gentsch JR,
Wecker J, Glass RI, Parashar UD. Realworld impact of rotavirus vaccination.
Pediatr Infect Dis J 2011;30:Suppl:S1-S5.
3. Tate JE, Cortese MM, Payne DC, et al.
Uptake, impact, and effectiveness of rotavirus vaccination in the United States: review of the first 3 years of postlicensure
data. Pediatr Infect Dis J 2011;30:Suppl:
S56-S60.
4. Tate JE, Mutuc JD, Panozzo CA, et al.
Sustained decline in rotavirus detections
in the United States following the introduction of rotavirus vaccine in 2006. Pediatr Infect Dis J 2011;30:Suppl:S30-S34.
5. Yen C, Armero Guardado JA, Alberto P,
et al. Decline in rotavirus hospitalizations
and health care visits for childhood diarrhea following rotavirus vaccination in
El Salvador. Pediatr Infect Dis J 2011;30:
Suppl:S6-S10.
6. Quintanar-Solares M, Yen C, Richardson V, Esparza-Aguilar M, Parashar UD,
Patel MM. Impact of rotavirus vaccination
on diarrhea-related hospitalizations among
children <5 years of age in Mexico. Pediatr Infect Dis J 2011;30:Suppl:S11-S15.
7. Molto Y, Cortes JE, De Oliveira LH,
et al. Reduction of diarrhea-associated
hospitalizations among children aged
<5 years in Panama following the introduction of rotavirus vaccine. Pediatr Infect Dis J 2011;30:Suppl:S16-S20.
8. Buttery JP, Lambert SB, Grimwood K,
et al. Reduction in rotavirus-associated
acute gastroenteritis following introduc-

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 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.
We thank Jacqueline Tate for supplying her data for the main
age adjustment; Ed Belongia for early guidance and adjudication; Michael Silverman for adjudication; Ruihua Yin for programming 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 Puenpatom, Marcus Wilson, and Amanda Rodriguez (HealthCore);
and Vinit Nair, Tom Stacey, and Qianli Ma (Humana).

tion of rotavirus vaccine into Australias

National Childhood vaccine schedule. Pediatr Infect Dis J 2011;30:Suppl:S25-S29.
[Erratum, Pediatr Infect Dis J 2011;30:916.]
9. Gastaaduy PA, Snchez-Uribe E,
Esparza-Aguilar M, et al. Effect of rotavirus vaccine on diarrhea mortality in different socioeconomic regions of Mexico.
Pediatrics 2013;131(4):e1115-e1120.
10. Buttery JP, Danchin MH, Lee KJ, et al.
Intussusception following rotavirus vaccine administration: post-marketing surveillance in the National Immunization
Program in Australia. Vaccine 2011;29:
3061-6.
11. Patel MM, Lpez-Collada VR, Bulhes
MM, et al. Intussusception risk and health
benefits of rotavirus vaccination in Mexico
and Brazil. N Engl J Med 2011;364:228392.
12. Velzquez FR, Colindres RE, Grajales C,
et al. Postmarketing surveillance of intussusception following mass introduction
of the attenuated human rotavirus vaccine
in Mexico. Pediatr Infect Dis J 2012;31:
736-44.
13. Haber P, Patel M, Izurieta HS, et al.
Postlicensure monitoring of intussusception after RotaTeq vaccination in the United States, February 1, 2006, to September
25, 2007. Pediatrics 2008;121:1206-12.
14. Belongia EA, Irving SA, Shui IM, et al.
Real-time surveillance to assess risk of
intussusception and other adverse events
after pentavalent, bovine-derived rotavirus
vaccine. Pediatr Infect Dis J 2010;29:1-5.
15. Shui IM, Baggs J, Patel M, et al. Risk
of intussusception following administration of a pentavalent rotavirus vaccine in
US infants. JAMA 2012;307:598-604.

16. Loughlin J, Mast TC, Doherty MC,

Wang FT, Wong J, Seeger JD. Postmarketing evaluation of the short-term safety of
the pentavalent rotavirus vaccine. Pediatr
Infect Dis J 2012;31:292-6.
17. Nguyen M, Ball R, Midthun K, Lieu
TA. The Food and Drug Administrations
Post-Licensure Rapid Immunization Safety
Monitoring program: strengthening the
federal vaccine safety enterprise. Pharmacoepidemiol Drug Saf 2012;21:Suppl 1:
291-7.
18. Platt R, Carnahan RM, Brown JS, et al.
The U.S. Food and Drug Administrations
Mini-Sentinel program: status and direction. Pharmacoepidemiol Drug Saf 2012;
21:Suppl 1:1-8.
19. Maro JC, Platt R, Holmes JH, et al. Design of a national distributed health data
network. Ann Intern Med 2009;151:341-4.
20. Curtis LH, Weiner MG, Boudreau DM,
et al. Design considerations, architecture,
and use of the Mini-Sentinel distributed
data system. Pharmacoepidemiol Drug Saf
2012;21:Suppl 1:23-31.
21. Glanz JM, McClure DL, Xu S, et al.
Four different study designs to evaluate
vaccine safety were equally validated with
contrasting limitations. J Clin Epidemiol
2006;59:808-18.
22. McClure DL, Glanz JM, Xu S, Hambidge SJ, Mullooly JP, Baggs J. Comparison of epidemiologic methods for active
surveillance of vaccine safety. Vaccine
2008;26:3341-5.
23. Kramarz P, DeStefano F, Gargiullo
PM, et al. Does influenza vaccination exacerbate asthma? Analysis of a large cohort of children with asthma. Arch Fam
Med 2000;9:617-23.

n engl j med 370;6nejm.orgfebruary 6, 2014

The New England Journal of Medicine

Downloaded from nejm.org on December 21, 2015. For personal use only. No other uses without permission.
Copyright 2014 Massachusetts Medical Society. All rights reserved.

511

Intussusception Risk after Rotavirus Vaccination

24. Klein NP, Hansen J, Lewis E, et al.

Post-marketing safety evaluation of a tetanus toxoid, reduced diphtheria toxoid and

3-component acellular pertussis vaccine
administered to a cohort of adolescents
in a United States health maintenance
organization. Pediatr Infect Dis J 2010;29:
613-7.
25. Tate JE, Simonsen L, Viboud C, et al.
Trends in intussusception hospitalizations among US infants, 1993-2004: implications for monitoring the safety of the
new rotavirus vaccination program. Pediatrics 2008;121(5):e1125-e1132.
26. 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.

27. Krishnamoorthy K, Lee M. New approximate confidence intervals for the
difference between two Poisson means
and comparison. J Stat Comput Simul
2013;83:2232-43.
28. Kulldorff M. A spatial scan statistic.
Comm Stat Theory Methods 1997;26:148196.
29. SaTScan v7.0: software for the spatial
and space-time scan statistics. Boston:
SaTScan (http://www.satscan.org).
30. Desai R, Cortese MM, Meltzer MI,
et al. Potential intussusception risk versus
benefits of rotavirus vaccination in the
United States. Pediatr Infect Dis J 2013;
32:1-7.

31. Haber P, Patel M, Pan Y, et al. Intus-

susception after rotavirus vaccines reported to US VAERS, 2006-2012. Pediatrics

2013;131:1042-9.
32. Weintraub E. Rotavirus vaccines and
intussusception in the Vaccine Safety Datalink (VSD). Presented to the Advisory Committee on Immunization Practices, Atlanta, June 20, 2013 (http://www.cdc.gov/
vaccines/acip/meetings/downloads/slides
-jun-2013/02-Rotavirus-Weintraub.pdf).
33. Carlin JB, Macartney K, Lee KJ, et al.
Intussusception risk and disease prevention associated with rotavirus vaccines
in Australias national immunization
program. Clin Infect Dis 2013;57:142734.
Copyright 2014 Massachusetts Medical Society.

512

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