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

Transcription

1 The new england journal of medicine established in 1812 february 6, 2014 vol. 370 no. 6 Intussusception Risk after Rotavirus Vaccination in U.S. Infants W. Katherine Yih, Ph.D., M.P.H., Tracy A. Lieu, M.D., M.P.H., Martin Kulldorff, Ph.D., David Martin, M.D., M.P.H., Cheryl N. McMahill-Walraven, M.S.W., Ph.D., Richard Platt, M.D., Nandini Selvam, Ph.D., M.P.H., Mano Selvan, Ph.D., Grace M. Lee, M.D., M.P.H., and Michael Nguyen, M.D. ABSTRACT 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 Children s 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: DOI: /NEJMoa 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.) n engl j med 370;6 nejm.org february 6,

2 The new england journal of medicine 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 Until quite recently, U.S. postlicensure studies of the safety of RV5 had not shown a significant increase in the risk of intussusception 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 intussusception 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 Methods 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 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) design 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 Current Procedural Terminology (CPT) codes and 90681, respectively. We sought medical records to validate vaccine exposure for all infants with cases of intussusception that were 504 n engl j med 370;6 nejm.org february 6, 2014

3 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. 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 (intussusception) or (other and unspecified diseases of the appendix, including intussusception) or CPT code (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 intussusception and were included in sensitivity analyses. Level 3 is the lowest level of diagnostic certainty and is defined by the presence of at least four fairly nonspecific clinical criteria. Level 3 cases were not included in the analysis. All discrepancies in classification were resolved by consensus. Statistical Analysis In the SCRI design, 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. n engl j med 370;6 nejm.org february 6,

4 The new england journal of medicine 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 100,000 no. of cases in the risk window [1 (1 relative risk)] [no. of vaccine doses C], 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 Lee 27 (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 intussusception 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 Results 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 506 n engl j med 370;6 nejm.org february 6, 2014

5 Intussusception Risk after Rotavirus Vaccination Table 1. Case Counts and Risk Estimates for Confirmed Intussusception after RV5.* Dose, Type of Analysis, and Design Age- Adjustment Method Days after Vaccination in Risk Window No. of Cases in Risk Window No. of Cases in Control Window Relative Risk (95% CI) Attributable Risk/ 100,000 Doses (95% CI) No. of Doses Resulting in One Excess Case (95% CI) Dose 1 SCRI Tate 1 to (2.2 to 38.6) 1.1 (0.3 to 2.7) 89,000 (37,000 to 307,000) SCRI Tate 1 to (1.1 to 16.0) 1.5 (0.2 to 3.2) 65,000 (31,000 to 519,000) Cohort PRISM 1 to (1.2 to 5.8) 1.2 (0.2 to 3.2) 80,000 (31,000 to 434,000) SCRI PRISM 1 to (1.7 to 29.2) 1.1 (0.3 to 2.6) 92,000 (38,000 to 376,000) SCRI PRISM 1 to (0.9 to 13.0) 1.4 ( 0.01 to 3.1) 70,000 (32,000 to ) Cohort Tate 1 to (1.4 to 6.0) 1.3 (0.3 to 3.3) 75,000 (30,000 to 316,000) Dose 2 SCRI Tate 1 to (0.4 to 7.2) 0.4 ( 0.3 to 1.9) 256,000 (52,000 to ) SCRI Tate 1 to (0.3 to 3.1) 0.1 ( 1.8 to 1.8) (57,000 to ) Cohort PRISM 1 to (0.4 to 2.2) 0.2 ( 1.1 to 1.8) (57,000 to ) SCRI PRISM 1 to (0.4 to 7.2) 0.4 ( 0.3 to 1.9) 258,000 (52,000 to ) SCRI PRISM 1 to (0.3 to 3.1) 0.1 ( 1.8 to 1.8) (57,000 to ) Cohort Tate 1 to (0.3 to 2.0) 0.3 ( 1.2 to 1.6) (62,000 to ) Dose 3 SCRI Tate 1 to (0.5 to 9.7) 0.6 ( 0.4 to 2.6) 159,000 (38,000 to ) SCRI Tate 1 to (0.2 to 3.9) 0.05 ( 2.3 to 2.1) (47,000 to ) Cohort PRISM 1 to (0.3 to 2.2) 0.3 ( 1.5 to 2.3) (43,000 to ) SCRI PRISM 1 to (0.5 to 10.2) 0.7 ( 0.3 to 2.7) 152,000 (38,000 to ) SCRI PRISM 1 to (0.2 to 4.0) 0.01 ( 2.1 to 2.2) 10,402,000 (46,000 to ) Cohort Tate 1 to (0.4 to 2.2) 0.2 ( 1.4 to 2.4) (42,000 to ) All doses** SCRI Tate 1 to (1.5 to 7.4) 0.8 (0.2 to 1.6) 131,000 (63,000 to 497,000) SCRI Tate 1 to (0.8 to 3.3) 0.6 ( 0.4 to 1.7) 154,000 (60,000 to ) Cohort PRISM 1 to (0.8 to 2.1) 0.4 ( 0.4 to 1.4) 272,000 (70,000 to ) SCRI PRISM 1 to (1.4 to 6.8) 0.7 (0.2 to 1.6) 135,000 (63,000 to 540,000) SCRI PRISM 1 to (0.7 to 3.1) 0.6 ( 0.4 to 1.6) 174,000 (62,000 to ) Cohort Tate 1 to (0.8 to 2.1) 0.4 ( 0.4 to 1.4) 273,000 (70,000 to ) * Cases of intussusception were adjudicated with the use of Brighton Collaboration criteria, 26 with level 1 cases considered as confirmed cases. We used two study designs: a self-controlled risk-interval (SCRI) design and a cohort design. In prespecified analyses, we adjusted for age in the SCRI design using age-specific background rates extracted by Tate et al. 25 from the U.S. hospital-discharge data of the Healthcare Cost and Utilization Project for 11 years during which no rotavirus vaccine was used, and we 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. n engl j med 370;6 nejm.org february 6,

6 The new england journal of medicine Table 2. Case Counts and Risk Estimates for Confirmed Intussusception after RV1.* Dose, Type of Analysis, and Design Dose 1 Age- Adjustment Method Days after Vaccination in Risk Window No. of Cases in Risk Window No. of Cases in Control Window Relative Risk (95% CI) Attributable Risk/ 100,000 Doses (95% CI) No. of Doses Resulting in One Excess Case (95% CI) SCRI Tate 1 to ,000 SCRI Tate 1 to ,000 Cohort PRISM 1 to (0.4 to 21.8) 1.6 ( 0.6 to 10.4) 63,000 (10,000 to ) SCRI PRISM 1 to ,000 SCRI PRISM 1 to ,000 Cohort Tate 1 to (0.4 to 22.9) 1.6 ( 0.5 to 10.4) 61,000 (6000 to ) Dose 2 SCRI Tate 1 to (0.5 to 25.1) 4.3 ( 1.8 to 17.8) 23,000 (6000 to ) SCRI Tate 1 to (0.3 to 10.1) 3.7 ( 10.0 to 19.4) 27,000 (5000 to ) Cohort PRISM 1 to (1.6 to 16.4) 7.3 (0.8 to 22.5) 14,000 (4000 to 131,000) SCRI PRISM 1 to (0.5 to 25.3) 4.4 ( 1.7 to 17.8) 23,000 (6000 to ) SCRI PRISM 1 to (0.3 to 10.2) 3.7 ( 9.8 to 19.5) 27,000 (5000 to ) Cohort Tate 1 to (1.5 to 14.7) 7.1 (0.6 to 22.3) 14,000 (4000 to 170,000) All doses SCRI Tate 1 to (0.9 to 34.2) 3.1 (0.01 to 9.3) 33,000 (11,000 to 13,810,000) SCRI Tate 1 to (0.4 to 12.8) 2.8 ( 2.9 to 9.9) 35,000 (10,000 to ) Cohort PRISM 1 to (1.4 to 10.4) 3.7 (0.3 to 10.5) 27,000 (10,000 to 288,000) SCRI PRISM 1 to (0.9 to 33.0) 3.1 ( 0.02 to 9.3) 33,000 (11,000 to ) SCRI PRISM 1 to (0.4 to 12.6) 2.8 ( 3.0 to 9.9) 35,000 (10,000 to ) Cohort Tate 1 to (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 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). Alternative Age Adjustment Results after alternative adjustment for age are shown in Tables 1 and 2; results after dose 1 of 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, with the attributable risk point estimates after dose 1 of RV5 ranging from 1.1 to 1.5 excess cases per 100,000 recipients of the first dose of 508 n engl j med 370;6 nejm.org february 6, 2014

7 Intussusception Risk after Rotavirus Vaccination 3.5 No. of Excess Cases of Intussusception per 100,000 First-Dose Recipients SCRI, original age adjustment using Tate et al. risk curve SCRI, age adjustment using study population risk function 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 1 7 Risk Window Days 1 21 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, 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 significant cluster of onset of intussusception 3 to 7 days after vaccination (P = for dose 1; P = for all doses). There was only a single case of intussusception after dose 1 of RV1; therefore, there were insufficient data for the analysis of clusters of onset after dose 1. For all doses of RV1, there was a significant cluster on day 4 after vaccination (P<0.001) (Fig. 2). 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 tenth the risk with Rotashield. 1 The lower boundary of the 95% confidence interval (representing the higher-risk boundary) was 1 case per 31,000 vaccinees. 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 of the benefits of vaccination, which include the prevention of a projected 53,444 hospitalizations (95% CI, 37,622 to 72,882) in a U.S. birth cohort of 4.3 million children. 30 Our results with respect to RV5 are similar to those of the Vaccine Adverse Event Reporting System (VAERS), which used an SCRI design to compare the numbers of spontaneously reported cases in the 3-to-6-day period after vaccination with those in the 0-to-2-day period after vaccination. That study showed an attributable risk of 0.74 excess cases (95% CI, 0.24 to 1.71) per 100,000 recipients of the first dose of vaccine and no significant results for the other doses. 31 In contrast, the population-based Vaccine Safety Datalink (VSD) has not shown a significant increase in the risk of intussusception after RV5. 14,15 The VSD, which used a cohort design n engl j med 370;6 nejm.org february 6,

8 The new england journal of medicine A RV5, Dose 1 3 No. of Intussusception Cases Days after Vaccination B RV5, All Doses 3 No. of Intussusception Cases Days after Vaccination C RV1, All Doses 3 3/6 cases Relative risk, 48 P< No. of Intussusception Cases 1 0 5/11 cases Relative risk, 9.7 P= /30 cases Relative risk, 4.5 P= Days after Vaccination Dose 1 Dose 3 Dose 2 Dose 1 Dose 2 Dose 1 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-9 coded 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 window 32 ; in contrast, 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 there 10 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 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. 510 n engl j med 370;6 nejm.org february 6, 2014

9 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 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 HHSF I). 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). References 1. Murphy TV, Gargiullo PM, Massoudi MS, et al. Intussusception among infants given an oral rotavirus vaccine. N Engl J Med 2001;344: 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-S Tate JE, Mutuc JD, Panozzo CA, et al. Sustained decline in rotavirus detections in the United States following the introduction of rotavirus vaccine in Pediatr Infect Dis J 2011;30:Suppl:S30-S 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-S 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-S 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-S Buttery JP, Lambert SB, Grimwood K, et al. Reduction in rotavirus-associated acute gastroenteritis following introduction of rotavirus vaccine into Australia s National Childhood vaccine schedule. Pediatr Infect Dis J 2011;30:Suppl:S25-S29. [Erratum, Pediatr Infect Dis J 2011;30:916.] 9. Gastañaduy PA, Sánchez-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-e 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: Patel MM, López-Collada VR, Bulhões MM, et al. Intussusception risk and health benefits of rotavirus vaccination in Mexico and Brazil. N Engl J Med 2011;364: Velázquez 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: 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, Pediatrics 2008;121: 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: Shui IM, Baggs J, Patel M, et al. Risk of intussusception following administration of a pentavalent rotavirus vaccine in US infants. JAMA 2012;307: 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: Nguyen M, Ball R, Midthun K, Lieu TA. The Food and Drug Administration s Post-Licensure Rapid Immunization Safety Monitoring program: strengthening the federal vaccine safety enterprise. Pharmacoepidemiol Drug Saf 2012;21:Suppl 1: Platt R, Carnahan RM, Brown JS, et al. The U.S. Food and Drug Administration s Mini-Sentinel program: status and direction. Pharmacoepidemiol Drug Saf 2012; 21:Suppl 1: Maro JC, Platt R, Holmes JH, et al. Design of a national distributed health data network. Ann Intern Med 2009;151: 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: 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: 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: 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: n engl j med 370;6 nejm.org february 6,

10 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: Tate JE, Simonsen L, Viboud C, et al. Trends in intussusception hospitalizations among US infants, : implications for monitoring the safety of the new rotavirus vaccination program. Pediatrics 2008;121(5):e1125-e 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: Krishnamoorthy K, Lee M. New approximate confidence intervals for the difference between two Poisson means and comparison. J Stat Comput Simul 2013;83: Kulldorff M. A spatial scan statistic. Comm Stat Theory Methods 1997;26: SaTScan v7.0: software for the spatial and space-time scan statistics. Boston: SaTScan ( 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: Haber P, Patel M, Pan Y, et al. Intussusception after rotavirus vaccines reported to US VAERS, Pediatrics 2013;131: Weintraub E. Rotavirus vaccines and intussusception in the Vaccine Safety Datalink (VSD). Presented to the Advisory Committee on Immunization Practices, Atlanta, June 20, 2013 ( 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 Australia s national immunization program. Clin Infect Dis 2013;57: Copyright 2014 Massachusetts Medical Society. 512 n engl j med 370;6 nejm.org february 6, 2014