The new england

journal of medicine
 Intussusception Risk after
Rotavirus Vaccination in U.S.
Infants February.2014
Background
International 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. 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 for the 7-day risk
window and 1.5 for the 21-day risk
window)
and in the secondary analysis
(attributable risk, 1.2 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
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.
In 1999, a tetravalent rhesus–human
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Wyeth Lederle) was voluntarily withdrawn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 bovine–human 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.
postlicensure 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.
Study Population
The study population consisted of children 5.0
through 36.9 weeks of age (to include the
recommended
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
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
Clusters of Intussusception Onset
In the analyses of dose 1 and of all
doses of RV5,
the temporal scan statistic showed a
significant
cluster of onset of intussusception 3 to
7 days
after vaccination (P = 0.008 for dose 1;
P = 0.004
for all doses). There was only a single
case of intussusception after dose 1 of
Discussion
After the first dose of RV5, with a
risk window of 21 days after
vaccination, we found a significant
increase in the risk of
intussusception, with approximately
1.5 excess cases per 100,000
recipients
of the vaccine, which was
approximately one
Subsequent doses of RV5 were not
associated
with a significant increase in the risk of
intussusception. However, an
increased risk associated
with those doses cannot be ruled out,
given the overlapping confidence
intervals of the
risk estimates for doses 1, 2, and 3.
These risks
must be considered in the context ofthe
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
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
Associated with the first-generation vaccine,
Rotashield. The risks of intussusception