Elsevier

The Lancet

Volume 349, Issue 9061, 3 May 1997, Pages 1277-1281
The Lancet

Articles
Randomised double-blind placebo-controlled study on adverse effects of rubella immunisation in seronegative women

https://doi.org/10.1016/S0140-6736(96)12031-6Get rights and content

Summary

Background

The objective of our study was to investigate the association of adverse clinical musculoskeletal and neurological events in healthy postpartum women with live attenuated (RA27/3 strain) rubella-virus vaccine, and to assess the frequency of acute and recurrent arthralgia and arthritis and associations with acute and recurrent muscle pain (myalgia) and neurological manifestations (paraesthesias).

Methods

We used a randomised placebo-controlled, double-blind design in a community setting. 636 women were enrolled and, after 90 women dropped out, 546 healthy women aged 18–41 years, who were rubella seronegative on routine screening were immunised parenterally with either monovalent live attenuated (RA27/ 3 strain) rubella vaccine (n=270) or saline placebo (n=276) in the postpartum period. Outcome measures were the occurrence of acute and persistent or recurrent joint manifestations (arthralgia or arthritis) at 1, 3, 6, 9, and 12 months after immunisation. Occurrence of muscle pain (myalgia), and neurological symptoms (paraesthesia) was also assessed at the same times.

Findings

543 women completed 1-month follow-up. 456 women completed the 12-month assessment. There were no differences at the time of immunisation between rubella vaccine and placebo groups in distribution of age, ethnic origin, parity, time between delivery and immunisation, breastfeeding history, or histories of earlier rubella vaccination or joint complaints. Results indicated a significantly higher incidence (p=0·006; odds ratio= 1·73 [95% Cl=1·17–2·57]) of acute joint manifestations in rubella-vaccine recipients (30%) than in placebo recipients (20%). Frequency of chronic (recurrent) arthralgia or arthritis was only marginally significant (p=0·042; 1·58 [1·01–2·45]).

Interpretation

RA27/3 rubella vaccine given to seronegative women during the postpartum period was significantly associated with development of acute arthralgia or arthritis. Although the numbers of women assessed and length of follow-up revealed only marginally significant differences in persistent or recurrent joint manifestations between rubella vaccine and placebo recipients, it is possible that susceptible women who are given rubella vaccination may experience this outcome.

Introduction

Association of acute arthropathy with administration of vaccine containing live attenuated rubella virus has been reported since the introduction of rubella vaccines in the late 1960s.1, 2, 3, 4, 5, 6, 7, 8, 9 Reports show consistently that rubella-vaccine-associated arthropathy is uncommon in men or prepubertal children of either sex, but can occur in 10–40% of women who are rubella seronegative.10 Joints most frequently affected include proximal interphalangeal and metacarpophalangeal joints, knees, ankles, and toes. About 50% of the women who experience acute arthropathy are expected to develop recurrent joint manifestations that may last for months to years after vaccination.11, 12, 13, 14, 15 The frequency of rubella-vaccine-associated arthropathy varies with the strain of vaccine used. The frequency is highest with the HPV77(DK) strain, intermediate with the RA27/3 strain, and lowest with the Cendehill strain, which is also less immunogenic.5, 6, 7, 16, 17, 18 Severity of rubella-vaccine-associated arthropathy seems to increase with age, and women older than 25 years are most at risk.19

Infection with wild-type rubella virus has been temporally associated with fibromyalgia, paraesthesias, and arthritis, from which muscle weakness may persist after resolution.20, 21, 22 A hypothesis has been put forward that vaccination with the RA27/3 strain may also be associated with fibromyalgia and chronic fatigue syndromes.22 As with arthropathy, these syndromes are found almost exclusively in adult women. Rubella infection or vaccination has also been associated temporally with the development of thrombocytopenic purpura and neuropathies, including paraesthesias, radiculoneuritis, carpal tunnel syndrome, peripheral neuropathy, optic neuritis, and Guillain-Barré syndrome.10

Rubella seronegativity is often identified in early pregnancy through routine screening and rubella vaccine is given in the early postpartum period to prevent rubella infection in future pregnancies. The safety and effectiveness of the currently used RA27/3 strain vaccine seen in infants and young children has been less well investigated in rubella-seronegative women, who constitute the second most important target population. An investigation of the adverse sequelae of immunisation with pertussis and rubella by the United States National Academy of Sciences' Institute of Medicine10 concluded that evidence suggests there is a causal relation between rubella vaccination and development of acute arthritis, and is consistent with a causal relation between rubella vaccination and chronic arthritis. These conclusions led to clinical trials to investigate the safety of RA27/3 vaccine for use in women.

The objective of our study was to investigate the frequency of clinical musculoskeletal and neurological reactions (acute and chronic) in postpartum women who had been vaccinated with either monovalent live attenuated RA27/3 strain rubella-virus vaccine or saline placebo to find the occurrence of acute and recurrent arthralgia and arthritis. Our primary null hypotheses were that there would be no differences between recipients of rubella vaccine or placebo recipients in the frequency of acute adverse joint reactions (arthralgia or arthritis) during the 1–28-day period after vaccination, or the frequency of persistent (unremittent or recurrent) adverse joint reactions (arthralgia or arthritis) during the 1–12-month period after vaccination.

Section snippets

Methods

Potential study participants were identified through prenatal rubella-antibody screening, done by the Provincial Virology Laboratory, British Columbia Centre for Disease Control, Vancouver, Canada. Between April 1, 1989, and April 30, 1992, 636 rubella-seronegative women were enrolled in the study, which was approved by the medical ethics committees of the University of British Columbia and participating hospitals. Women were eligible for enrolment if they were: found to be seronegative with

Results

1683 rubella-seronegative women who lived in the study area were identified as potential participants (figure). 322 did not meet the inclusion criteria (did not speak English 86, moved away 52, miscarried or gave birth before enrolment 64, had medical reasons 38, physician refused 24, had been immunised previously 24, wrong age two, other 32). Of the 1361 eligible women 725 were not enrolled (lost to follow-up 178, no reason given 89, wanted vaccine immediately 88, planned pregnancy soon 78,

Discussion

Evidence that rubella-virus infection or vaccination is associated with chronic forms of arthritis in children and adults has come from many case reports.4, 12, 13, 14, 15, 24, 25, 26, 27, 28, 29, 30 Small epidemiological studies have shown an unacceptably high (13–15%) frequency of acute arthritis after immunisation of rubella-seronegative women with live attenuated RA27/3 rubella-virus vaccine. Polk and colleagues7 reported that 14 (26%) of 53 women who were given RA27/3 vaccine developed

References (35)

  • SL Spruance et al.

    Joint complications associated with derivatives of HPV-77 rubella virus vaccine

    Am J Dis Child

    (1971)
  • EK Barnes et al.

    Joint reactions in children vaccinated against rubella, study II: comparison of the three vaccines

    Am J Epidemiol

    (1972)
  • BF Polk et al.

    A controlled comparison of joint reactions among women receiving one of two rubella vaccines

    Am J Epidemiol

    (1982)
  • AJ Tingle et al.

    Prospective immunological assessment of arthritis induced by rubella vaccine

    Infect Immun

    (1983)
  • AJ Tingle et al.

    Postpartum rubella immunization: association with development of prolonged arthritis, neurological sequelae, and chronic rubella viremia

    J Infect Dis

    (1985)
  • AJ Tingle et al.

    Rubella-associated arthritis: comparative study of joint manifestations associated with natural rubella infection and RA27/3 rubella immunisation

    Ann Rheum Dis

    (1986)
  • Cited by (82)

    • Arthritis and arthralgia as an adverse event following immunization: A systematic literature review

      2019, Vaccine
      Citation Excerpt :

      The weakest causality assessment methods were identified in case reports (n = 6, 66.7%), two clinical trials and one passive surveillance study, relying on temporal associations [22–30]. A total of 19 (5.5%) studies provided measures of association with corresponding estimates of variance and reported the number of cases and population at-risk [10–12,31–46] (Tables 2 and 3). Seven (36.8%) of these studies were clinical trials of which two assessed arthritis, four assessed arthralgia, and one used a composite endpoint for the adverse event of interest.

    • Active Immunization

      2018, Principles and Practice of Pediatric Infectious Diseases
    • Rubella Vaccines

      2017, Plotkin's Vaccines
    • Legal Issues

      2017, Plotkin's Vaccines
    • The key role of rubella virus glycoproteins in the formation of immune response, and perspectives on their use in the development of new recombinant vaccines

      2016, Vaccine
      Citation Excerpt :

      Vaccination of adult women has been associated with chronic arthritis which is thought to be due to persistence of the vaccine virus [4,6]. The rate of vaccine-associated chronic arthritis appears to be extremely low [7–9], however chronic arthritis following rubella vaccination is included in the National Vaccine Injury Compensation Program [10]. Furthermore another complications of vaccination may occur such as post-infections encephalopathy, Guillain–Barré syndrome, haematological complications: transient thrombocytopenia, purpuric rash, haemolytic anemia [4,11–13].

    View all citing articles on Scopus
    View full text