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n engl j med 370;6 nejm.org february 6, 2014 503

The

new englandjournalofmedicineestablished 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 B S T RA C T

From the Department of Population

Medicine, Harvard Medical School andHarvard Pilgrim Health Care Institute(W.K.Y., T.A.L., M.K., R.P., G.M.L.), andthe Division of Infectious Diseases andDepartment of Laboratory Medicine, Bos-ton Childrens Hospital (G.M.L.) all inBoston; the Division of Research, KaiserPermanente Northern California, Oakland(T.A.L.); the Center for Biologics Evalua-tion and Research, Food and Drug Ad-ministration, Rockville, MD (D.M., M.N.);Aetna, Blue Bell, PA (C.N.M.-W.); Govern-ment and Academic Research, HealthCore,Alexandria, VA (N.S.); and ComprehensiveHealth Insights, Humana, Louisville, KY(M.S.). Address reprint requests to Dr. Yihat the Department of Population Medicine,Harvard Medical School and Harvard Pil-grim Health Care Institute, 133 BrooklineAve., 6th Fl., Boston, MA 02215, or [email protected].

This article was published on January 14,2014, at NEJM.org.

N Engl J Med 2014;370:503-12.

DOI: 10.1056/NEJMoa1303164Copyright 2014 Massachusetts Medical Society.

Background

International postlicensure studies have identif ied an increased risk of intussuscep-

tion after vaccination with the second-generation rotavirus vaccines RotaTeq (RV5,a pentavalent vaccine) and Rotarix (RV1, a monovalent vaccine). We studied thisassociation among infants in the United States.

Methods

The study included data from infants 5.0 to 36.9 weeks of age who were enrolled inthree U.S. health plans that participate in the Mini-Sentinel program sponsored bythe Food and Drug Administration. Potential cases of intussusception and vaccineexposures from 2004 through mid-2011 were identified through procedural anddiagnostic codes. Medical records were reviewed to confirm the occurrence of intus-susception and the status with respect to rotavirus vaccination. The primary analy-sis used a self-controlled risk-interval design that included only vaccinated children.The secondary analysis used a cohort design that included exposed and unexposedperson-time.

Results

The analyses included 507,874 first doses and 1,277,556 total doses of RV5 and53,638 first doses and 103,098 total doses of RV1. The statistical power for theanalysis of RV1 was lower than that for the analysis of RV5. The number of excesscases of intussusception per 100,000 recipients of the first dose of RV5 was signifi-cantly elevated, both in the primary analysis (attributable risk, 1.1 [95% confidenceinterval, 0.3 to 2.7] for the 7-day risk window and 1.5 [95% CI, 0.2 to 3.2] for the21-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 seenafter dose 2 or 3. The results with respect to the primary analysis of RV1 were notsignificant, 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 ofRV1 suggested a potential risk, although the study of RV1 was underpowered. Theserisks must be considered in light of the demonstrated benefits of rotavirus vaccina-tion. (Funded by the Food and Drug Administration.)

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.

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Th e n e w e n g l a n d j o u r n a l o f medicine

n engl j med 370;6 nejm.org february 6, 2014504

In 1999, a tetravalent rhesushuman

reassortant rotavirus vaccine (RotaShield,Wyeth Lederle) was voluntarily withdrawn

from the U.S. market within a year after licen-sure owing to an association with intussuscep-tion. The excess risk of intussusception was esti-mated at approximately 1 to 2 cases per 10,000

recipients of the vaccine.1In 2006 and 2008, re-spectively, a pentavalent bovinehuman reassortantrotavirus vaccine (RV5; RotaTeq, Merck) and amonovalent human rotavirus vaccine (RV1; Ro-tarix, GlaxoSmithKline) were licensed after eval-uation in clinical trials involving more than60,000 infants, which provided enough statisti-cal power to allow detection of an intussuscep-tion risk of a magnitude similar to that after vac-cination with RotaShield. In countries adoptingthese newer rotavirus vaccines, the burden ofrotavirus gastroenteritis and severe childhood

diarrhea has been substantially reduced.2-9

After licensure, studies conducted outside theUnited States began to point to an association ofRV5 and RV1 with intussusception, although therisks were much lower than those seen withRotaShield.10-12Until quite recently, U.S. post-licensure studies of the safety of RV5 had notshown a significant increase in the risk of intus-susception.13-16However, a small increase in riskcould not be ruled out.13,15RV1 has been usedless commonly in the United States, and no ad-equately powered U.S. postlicensure studies ofthe safety of this vaccine have been published.

Owing to the emerging international evidenceof an association with intussusception10-12andconcerns about the lack of statistical power inthe U.S.-based studies that had been conducted,the Center for Biologics Evaluation and Researchof the Food and Drug Administration (FDA) ini-tiated the current study of RV5 and RV1 in thePost-Licensure Rapid Immunization Safety Mon-itoring (PRISM) program,17a component of theMini-Sentinel pilot program that was developed

to conduct active surveillance of the safety ofmedical products.18

Methods

Study Population

The study population consisted of children 5.0through 36.9 weeks of age (to include the recom-

mended ages for vaccination plus adequate fol-low-up time) who were members of an Aetna,HealthCore, or Humana health plan betweenJanuary 2004 and September 2011. Using a dis-tributed database system,19,20each of these datapartners provided at least 3 consecutive years ofclaims and other administrative data during this

period, resulting in approximately 613,000 in-fant-years observed.

Study Design

We used both a self-controlled risk-interval (SCRI)design21-24and a cohort design. A major advan-tage of the former, which was prespecified as theprimary design, is that it inherently controls forall f ixed potential confounders such as sex, raceor ethnic group, and chronic predisposing condi-tions. Another advantage is that it uses data onlyfrom exposed children, thus minimizing poten-

tial misclassification bias due to incomplete dataon vaccine exposure. The cohort design has high-er statistical power than the SCRI design, owingto the relatively large amount of historical andconcurrent unexposed person-time used in thegeneration of expected case counts. However, theability to control for confounding is not as goodwith this design as with the SCRI design. Thecohort design may also be subject to bias towardthe null owing to misclassification of exposure ifsome vaccinations are missed. A major challengein studying rotavirus vaccines and intussuscep-tion is the strong confounding effect of age,since both vaccination and the risk of intussus-ception are age-dependent. The recommendedages for vaccination are 2, 4, and 6 months forRV5 and 2 and 4 months for RV1, and the inci-dence of hospitalizations for intussusception inthe United States steadily increases from 2 casesper 100,000 person-years at birth to a peak of 62cases per 100,000 person-years at 26 to 29 weeksof age, subsequently falling to 26 cases per100,000 person-years by 52 weeks of age.25

Vaccine Exposures

Vaccination with RV5 and with RV1 was initiallyidentified in administrative data on the basis ofCurrent Procedural Terminology (CPT) codes90680 and 90681, respectively. We sought medi-cal records to validate vaccine exposure for allinfants with cases of intussusception that were




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Intussusception Risk after Rotavirus Vaccination


determined to be confirmed or possible (seedefinitions below), regardless of whether a recordof 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 inadministrative data on the basis of any of threecodes 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 ofthe appendix, including intussusception) or CPTcode 74283 (therapeutic enema, contrast or air).Only first-ever diagnoses were included.

Case status was determined by adjudicationthat was based on a review of deidentified full-

text medical records. Cases were excluded if nointussusception had been seen or an alternativediagnosis had been made after surgery or air orliquid-contrast enema. Each remaining potentialcase was independently reviewed by one or moreadjudicators; the two main adjudicators werepediatricians, and the third was an internist.

Adjudicators were unaware of the infants vac-cination history and were instructed to classifyintussusception cases with the use of BrightonCollaboration criteria.26Level 1 cases were casesof intussusception confirmed on the basis ofsurgical, radiologic, or autopsy criteria and wereused in the primary analyses. Classificationrules 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 intussusceptionon the basis of positive, equivocal, or discordantresults 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 evidencedby normal radiologic results). Level 2A casescombined with inconclusive cases, for whichthe record stated a diagnosis of intussusceptionbut contained insufficient evidence to allow caseclassification, were classified as possible in-tussusception and were included in sensitivityanalyses. Level 3 is the lowest level of diagnostic

certainty and is defined by the presence of atleast four fairly nonspecific clinical criteria.Level 3 cases were not included in the analysis.All discrepancies in classif ication were resolvedby consensus.

Statistical Analysis

In the SCRI design,21-24we used two alternativerisk intervals, 1 to 7 days after vaccination and1 to 21 days after vaccination, and a control in-terval from day 22 to day 42. We compared thenumber of cases of intussusception in the riskintervals and the control interval after each doseand after all doses combined. Only cases of in-tussusception that occurred within 42 days aftervaccination were included. We used logistic re-gression, with an offset term to adjust for thedifferential risk of intussusception according toage in the risk and control intervals. For the off-

set term, we used age-specific background ratesextracted by Tate et al.25from the U.S. hospital-discharge data of the Healthcare Cost and Utili-zation Project (HCUP) for 11 years during whichno rotavirus vaccine was used (with data provid-ed by J. Tate, personal communication). Theseestimates were based on 3463 cases and thuswere quite precise,25making it preferable to usethese rates rather than a risk function estimatedfrom the study population in the cohort design(described below).

In the cohort design, which was our second-ary approach, exposed person-time was definedas person-time in the 1 to 21 days after rotavirusvaccination. Unexposed person-time includedtime during 5.0 to 36.9 weeks of age amongunvaccinated infants and among vaccinated in-fants, excluding the day of vaccination and the21 days after any dose of any rotavirus vaccine.We used a Poisson regression model that includedadjustment for age with the use of a quadraticrisk function. Data from the study populationitself were used for age adjustment in con-

trast to the method used in the SCRI design with the uncertainty in the age-dependent ratestaken into account by the regression. Calendartime, various age functions, and several interac-tion terms were examined during the building ofthe model. Age, sex, data partner, and exposurestatus were retained as independent covariatesin the final model.




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Since the risk of intussusception varies great-ly by age in weeks, the attributable risk may varyaccording to the age of the child at the time ofvaccination. We present the average attributablerisk on the basis of the observed age distributionof the vaccinated children. The attributable riskwas calculated as the number of excess cases of

intussusception per 100,000 doses administered,according to the formula 100,000 no. of casesin the risk window [1 (1 relative risk)] [no.of vaccine doses C], where C is the proportion ofpotential cases for which we were able to conducta chart review. By including C in the equation,we adjusted the attributable risk for the missingcharts. We calculated the 95% confidence in-tervals using the methods of Krishnamoorthyand 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 andpublic health perspectives and are less sensitiveto differences in the lengths of risk intervals. Incomparing our risk estimates with those ofother studies, we sometimes use relative risks,either because a study with which we are com-paring our results reported only relative risksor because comparing attributable risks acrosscountries with different background rates of in-tussusception can be misleading.

To ensure that our findings were robust, weused alternative methods for age adjustment inpost hoc analyses. For the SCRI design, we usedthe quadratic risk function from the unexposedcohort person-time as the alternative, and forthe cohort design, we used the rates from Tateet al.25 In addition, we conducted a series ofsensitivity analyses, which are described in theSupplementary Appendix.

To identify clusters of intussusception onsetswithin the 1-to-42-day period after rotavirus vac-cination, we used the temporal scan statistic,28

a self-controlled design, with only vaccinatedchildren who had intussusception 1 to 42 daysafter exposure included in the analysis. We evalu-ated all potential risk windows starting 1 to 14days after vaccination and ending 1 to 21 daysafter vaccination, with adjustment for the multi-ple testing inherent in the 203 intervals consid-ered. The test statistic is the maximum likelihoodobtained among these intervals. To adjust forage, we used the HCUP rates from Tate et al.25to randomize the day of age at the onset of in-

tussusception according to the age-dependentincidence curve, in order to obtain the distribu-tion of the test statistic under the null hypothe-sis. For example, for a child receiving the vaccineat 100 days of age, the random case was assigneda day of age in the interval of 101 to 142 days inproportion to the incidence curve in that inter-

val. Analyses were conducted with the use of theSaTScan software.29

Results

Vaccine Doses Administered

The analyses included 1,277,556 doses of RV5, ofwhich 507,874 were first doses, and 103,098 dosesof RV1, of which 53,638 were first doses. Thedistribution of RV5 doses and RV1 doses admin-istered was very similar across the data partnersin the study. The results of the chart review re-

garding the vaccination status of infants withconfirmed cases of intussusception are shown inFigure S1 in the Supplementary Appendix.

Intussusception Cases

Within the targeted age range, 343 potential casesof intussusception were identified in the elec-tronic data. The medical records for 267 of thesecases (78%) were reviewed and classified at thefollowing Brighton or modified Brighton levelsof diagnostic certainty: level 1, 124 cases; level2A, 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-findingalgorithm was thus 46% (124 of 267 cases).Charts for the children with the remaining 76potential cases (22%) were unobtainable.

Risk Estimates

RV5

In the SCRI analysis, the attributable risk of intus-susception after dose 1 was significantly elevatedfor 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 riskwindow). No significant increase in risk was seenafter dose 2 or dose 3. In the cohort analysis(with a 21-day risk interval), there was a signif i-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




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

Dose, Typeof Analysis,and Design

Age-Adjustment

Method

Days afterVaccination

in Risk Window

No. of Casesin Risk

Window

No. of Casesin ControlWindow

Relative Risk(95% CI)

Attributable Risk/100,000 Doses

(95% CI)

No. of Doses Resultingin One Excess Case

(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 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 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 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)


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,26with level 1 cases considered as confirmedcases. 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.25from 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-timeexcept 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 attributablerisk 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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cases in the control interval. The attributable riskin the SCRI analysis was not signif icant for eitherdose. However, the cohort (secondary) analysisshowed a significant attributable risk after dose 2(7.3 [95% CI, 0.8 to 22.5]) (Table 2).

Alternative Age Adjustment

Results after alternative adjustment for age areshown in Tables 1 and 2; results after dose 1 of

RV5 are also shown in Figure 1. In both the SCRIand cohort analyses, when the quadratic riskfunction from the study population was usedinstead of the rates from Tate et al.,25the dose 1risk estimates were somewhat lower. However,the attributable risk estimates were quite robust,with the attributable risk point estimates afterdose 1 of RV5 ranging from 1.1 to 1.5 excesscases per 100,000 recipients of the first dose of

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

Dose, Typeof Analysis,and Design

Age-Adjustment

Method

Days afterVaccination

in Risk Window

No. of Casesin Risk

Window

No. of Casesin ControlWindow

Relative Risk(95% CI)

Attributable Risk/100,000 Doses

(95% CI)

No. of Doses Resultingin One Excess Case

(95% CI)

Dose 1

Prespecified

SCRI Tate 1 to 7 1 0 2.4 42,000SCRI 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)


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 hocSCRI 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 )


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 casesascertained). 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 anegative 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.




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vaccine, regardless of study design, risk window,or age-adjustment method.

Clusters of Intussusception Onset

In the analyses of dose 1 and of all doses of RV5,the temporal scan statistic showed a significantcluster of onset of intussusception 3 to 7 daysafter vaccination (P = 0.008 for dose 1; P = 0.004for all doses). There was only a single case of in-tussusception after dose 1 of RV1; therefore,there were insufficient data for the analysis ofclusters of onset after dose 1. For all doses ofRV1, there was a significant cluster on day 4 aftervaccination (P

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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 afterdose 1, for a 7-day risk window32; in contrast,

with a similar number of doses administered,the PRISM program reported a relative risk of9.1 (95% CI, 2.2 to 38.6) for that dose and riskwindow (Table 1). These results are not neces-sarily inconsistent, because the confidence inter-vals overlap. Recently published results fromAustralia confirm earlier findings there10of an

association between rotavirus vaccines and intus-susception. Using a self-controlled case-seriesdesign, investigators found a relative incidenceof intussusception of 9.9 (95% CI, 3.7 to 26.4)with a 7-day risk window after dose 1 of RV5 (afinding similar to the relative risk in the PRISMprogram), with smaller but also significantlyincreased risks for the 8-to-21-day risk windowafter dose 1 and for the 7-day risk window afterdose 2.33

The number of RV1 doses administered wasan order of magnitude lower than the number of

RV5 doses. As a result, the confidence intervalsaround the risk estimates for RV1 were widerthan those for RV5. None of the attributablerisks from the SCRI (primary) analyses weresignificant for RV1. However, the significant at-tributable risk from the cohort (secondary) anal-ysis of the incidence of intussusception afterdose 2 suggests some increase in risk, an obser-vation that is consistent with findings in Mexicoand Brazil,11Australia,33and the United States.32The relatively small number of children who re-ceived RV1 makes for imprecise risk estimatesand precludes accurate comparisons of the safe-ty of RV5 and RV1.

Table S6 in the Supplementary Appendixsummarizes risk estimates from the literature,for approximately a 7-day risk interval after RV5and RV1. Variation in point estimates could bedue to chance, especially because of the smallsamples in some studies; to differences in studydesigns or populations; or to some combinationof these factors.

There are several limitations of our study.

First, we were unable to obtain medical recordsto validate the diagnosis for 22% of the potentialcases initially ascertained. However, our f indingof a significant increase in risk in the 7 daysafter dose 1 of RV5 was quite robust when sub-jected to various assumptions about which caseswould have been confirmed if the medicalrecords had been available (see the Supplemen-tary Appendix). Also, all estimates of attributablerisk were adjusted for the unobtainable charts.

No.ofIntuss

usceptionCases

3

1

2

01 3 5 7 11 13 15 17 21 23 25 27 319 19 29 33 35 37 4139

Days after Vaccination

B RV5, All Doses

A RV5, Dose 1

Dose 1

No.ofIntussusceptio

nCases

3

1

2

01 3 5 7 11 13 15 17 21 23 25 27 319 19 29 33 35 37 4139


Dose 3

Dose 2

Dose 1

C RV1, All Doses

No.ofIntussusceptionCases

3

1

2

01 3 5 7 11 13 15 17 21 23 25 27 319 19 29 33 35 37 4139


Dose 2

Dose 13/6 casesRelative risk, 48P

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Second, the statistical power was low for theanalysis of RV1 and was also an issue with re-spect to the analysis of RV5. The missing chartsreduced the power and precision of the study,affecting especially the self-controlled effect es-timates and confidence intervals. A strength ofthe study is the generally consistent results ob-

tained from two complementary designs andfrom sensitivity analyses. In particular, the esti-mates of attributable risk with respect to bothvaccines were robust with respect to alternativeage adjustments.

In conclusion, using two complementary ana-lytic designs, we found evidence of an associa-tion between RV5 and intussusception. The riskwas highest in the 3-to-7-day period after thefirst dose. The estimated risk associated withdose 1 of RV5 was about 1.5 excess cases per100,000 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 beconsidered in light of the demonstrated benefitsof 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 interestrelevant to this article was reported.

Disclosure forms provided by the authors are available withthe full text of this article at NEJM.org.

We thank Jacqueline Tate for supplying her data for the mainage adjustment; Ed Belongia for early guidance and adjudica-tion; Michael Silverman for adjudication; Ruihua Yin for pro-gramming the statistical analyses; and the following peoplefrom the Mini-Sentinel program and the participating healthplans: Carolyn Balsbaugh, David Cole, Claudia Coronel-Moreno,Lingling Li, Linda Pointon, Megan Reidy, Robert Rosofsky, andDiana 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).

References

1. Murphy TV, Gargiullo PM, MassoudiMS, et al. Intussusception among infantsgiven an oral rotavirus vaccine. N Engl JMed 2001;344:564-72.2. Patel MM, Steele D, Gentsch JR,Wecker J, Glass RI, Parashar UD. Real-world impact of rotav irus vaccinat ion.Pediatr Infect Dis J 2011;30:Suppl:S1-S5.3. Tate JE, Cortese MM, Payne DC, et al.Uptake, impact, and effectiveness of rota-virus vaccination in the United States: re-view of the f irst 3 years of postlicensuredata. Pediatr Infect Dis J 2011;30:Suppl:S56-S60.4. Tate JE, Mutuc JD, Panozzo CA, et al.Sustained decline in rotavirus detectionsin the United States following the intro-duction of rotavirus vaccine in 2006. Pedi-atr Infect Dis J 2011;30:Suppl:S30-S34.5. Yen C, Armero Guardado JA, Alber to P,et al. Decline in rotavirus hospitalizationsand health care visits for childhood diar-rhea following rotavirus vaccination inEl Salvador. Pediatr Infect Dis J 2011;30:Suppl:S6-S10.6. Quintanar-Solares M, Yen C, Richard-son V, Esparza-Aguilar M, Parashar UD,

Patel MM. Impact of rotavirus vaccinationon diarrhea-related hospitalizations amongchildren

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Trends in intussusception hospitaliza-tions among US infants, 1993-2004: im-plications for monitoring the safety of thenew rotavirus vaccination program. Pedi-atrics 2008;121(5):e1125-e1132.26. Bines JE, Kohl KS, Forster J, et al.Acute intussusception in infants and chil-dren as an adverse event following immu-nization: case definition and guidelines

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96.29. SaTScan v7.0: software for the spatialand space-time scan statistics. Boston:SaTScan (http://www.satscan.org).30. Desai R, Cortese MM, Meltzer MI,et a l. Potential intussusception risk versusbenefits of rotavirus vaccination in theUnited States. Pediatr Infect Dis J 2013;32:1-7.

31. Haber P, Patel M, Pan Y, et al. Intus-susception after rotavirus vaccines report-ed to US VAERS, 2006-2012. Pediatrics2013;131:1042-9.32. Weintraub E. Rotavirus vaccines andintussusception in the Vaccine Safety Data-link (VSD). Presented to the Advisory Com-mittee on Immunization Practices, At-lanta, 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 preven-tion associated with rotavirus vaccinesin Australias national immunizationprogram. Clin Infect Dis 2013;57:1427-34.Copyright 2014 Massachusetts Medical Society.



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