Rotavirus Vaccine and

Intussusception Hospitalizations
Emmanuel B. Walter, MD, MPH,a Mary Allen Staat, MD, MPHb

There are 2 US Food and Drug

Administrationapproved vaccines
for the prevention of rotavirus
gastroenteritis in infants. Rotarix is a
live, oral, monovalent rotavirus vaccine
(RV1) administered as a 2-dose series,
and RotaTeq is a live, oral, pentavalent
rotavirus vaccine (RV5) administered
as a 3-dose series. RV1 and RV5 are
typically administered along with other
routinely recommended vaccines at the
2- and 4-month well-child visits, with
the third dose of RV5 administered at
the 6-month visit. Because a previously
licensed rotavirus vaccine, RotaShield,
was associated with an increased risk
of intussusception, prelicensure safety
studies of >60000 children for both
RV1 and RV5 were conducted to assess
for the occurrence of intussusception.1,2
Although these studies showed no
increased risk of intussusception,
subsequent postmarketing studies
have demonstrated small increased
risks of intussusception for both
vaccines, primarily after first doses
and, to a lesser extent, after the second
doses.38
In this issue of Pediatrics, Tate and
colleagues compared the years preand postintroduction of rotavirus
vaccines in the United States and
found no significant difference in
intussusception hospitalization rates in
children <12 months of age comparing
the 2 time periods.9 However, in
children 8 to 11 weeks of age, the
age range when the majority of the
first doses of rotavirus vaccines were
given, they found intussusception
hospitalization rates to be significantly
higher in the postlicensure period
compared with the prelicensure
period. Tate et als observation that

an additional 7 to 26 US children aged

8 to 11 weeks may be hospitalized
for intussusception annually is not so
surprising given the findings from the
postmarketing studies. In addition
to those hospitalized cases noted
by Tate et al, there are likely also a
significant number of nonhospitalized
cases that either self-reduce or are
managed nonsurgically in emergency
departments. Thus, on a populationbased level, the effect may be
somewhat larger than Tate et al noted.
Given that 4 million children are born
in the United States annually, with an
individual risk for intussusception
of 1 in 20000 to 1 in 100000 after
rotavirus vaccine, we could expect
between 40 to 200 US children could
have rotavirus vaccinerelated
intussusception each year.10
Although the evidence is building
that there is an increased risk, albeit
uncommon, of intussusception with
the receipt of rotavirus vaccine, the
benefits of the rotavirus vaccination
program have been dramatic. Before
the introduction of RV5 and RV1,
there were between 55000 and
70000 children hospitalized each year
in the United States and >400000
children with outpatient visits due
to rotavirus-related disease.11 In the
years after introduction of rotavirus
vaccines, national rates of rotavirus
detection declined by 58% to 90%.12
More important, serious disease due to
rotavirus resulting in hospitalization
or emergency department visits have
been reduced by 90%.1315 The huge
impact of the US rotavirus vaccine
program far outweighs the small
increased risk of intussusception found
in postlicensure studies.

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PEDIATRICS Volume 138, number 3, September 2016:e20161952

aDuke

Clinical Vaccine Unit, Department of Pediatrics, Duke

University School of Medicine, Durham, North Carolina; and
bDepartment of Pediatrics, University of Cincinnati College
of Medicine, Cincinnati Childrens Hospital Medical Center,
Cincinnati, Ohio

Opinions expressed in these commentaries are

those of the author and not necessarily those of the
American Academy of Pediatrics or its Committees.
DOI: 10.1542/peds.2016-1952
Accepted for publication Jun 20, 2016
Address correspondence to Emmanuel B. Walter,
MD, MPH, Duke Clinical Vaccine Unit, 2608 Erwin Rd,
Suite 210, Durham, NC 27705. E-mail: walte002@
mc.duke.edu
PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online,
1098-4275).
Copyright 2016 by the American Academy of
Pediatrics
FINANCIAL DISCLOSURE: Dr Walter has received
funding from GlaxoSmithKline, Merck, Novartis,
Novavax, and Pzer to conduct clinical research
studies. He has received support from Novartis as
a member of a Data Safety Monitoring Board and
from Merck as a consultant. Dr Staat has indicated
she has no nancial relationships relevant to this
article to disclose.
FUNDING: No external funding.
POTENTIAL CONFLICT OF INTEREST: Dr Walter has
received funding from GlaxoSmithKline, Merck,
Novartis, Novavax, and Pzer to conduct clinical
research studies. He has received support from
Novartis as a member of a Data Safety Monitoring
Board and from Merck as a consultant. Dr Staat
has indicated she has no nancial relationships
relevant to this article to disclose.
To cite: Walter EB and Staat MA. Rotavirus Vaccine
and Intussusception Hospitalizations. Pediatrics.
2016;138(3):e20161952

COMMENTARY

Although the risk of rotavirus

vaccineassociated intussusception
is low, it is still important that we
learn more about the mechanisms
through which rotavirus vaccines
increase the risk for intussusception.
To date, this is still unclear. Possible
mechanisms include theories that a
gastrointestinal infection may lead
to enlargement of the Peyer patches
in the terminal ileum, which in turn
acts as a lead point for the occurrence
of intussusception, and that there
are alterations in the motility of
the intestine that contribute to the
risk of intussusception. However,
it is not understood whether the
live, attenuated rotavirus vaccines
cause this to happen and, if this does
occur, why it occurs only in some
children. Currently, the Center for
Disease Control and Preventions
Clinical Immunization Safety
Assessment Project is undertaking
a pilot study to further elucidate
mechanisms underlying rotavirus
vaccineinduced intussusception
by examining anatomic and motility

changes in young infants after

the first dose of rotavirus vaccine
(ClinicalTrials.gov; identifier
NCT02542462). By increasing our
knowledge about intussusception,
we may be able to better understand
the intriguing age-related findings
in this study where there were no
differences in the overall rate of
intussusception hospitalizations
for children <12 months of age
pre- and postlicensure. A possible
explanation could be due to a
shift in intussusception events for
certain susceptible children that is
induced by rotavirus vaccine and
a lower rate of intussusception in
older children due to the prevention
of wild-type rotavirus-associated
intussusception. It will be important
to better understand the role of
rotavirus and rotavirus vaccines
and intussusception with increased
uptake of rotavirus vaccines around
the world, especially when diagnosis
and management of intussusception
will be more challenging in resourcepoor countries.

When discussing rotavirus vaccine

with parents, pediatricians
should acknowledge and discuss
any potential risks, including
intussusception, noting that the
risk is low but can be serious
when it occurs. The discussion
should be couched in terms that,
independent of rotavirus vaccination,
intussusception is the most common
abdominal emergency in children
younger than 2 years of age, and
parents should be advised to seek
urgent medical care for symptoms
and signs where the diagnosis is
suspect.16 While acknowledging
vaccination risks, it is paramount
as pediatricians that we also
communicate to parents and families
the enormous benefits of rotavirus
vaccination in preventing rotavirus
disease in the United States.

ABBREVIATIONS
RV1:monovalent rotavirus vaccine
RV5:pentavalent rotavirus vaccine

COMPANION PAPER: A companion to this article can be found online at www.pediatrics.org/cgi/doi/10.1542/peds.2016-1082.

REFERENCES
1. Ruiz-Palacios GM, Prez-Schael
I, Velzquez FR, et al; Human
Rotavirus Vaccine Study Group.
Safety and efcacy of an attenuated
vaccine against severe rotavirus
gastroenteritis. N Engl J Med.
2006;354(1):1122
2. Vesikari T, Matson DO, Dennehy P,
et al; Rotavirus Efcacy and Safety Trial
(REST) Study Team. Safety and efcacy
of a pentavalent human-bovine (WC3)
reassortant rotavirus vaccine. N Engl J
Med. 2006;354(1):2333
3. Carlin JB, Macartney KK, Lee KJ,
et al. Intussusception risk and disease
prevention associated with rotavirus
vaccines in Australias National
Immunization Program. Clin Infect Dis.
2013;57(10):14271434
4. Haber P, Parashar UD, Haber M,
DeStefano F. Intussusception after
monovalent rotavirus vaccineUnited

States, Vaccine Adverse Event

Reporting System (VAERS), 20082014.
Vaccine. 2015;33(38):48734877
5. Haber P, Patel M, Pan Y, et al.
Intussusception after rotavirus
vaccines reported to US
VAERS, 20062012. Pediatrics.
2013;131(6):10421049
6. Patel MM, Lpez-Collada VR, Bulhes
MM, et al. Intussusception risk and
health benets of rotavirus vaccination
in Mexico and Brazil. N Engl J Med.
2011;364(24):22832292
7. Weintraub ES, Baggs J, Duffy J,
et al. Risk of intussusception after
monovalent rotavirus vaccination.
N Engl J Med. 2014;370(6):513519
8. Yih WK, Lieu TA, Kulldorff M, et al.
Intussusception risk after rotavirus
vaccination in U.S. infants. N Engl J
Med. 2014;370(6):503512

Downloaded from by guest on September 3, 2016

9. Tate JE, Yen C, Steiner CA, Cortese

MM, Parashar UD. Intussusception
hospitalizations pre and post-rotavirus
vaccine introduction in the US, 2000.
Pediatrics. 2016;138(3):e20161082
10. Parashar UD, Cortese MM, Payne DC,
Lopman B, Yen C, Tate JE. Value of postlicensure data on benets and risks of
vaccination to inform vaccine policy:
the example of rotavirus vaccines.
Vaccine. 2015;33(suppl 4):D55D59
11. Tate JE, Cortese MM, Payne DC, et al.
Uptake, impact, and effectiveness of
rotavirus vaccination in the United
States: review of the rst 3 years of
postlicensure data. Pediatr Infect Dis J.
2011;30(suppl 1):S56S60
12. Aliabadi N, Tate JE, Haynes AK,
Parashar UD; Centers for Disease
Control and Prevention. Sustained
decrease in laboratory detection of
rotavirus after implementation of

WALTER and STAAT

routine vaccinationUnited States,

20002014. MMWR Morb Mortal Wkly
Rep. 2015;64(13):337342
13. Donauer S, Payne DC, Edwards KM,
et al. Determining the effectiveness
of the pentavalent rotavirus vaccine
against rotavirus hospitalizations
and emergency department visits
using two study designs. Vaccine.
2013;31(24):26922697

PEDIATRICS Volume 138, number 3, September 2016

14. Leshem E, Moritz RE, Curns AT, et al.

Rotavirus vaccines and health care
utilization for diarrhea in the United
States (20072011). Pediatrics.
2014;134(1):1523
15. Payne DC, Staat MA, Edwards KM,
et al; New Vaccine Surveillance
Network. Direct and indirect effects
of rotavirus vaccination upon
childhood hospitalizations in 3 US

Downloaded from by guest on September 3, 2016

Counties, 20062009. Clin Infect Dis.

2011;53(3):245253
16. Kliegman RM, Stanton BF, St Geme
JW, Schor BF. Ileus, adhesions,
intussusception, and closed-loop
obstructions. In: Kliegman RM,
Behrman RE, Nelson WE, eds.
Nelson Textbook of Pediatrics.,
20th ed. Philadelphia, PA: Elsevier;
2016:18121814

Rotavirus Vaccine and Intussusception Hospitalizations

Emmanuel B. Walter and Mary Allen Staat
Pediatrics 2016;138;; originally published online August 24, 2016;
DOI: 10.1542/peds.2016-1952
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PEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly

publication, it has been published continuously since 1948. PEDIATRICS is owned, published,
and trademarked by the American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk
Grove Village, Illinois, 60007. Copyright 2016 by the American Academy of Pediatrics. All
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Rotavirus Vaccine and Intussusception Hospitalizations

Emmanuel B. Walter and Mary Allen Staat
Pediatrics 2016;138;; originally published online August 24, 2016;
DOI: 10.1542/peds.2016-1952

The online version of this article, along with updated information and services, is
located on the World Wide Web at:
/content/138/3/e20161952.full.html

PEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly

publication, it has been published continuously since 1948. PEDIATRICS is owned,
published, and trademarked by the American Academy of Pediatrics, 141 Northwest Point
Boulevard, Elk Grove Village, Illinois, 60007. Copyright 2016 by the American Academy
of Pediatrics. All rights reserved. Print ISSN: 0031-4005. Online ISSN: 1098-4275.

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