A key issue for rotavirus immunization programs in the postlicensure era is the need for safety monitoring with regard to intussusception 
. Our review of the intussusception literature from the past decade provides pertinent information that should facilitate implementation of intussusception surveillance for monitoring the postlicensure safety of rotavirus vaccines.
First, we demonstrate that natural intussusception is a very rare condition in most regions of the world, particularly among infants <3–4 months of age when the first dose of rotavirus vaccine is typically administered. Because any potential risk with rotavirus vaccines is greatest after the first dose of vaccine which is typically recommended to be administered at 6–15 weeks of age, 
the lower rates of intussusception in this age group suggests that timely administration of vaccine would minimize the attributable risk of vaccine 
. That is, the higher rates of intussusception among infants older than 3–4 months indicates that any vaccine associated risk of intussusception could lead to more cases of intussusception associated with vaccine in settings where delays in vaccination are common. If vaccine is linked to a potential risk of intussusception, age stratified data on intussusception are necessary for interpreting these estimates of vaccine-associated risk and calculating the number of cases that are potentially attributable to vaccine after the implementation of a vaccine program 
. The age-stratified data in this review will be a valuable resource for conducting benefit risk analyses, should a rotavirus vaccine program be linked to any potential risk of intussusception.
Second, the incidence of intussusception varies substantially by region, thus highlighting the importance of the need for regional baseline data when evaluating postlicensure trends of intussusception for assessing any potential vaccine-associated risk. Risk of intussusception after the current rotavirus vaccines has also varied by region. In Mexico and Australia, postlicensure studies have identified an increased low-level risk of intussusception after the first dose of both rotavirus vaccines, ranging from 1 to 2 cases of intussusception per 100,000 vaccinated infants 
. While an early study in the United States did not identify a risk of intussusception after RV5 
, a recent study has shown that a low level risk of intussusception is likely to exist with both vaccines 
. However, a similar level of risk was not observed in Brazil after RV1 
. While these differences in risk might be related to a chance finding, effect modification of risk related to an environmental or genetic factor that differs between the populations cannot be excluded. In our review, we observed a wide range in the incidence of intussusception globally. The cause of natural intussusception in a majority of infants is not known and has been previously reviewed. Differences in infant diet, breastfeeding, maternal antibody levels, prevalence of enteropathogens (e.g., respiratory adenovirus, rotavirus) might all contribute to the differences in background rates of intussusception 
. It remains unclear whether populations with higher background risk of intussusception also would carry a higher risk of vaccine-associated risk. However, any potential risk of intussusception associated with vaccine in populations with higher background risk would lead to higher number of excess cases that would be attributable to vaccine.
Third, the clinical management of intussusception in Africa differs markedly from other regions of the world where data exist, predominantly relying on clinical manifestations for diagnosis and surgery for treatment. The paucity of data on method of diagnosing intussusception from Eastern Mediterranean, Americas, and Oceania region limits the generalizability of this information in countries from these regions. In addition, limited published data are available on clinical management and outcome of intussusception in high mortality Asian countries but it would seem that surgical rates are likely to be higher than the lower mortality Asian countries. The differences in clinical management of intussusception in high mortality settings compared to low mortality settings emphasizes the need for augmenting surveillance practices depending on the location. For example, strengthening collaborations with surgeons to improve case-capture should be prioritized when monitoring the postlicensure safety of rotavirus vaccines in Africa. As rotavirus vaccines are more broadly introduced into immunization programs in Africa and Asia, these current data on the epidemiology and clinical management of intussusception should facilitate the future implementation of intussusception surveillance and inform benefit risk calculations for defining policy and decision making.
Studies assess the role of wild-type rotavirus infection as a cause of intussusception have led to conflicting findings with several studies suggesting that a significant association is unlikely 
. The absence of any marked seasonal patterns in intussusception, particularly in settings of Europe, Oceania, and Central and South America where rotavirus disease is quite seasonal supports the contention that rotavirus is unlikely to be a prominent etiologic cause of natural intussusception. This has some implications for postlicensure monitoring because attempts have previously been made to assess whether rotavirus vaccination would have a protective effect against intussusception vis-à-vis protecting against wild-type rotavirus infection. Establishing whether vaccine confers protection against intussusception might be challenging if only a small etiologic fraction of naturally occurring intussusception is related to wild-type rotavirus infection 
Our review provides background rates of intussusception against which rates of intussusception after the introduction of vaccine could be compared for assessing potential vaccine-associated risk. However, the paucity of background rates from most settings supports the need for relying on other analytic methods of safety monitoring after the introduction of rotavirus vaccine 
. The self-controlled case-series method has now been successfully applied in several settings for assessing a potential link between vaccine and intussusception 
. This method relies on active, hospital based surveillance of intussusception and does not require information on background rates of intussusception in the population under surveillance 
. Our review provides important considerations when establishing surveillance for intussusception. First, in resource poor settings of Africa, specific attention should be placed on hospitals with surgery suites which are likely to manage most intussusception events. While background rates are not specifically needed for the case-series method, in settings where no background rates are available, some efforts could be made to establish population-based studies which would be necessary for determining the attributable risk of vaccine, should any increased risk be identified. Lastly, the varying incidence of intussusception during the first six months of life when rotavirus vaccines are administered strongly indicates the need for addressing confounding effects of age when determining whether a causal link exists between rotavirus vaccine and intussusception cases identified through surveillance.
Intussusception case-fatality was <1% in all developed countries of the world. However, the marked difference in case-fatality between Asia (<1%) and Africa (9%) was intriguing. This finding might reflect differences in healthcare infrastructure or delays in care, or perhaps might be related to a publication bias with a paucity of surveillance data in the poorest populations of Asia. Previous analyses of benefits versus risk of rotavirus vaccine have conservatively assumed intussusception case-fatality rate of 25% in Asia, which in light of this review is high and could be reconsidered for future benefit risk deliberations 
. Even if case-fatality rates were to be higher than those identified in this review, some adjustment would be prudent for obtaining valid estimates of any potential risk associated with rotavirus vaccine in Asia.
Our review must be considered with some limitations. Because intussusception is a very rare condition, a fair amount of heterogeneity in surveillance practice is likely to exist across regions. In particular, establishing incidence of intussusception is rather challenging in many settings without established national or regional electronic records and thus published rates of intussusception might be prone to over or underestimation. The availability of a standardized case definition by the Brighton Collaboration reduces case misclassification but sensitivity of the case-definition might be reduced in resource poor settings where diagnostic modalities are not available and relying on clinical judgment and surgery is required for diagnosis 
. The case-fatality from these hospital based surveillance studies in resource poor settings also certainly underestimates the true case-fatality because deaths are likely to occur out of hospital. While some 30 countries had introduced a rotavirus between 2006 and 2011, all but one of the studies included in this review 
captured data before the introduction of a rotavirus vaccine.
In summary, this review of current epidemiology and clinical management of intussusception should prove to be a valuable resource for establishing intussusception surveillance and interpreting these surveillance data from various regions of the world where rotavirus vaccines are likely to be introduced in the next several years.
Because these are publicly available non-identifiable data, an ethics statement was not required for this work.