Association Between Rotavirus Vaccination and Risk of Intussusception Among Neonates and Infants: A Systematic Review and Meta-analysis

Abstract

Importance: The conclusions from the multiple randomized clinical trials exploring the relationship between development of intussusception and rotavirus vaccination among neonates and infants have been controversial.

Objective: To evaluate the association between rotavirus vaccination and risk of intussusception.

Data sources: For this systematic review and meta-analysis, PubMed, Web of Science, Cochrane library, and Embase databases were searched from January 1, 1999, through December 31, 2018, using no language restrictions. The search terms were rotavirus or RV (rotavirus vaccine) or HRV (human rotavirus vaccine), vaccin*, and intussusception.

Study selection: Randomized clinical trials of neonates and infants that compared the risk of intussusception after the vaccination with a placebo group were included.

Data extraction and synthesis: A fixed-effects model was used to pool the data. Statistical heterogeneity was assessed with Q test and I2 statistic; relative risk (RR), risk difference (RD), and 95% CIs were calculated using the Mantel-Haenszel method.

Main outcomes and measures: The main outcome was the diagnosis of intussusception in the analysis. The pooled and subtotal results of RR, RD, and 95% CI for the risk of intussusception were estimated at 31 days, 1 year, and 2 years after vaccination.

Results: A total of 25 randomized clinical trials including 200 594 participants (104 647 receiving vaccine and 95 947 receiving placebo) in 33 countries from 4 continents were included in this meta-analysis. Twenty cases of definite intussusception were diagnosed within 31 days after rotavirus vaccination, with 11 cases (55%) in the vaccine group and 9 cases (45%) in the placebo group (RD, 0.17 per 10 000 infants [95% CI, -1.16 to 1.50 per 10 000 infants], P = .80; RR, 1.14 [95% CI, 0.49 to 2.64], P = .77). Seventy-four cases were reported within 1 year, with 37 cases (50%) in the vaccine group and 37 cases (50%) in the placebo group (RD, -0.65 per 10 000 infants [95% CI, -2.68 to 1.39 per 10 000 infants], P = .53; RR, 0.84 [95% CI, 0.53 to 1.32], P = .45). Fifty-nine cases were reported within 2 years, with 29 cases (49%) in the vaccine group and 30 cases (51%) in the placebo group (RD, -0.48 per 10 000 infants [95% CI, -3.64 to 2.69 per 10 000 infants], P = .77; RR, 0.91 [95% CI, 0.55 to 1.52], P = .73).

Conclusions and relevance: Results of this systematic review and meta-analysis suggest that monovalent, pentavalent, monovalent human-bovine, oral bovine pentavalent, and human neonatal rotavirus vaccination was not associated with an elevated risk of intussusception among neonates or infants.

Figure 1.. Flow Diagram

BRV-PV indicates oral bovine rotavirus pentavalent vaccine (Rotasiil); RRV-TV, human reassortant rotavirus tetravalent vaccine; RV1, monovalent rotavirus vaccine (Rotarix); RV3-BB, human neonatal rotavirus vaccine; RV5, pentavalent rotavirus vaccine (Rotateq); 116E, monovalent human-bovine rotavirus vaccine (Rotavac).

Figure 2.. Subgroup Analysis for Intussusception Between Rotavirus (RV) Vaccine and Placebo Groups at Different Follow-up Times

Relative risk and 95% CIs were calculated using the Mantel-Haenszel method, with a fixed-effects model used to pool data. Randomized clinical trials with 0 cases of intussusception among the vaccine and placebo groups were not included in the relative risk statistics but were included in the statistics of the risk difference. Other vaccines included monovalent human-bovine (116E) (Rotavac), human neonatal (RV3-BB), and oral bovine pentavalent (BRV-PV). Boxes represent means, with the size of the box corresponding with the weight; horizontal lines represent 95% CIs; and diamonds indicate pooled means with the horizontal points of the diamonds representing 95% CIs. RV1 indicates monovalent rotavirus vaccine (Rotarix); RV5, pentavalent rotavirus vaccine (Rotateq).