Risk of intussusception following rotavirus immunisation in Singapore

In recent years, post-licensure studies have detected a small risk of intussusception associated with the newer rotavirus vaccines, namely the monovalent (RV1) Rotarix^® (GlaxoSmithKline Pte Ltd) and the pentavalent (RV5) RotaTeq^TM (MSD Pharma (Singapore) Pte Ltd), in some populations. As the risk of intussusception could vary depending on geography, ethnicity, maternal and infant factors as well as environmental factors, a local study at KK Women’s and Children’s Hospital (KKH) was initiated to determine the risk of intussusception following rotavirus immunisation in Singapore.¹

Background

The safety concern of intussusception with rotavirus immunisation was first identified in 1999 with RotaShield^®, which led to its withdrawal from the market.² The risk of intussusception was estimated at 10-20 cases per 100,000 Rotashield® recipients.³ Consequently, two newer oral rotavirus vaccines, RV1 and RV5, underwent large-scale clinical trials to ensure that there was no elevated risk with intussusception prior to their market approval in many countries (including US, Europe and Singapore) in the mid to late 2000s. However, recent post-licensure studies in some settings, namely Latin America (Mexico and Brazil), Australia and the US, have estimated the attributable risk of intussusception after rotavirus vaccination to be approximately 1.5 to 6 per 100,000 infants vaccinated.^4-6

Local study on the risk of intussusception with RV1¹

A total of 86 infants hospitalised with intussusception at KKH prior to one year of age between 1 October 2005 and 30 September 2012 were identified. Of these, 20 infants had received either one (n=2) or two (n=18) doses of RV1. Four infants developed intussusception within three weeks of vaccination with RV1 dose 1 or 2. Using the self-controlled case series method, the authors found a significant increase in risk of intussusception in the 1- to 7-day risk period after RV1 dose 1, which did not change after adjusting for age (Relative incidence [RI] 8.36; 95% CI 2.42-28.96) (Table 1). No cases were reported during the 8- to 21-day risk period post dose 1. There was a smaller but non-significant elevated risk in the 1- to 7-day and 8- to 21-day risk period after RV1 dose 2. Although an eight-fold relative increase in risk may seem high, the actual excess risk associated with RV1 immunisation translates to about 1.5 cases per 100,000 infants immunised. This is the first study involving infants of Asian ancestry which demonstrated that the relative risk of intussusception post-RV1 immunisation is not higher in Asia despite differences in background intussusception incidence compared with United States, Latin America and Australia.

Table 1. Age-adjusted RI of intussusception during risk periods by rotavirus vaccination dose

Dose (risk period)	No. of cases	Age (days)-adjusted RI (95% CI)	p value
Dose 1 (1-7 days)	2	8.36 (2.42-28.96)	0.001
Dose 2 (1-7 days)	1	3.09 (0.41-23.37)	0.28
Dose 2 (8-21 days)	1	1.54 (0.20-11.69)	0.67

Rotavirus infection accounts for about a third of all acute gastroenteritis hospital admissions in children younger than five years in Singapore.⁷ This study showed that a national rotavirus vaccination program with 90% coverage could potentially prevent 71% of all childhood hospitalisations due to rotavirus, with only a low risk of excess intussusception.

Local situation

Since the approval of RV1 in October 2005, more than 300,000 doses have been sold locally. To date, HSA has received 16 reports* of intussusception suspected to be associated with this vaccine, including the cases mentioned in the KKH study. Ten cases occurred within seven days of vaccination and one occurred on day eight of vaccination. Of these 11 cases, eight cases were reported with dose 1 and three cases with dose 2. The remaining five cases occurred beyond the 21-day risk period identified with rotavirus vaccination.⁶ There were also three reports of intussusception associated with RV5, which is less commonly used in Singapore. All the patients had either recovered or were recovering at the time of reporting.

*The data provided should not be used to draw comparisons on the safety of the different brands of rotavirus vaccines as this is confounded by factors such as extent of use and patient factors. The temporal association of these cases with rotavirus immunisation does not mean they were caused by the vaccine.

HSA’s advisory

Healthcare professionals are advised to be vigilant to any symptoms indicative of intussusception (e.g., vomiting, palpable abdominal mass, abdominal pain or diarrhoea) following rotavirus vaccination. They are also advised to inform parents or caregivers to seek treatment early if the child experiences abdominal pain or bloating, often accompanied with persistent or bouts of crying, vomiting, blood in the stool or change in bowel movements at any time after each dose of the vaccine.

Healthcare professionals are encouraged to report any adverse events suspected to be associated with rotavirus vaccines to HSA as we continue to monitor these reports closely.

The editorial team would like to thank Dr Yung Chee Fu (Epidemiologist, Infectious Disease Service, Department of Paediatric Medicine, KKH) for his contribution to the above article.

References

1. J Pediatr 2015; 167:163-8
2. World Health Organisation position paper on rotavirus vaccines, Jan 2013
3. J Infect Dis 2003; 187: 1309-13
4. N Eng J Med 2011; 364: 2283-92
5. Clin Infect Dis 2013; 57: 1427-34
6. N Eng J Med 2014; 370: 503-12
7. Pediatr Infect Dis J 2013; 32: e426-31

Published: 30 Sep 2015

Safety Alerts