Intussusception and Oral Poliovirus Vaccination: Is There an Association?

Su-Ting T. Li1 , Robert L. Davis2 and Noel S. Weiss3

1 Department of Pediatrics, School of Medicine, University of California, Davis, Sacramento, CA.
2 Office of Genomics and Disease Prevention, Centers for Disease Control and Prevention, Atlanta, GA.
3 Department of Epidemiology, School of Public Health and Community Medicine, University of Washington, Seattle, WA.

Received for publication June 14, 2003; accepted for publication April 15, 2004.


    ABSTRACT
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Oral rotavirus vaccine was voluntarily withdrawn from the market after studies observed an increased risk of intussusception within 2 weeks after immunization. Concern has been raised that other orally administered vaccines, such as oral poliovirus vaccine (OPV), may also be associated with intussusception. In this 1990–1998 case-control study, the authors examined the association between OPV and intussusception in the Washington State Medicaid population, evaluating receipt of OPV during the month prior to intussusception among 119 cases and 589 controls matched by date of birth. Analysis was conducted via matched conditional logistic regression, controlling for sex. Between 1990 and 1998, 119 children younger than age 2 years had a therapeutic enema, surgical reduction, or hospitalization for intussusception and had been enrolled in Medicaid for at least 1 month prior to their intussusception date. There was no significantly elevated risk of intussusception associated with receipt of OPV; 9.2% (11/119) of cases and 8.5% (50/589) of controls were given OPV 0–28 days prior to the case’s intussusception date (odds ratio = 1.1, 95% confidence interval: 0.5, 2.2). However, to address the hypothesis that risk of intussusception is related to receipt of a particular dose of OPV, a larger study would be required.

intussusception; poliovirus vaccine, oral

Abbreviations: Abbreviations: CI, confidence interval; OPV, oral poliovirus vaccine.


    INTRODUCTION
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Intussusception, the telescoping of one segment of intestine into another, is the most common cause of bowel obstruction in children aged 3 months to 5 years (1). The incidence of intussusception among children under 1 year of age is 18–56 per 100,000 per year, with a peak incidence at 5–7 months of age (1). Oral rotavirus vaccine (rhesus-based rotavirus vaccine–tetravalent) was voluntarily withdrawn from the market in 1999 after studies showed an increased risk of intussusception within 2 weeks of the receipt of this vaccine. Subsequently, concern has been raised that other orally administered vaccines, such as oral poliovirus vaccine (OPV), may also be associated with intussusception.

The results of previous studies of OPV have been inconsistent. Initial studies reported relative risks of intussusception ranging from 2.1 to 2.6 during the month following receipt of the second or third dose of OPV (2). However, several later studies reported no association (36). We conducted this study to try to shed further light on this question.


    MATERIALS AND METHODS
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
We conducted a case-control study using Washington State Medicaid claims and encounter data. Institutional review board approval was obtained from the Washington Department of Social and Health Services (Olympia, Washington) and the University of Washington (Seattle, Washington).

Infants with intussusception
The study population consisted of children who were enrolled in Washington State’s Medicaid program between 1990 and 1998. Infants with intussusception were identified through the use of International Classification of Diseases, Ninth Revision (7), code 560.0 (intussusception).

Infants were eligible for the study if they had received a diagnosis of intussusception during the study period (1990–1998), if they were at least 1 but less than 24 months of age at the time of diagnosis, if they had been enrolled in Medicaid for at least 2 months (including 1 month prior to their diagnosis of intussusception and the month of their diagnosis of intussusception), and if their diagnosis was accompanied by a Current Procedural Terminology (8) code of 74283 (therapeutic enema for the reduction of intussusception) or 44050 (surgical reduction of intussusception) or they had a discharge diagnosis of intussusception.

Controls
Five controls were matched to each case according to the case’s date of birth, plus or minus 3 days. Similar to the cases, controls had to have been enrolled in Medicaid for at least 2 months (including 1 month prior to the case’s diagnosis of intussusception and the month of the case’s diagnosis of intussusception).

Immunization information
Receipt of OPV was identified through the use of code 90712 from Current Procedural Terminology (8). Information about the receipt of inactivated poliovirus vaccine (code 90713) and rotavirus vaccine (code 90680) was also obtained.

Statistical analysis
We used matched conditional logistic regression, controlling for sex, to obtain odds ratios as estimates of the relative risks associated with OPV vaccination during predefined time intervals within the 28 days prior to intussusception (0–28, 0–14, 15–21, and 22–28 days prior to intussusception). For our analysis of receipt of any OPV more than 28 days prior to intussusception, our reference category was children who did not receive OPV prior to the case’s intussusception date. For all other analyses, our reference category was children who did not receive OPV prior to the case’s intussusception date or received OPV more than 28 days prior to the case’s intussusception date. We evaluated both the overall odds of any OPV administered 0–28 days prior to intussusception and the specific odds for the first dose of OPV, the second dose of OPV, and the third dose of OPV in the same predefined time intervals. Since some previous studies (2) had found an increased risk of intussusception during the 14–27 days following the third dose of OPV and during the 22–28 days following the second dose of OPV, these were predefined time intervals of particular interest in our study.

In addition, we examined the possible association between OPV and intussusception by age, since the two previous studies with significantly increased risks of intussusception after OPV were following doses received at approximately 4 months of age (when the second OPV dose is customarily given in the United States and the third OPV dose is customarily given in the United Kingdom). For our analysis by age window, our reference category was children who were not immunized or were immunized outside of the age window.

To address problems involved in identifying the number of OPV doses given, we conducted a subanalysis restricted to infants under 1 year of age who were enrolled in the Medicaid program prior to age 6 weeks (the earliest age at which OPV is administered in the United States), with no inactivated poliovirus vaccine administered prior to the case’s intussusception.


    RESULTS
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Of 222 children under 2 years of age who received an International Classification of Diseases, Ninth Revision (7), intussusception diagnosis between 1990 and 1998, 81.5 percent (n = 181) had an associated Current Procedural Terminology (8) code for diagnostic enema (codes 74285, 74270, and 74280), therapeutic enema, surgical reduction, or hospital admission for intussusception. Of these children, 119 had their diagnosis confirmed by coding for treatment of intussusception with therapeutic enema, surgical reduction, or hospital admission for intussusception, while 62 had only a code for diagnostic enema. Of the 119 children with verified intussusception, 64 percent were male (mean age = 7.9 months). No patients had received rotavirus vaccination. Most cases (93 percent) and controls (96 percent) had received no inactivated poliovirus vaccine prior to the case’s intussusception date (table 1).


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TABLE 1. Receipt of oral poliovirus vaccine and inactivated poliovirus vaccine among infants with intussusception and controls prior to the case’s date of intussusception diagnosis, Washington State Medicaid population, 1990–1998
 
Among children with intussusception, 9.2 percent had received OPV within the previous 28 days. This was nearly the same as the percentage in controls (8.5 percent; odds ratio = 1.1, 95 percent confidence interval (CI): 0.5, 2.2) (table 2). Similarly, we found no association between intussusception and any particular dose of OPV. Odds ratios were 1.9 (95 percent CI: 0.8, 4.5) for the first dose, 0.4 (95 percent CI: 0.1, 1.6) for the second dose, and 2.2 (95 percent CI: 0.2, 22.0) for the third dose. We found no association between intussusception and any time interval after OPV administration. Odds ratios were 1.3 (95 percent CI: 0.5, 3.3) 0–14 days after any OPV, 1.3 (95 percent CI: 0.3, 4.6) 15–21 days after any OPV, and 0.6 (95 percent CI: 0.1, 3.0) 22–28 days after any OPV. There was no combination of OPV dose and time interval following immunization in which the risk of intussusception was elevated.


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TABLE 2. Receipt of oral poliovirus vaccine among infants with intussusception and controls, Washington State Medicaid population, 1990–1998
 
Finally, we found no association between OPV given during particular age windows and intussusception 0–28 days later. Odds ratios were 1.3 (95 percent CI: 0.2, 7.7) for OPV administered at 6 weeks–<3.5 months of age, 0.9 (95 percent CI: 0.3, 2.7) for OPV administered at 3.5–<6 months of age, and 1.3 (95 percent CI: 0.4, 4.2) for OPV administered at 6–<24 months of age (table 3). Neither was there any association between intussusception and any combination of OPV given during a particular age window and predefined time interval. When the analysis was restricted to children under 1 year of age at the time of the case’s intussusception who were enrolled in Medicaid prior to age 6 weeks and had received no inactivated poliovirus vaccine prior to the case’s intussusception date, the odds ratio associated with receipt of OPV during the preceding 28 days was 1.2 (95 percent CI: 0.7, 2.0).


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TABLE 3. Receipt of oral poliovirus vaccine among infants with intussusception and controls, by age window, Washington State Medicaid population, 1990–1998
 

    DISCUSSION
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
We found no evidence of an increased risk of intussusception in the 28 days following receipt of OPV. Of five previous studies (25), two did observe such an increased risk, at least in some exposure subgroups. Findings from both of these studies were published by the World Health Organization as a brief report in their weekly epidemiologic record (2). Methods and results were incompletely described. One study was a cohort study conducted in the United States by the Centers for Disease Control and Prevention through the Vaccine Safety Datalink network (2). Investigators observed a higher proportion of cases than of controls to have received the second dose of OPV in the 22–28 days prior to the date of onset of the case’s intussusception (odds ratio = 2.6, 95 percent CI: 1.3, 3.3) (2). That study found no association between intussusception and the first or third dose of OPV, but actual results were not provided.

One case-series study conducted in the United Kingdom, the Health Episode Statistics-1 study, found an increased relative incidence of intussusception during the period 14–27 days after the third dose of OPV (relative incidence = 2.1, 95 percent CI: 1.3, 3.7) (2, 3). The authors found no increased relative incidence of intussusception in the two flanking 2-week intervals following the third dose of OPV. The relative incidence was 0.89 (95 percent CI: 0.48, 1.65) 0–13 days after the third dose of OPV and 1.40 (95 percent CI: 0.76, 2.55) 28–41 days after the third dose of OPV. In addition, the authors found no association in the 14–27 days following the first or second dose of OPV. The relative incidence was 0.31 (95 percent CI: 0.11, 0.90) after the first dose of OPV and 1.27 (95 percent CI: 0.67, 2.42) after the second dose of OPV.

The investigators in the Health Episode Statistics-1 study (2) extended their research using an additional 2 years of information from the Health Episode Statistics-2 study and one other administrative database, the General Practice Research Database, using the same case-series methods and found no evidence of an association between intussusception and OPV in any dose or time period studied (3). In particular, the relative incidence was not increased for the 14–27 days after the third dose of OPV. It was 0.64 (95 percent CI: 0.22, 1.85) in the Health Episode Statistics-2 study and 1.26 (95 percent CI: 0.69, 2.29) in the General Practice Research Database study (3).

A nested case-control study using the General Practice Research Database also found no association between intussusception and receipt of OPV in the preceding 0–42 days. Odds ratios were 1.0 (95 percent CI: 0.4, 2.3) for the period 15–21 days after any OPV and 0.9 (95 percent CI: 0.4, 2.0) for the period 22–28 days after any OPV (5). The authors found no increased risk of intussusception following any particular dose in any time period after OPV vaccination, with odds ratios being close to 1.0.

A case-series study performed in Cuba, where OPV is administered twice yearly (February and April) in mass vaccination campaigns, found no association between OPV and intussusception (4). In particular, the authors found no increased relative incidence of intussusception 22–28 days following the first OPV dose (relative incidence = 0.77, 95 percent CI: 0.29, 2.04) or the second OPV dose (relative incidence = 1.20, 95 percent CI: 0.44, 3.28), after controlling for age and season. They also found no association between OPV vaccination and intussusception at specific ages.

A case-control study performed in India found no association between intussusception and OPV received during the prior month (odds ratio = 0.9, 95 percent CI: 05, 1.3) (6). The authors found no increased risk of intussusception in any particular 3-month age group; all odds ratios were close to 1.0.

In the United States, the primary OPV administration schedule was 2 months, 4 months, and 6–18 months during the time period of the Vaccine Safety Datalink study (2). In the United Kingdom, the primary OPV administration schedule was 2 months, 3 months, and 4 months (2). Both the second dose of OPV in the United States and the third dose of OPV in the United Kingdom are administered at 4 months of age, approximately 1 month prior to the time when the peak incidence of intussusception occurs. Since the two studies that showed an association between intussusception and OPV reported an association with OPV given at age 4 months—the second dose in the United States and the third dose in the United Kingdom—it was unclear whether a particular dose or a particular age of immunization was important. Therefore, we sought to identify an association between intussusception and the dose of OPV or the age at which OPV is given.

Since both the incidence of intussusception and OPV vaccination change month-to-month according to age, it was important that we tightly control for age in our analyses. An advantage of our study was that we were able to control tightly for age by matching on the case’s date of birth, plus or minus 3 days. This allowed better control for age than was achieved in previous case-series studies that controlled for age in 1-month categories or the previous case-control studies that matched only to month and year of birth.

This study had several limitations. First, cases were defined on the basis of an International Classification of Diseases, Ninth Revision (7), diagnosis of intussusception. The accuracy of this diagnosis could not be confirmed; however, the additional requirement of an associated Current Procedural Terminology (8) code for therapeutic enema, surgical reduction, or hospitalization for intussusception helped to minimize misclassification.

Second, exposure was also based on administrative data, a Current Procedural Terminology code for receipt of oral poliovirus vaccine. The accuracy of this measure of exposure could not be confirmed. It is also possible that some children received immunizations from sources that do not bill Medicaid, such as free clinics.

Third, our study was limited by the lack of complete immunization records from birth in our study population. We were only able to capture data on OPV immunizations given during the time of Medicaid enrollment. It is possible that children who were enrolled in Medicaid sometime after birth received immunizations that were not recorded in Medicaid claims and encounter data. Lack of complete immunization records made it difficult to reliably count the number of OPV immunizations given prior to intussusception, which may have affected the results of the OPV dose analysis. However, this would not have affected the analysis conducted by age. Ascertainment of OPV immunization prior to the case’s intussusception date would probably be similar in cases and controls, since we used administrative data collected prior to the case’s intussusception and we required both cases and controls to be enrolled during the month prior to and during the month of the case’s intussusception date. Therefore, it is unlikely that the lack of complete immunization records substantially affected the results. In addition, our subanalysis, which was restricted to infants who were enrolled in Medicaid prior to the age of 6 weeks, the earliest age at which OPV is administered in the United States, also found no association between OPV and intussusception.

Last, our study was limited by the small number of cases of intussusception in our population. Therefore, our study lacked the statistical power to reject the hypothesis of an association between intussusception and particular doses of OPV or intussusception and OPV given at particular ages. We had a similar number of intussusception cases in our study (n = 119) as the previous US study (n = 133) (2). The other study with positive findings, the Health Episode Statistics-1 study (2), had 218 cases of intussusception.

Overall, we found no association between intussusception and OPV administered during the preceding 4 weeks (odds ratio = 1.1, 95 percent CI: 0.5, 2.2). If there is an overall association between OPV and intussusception, it does not appear to be very large. Given the lack of consistency of the positive results obtained in some previous studies and the presence of several studies with completely negative findings, we suggest that receipt of OPV does not transiently increase an infant’s risk of intussusception.


    NOTES
 
Correspondence to Dr. Su-Ting T. Li, Department of Pediatrics, University of California, Davis, 2516 Stockton Boulevard, 3rd floor, Sacramento, CA 95817-5177 (e-mail: su-ting.li{at}ucdmc.ucdavis.edu). Back


    REFERENCES
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

  1. Parashar UD, Holman RC, Cummings KC, et al. Trends in intussusception-associated hospitalizations and deaths among US infants. Pediatrics 2000;106:1413–21.[Abstract/Free Full Text]
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  4. Sardinas MA, Cardenas AZ, Marie GC, et al. Lack of association between intussusception and oral polio vaccine in Cuban children. Eur J Epidemiol 2001;17:783–7.[CrossRef][ISI][Medline]
  5. Jick H, Vasilakis-Scaramozza C, Jick SS. Live attenuated polio vaccine and the risk of intussusception. Br J Clin Pharmacol 2001;52:451–3.[CrossRef][ISI][Medline]
  6. Raman T, Mukhopadhyaya A, Eapen CE, et al. Intussusception in southern Indian children: lack of association with diarrheal disease and oral polio vaccine immunization. Indian J Gastroenterol 2003;22:82–4.[Medline]
  7. World Health Organization. International classification of diseases. Manual of the international statistical classification of diseases, injuries, and causes of death. Ninth Revision. Geneva, Switzerland: World Health Organization, 1977.
  8. American Medical Association. CPT 2004: current procedural terminology. Chicago, IL: American Medical Association, 2003.