Post-exposure passive immunisation for preventing rubella and congenital rubella syndrome

  • Review
  • Intervention

Authors


Abstract

Background

Control of rubella is desired because infection in early pregnancy can result in miscarriage, foetal death or congenital abnormality. Primary studies examining the effectiveness of immunoglobulins for post-exposure prophylaxis of rubella have small sample sizes and varying results. National public health recommendations suggest a degree of effectiveness.

Objectives

To assess the effectiveness of intramuscular injection or intravenous infusion of polyclonal immunoglobulins of human sera or plasma origin for preventing rubella and congenital rubella syndrome when administered to exposed susceptible people before the onset of disease.

Search methods

We searched CENTRAL (2014, Issue 7), MEDLINE (1946 to August week 2, 2014), EMBASE (1974 to August 2014), CINAHL (1981 to August 2014), LILACS (1982 to August 2014) and Web of Science (1955 to August 2014). We searched ClinicalTrials.gov and the World Health Organization International Clinical Trials Registry on 16 October 2014. We searched the reference lists of relevant retrieved reviews and studies and identified national public health guidelines.

Selection criteria

For the outcome 'preventing cases of rubella', we included randomised controlled trials (RCTs) and quasi-RCTs. We found several studies addressing this outcome where the design was a controlled clinical trial (CCT) (with exposure to rubella virus controlled by the investigators) but the method of allocation of participants to groups was not reported. We found an alternative report of one of these studies that indicated participants were assigned to groups randomly. We therefore included such studies as meeting criteria for RCTs or quasi-RCTs and undertook sensitivity analyses. For the outcomes, 'congenital rubella infection' and 'congenital rubella syndrome', we included RCTs, quasi-RCTs and prospective controlled (cohort) studies. Participants were necessarily susceptible and exposed to rubella. Polyclonal immunoglobulins derived from human sera or plasma must have been administered intramuscularly or intravenously as the only intervention in at least one group.

Data collection and analysis

We used the standard methodological procedures expected by The Cochrane Collaboration.

Main results

We included 12 studies (430 participants) in the review: seven RCTs and five CCTs where it was not clear whether participants were randomly allocated to groups. We did not include any unpublished studies. Participants included children and adults of both sexes. Only one study included pregnant women. All studies were conducted in high-income countries.

The quality of the 11 studies in the initial meta-analysis was moderate, although we classified no study as having a low risk of bias on all criteria.

We included 11 studies in the initial meta-analysis of gamma-globulin (concentrated polyclonal immunoglobulins) versus control (saline or no treatment) for rubella cases. The result favoured the intervention group (risk ratio (RR) 0.61, 95% confidence interval (CI) 0.45 to 0.83) but was heterogenous (Chi² test = 36.59, df = 10 (P value < 0.0001); I² statistic = 73%). Heterogeneity was explained by subgrouping studies according to the estimated volume of gamma-globulin administered per pound of bodyweight and then removing those studies where the intervention was administered more than five days after participant exposure to rubella (post hoc analysis). The test of subgroup differences demonstrated heterogeneity between subgroups according to our protocol definition (P value < 0.1; I² statistic > 60%) and there appeared to be greater effectiveness of the intervention when a greater volume of gamma-globulin was administered ('0.027 to 0.037 ml/lb' RR 1.60 (95% CI 0.57 to 4.52); '0.1 to 0.15 ml/lb' RR 0.53 (95% CI 0.29 to 0.99); '0.2 to 0.5 ml/lb' RR 0.20 (95% CI 0.04 to 1.00)).

None of the studies reported the outcome 'congenital rubella infection'. One included study reported on congenital rubella syndrome, with no cases among participants who were fewer than nine weeks pregnant at enrolment and who were randomised to one of two gamma-globulin groups ('high' or 'low' rubella titre). However, the study did not report how congenital rubella syndrome was measured and did not report the length of follow-up according to intervention group. This study did not include a non-treatment group.

No included study measured adverse events.

Authors' conclusions

Compared to no treatment, polyclonal immunoglobulins seem to be of benefit for preventing rubella. The available evidence suggests that this intervention may be of benefit up to five days after exposure, and that effectiveness is dependent on dose. Considering the attack rate for rubella cases in the control group of the highest volume gamma-globulin subgroup (333 per 1000), the absolute risk reduction (calculated from the RR) for this volume of gamma-globulin was 266 (95% CI 0 to 320) and the number needed to treat to benefit is four (95% CI 3 to incalculable).

The included studies did not measure rubella-specific antibodies in the immunoglobulin products used in a standard way and thus estimation of the dose of rubella-specific antibodies in international units administered was not possible. As the concentration of rubella-specific antibodies in today's polyclonal immunoglobulin products may vary from those products used in the studies in the review, the volume required per pound of bodyweight to produce similar results may also vary.

There is insufficient evidence to make direct conclusions about the effectiveness of polyclonal immunoglobulins for preventing congenital rubella syndrome. This is an area requiring further research.

Plain language summary

Passive immunisation (giving antibodies) for preventing rubella (German measles) after contact with it

Background and review question
People who have had rubella (German measles), or rubella vaccine, have antibodies against the virus in their blood. These antibodies protect them from getting rubella should they come into contact with it again. These antibodies can be extracted from blood donated by these people.

If people without antibodies come into contact with someone who is contagious with rubella, they can contract it. Rubella can be serious. The baby of a woman who is infected with rubella, especially early in pregnancy, may be born with a range of birth defects including heart, eye and hearing problems. One way of preventing rubella in people who come into contact with a contagious person is to inject them with antibodies that have been extracted from blood donations. This was done in the 1950s and 1960s and is still recommended for rubella control in some circumstances in some countries. Whether this is effective is unclear. We sought to answer this question.

Study characteristics
The evidence is current to August 2014. We included 12 studies (430 participants). People of all ages were included in the studies, which were conducted in high-income countries.

Key results and quality of the evidence
Eleven studies (389 participants) compared injecting antibodies into the muscle or vein of participants to injecting salt water or giving no treatment. The study participants did not have their own antibodies. They had been in contact with rubella between one and 28 days prior to receiving the antibodies. The antibodies seemed to be effective at preventing participants from catching rubella, with those receiving antibodies 39% less likely to develop rubella than those not given antibodies. In an analysis of the seven studies (89 participants) where participants had been in contact with rubella only up to five days earlier, people given the highest doses used in the studies were 80% less likely to develop rubella than those not given antibodies. The studies assessing the prevention of rubella were of moderate quality because of some methodological issues and the fairly small number of participants. It is important to consider that the amount of rubella antibodies in today's blood donations may differ from those used in the studies. Therefore, doses given today may need to vary from those of the studies in order to obtain the same effect.

Only one study included pregnant women. All of the women were given one of two different doses of antibodies. They did not measure whether the babies born to the women were infected with rubella, but did consider whether birth defects that may be related to rubella were present. Key details about the study methods were missing and unobtainable, so the quality of this study was unclear. None of the babies born to these women were identified as having birth defects related to rubella. However, we cannot draw direct conclusions from this single study about the effectiveness of injecting antibodies after contact with rubella for preventing rubella-related birth defects in pregnant women. This is an area that needs further research.

The included studies did not report adverse events. Future studies should report this outcome.

Laički sažetak

Pasivna imunizacija (davanje protutijela) za sprječavanje rubeole (crljenca) nakon kontakta s virusom

Dosadašnje spoznaje i istraživačka pitanja:
Osobe koje su preboljele rubeolu (crljenac) ili su cijepljena protiv rubeole imaju protutijela protiv tog virusa u svojoj krvi. Njihova protutijela štite ih da ne dobiju rubeolu ako opet dođu u kontakt s njom. Ta protutijela mogu se izolirati iz njihove donirane krvi.

Ako osobe bez protutijela dođu u kontakt s nekim tko prenosi rubeolu, može se zaraziti. Rubeola može uzrokovati ozbiljne probleme. Plod žene koja je zaražena rubeolom može imati razne urođene probleme, uključujući probleme sa srcem, očima i sluhom, pogotovo ako se zaraza dogodi u ranim stadijima trudnoće. Jedan način sprječavanja rubeole je davanje protutijela iz donacija krvi koja imaju protutijela. To je učinjeno 1950.-ih i 60.-ih za liječenje rubeole i još uvijek se preporučuje u nekim situacijama u nekim državama. Nisu poznati učinci tog postupka. U ovom Cochrane sustavnom pregledu traži se odgovor na ovo pitanje.

Obilježja studija:
Dokazi se odnose na studije dostupne do kolovoza 2015. Uključeno je 12 istraživanja (430 sudionika). Uključeni su ljudi svih dobnih skupina u državama s visokim prihodima.

Ključni rezultati i kvaliteta dokaza:
Jedanaest studija (389 sudionika) uspoređivale su unošenje protutijela kroz venu ili mišić s korištenjem fiziološke otopine (slane vode) ili ničega. Sudionici studije nisu imali svoja protutijela. Bili su u kontaktu s rubeolom maksimalno 28 dana prije primanja protutijela. Čini se da bi protutijela mogla biti učinkovita u prevenciji infekcije rubeolom. Osobe koje su primale protutijela imale su 39% manju pojavnost rubeole. U analizi sedam studija (89 sudionika) u kojima su ispitanici bili u kontaktu s rubeolom maksimalno 5 dana prije primanja protutijela. Oni ispitanici koji su dobili najviše doze imali su 80% manju pojavnost rubeole od onih koji nisu primali protutijela. Studije su bile umjerene kvalitete zbog određenih problema u provedenim metodama i relativno malog broja ispitanika. Važno je uzeti u obzir da današnja količina protutijela u krvi na rubeolu ne mora odgovarati količini dobivenoj u studijama. Stoga doze koje se daju danas možda se trebaju razlikovati u odnosu one korištene u studijama kako bi se postigao isti učinak.

Jedno istraživanje uključivalo je trudne žene. Svim ženama dane su jedna ili dvije doze protutijela. Nije zabilježeno je li novorođenčad imala rubeolu, ali praćeni su urođeni poremećaji povezani s rubeolom. Ključni detalji o metodi istraživanja nisu zabilježeni i nije im moguće pristupiti, tako da kvaliteta istraživanja nije poznata. Nijedno od rođene djece nije imalo urođene poremećaje povezane s rubeolom. Ne mogu se izvući zaključci o djelotvornosti iz ovog jednog istraživanja. Postoji velika potreba za daljnjim istraživanjem u tom području.

Nijedna uključena studija nije opisala nuspojave. Buduće studije trebale bi uključiti ovaj ishod.

Bilješke prijevoda

Hrvatski Cochrane
Preveo: Ante Begonja
Ovaj sažetak preveden je u okviru volonterskog projekta prevođenja Cochrane sažetaka. Uključite se u projekt i pomozite nam u prevođenju brojnih preostalih Cochrane sažetaka koji su još uvijek dostupni samo na engleskom jeziku. Kontakt: cochrane_croatia@mefst.hr

Summary of findings(Explanation)

Summary of findings for the main comparison. Gamma-globulin compared to control (saline or no treatment) for preventing rubella or congenital rubella syndrome
  1. 1Downgraded one level for risk of bias. Most information was from studies at low and unclear risk of bias. Two studies were at high risk of detection bias only. Three studies were at high risk of selective reporting only, and this was unlikely to affect their results.
    2Downgraded one level for inconsistency. The studies' results were statistically heterogenous.
    3Upgraded one level for plausible confounding would reduce the measure of effect. The plausible confounding factors we listed a priori were: dose, time between exposure and intervention, immunosuppression, age and gestation. No studies in this meta-analysis included pregnant women or identified immunosuppressed individuals. Subgroup analysis by age showed no difference between the subgroups. This analysis includes studies where the intervention was administered longer than five days after exposure and includes studies that administered lower volumes of immunoglobulin per unit weight than others. Both of these factors would reduce the measure of effect.
    4Downgraded one level for risk of bias. The sole study in this subgroup was at high risk of detection bias as the outcome was assessed subjectively and there was no reported blinding of outcome assessors.
    5Downgraded two levels for imprecision. The sole study in this subgroup had a small sample size and the resulting confidence interval is wide.
    6Upgraded one level for apparent dose response effect. While there is overlap in the confidence intervals, there appeared to be heterogeneity across estimated dose subgroups (P value = 0.07; I² = 62.4%) and the estimates of effect seemed to indicate greater effectiveness with greater estimated dose.
    7Downgraded one level for imprecision. Each trial in this subgroup was of small sample size and the overall sample size for the subgroup is small. However, the confidence interval does not include one.
    8Downgraded one level for risk of bias. Two of the three studies in this subgroup had a high risk of selective reporting bias.
    9Downgraded two levels for imprecision. The trials in this subgroup were small, the overall sample size of the subgroup was small and the confidence interval of the pooled estimate of effect extended to 1.00.
    10Upgraded one level for large effect estimate. The pooled estimate of effect for this subgroup was 0.2.
    11This subgroup analysis excluded studies where the intervention was provided more than five days after exposure.
    12One study included in the review compared a 'high' titre gamma-globulin with a 'low' titre gamma-globulin control group. This study did not identify any cases of congenital rubella syndrome among any of the infants born to participants although the means of assessment was not reported and the length of follow-up was not given by study group.

Gamma-globulin compared to control (saline or no treatment) for preventing rubella or congenital rubella syndrome
Patient or population: susceptible people exposed to rubella
Settings: community, different residential institutions, universities and medical settings
Intervention: gamma-globulin
Comparison: saline or no treatment
OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of participants
(studies)
Quality of the evidence
(GRADE)
Comments
Assumed riskCorresponding risk
Control (saline or no treatment) Gamma-globulin
Rubella cases
Initial meta-analysis - clinical diagnosis or serology +/- virus isolation +/- clinical signs
Follow-up: 3 to 8 weeks
Study population RR 0.61
(0.45 to 0.83)
389
(11 studies)
⊕⊕⊕⊝
moderate 1,2,3
273 per 1000 166 per 1000
(123 to 226)
Moderate
571 per 1000 348 per 1000
(257 to 474)
Subgroup: rubella cases Estimated dose 0.027 to 0.037 ml/lb11
Clinical diagnosis by 2 physicians
Follow-up: 21+ days
Study population RR 1.6
(0.57 to 4.52)
24
(1 study)
⊕⊕⊝⊝
low 4,5,6
333 per 1000 533 per 1000
(190 to 1000)
Moderate
571 per 1000 914 per 1000
(325 to 1000)
Subgroup: rubella cases Estimated dose 0.1 to 0.15 ml/lb11
Serology +/- virus isolation +/- clinical signs
Follow-up: 6 to 8 months
Study population RR 0.53
(0.29 to 0.99)
37
(3 studies)
⊕⊕⊕⊕
high 6,7
765 per 1000 405 per 1000
(222 to 757)
Moderate
571 per 1000 303 per 1000
(166 to 565)
Subgroup: rubella cases Estimated dose 0.2 to 0.5 ml/lb11
Serology +/- virus isolation +/- clinical signs
Follow-up: 3 to 6 weeks
Study population RR 0.2
(0.04 to 1)
28
(3 studies)
⊕⊕⊕⊝
moderate 6,8,9,10
333 per 1000 67 per 1000
(13 to 333)
Moderate
571 per 1000 114 per 1000
(23 to 571)
Cases of congenital rubella infection - not measuredSee commentSee commentNot estimableSee commentNo included studies measured the outcome congenital rubella infection
Cases of congenital rubella syndrome - not measuredSee commentSee commentNot estimableSee commentNo included studies of gamma-globulin versus control measured the outcome congenital rubella syndrome12
Adverse events - not measuredSee commentSee commentNot estimableSee commentNo included studies measured adverse events
*The basis for the assumed risk is the median control group risk across studies included in the initial meta-analysis. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: confidence interval; RR: risk ratio
GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

Background

Global rubella control has progressed since the introduction of rubella vaccine (Usonis 2011; WHO 2011). However, country-specific control varies greatly, with some countries citing evidence of rubella elimination (Best 2007; Reef 2011), while the burden of disease is unknown and rubella vaccination is still unavailable in others (Goodson 2011). Many countries report large numbers of cases and outbreaks of rubella (Muscat 2012; Usonis 2011; WHO 2011). Though vaccination is available in these countries, rates are not sufficiently high to achieve adequate rubella control (Muscat 2012; Usonis 2011). In 2009, more than 120,000 cases of rubella and 165 cases of congenital rubella syndrome (CRS) (see Description of the condition) were reported to the World Health Organization (WHO) by member states (Strebel 2010). However, these figures are believed to be a gross underestimate of the global burden of disease, with modelling predicting 110,000 cases of CRS in low-income countries during the non-epidemic year of 1996 (Cutts 1999). Under-reporting of rubella and CRS is thought to be a particular problem in the WHO's African, South-East Asia and Eastern Mediterranean Regions (Strebel 2010). Even in countries with low incidences of rubella, groups with low vaccination coverage persist and cases of CRS are still reported (Muscat 2012; Song 2012).

The proportion of women of child bearing age who are not immune to rubella also varies around the world. Some countries, such as Sweden, the Czech Republic and Australia, have recorded figures of less than 5% (between 1996 and 2004) (Nardone 2008), while others have much higher proportions; for example, Bangladesh (16% in 2004 to 2005) (Nessa 2008), Singapore (16% in 2004) (Ang 2010), Morocco (17% in 2000) (Caidi 2009), India (12% to 23% between 2000 to 2008) (Dewan 2012) and Turkey (45% in one city in 2005) (Sasmaz 2007).

The cost of treating a child with CRS has been estimated in several countries. In Panama in 1989, the annual treatment cost was estimated as USD 2291, while in Jamaica in 1997, it was estimated as USD 13,482 (Hinman 2002). The lifetime cost of treating a child with CRS was estimated to be USD 50,000 and USD 63,990 in Barbados and Guyana respectively in 1997 and USD 300,000 in the United States of America in the 1980s (Hinman 2002).

While vaccination is the cornerstone for the prevention of CRS at the population level, there is little in the way of prevention to offer susceptible pregnant woman exposed to the rubella virus. Before rubella vaccine became available, passive immunisation was investigated as a means of preventing rubella infection, with mixed results (Green 1965a; Green 1965b; Green 1965c; McDonald 1963). Countries with low incidences of rubella still recommend the use of passive immunisation for the individual exposed and susceptible pregnant woman in certain circumstances.

The national recommendations in the United States (US), the United Kingdom (UK) and New Zealand (NZ) suggest offering passive immunisation (a single injection of human immunoglobulin (IG)) to exposed pregnant women for whom termination of pregnancy is not acceptable should rubella infection occur (CDC 1998; CDC 2001; IDHPA 2009; NZMoH 2014; PHE 2013). Australian recommendations are similar but do not include consideration of termination of pregnancy (ATAGI 2013). The rationales for these recommendations differ. For example, the UK Immunoglobulin Handbook suggests IG "does not prevent infection in non-immune contacts but may reduce the likelihood of clinical symptoms, which may possibly reduce the risk to the foetus" (IDHPA 2009); the NZ Immunisation Handbook states "Although IG has been shown to reduce clinically apparent infection in the mother, there is no guarantee that foetal infection will be prevented" (NZMoH 2014 p452); and the Australian Immunisation Handbook states that IG may prolong the incubation period, which may reduce the risk to the foetus (ATAGI 2013). The recommended doses of IG also differ.

Despite the differences, these countries' national recommendations suggest some degree of effectiveness of passive immunisation for preventing rubella. However, they do not indicate the magnitude of the effect, nor (where applicable) adequately explain why a woman's thoughts about termination should influence the practice of passive immunisation in this situation.

Description of the condition

Rubella is a single-stranded ribonucleic acid (RNA) virus that is transmitted by respiratory droplets or direct contact with the respiratory secretions of an infectious person (Heymann 2008). Someone with rubella is infectious from up to seven days before and until 14 days after the onset of rash, though the time of greatest infectivity is at rash onset (Usonis 2011; WHO 2011). A susceptible person exposed to rubella will develop the disease between 12 and 23 days after exposure (WHO 2011).

Rubella is typically a mild, self limiting disease in susceptible children and adults (WHO 2011). Up to 50% of rubella virus infections are asymptomatic (Heymann 2008; Pattison 1975). When present, symptoms include fever, headache, a generalised red blotchy rash, tender enlarged lymph nodes, joint pain and mild conjunctivitis (Usonis 2011). Occasionally (one in 6000 cases), rubella infection may be complicated by encephalitis (WHO 2011).

The diagnosis of rubella is typically confirmed by measuring the increase in a particular type of rubella-specific antibody (rubella-specific IgG) in blood or by growing the virus from, or detecting the virus in, respiratory secretions, urine or blood (PHLN 2010). The presence of another type of rubella-specific antibody (rubella-specific IgM) is also indicative of disease (CDC 2001).

Control of rubella is desired because infection during the early part of pregnancy can result in miscarriage, foetal death or congenital abnormality (Usonis 2011). An infant born with any of the common congenital defects resulting from foetal rubella infection is said to have CRS. This includes cataracts, congenital heart disease, hearing impairment and microcephaly (WHO 2011). Estimates of the risk of CRS after rubella infection during pregnancy vary considerably but it is agreed that the risk decreases as the pregnancy progresses (Best 2007; De Santis 2006). De Santis et al have summarised a large number of studies, indicating that the risk of CRS when rubella infection occurs in the first trimester (12 weeks) of pregnancy is between 38% and 100%, when infection occurs in the second trimester is between 4% and 60% and when infection occurs in the third trimester is between 0% and 18% (De Santis 2006). The types of defects likely to manifest also vary according to the stage of pregnancy when infection occurs (Banatvala 2004). Multiple defects are more likely to occur when infection is early in the pregnancy (Best 2007). Hearing impairment is typically the only defect resulting from infection after the 16th week of pregnancy (WHO 2011), while impairment of foetal growth may continue to occur as a result of infection in the third trimester (De Santis 2006).

The diagnosis of congenital rubella syndrome is confirmed in babies with suggestive congenital malformations by detecting rubella-specific IgM in their blood, measuring the increase in rubella-specific IgG in the first year of life, or by growing the virus from, or detecting the virus in, respiratory secretions or urine (PHLN 2010).

Description of the intervention

In the early days of passive immunisation, a number of formulations of immunoglobulins were used. These included the serum of someone who was convalescing from the disease; the serum of an animal that had been actively immunised against the disease; or concentrated gamma-globulins (one class of immunoglobulins) derived from either pooled extracts from human placentas, pooled blood from human placentas or pooled human blood (McDonagh 1966). Modern passive immunisation has changed little from this last technique. It involves administration of concentrated immunoglobulins, mostly gamma-globulins, derived from at least 1000 adult blood donations (WHO 1994). Different products are available for intramuscular and intravenous administration (Burnouf 2007). With respect to rubella, the product recommended is usually human polyclonal immunoglobulins for intramuscular injection (IG). The concentration of rubella-specific immunoglobulins (antibodies) in polyclonal immunoglobulin products may vary depending on manufacturing processes and the average level of rubella-specific antibodies in the donated blood (Simon 2003).

How the intervention might work

Whether injected or infused, the administered immunoglobulins distribute throughout the recipient's body into the spaces between cells (Birdsall 2009). The mechanism by which the recipient might be protected from disease involves interaction between the immunoglobulins (antibodies), the invading rubella virus particles and the cells and molecules of the recipient's immune system (Reading 2007). The exact mechanisms by which viral infectivity is mitigated by antibodies within the body are not comprehensively understood but vary according to the structure and functionality of the particular antibodies as they encounter the particular virus particles (Reading 2007). For viruses in general, several mechanisms of action are thought to occur. Firstly and most importantly, antibodies bind to the invading particles, directly preventing their entry into cells; a process called neutralisation (Birdsall 2009; Burton 2002). Secondly, antibodies may block cell surface receptors, preventing the virus from entering the cell (Reading 2007). Thirdly, antibodies can activate other parts of the immune system resulting directly in viral destruction (Birdsall 2009; Law 2008). Finally, antibodies bind to infected cells facilitating their destruction (Burton 2002; Law 2008).  

Why it is important to do this review

No systematic review of the effectiveness of passive immunisation for the prevention of rubella currently exists and the evidence on which public health practice is based with regards to non-immune pregnant rubella contacts is limited and somewhat contradictory.

UK guidelines do not reference the statement that "there is no evidence that it is effective" (referring to using IG for post-exposure prophylaxis for pregnant women) (IDHPA 2009 p359). The Australian Immunisation Handbook references the US guidelines for each of the statements about post-exposure passive immunisation for rubella (ATAGI 2013). These Australian guidelines state that post-exposure passive immunisation "does not prevent infection in non-immune contacts" (ATAGI 2013 p396), whereas the NZ guidelines state that "IG has been shown to reduce clinically apparent infection in the mother" but do not reference this statement (NZMoH 2014 p452). The US guidelines provide two references at the end of the paragraph on post-exposure passive immunisation against rubella (CDC 1998). One is a primary controlled study on passive immunisation under experimental conditions that indicated efficacy of high-dose immunoglobulin within 24 hours of exposure but limited efficacy at lower doses (Schiff 1969d). The other is a book chapter that does not include in-text citations (Waagner 1993). It states that: "Immune globulin may reduce clinical findings but does not prevent viraemia". There is no indication of the dose of IG, anti-rubella antibody concentration or timing of administration to which this statement is referring. The statement conflicts with the study by Schiff 1969d (the other reference used in the US guidelines) that concluded viraemia was prevented with high-dose IG. Waagner's book chapter goes on to indicate the author's personal preference for only using immunoglobulin for pregnant women presenting within 72 hours of exposure for whom therapeutic abortion is not an option (Waagner 1993). In addition to the claim that IG given post-exposure will not prevent viraemia, the author reasons that asymptomatic infection may occur in the mother post-IG, anti-rubella antibody titres in IG vary and there have been infants born with CRS despite post-exposure prophylaxis with IG. Again, each of these points is unreferenced. The author does not consider the possibility of detecting asymptomatic infection in the women post-IG administration using serial serological testing, despite the recommendation that exposed pregnant women undergo such testing immediately post-exposure and then at two to three and six weeks post-exposure.

No primary research evidence has been published in the last three decades on the use of IG or immunoglobulins generally for preventing rubella in non-immune exposed pregnant women. However, a number of controlled studies have been identified that examine the effectiveness or efficacy of passive immunisation against rubella post-exposure (Bass 1949; Doege 1967; Green 1965a; Green 1965b; Green 1965c; Macrae 1968; McCallin 1972; Neumann-Haefelin 1975; Petersen 1978; Schiff 1969d). Each of these studies includes small numbers of participants and varying conclusions are drawn about the effectiveness of the intervention. No significant adverse events are noted. 

A systematic review of the evidence provides a firm foundation on which to review current policy and practice of passive immunisation for preventing rubella and congenital rubella syndrome.

Objectives

To assess the effectiveness of intramuscular injection or intravenous infusion of polyclonal immunoglobulins of human sera or plasma origin for preventing rubella and congenital rubella syndrome when administered to exposed susceptible people before the onset of disease.

Methods

Criteria for considering studies for this review

Types of studies

To assess the effectiveness of polyclonal immunoglobulins for preventing cases of rubella:

We included randomised controlled trials (RCTs) and quasi-RCTs that examined this outcome, irrespective of blinding, publication status, language or unit of randomisation.

(To note: We found several studies addressing this outcome where the design was a controlled clinical trial (with exposure to rubella virus controlled by the investigators) but the method of allocation of participants to groups was not reported. We found an alternative report of one of these studies that indicated participants were assigned to groups randomly. We therefore included such studies as meeting the criteria for RCTs or quasi-RCTs and undertook sensitivity analyses.)

To assess the effectiveness of polyclonal immunoglobulins for preventing congenital rubella infection and congenital rubella syndrome:

We included RCTs, quasi-RCTs and prospective controlled studies (cohort studies) that examined either or both of these outcomes, irrespective of blinding, publication status, language or unit of randomisation. We included prospective controlled studies for these outcomes given that pregnant women would ethically not have been randomised to treatment and control groups, given that this intervention was felt to be beneficial from the time it was first used.

To be considered an eligible prospective controlled study, the intervention and control groups of relevance needed to be recruited over the same (or similar and overlapping) timeframe and from the same population and the study must have specified that the intervention and control populations of relevance were exposed to rubella during pregnancy and were susceptible to rubella at the time of exposure. We excluded the study if any of these points could not be determined from the information available either in the publication or from the study authors.

To assess adverse events:

We included data on adverse events from any of the studies included in the review as above.

Types of participants

Participants were people of any age, sex or ethnic origin who were susceptible (no history of rubella and not vaccinated against rubella and/or rubella IgG negative) and exposed to rubella virus or exposed to someone diagnosed with rubella and who did not already have rubella at the time of intervention or control administration. We accepted the primary study's definition of exposed and explored any differences via subgroup analysis. For the congenital rubella infection and congenital rubella syndrome outcomes, participants must have been pregnant at the time of rubella exposure.

Types of interventions

To assess the effectiveness of polyclonal immunoglobulins for preventing cases of rubella:

Intervention:

  1. intramuscular injection of polyclonal immunoglobulins;

  2. intravenous infusion of polyclonal immunoglobulins.

Control:

  1. no intervention or placebo;

  2. live attenuated rubella virus vaccine;

  3. different preparation and/or dosage of polyclonal immunoglobulins.

To assess the effectiveness of polyclonal immunoglobulins for preventing congenital rubella infection and congenital rubella syndrome:

Intervention:

  1. intramuscular injection of polyclonal immunoglobulins;

  2. intravenous infusion of polyclonal immunoglobulins.

Control:

  1. no intervention or placebo;

  2. different preparation and/or dosage of polyclonal immunoglobulins.

For all outcomes, polyclonal immunoglobulins must have originated from human plasma or serum. We excluded studies of immunoglobulins of animal origin and studies of immunoglobulins derived from placentas or given as human whole blood as these are not used in modern day practice.

Types of outcome measures

Primary outcomes
  1. Cases of rubella. The diagnosis may have been made by detection or isolation of rubella virus in urine, respiratory secretions or blood; by rubella-specific IgG seroconversion or a four-fold or greater rise in titre; by serological detection of IgM to rubella in the presence of a compatible clinical illness and no recent vaccination; or by symptoms consistent with rubella (fever, a generalised maculopapular rash and one or more of arthralgia/arthritis, lymphadenopathy, conjunctivitis) in the absence of other diagnoses as judged by a medical professional.

  2. Cases of congenital rubella infection. The diagnosis may have been made by detection or isolation of rubella virus in the infant's urine, respiratory secretions or blood or in the products of conception; by serological detection of rubella-specific IgM in the infant's serum; or by rising rubella-specific IgG in the infant's serum in the first year of life.

  3. Cases of congenital rubella syndrome. A live or stillborn infant with any of the following compatible defects: cataracts, congenital glaucoma, congenital heart disease, hearing impairment, pigmentary retinopathy, microcephaly, mental retardation, purpura, hepatosplenomegaly, meningoencephalitis, radiolucent bone disease; and evidence of congenital rubella infection or maternal antepartum rubella infection.

Secondary outcomes
  1. Occurrence of serious adverse events.

  2. Occurrence of non-serious adverse events.

A serious adverse event was defined as "any untoward medical occurrence that at any dose: results in death; is life-threatening; requires inpatient hospitalisation or prolongation of existing hospitalisation; results in persistent or significant disability/incapacity; or is a congenital anomaly/birth defect" (EMEA 1995; p4). We classified all other events as non-serious.

We specifically extracted data on blood-borne virus infection; anaphylaxis (a rapidly evolving generalised multi-system allergic reaction characterised by one or more symptoms or signs of respiratory and/or cardiovascular involvement AND involvement of other systems such as skin or gastrointestinal tract (ATAGI 2008 p360); generalised hypersensitivity/generalised allergic reaction (non-anaphylactic generalised reaction characterised by one or more symptoms or signs of skin and/or gastrointestinal tract involvement without respiratory or cardiovascular involvement (ATAGI 2008 p360); and injection site reactions. We also included any other adverse event reported as such by study authors.

Search methods for identification of studies

Electronic searches

We searched the Cochrane Central Register of Controlled Trials (CENTRAL 2014, Issue 7), which contains the Cochrane Acute Respiratory Infections (ARI) Group's Specialised Register, MEDLINE (OVID) (1946 to August week 2, 2014), CINAHL (1981 to August 2014), EMBASE (1974 to August 2014), LILACS (1982 to August 2014) and Web of Science (1955 to August 2014). We used the search strategy in Appendix 1 to search MEDLINE and CENTRAL. We adapted the strategy for EMBASE (Appendix 2), CINAHL (Appendix 3), LILACS (Appendix 4) and Web of Science (Appendix 5). We combined the MEDLINE and EMBASE searches with the filter for study type in Appendix 6.

Searching other resources

We searched the reference lists of retrieved relevant studies and reviews. To locate further published or unpublished studies, we attempted to contact companies manufacturing IG products for countries with low rubella incidences and also attempted to contact the corresponding author of any included studies. We searched the reference lists of published national public health guidelines on rubella control. We searched ClinicalTrials.gov and the World Health Organization International Clinical Trials Registry (WHO ICTRP) using the terms "rubella" OR ("German" AND "measles") on 16 October 2014.

Data collection and analysis

Selection of studies

Two review authors (MY, GN) independently inspected the title and abstract (as available) of each reference identified by the electronic searches and determined the potential relevance of each article. If identified by either review author as potentially relevant, we retrieved the full article. One review author (MY) searched the trials databases and the reference lists of relevant retrieved full-text articles for further studies. We retrieved these articles where the title indicated possible relevance and exclusion was not possible based on the abstract where this was available. Both review authors inspected each retrieved full-text article independently, using an eligibility checklist based on the inclusion criteria, to determine inclusion in the review. We resolved any disagreements through discussion. We excluded studies not meeting the eligibility criteria and stated the reasons for exclusion. Among the articles retrieved in full text, we found several studies where the design was a controlled clinical trial (CCT) (with exposure to rubella virus controlled by the investigators) but the method of allocation of participants to groups was not reported. An alternative report of one of these studies indicated participants were assigned to groups randomly, therefore we mutually agreed to include such studies and then undertake sensitivity analysis.

We listed duplicate publications with the main publication for included studies. 

Data extraction and management

Two review authors (MY, AC) independently extracted data from the included studies using pre-designed data extraction forms. We resolved disagreement by discussion. We attempted to contact study authors for clarification or further information as necessary.  

We extracted the following data.

  1. The study

    1. First author, publication year/not published.

    2. Setting of the study.

    3. Date study undertaken.

    4. Study design: RCT, quasi-RCT, CCT or non-randomised.

  2. Participants

    1. Number in each group.

    2. Age range in each group.

    3. Gender distribution in each group.

    4. Range of gestation in each group if relevant.

    5. Range of time since exposure in each group.

    6. Average time since exposure in each group.

    7. Any measure of baseline comparability and result of this, if calculated.

  3. Intervention

    1. Intervention group: product used, concentration of rubella antibody if known, volume given, route of administration.

    2. Control group: placebo/vaccine/product/other, concentration of rubella antibody if relevant and known, volume given, route of administration.

  4. Outcomes

    1. Primary and secondary (as above).

    2. Length of follow-up.

    3. Loss to follow-up.

Assessment of risk of bias in included studies

Two review authors (MY, AC) independently assessed the risk of bias for included studies. We resolved any disagreements by discussion. 

The 12 included studies were either RCTs or controlled clinical trials (CCTs) where the means of allocation of participants to groups was not reported. An alternative report of one of these latter studies indicated that participants were assigned to groups randomly, therefore we included such studies as meeting the criteria for RCTs/quasi-RCTs.

We therefore assessed randomisation sequence generation; allocation concealment; blinding of participants, personnel and outcome assessors; incomplete outcome data; drop-out/selective reporting; and other potential sources of bias. We reported the risk of bias using The Cochrane Collaboration's tool for assessing 'Risk of bias' (Higgins 2011). 

We conducted sensitivity analyses based on the study type and the risk of bias of included studies. We reported these results descriptively.

Measures of treatment effect

We undertook data analyses in RevMan 5.3 (RevMan 2014). Outcomes, as identified above, are dichotomous. We expressed these outcomes as risk ratios (RR) and calculated 95% confidence intervals (CIs) for each.

Unit of analysis issues

Our protocol specified that should cluster-randomised trials be included in the review, we would attempt to extract RRs and 95% CIs resulting from analyses that have accounted for the clustering directly from the article/s. If this had been possible, we would have proceeded to meta-analyse the data using the inverse variance method. If this had not been possible, we would have extracted the number of clusters, the average size of each cluster, the outcome data at the level of the individuals and an estimate of the intra cluster correlation coefficient and proceeded to reduce the trial/s to their 'effective sample size' for meta-analysis following the recommendations in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). However, we did not identify any cluster-randomised trials that met our inclusion criteria.

Our protocol specified that should studies with multiple intervention groups, for example, different doses of immunoglobulins compared to control, be included in the review, we would initially split the shared group/s and include the relevant pair-wise comparisons in the meta-analysis (Higgins 2011). Then, if there was no significant heterogeneity between the different interventions/controls from the same study, we would combine the groups and include the single intervention and single control group in the final meta-analysis, or if significant heterogeneity existed, we would explore the differences in subgroup analyses. However, we did not identify any studies with multiple intervention groups, for example, different doses of immunoglobulins compared to control, which met our inclusion criteria.

Dealing with missing data

Our protocol specified that we would attempt to contact the trial authors for any missing data. Then, for remaining missing data we would analyse using the intention-to- treat (ITT) principle with all missing data considered treatment failures. If we undertook ITT analysis, we would undertake sensitivity analysis assuming worst-case (all missing data are treatment failures) and best-case scenarios (missing data assigned as successful as in reported data or last observation carried forward or all missing data considered successful). However, for all included studies, follow-up of participants was complete.

Assessment of heterogeneity

We considered heterogeneity firstly by considering the populations, settings, methods and outcomes of the different studies. We were not able to undertake meta-analysis for the primary outcomes 'congenital rubella infection' (no studies assessed this outcome) and 'congenital rubella syndrome' (only one study assessed this outcome). We described the results of the study assessing congenital rubella syndrome descriptively. We did not identify clinically important heterogeneity that would have required reporting results descriptively for the primary outcome 'rubella cases', so we inspected the forest plot for this outcome.  As per our protocol, we considered an I2 statistic estimate of 60% or more, alongside a Chi2 test P value of 0.1 or less to indicate important heterogeneity and proceeded to subgroup and sensitivity analyses.

Assessment of reporting biases

In the event of multiple publications of the same study, we listed the subsequent articles with the main article and only entered data once. 

Our protocol indicated that we would assess publication bias by examining funnel plots if sufficient studies (at least 10) were included. However, our final meta-analysis included only seven studies. Further, all included studies had fairly small sample sizes. The largest study was of 179 participants.

Data synthesis

We calculated the RRs and 95% CI for each outcome measured in each study. 

We initially included all studies relevant to the outcome subject to meta-analysis and examined the forest plot to assess heterogeneity. We explored possible reasons for apparent heterogeneity via subgroup and sensitivity analyses. As per our protocol, we pooled the results using a fixed-effect model. 

We reported the results of those outcomes where meta-analysis was not undertaken descriptively. We reported the results of the secondary outcomes descriptively.

Subgroup analysis and investigation of heterogeneity

Our protocol listed the following subgroup analysis that we were unable to perform:

  • dose of rubella-specific immunoglobulins (most studies reported rubella-specific antibody titres for the immunoglobulin product/s used, however, none of the included studies reported the rubella-specific antibody concentration in international units or reported using an internationally recognised standard control when assessing this measure. It was thus not possible to compare and categorise the products used into similar rubella-specific antibody concentrations.)

Further, the following subgroup analyses were not relevant to the review:

  • stage of gestation (trimester of pregnancy) (none of the studies included in meta-analyses included pregnant participants);

  • route of administration of immunoglobulins (all except Martin du Pan 1972 administered IG via the intramuscular route);

  • per protocol versus ITT analysis (to account for missing data) (participant follow-up was complete for all studies).

We undertook the following subgroup analyses as identified in our protocol:

  • study type (CCT and RCT);

  • age of participants (children, adults, mixed) (adults were defined using the widely accepted, legal 'age of majority' definition for most countries (World Law Direct 2009; Zeldin 2007), 18 years and over);

  • dose of immunoglobulins (0.027 to 0.037 ml/lb; 0.1 to 0.15 ml/lb; 0.2 to 0.5 ml/lb). In those studies where the same volume was administered to each adult participant and participant weights were not reported (Martin du Pan 1972; Petersen 1978; Schiff 1969b), the volume administered by weight was estimated using 70 kg (154 lb) as the weight of an adult. Similarly, the 50th percentile weight for age for males according to current Australian growth charts (NSW Health 2014) was used (126 to 150 lb) for the study where participants were adolescent boys aged 15 to 18 years in Australia but no participant weights were reported (Anderson 1953b). We then determined dose categories by visually assessing the number and range of volumes per pound administered in the different studies. We excluded McDonald 1963 because the amount of IG given was given in milligrams instead of as a volume;

  • timing of administration of intervention in relation to exposure (exposure 24 hours to five days prior to IG; and exposure up to eight to 28 days prior to IG) (we excluded Green 1965c and McDonald 1963 because the timing of the intervention in relation to exposure was not reported);

  • differences in primary study definitions of 'exposed' (artificial exposure; controlled exposure to an infected person; household contact with a diagnosed case) (we excluded McDonald 1963 because the nature of exposure was not reported);

  • differences in primary study measurement of outcomes (laboratory-confirmed; and cases defined on clinical grounds only) (we excluded McDonald 1963 because no information was reported on how rubella cases were assessed);

  • funder (those with potential conflict of interest (gamma-globulin provided by a company); and no known conflict of interest) (we included Martin du Pan 1972; McDonald 1963; Petersen 1978 in the subgroup "no known conflict of interest" but we noted that the funding source was not reported).

Sensitivity analysis

We performed sensitivity analyses as per our protocol to assess the impact of heterogeneity and risk of bias on the pooled estimate/s of meta-analyses. For heterogeneity, we gradually removed single trials that seemed to contribute to heterogeneity upon inspection of the forest plots. For risk of bias, we pooled the studies with the lowest risk of bias and then gradually added the studies assessed as having a higher risk of bias.

We undertook additional sensitivity analyses because of the inclusion of controlled clinical trials where the means of allocation of participants was not reported and because we noted some included studies used history only to assess susceptibility for rubella whereas the majority identified those susceptible according to serology. We gradually removed the controlled clinical trials from the analysis firstly in order of the magnitude of the effect estimate (largest to smallest) and then separately in order of the size of the trial (largest to smallest). We simultaneously removed the three studies that used history only to assess susceptibility of participants to rubella at the beginning of the respective trials.

Overall quality of the evidence

We used the GRADE approach to assess the overall quality of the evidence (GRADE Working Group 2004). One author (MY) entered the information into GRADEpro (GRADEpro 2015) and produced the 'Summary of findings' table for the primary outcomes and adverse events (Summary of findings for the main comparison). For the primary outcome 'Rubella cases', we included both the initial meta-analysis and the final (subgroup analysis that explained heterogeneity) meta-analysis results.

Results

Description of studies

Results of the search

The number of search results obtained from each database prior to duplicate removal was CENTRAL (168), MEDLINE (1664), EMBASE (747), CINAHL (78), LILACS (120) and Web of Science (563). Of these, we retrieved 71 full-text articles resulting in eight included studies.

Searching the reference lists of relevant retrieved full-text articles identified a further 79 unique records, of which we retrieved 69 full-text articles resulting in four additional included studies (Figure 1).

Figure 1.

Study flow diagram.

Searching ClinicalTrials.gov returned 108 records and WHO ICTRP returned 157 records. We did not identify any additional relevant studies.

We sent electronic written requests to 13 separate companies that manufacture immunoglobulin products (Appendix 8) and the Australian Technical Advisory Group on Immunisation (ATAGI). Six companies and ATAGI responded. We did not identify any additional relevant studies.

We searched the reference lists of 18 documents we identified as published national public health guidelines on rubella control (Appendix 9). We did not identify any additional relevant studies.

The age of the included studies and absent up-to-date contact details for authors meant that we were not able to contact the authors of any included studies.

Included studies

We included 12 studies in the review: seven RCTs and five presumed RCTs (see Characteristics of included studies). In these last five studies, susceptible participants were intentionally exposed to rubella virus by the investigators. Included studies were published between 1953 and 1978. We included no unpublished studies.

Included studies were undertaken in five different countries: the United States (Doege 1967; Green 1965a; Green 1965b; Green 1965c; McCallin 1972; Schiff 1969a; Schiff 1969b), United Kingdom (McDonald 1963), Germany (Petersen 1978), Switzerland (Martin du Pan 1972), and Australia (Anderson 1953a; Anderson 1953b). A total of 430 participants were recruited from the community, different residential institutions, universities and medical settings. Sample sizes ranged from seven to 179.

Six studies included only adult participants (Anderson 1953a; Martin du Pan 1972; McCallin 1972; Petersen 1978; Schiff 1969a; Schiff 1969b), and four studies included only children (Green 1965a; Green 1965b; Green 1965c; McDonald 1963). One study included adolescents (aged 15 to 18 years) (Anderson 1953b). One study included children and adults (Doege 1967). The entire study population for this study included participants aged three to 50+ years, however only results from those who were known to be susceptible to rubella were included in the review. This group was aged three to 19 years.

Three studies included only male participants (Anderson 1953b; Schiff 1969a; Schiff 1969b), two studies included only female participants (Anderson 1953a; McCallin 1972), and the remainder did not report the gender distribution of their participants. Participants in one of the all-female studies were fewer than nine weeks pregnant (McCallin 1972).

Susceptibility was defined as no history of rubella infection by three studies (Anderson 1953a; Anderson 1953b; McDonald 1963). The remainder determined susceptibility by serology.

Participants were artificially exposed to rubella virus in five studies (Anderson 1953a; Martin du Pan 1972; Petersen 1978; Schiff 1969a; Schiff 1969b). In three studies, participants were exposed under controlled conditions to children who had been artificially exposed and were known to be infected with rubella virus (Green 1965a; Green 1965b; Green 1965c). In two studies, participants were living with diagnosed cases of rubella (Anderson 1953b; Doege 1967). Participants self reported exposure in one study (McCallin 1972) and in one study, no detail was given on the means of exposure (McDonald 1963).

The time between exposure and intervention ranged from 24 hours to five days in the studies where exposure was via inoculation with the virus (Anderson 1953a; Martin du Pan 1972; Petersen 1978; Schiff 1969a; Schiff 1969b). Green 1965b controlled the time of exposure to a known case and administered immunoglobulin 24 hours after exposure. The interval between exposure and intervention was much less precise (up to 11 days - Anderson 1953b; up to eight days - Green 1965a; up to four weeks - Doege 1967) and unknown or not reported (Green 1965c; McCallin 1972; McDonald 1963) for the other studies.

The intervention was gamma-globulin given intramuscularly in 10 studies (Anderson 1953a; Anderson 1953b; Green 1965a; Green 1965b; Green 1965c; McCallin 1972; McDonald 1963; Petersen 1978; Schiff 1969a; Schiff 1969b). Gamma-globulin was given intravenously in one study (30 ml to 60 ml diluted in 200 ml saline) (Martin du Pan 1972), and 'poliomyelitis immune globulin' with a rubella antibody concentration of 1:300 was given intramuscularly in one study (at 0.5 ml per unit of bodyweight - unit not specified) (Doege 1967). Of those administering gamma-globulin intramuscularly: three studies dosed by weight (Green 1965a; Green 1965b; Green 1965c) at 0.15 ml to 0.2 ml per pound, three studies administered 20 ml (McCallin 1972; Schiff 1969a; Schiff 1969b), two studies administered 4 ml (Anderson 1953a; Anderson 1953b), one study administered 15 ml after giving 20 ml six weeks earlier to the same participants (Petersen 1978), and one study administered 250 mg (McDonald 1963).

None of the included studies reported antibody titres of the immunoglobulin products used in international units. The rubella antibody titre of the immunoglobulin product used was not reported in three studies (Anderson 1953a; Anderson 1953b; McDonald 1963). Three studies reported a rubella antibody titre as assessed by hemagglutinin inhibition: one had a titre of 512 (McCallin 1972), one had a titre of 1000 (Martin du Pan 1972), and one had a titre of 2560 (Petersen 1978). Five studies reported rubella antibody titre as assessed by neutralisation assay: one had a titre of 1024/0.1 ml (Schiff 1969a), one had a titre of 256/0.1 ml (Schiff 1969b), two had titres of 64 (Green 1965b; Green 1965c), and one had a titre of 32 (Green 1965a). One study reported rubella antibody titre but did not report the means by which it was assessed. The reported titre was 1:300 (Doege 1967).

Of the studies trialing intramuscular gamma-globulin, six used 'no treatment' control groups (Anderson 1953a; Green 1965a; Green 1965b; Green 1965c; McDonald 1963; Petersen 1978), three gave saline of the same volume as the intervention intramuscularly to the control group (Anderson 1953b; Schiff 1969a; Schiff 1969b), and one gave gamma-globulin intramuscularly in the same volume but of a lower rubella antibody titre (McCallin 1972). The study trialing intravenous gamma-globulin used a 'no treatment' control group (Martin du Pan 1972), as did the study trialing 'poliomyelitis immune globulin' (Doege 1967).

All included studies assessed the number of rubella cases in each group as the primary outcome. Serological survey with or without other laboratory testing was undertaken to determine rubella infection in all but three studies (Anderson 1953a; Anderson 1953b; McDonald 1963). Cases were determined on clinical grounds only by two of these studies (Anderson 1953a; Anderson 1953b). McDonald 1963 did not report how participants were assessed for rubella infection. One study assessed cases of congenital rubella syndrome (McCallin 1972). No studies assessed cases of congenital rubella infection. No studies assessed or reported on adverse events.

In three studies, the intervention product used was supplied by a company. These were: Red Cross Blood Transfusion Service and CSL, Australia (Anderson 1953a; Anderson 1953b), and Parke, Davis & Co, Detroit (Doege 1967). The study by Doege 1967 was also supported by a US Public Health Service infectious diseases training grant. Green 1965a, Green 1965b and Green 1965c were funded by a grant from the National Institute of Allergy and Infectious Diseases, US Public Health Service and a contract with the US Army Medical Research and Development Command, Office of the Surgeon General. Schiff 1969a and Schiff 1969b were supported by the 'National Foundation' and a 'Career Research Development Award from the National Institutes of Health'. Martin du Pan 1972, McCallin 1972, McDonald 1963 and Petersen 1978 did not report any sources of funding.

Excluded studies

We excluded 129 of the 140 articles retrieved in full text. The reasons for exclusion of individual articles are given in the Characteristics of excluded studies table.

Risk of bias in included studies

Five studies where exposure to rubella was controlled by the investigators did not specify that participants were allocated randomly to groups (Green 1965a; Green 1965b; Green 1965c; Martin du Pan 1972; Petersen 1978). However, an alternative report of a study initially categorised with these studies did specify that participants were assigned to groups randomly and hence we included these studies in the review as meeting criteria for RCTs/quasi-RCTs.

No study was at low risk of bias for all criteria (Figure 2; Figure 3; Characteristics of included studies). The quality of the 11 studies in the initial meta-analysis was moderate (Summary of findings for the main comparison).

Figure 2.

'Risk of bias' summary: review authors' judgements about each risk of bias item for each included study.

Figure 3.

'Risk of bias' graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

Allocation

Random sequence generation and the means of allocation concealment was not reported in any included study. We thus assessed all to have unclear risk of bias for this criteria.

Blinding

The intervention, administration of polyclonal immunoglobulins, is very unlikely to be subject to variation due to performance and, as such, we deemed all studies at low risk of performance bias.

We assessed detection bias for the outcomes cases of rubella and cases of congenital rubella syndrome, as no study examined the outcome cases of congenital rubella infection. The study that assessed cases of congenital rubella syndrome did not report whether participants or outcome assessors were blinded, although the control group was given gamma-globulin of a lower rubella antibody titre at the same volume as the intervention group (McCallin 1972). There was no reported definition of congenital rubella syndrome nor method of assessment of the infants of participants. Infants of participants were followed up for between six months and three years but it was not reported whether there was a difference in average length of follow-up between groups. Due to the lack of information on the methodology, we assessed the study as at an unclear risk of detection bias for cases of congenital rubella syndrome. The same study defined cases of maternal rubella by seroconversion. This objective measure led us to assess this study as being of low risk of detection bias for the outcome cases of rubella.

We deemed two studies at high risk of detection bias in relation to cases of rubella (Anderson 1953a; McDonald 1963). This was because no blinding was reported and the outcome was assessed by means of clinical signs. We deemed Anderson 1953b at low risk of detection bias for rubella cases. Although the outcome was measured clinically, both the participants and the outcome assessor were blinded. We assessed the remaining studies as at low risk of detection bias for cases of rubella because, irrespective of blinding, the outcome was objectively measured.

Incomplete outcome data

All studies reported complete follow-up for cases of rubella. Doege 1967 had complete clinical follow-up and complete follow-up of the subset of participants from whom oropharyngeal swabs were collected but did report collection of paired sera on 43 of the 47 participants in the subgroup (91.5%). McCallin 1972 reported complete follow-up for cases of congenital rubella syndrome. We deemed all studies at low risk of attrition bias.

Selective reporting

Among the three studies reported by Green et al, Green 1965a, Green 1965b and Green 1965c, is a comparison of the results of serum samples tested for viraemia on a subset of five intervention participants and five control participants. The methods indicate that nasopharyngeal swabs were collected from participants but do not include details of serum sampling. We deemed these studies at high risk of reporting bias. Each of the other included studies reported on all outcomes specified in the methods sections and we deemed them to be at low risk of reporting bias.

Other potential sources of bias

We were unable to examine a funnel plot to assess for publication bias as there were only seven studies in the analysis that explained the heterogeneity of the original pooled result. However, small study effects were unlikely in our review given the only study with an independently statistically significant result was the largest study.

Effects of interventions

See: Summary of findings for the main comparison Gamma-globulin compared to control (saline or no treatment) for preventing rubella or congenital rubella syndrome

Primary outcomes  

1. Cases of rubella

We entered 11 of the 12 included studies into a meta-analysis of the primary outcome 'cases of rubella'. The result favoured the intervention group (risk ratio (RR) 0.61, 95% confidence interval (CI) 0.45 to 0.83) but was heterogenous (Chi² test = 36.59, df = 10 (P value < 0.0001); I² statistic = 73%) (Analysis 1.1).

We excluded McCallin 1972 from this meta-analysis due to heterogeneity of the control group (a lower titre gamma-globulin was given to the controls) as compared to the other studies ('do nothing' or placebo in the form of saline). The result of this study also favoured the intervention group although it was not statistically significant (RR 0.70, 95% CI 0.13 to 3.76).

Subgroup analyses

Subgrouping studies by study type (Analysis 1.2) did not explain the heterogeneity (overall heterogeneity: Chi² test = 36.59, df = 10 (P value < 0.0001); I² statistic = 73%) and we found no difference between the subgroup estimates of effect (test for subgroup differences: Chi² test = 0.09, df = 1 (P value = 0.77), I² statistic = 0%).

Subgrouping studies according to age group (adults, children, mixed) (Analysis 1.3) did not explain the heterogeneity (overall heterogeneity: Chi² test = 36.59, df = 10 (P value < 0.0001); I² statistic = 73%) and we found no difference between the subgroup estimates of effect (test for subgroup differences: Chi² = 1.09, df = 2 (P value = 0.58), I² = 0%).

Subgrouping studies according to categories of estimated dose of immunoglobulins (Analysis 1.4) somewhat reduced heterogeneity (overall heterogeneity: Chi² test = 21.92, df = 9 (P value = 0.009); I² statistic = 59%). The subgroup 'estimated 0.1 to 0.15 ml/lb' did not demonstrate significant heterogeneity, while the other two subgroups did ('estimated 0.027 to 0.037 ml/lb', heterogeneity: Chi² test = 3.07, df = 1 (P value = 0.08); I² statistic = 67%; 'estimated 0.2 to 0.5 ml/lb' heterogeneity: Chi² test = 16.48, df = 3 (P value = 0.0009); I² statistic = 82%). There was no difference in the estimates of effect between subgroups (test for subgroup differences: Chi² test = 0.12, df = 2 (P value = 0.94), I² statistic = 0%). The overall estimate of effect was smaller than the original meta-analysis (overall RR 0.70, 95% CI 0.52 to 0.95).

Subgrouping studies according to categories of time between exposure to rubella and intervention (Analysis 1.5) somewhat reduced heterogeneity (overall heterogeneity: Chi² test = 20.07, df = 8 (P value = 0.01); I² statistic = 60%). The subgroup 'Exposure 24 hours to five days prior to IG' did not demonstrate significant heterogeneity (heterogeneity: Chi² test = 7.84, df = 5 (P value = 0.17); I² statistic = 36%), while the subgroup 'Exposure up to eight to 28 days prior to IG' did (heterogeneity: Chi² = 6.65, df = 2 (P value = 0.04); I² statistic = 70%). There was no difference in the estimates of effect between the subgroups (test for subgroup differences: Chi² test = 0.62, df = 1 (P value = 0.43), I² statistic = 0%). The overall estimate of effect was smaller than the original meta-analysis (overall RR 0.72, 95% CI 0.53 to 0.97).

Subgrouping studies according to the study definition of exposure (Analysis 1.6) somewhat reduced heterogeneity (overall heterogeneity: Chi² test = 21.92, df = 9 (P value = 0.009); I² statistic = 59%). No significant heterogeneity was demonstrated for the subgroups 'Artificial exposure' and 'Controlled exposure to an infected person'. The subgroup 'Household contact with a diagnosed case' demonstrated significant heterogeneity (heterogeneity: Chi² test = 10.81, df = 1 (P value = 0.001); I² statistic = 91%). There was no difference in the estimates of effect between the subgroups (test for subgroup differences: Chi² test = 0.29, df = 2 (P value = 0.86), I² statistic = 0%). The overall estimate of effect was smaller than the original meta-analysis (overall RR 0.70, 95% CI 0.52 to 0.95).

Subgrouping studies according to the definition of rubella cases (Analysis 1.7) somewhat reduced heterogeneity (overall heterogeneity: Chi² test = 21.92, df = 9 (P value = 0.009); I² statistic = 59%), although both subgroups still demonstrated significant heterogeneity and there was no difference in the estimates of effect between subgroups (test for subgroup differences: Chi² test = 0.10, df = 1 (P value = 0.75), I² statistic = 0%). The overall estimate of effect was smaller than the original meta-analysis (overall RR 0.70, 95% CI 0.52 to 0.95).

Subgrouping studies according to funder (Analysis 1.8) demonstrated a difference between the subgroups (test for subgroup differences: Chi² test = 4.21, df = 1 (P value = 0.04), I² statistic = 76.3%). The studies classified as having funding with potential conflict of interest were homogenous according to our protocol-specified definition (heterogeneity: Chi² test = 4.52, df = 2 (P value = 0.10); I² statistic = 56%) and had a pooled estimate of effect of RR 0.87 (95% CI 0.57 to 1.33). The subgroup with no known funder with a potential conflict of interest was heterogenous (heterogeneity: Chi² test = 17.58, df = 7 (P value = 0.01); I² statistic = 60%) and had a pooled estimate of effect of RR 0.46 (95% CI 0.29 to 0.72). Three studies included in the subgroup without known conflict of interest did not report funder information (Martin du Pan 1972; McDonald 1963; Petersen 1978). Excluding these studies reduced the difference between the subgroups so that it was no longer significant (test for subgroup differences: Chi² test = 1.25, df = 1 (P value = 0.26), I² statistic = 19.9%), but did not reverse the direction of the difference (no known conflict of interest subgroup RR 0.60, 95% CI 0.35 to 1.00).

Post hoc subgroup analysis

It is well established that the most important factors that impact on the effectiveness of post-exposure passive immunisation for other viral infections such as measles and hepatitis A are the dose of immunoglobulins administered and the time between exposure and intervention (Ramsay 2009; Thomas 2009). Given the variability in both of these factors across the included studies, we undertook a post hoc analysis to consider these simultaneously. The limited number of included studies meant that these factors could not be explored in a combined subgroup analysis. However, removing those studies where the time between exposure and intervention was up to eight to 28 days (Anderson 1953b; Doege 1967; Green 1965a) from the subgroup analysis that explored the impact of dose on effectiveness (Analysis 1.4) explained the heterogeneity within the subgroups and demonstrated a difference between subgroups (test for subgroup differences: Chi² test = 5.32, df = 2 (P value = 0.07), I² statistic = 62.4%). The estimates of effect were: 'estimated 0.027 to 0.037 ml/lb' RR 1.60 (95% CI 0.57 to 4.52); 'estimated 0.1 to 0.15 ml/lb' RR 0.53 (95% CI 0.29 to 0.99); and 'estimated 0.2 to 0.5 ml/lb' RR 0.20 (95% CI 0.04 to 1.00) (Analysis 1.9).

Sensitivity analyses

As seen in Figure 2, five studies were at a higher risk of bias than the others (Anderson 1953a; Green 1965a; Green 1965b; Green 1965c; McDonald 1963). We deemed each of these at high risk of bias for one item. Excluding these from the original pooled analysis marginally altered the estimate of effect away from the null (RR 0.58, 95% CI 0.40 to 0.83; heterogeneity: Chi² test = 30.82, df = 5 (P value < 0.0001), I² statistic = 84%). Returning the three studies at high risk of selective reporting (Green 1965a; Green 1965b; Green 1965c) marginally altered this result toward the null (RR 0.62, 95% CI 0.45 to 0.86), while returning instead the two studies at high risk of detection bias (Anderson 1953a; McDonald 1963) did not alter the result (RR 0.58, 95% CI 0.41 to 0.81).

Three studies assessed susceptibility to rubella on history alone (Anderson 1953a; Anderson 1953b; McDonald 1963). Removing these studies from the meta-analysis marginally reduced the size of the effect estimate (RR 0.68, 95% CI 0.50 to 0.92). Heterogeneity was still apparent (heterogeneity: Chi² test = 21.24, df = 7 (P value = 0.003); I² statistic = 67%).

Five studies did not specify how participants were allocated to groups (Green 1965a; Green 1965b; Green 1965c; Martin du Pan 1972; Petersen 1978). With all five studies removed, the results were unaltered (RR 0.59, 95% CI 0.41 to 0.86; heterogeneity: Chi² test = 32.12, df = 5 (P value < 0.0001), I² statistic = 84%). When sequentially removing these studies in order of effect size and then separately in order of study size, the pooled effect estimate ranged from RR 0.66 (95% CI 0.48 to 0.91) to RR 0.54 (95% CI 0.37 to 0.78).

During subgroup analyses, we noted the following subgroups to demonstrate significant heterogeneity while the other subgroups in the relevant analysis did not: 'RCTs', 'children' and 'mixed (adult and child participants)', 'estimated 0.027 to 0.037 ml/lb' and 'estimated 0.2 to 0.5 ml/lb', 'exposure up to 8 to 28 days prior to IG' and 'household contact with a diagnosed case'. The subgroups 'mixed (adult and child participants)', 'estimated 0.027 to 0.037 ml/lb' and 'household contact with a diagnosed case' contained only two studies each. We therefore listed each of these studies as seeming to contribute to heterogeneity and thus subject to the sensitivity analysis for the original meta-analysis. The other subgroups contained more than two studies. In each of these subgroups, we removed each study in turn to assess its impact on the heterogeneity of the subgroup. Where removal of the study resulted in an I² statistic proportion below 60% for the subgroup we listed it as seeming to contribute to heterogeneity and thus subject to the sensitivity analysis for the original meta-analysis. The studies thus listed for removal during sensitivity analyses were: Anderson 1953a; Anderson 1953b; Doege 1967; Green 1965a; and McDonald 1963. We removed studies in each analysis until overall heterogeneity did not meet our protocol specified definition of important heterogeneity (I² statistic < 60% and P value < 0.1). Removing the specified studies in order of the magnitude of the estimate of effect from lowest to highest resulted in removal of Anderson 1953a, Doege 1967 and Green 1965a (heterogeneity: Chi² test = 10.36, df = 7 (P value = 0.17); I² statistic = 32%) and RR 0.36 (95% CI 0.21 to 0.60). Removing these studies in order of the magnitude of the estimate of effect from highest to lowest resulted in removal of Anderson 1953b, Doege 1967 and McDonald 1963 (heterogeneity: Chi² test = 10.50, df = 7 (P value = 0.16); I² statistic = 33%) and RR 0.70 (95% CI 0.46 to 1.04). Removing the studies according to study size from largest to smallest resulted in removal of all five studies identified as seeming to contribute to heterogeneity (heterogeneity: Chi² test = 7.26, df = 5 (P value = 0.20); I² statistic = 31%) and RR 0.43 (95% CI 0.24 to 0.77). Removing the studies according to study size from smallest to largest resulted in removal of Anderson 1953a, Doege 1967 and Green 1965a (heterogeneity: Chi² test = 10.36, df = 7 (P value = 0.17); I² statistic = 32%) and RR 0.36 (95% CI 0.21 to 0.60).

2. Cases of congenital rubella infection

No included study measured the outcome cases of congenital rubella infection.

3. Cases of congenital rubella syndrome

One included study reported on cases of congenital rubella syndrome (McCallin 1972). This study did not identify any cases of congenital rubella syndrome among the infants born to the participants in either the 'high' titre (HI titre 512) intervention or the 'low' titre (HI titre 64) control group. The study reported that the rate of stillbirths (one of 83 participants) and spontaneous abortions (five of 83 participants) was within that expected, however the rates among those who were found to be susceptible to rubella prior to gamma-globulin administration was not reported (total of 41 of the original 83 participants). One of the five participants diagnosed as contracting rubella during their early pregnancy was the participant who suffered a stillbirth. The study did not report whether this participant had been in the high titre or low titre gamma-globulin group.

Secondary outcomes  

1. Occurrence of serious adverse events.

No included studies measured or reported on adverse events.

2. Occurrence of non-serious adverse events.

No included studies measured or reported on adverse events.

Discussion

Summary of main results

We included 12 studies in this review: seven randomised controlled trials (RCTs) and five controlled clinical trials (CCTs) where the means of allocation of participants was not reported. We did not include any unpublished studies.

We included 11 studies in meta-analysis of gamma-globulin versus control (saline or no treatment) for rubella cases. The result favoured the intervention group (risk ratio (RR) 0.61, 95% confidence interval (CI) 0.45 to 0.83) but was heterogenous (Chi² test = 36.59, df = 10 (P value < 0.0001); I² statistic = 73%). This result was robust to sensitivity analyses.

Heterogeneity was not explained by protocol specified subgroup analyses that considered a single factor, but was explained in a post hoc analysis that considered two of these factors simultaneously. We subgrouped studies according to the estimated volume of gamma-globulin administered per pound of bodyweight and then removed those studies where the intervention was administered more than five days after participant exposure to rubella. The test of subgroup differences demonstrated heterogeneity between subgroups according to our protocol definition and there appeared to be greater effectiveness of the intervention when a greater volume of gamma-globulin was administered ('0.027 to 0.037 ml/lb' RR 1.6 (95% CI 0.57 to 4.52); '0.1 to 0.15 ml/lb' RR 0.53 (95% CI 0.29 to 0.99); '0.2 to 0.5 ml/lb' RR 0.2 (95% CI 0.04 to 1.00)).

No studies measured the outcome congenital rubella infection. One included study reported on congenital rubella syndrome, reporting no cases among participants who were fewer than nine weeks pregnant at enrolment and who were randomised to one of two gamma-globulin groups ('high' or 'low' rubella titre). However, the study did not report how congenital rubella syndrome was measured and did not report the length of follow-up according to intervention group. This study did not include a non-treatment group.

No included study measured adverse events.

Overall completeness and applicability of evidence

Pregnant women were not recruited in any of the studies included in meta-analyses and only one study attempted to assess the effect of post-exposure passive immunisation for preventing congenital rubella syndrome. The evidence is therefore insufficient to directly conclude the effectiveness of passive immunisation for preventing congenital rubella syndrome.

The evidence for preventing rubella cases included participants with a range of ages and both genders. Included studies were undertaken in high-income countries with predominantly Caucasian populations. The health status of participants apart from their exposure to rubella was not reported but it is likely that most were otherwise healthy individuals. Given this, it seems reasonable to generalise the results to the susceptible, healthy, non-pregnant population of high-income countries. While it is likely that rubella could also be prevented by post-exposure passive immunisation of other susceptible individuals, no conclusions can be drawn about possible differences in the magnitude of effect.

None of the included studies measured adverse events associated with passive immunisation. Other literature must be examined in this respect.

Quality of the evidence

We rated no included studies at a low risk of bias for all criteria. Critical appraisal was constrained by a lack of information in most studies, yet study authors could not be contacted to supplement the information reported because of the age of the studies. Despite these limitations, we have rated the quality of the evidence as moderate based on the initial meta-analysis (see Summary of findings for the main comparison).

Subgrouping according to study type to account for those included studies where allocation of participants was not specified as random demonstrated that the subgroup of CCTs had an estimate of effect closer to the null than the subgroup of RCTs. Thus if these studies were not randomised trials, their inclusion has biased the overall effect estimate towards, rather than away from the null.

Subgrouping according to funder to examine those studies with potential conflicts of interest demonstrated that the subgroup where gamma-globulin was provided by a company had an estimate of effect closer to the null than the subgroup with no known potential conflicts of interest. While three studies included in those without known conflict of interest did not report funder information, excluding these studies reduced, but did not reverse the direction of the difference between the subgroups. Thus, the inclusion of studies with known potential conflicts of interest may underestimate rather than overestimate the effect size.

Sensitivity analyses also supported the overall beneficial result. The overall effect estimate was either unaltered or larger when we removed studies with a higher risk of bias. Removing studies seeming to contribute to heterogeneity in various sequences did not reverse the direction of effect and in three of the four analyses the estimate of effect increased rather than decreased.

Acknowledging that volume of gamma-globulin per pound of bodyweight was approximated for some studies, we observed an apparent dose effect when the time between exposure and intervention was simultaneously accounted for, increasing confidence in the results.

Potential biases in the review process

We used a filter for study design to reduce the results of the electronic searches to a manageable number. However, the use of the filter may have excluded relevant studies.

We were unable to contact the study authors of the retrieved studies, therefore we necessarily relied on reported information. We therefore may have excluded relevant studies because of the lack of information reported. Similarly, we may have over- or underestimated the potential bias in included studies.

Including studies that did not specify that they used a randomised process for allocating participants to subgroups may be seen as a bias in the review process. However, subgroup analysis and sensitivity analysis both reinforced that the studies included in the meta-analysis in that way reduced rather than increased the estimate of effect.

We specified the subgroup analyses to be conducted in our protocol, but were unable to define the specific subgroups for some of these: dose of immunoglobulins; dose of rubella-specific immunoglobulins; timing of administration of intervention in relation to exposure. This was because categories with clinical relevance had not been defined by the scientific or clinical communities. We therefore defined these categories based on the included studies.

When subgrouping studies by volume of immunoglobulin administered, we used standard weights for adults and adolescents to estimate the volume administered per pound of bodyweight where participant weights were not given. While this would have resulted in imprecision, it was unlikely to have resulted in misclassification between subgroups given there was a considerable degree of separation between the range of volumes defining each subgroup.

We undertook Analysis 1.9, which combined dose of immunoglobulin subgroups with time between exposure and intervention, post hoc based on immunological and clinical principles. This brought the number of subgroup analyses to eight, which may be felt to possibly result in false negative or false positive significance tests. However, the results of Analysis 1.9 are supported by the indirect evidence of the impact of dose and timing of the intervention in relation to post-exposure passive immunisation for preventing both measles (Ramsay 2009) and hepatitis A (Thomas 2009); the magnitude of the difference in the estimates of effect between subgroups within Analysis 1.9; and that this between-study relationship is replicated (although not statistically significantly) within McCallin 1972, which was not included in this meta-analysis.

Agreements and disagreements with other studies or reviews

No previous systematic review has examined passive immunisation for the prevention of rubella or congenital rubella syndrome.

Authors' conclusions

Implications for practice

Compared to no treatment, passive immunisation seems to be of benefit for preventing rubella. The available evidence suggests that this intervention may be of benefit up to five days after exposure, and that effectiveness is dependent on sufficient dose. Considering the attack rate for rubella cases in the control group of the highest volume gamma-globulin subgroup (333 per 1000), the absolute risk reduction (calculated from the risk ratio (RR) (Higgins 2011)) for this volume of gamma-globulin was 266 (95% CI 0 to 320) and the number needed to treat to benefit (NNTB) is four (95% confidence interval (CI) 3 to incalculable).

The included studies did not measure rubella-specific antibodies in the gamma-globulin products used in a standard way and thus estimation of the dose of rubella-specific antibodies in international units administered was not possible. As the concentration of rubella-specific antibodies in today's gamma-globulin products may vary from those products used in the studies in the review (Barlinn 2014; Vauloup-Fellous 2007), the volume required per pound of bodyweight to produce similar beneficial results may also vary.

There is insufficient evidence to make direct conclusions about the effectiveness of post-exposure passive immunisation for preventing congenital rubella syndrome.

The benefits of an intervention should always be weighed against the risks. While the studies included in this review did not measure or report adverse events, potential adverse events related to passive immunisation can be found in the published literature and product information (for example Ashwell 1997, CSL 2014, EMC 2014, EMEA 2002 and Sawyer 2000).

Implications for research

Preventing rubella infection among those susceptible after they have been exposed is most important for the subpopulation of exposed susceptible pregnant women. Given the paucity of evidence in this population, and because it would be unethical to design a study with an investigator-controlled placebo comparison group, observational studies comparing the infection status and pregnancy outcomes of exposed susceptible pregnant women with and without post-exposure passive immunisation would be of benefit. Studies should include careful recording of any potential adverse events. Given that dose appears to be important to the magnitude of effectiveness, studies should also include measurement of the concentration of rubella-specific antibodies in the blood product/s used.

Acknowledgements

We would like to thank Liz Dooley and Clare Dooley for their support and guidance on the development of the protocol. We would like to thank Sarah Thorning for her guidance on the electronic search strategies, running the searches and assisting with language translations. We would like to thank Dr Vittoria Lutje for assisting with Italian translations. We would like to thank the referees of the both the protocol and the review: Theresa Wrangham, Sallie Bernard, Roger Thomas, Vittorio Demicheli, Mark Jones and Robert Ware. And finally to Susan Smith, the Contact Editor, for her guidance and support throughout the editorial process.

Data and analyses

Download statistical data

Comparison 1. Gamma-globulin versus control (no treatment or saline)
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Rubella cases11389Risk Ratio (M-H, Fixed, 95% CI)0.61 [0.45, 0.83]
2 Rubella cases11389Risk Ratio (M-H, Fixed, 95% CI)0.61 [0.45, 0.83]
2.1 RCT6332Risk Ratio (M-H, Fixed, 95% CI)0.59 [0.41, 0.86]
2.2 Controlled clinical trial557Risk Ratio (M-H, Fixed, 95% CI)0.65 [0.38, 1.12]
3 Rubella cases11389Risk Ratio (M-H, Fixed, 95% CI)0.61 [0.45, 0.83]
3.1 Adult participants568Risk Ratio (M-H, Fixed, 95% CI)0.65 [0.40, 1.07]
3.2 Child participants4213Risk Ratio (M-H, Fixed, 95% CI)0.46 [0.24, 0.91]
3.3 Mixed (adult and child participants)2108Risk Ratio (M-H, Fixed, 95% CI)0.71 [0.45, 1.12]
4 Rubella cases10210Risk Ratio (M-H, Fixed, 95% CI)0.70 [0.52, 0.95]
4.1 Estimated 0.027 to 0.037 ml/lb2115Risk Ratio (M-H, Fixed, 95% CI)0.77 [0.36, 1.67]
4.2 Estimated 0.1 to 0.15 ml/lb450Risk Ratio (M-H, Fixed, 95% CI)0.69 [0.44, 1.08]
4.3 Estimated 0.2 to 0.5 ml/lb445Risk Ratio (M-H, Fixed, 95% CI)0.67 [0.45, 0.99]
5 Rubella cases9199Risk Ratio (M-H, Fixed, 95% CI)0.72 [0.53, 0.97]
5.1 Exposure 24 hours to 5 days prior to IG678Risk Ratio (M-H, Fixed, 95% CI)0.63 [0.38, 1.04]
5.2 Exposure up to 8 to 28 days prior to IG3121Risk Ratio (M-H, Fixed, 95% CI)0.81 [0.56, 1.17]
6 Rubella cases10210Risk Ratio (M-H, Fixed, 95% CI)0.70 [0.52, 0.95]
6.1 Artificial exposure568Risk Ratio (M-H, Fixed, 95% CI)0.65 [0.40, 1.07]
6.2 Controlled exposure to infected person334Risk Ratio (M-H, Fixed, 95% CI)0.82 [0.42, 1.61]
6.3 Household contact with diagnosed case2108Risk Ratio (M-H, Fixed, 95% CI)0.71 [0.45, 1.12]
7 Rubella cases10210Risk Ratio (M-H, Fixed, 95% CI)0.70 [0.52, 0.95]
7.1 Cases defined on clinical grounds2115Risk Ratio (M-H, Fixed, 95% CI)0.77 [0.36, 1.67]
7.2 Laboratory-confirmed cases895Risk Ratio (M-H, Fixed, 95% CI)0.68 [0.50, 0.92]
8 Rubella cases11389Risk Ratio (M-H, Fixed, 95% CI)0.61 [0.45, 0.83]
8.1 No known conflict of interest8257Risk Ratio (M-H, Fixed, 95% CI)0.46 [0.29, 0.72]
8.2 Potential conflict of interest3132Risk Ratio (M-H, Fixed, 95% CI)0.87 [0.57, 1.33]
9 Rubella cases7 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
9.1 Estimated 0.027 to 0.037 ml/lb124Risk Ratio (M-H, Fixed, 95% CI)1.6 [0.57, 4.52]
9.2 Estimated 0.1 to 0.15 ml/lb337Risk Ratio (M-H, Fixed, 95% CI)0.53 [0.29, 0.99]
9.3 Estimated 0.2 to 0.5 ml/lb328Risk Ratio (M-H, Fixed, 95% CI)0.20 [0.04, 1.00]
Analysis 1.1.

Comparison 1 Gamma-globulin versus control (no treatment or saline), Outcome 1 Rubella cases.

Analysis 1.2.

Comparison 1 Gamma-globulin versus control (no treatment or saline), Outcome 2 Rubella cases.

Analysis 1.3.

Comparison 1 Gamma-globulin versus control (no treatment or saline), Outcome 3 Rubella cases.

Analysis 1.4.

Comparison 1 Gamma-globulin versus control (no treatment or saline), Outcome 4 Rubella cases.

Analysis 1.5.

Comparison 1 Gamma-globulin versus control (no treatment or saline), Outcome 5 Rubella cases.

Analysis 1.6.

Comparison 1 Gamma-globulin versus control (no treatment or saline), Outcome 6 Rubella cases.

Analysis 1.7.

Comparison 1 Gamma-globulin versus control (no treatment or saline), Outcome 7 Rubella cases.

Analysis 1.8.

Comparison 1 Gamma-globulin versus control (no treatment or saline), Outcome 8 Rubella cases.

Analysis 1.9.

Comparison 1 Gamma-globulin versus control (no treatment or saline), Outcome 9 Rubella cases.

Appendices

Appendix 1. MEDLINE and CENTRAL search strategy

1 exp Rubella/ (7373)
2 Rubella virus/ (3235)
3 (rubella or rubeole).tw. (10177)
4 german measles.tw. (194)
5 or/1-4 (12092)
6 exp Immunoglobulins/ (767065)
7 (immunoglobulin* or immuno-globulin* or immun* globulin*).tw,nm. (305857)
8 (gammaglobulin* or gamma-globulin* or gamma globulin*).tw,nm. (24893)
9 exp Immunization, Passive/ (29747)
10 (passiv* adj2 (immuni* or antibody transfer* or prophyla*)).tw. (4067)
11 Post-Exposure Prophylaxis/ (386)
12 ((post exposur* or post-exposur* or postexposur*) adj2 (prophyla* or prevent* or immuni*)).tw. (2002)
13 or/6-12 (824561)
14 5 and 13 (4070)

Appendix 2. EMBASE (Elsevier) search strategy

#1.17 #1.6 AND #1.16 1740
#1.16 #1.7 OR #1.8 OR #1.9 OR #1.10 OR #1.11 OR #1.12 OR #1.13 OR #1.14 OR #1.15
#1.15 (('post exposure' OR 'post-exposure' OR postexposur*) NEAR/2 (prophyla* OR prevent* OR immuni*)):ab,ti AND [embase]/lim
#1.14 'post exposure prophylaxis'/de AND [embase]/lim
#1.13 (passiv* NEAR/2 (immuni* OR 'antibody transfer' OR 'antibody transfers' OR prophyla*)):ab,ti AND [embase]/lim
#1.12 'adoptive immunotherapy'/de AND [embase]/lim
#1.11 'adoptive transfer'/de AND [embase]/lim
#1.10 'passive immunization'/de AND [embase]/lim
#1.9 gamma globulin*:ab,ti OR 'gamma-globulin':ab,ti OR 'gamma-globulins':ab,ti OR (gamma NEXT/1 globulin*):ab,ti AND [embase]/lim
#1.8 immunoglobulin*:ab,ti OR 'immuno-globulin':ab,ti OR 'immuno-globulins':ab,ti OR (immun* NEXT/1 globulin*):ab,ti AND [embase]/lim
#1.7 'immunoglobulin'/exp AND [embase]/lim
#1.6 #1.1 OR #1.2 OR #1.3 OR #1.4 OR #1.5
#1.5 'german measles':ab,ti AND [embase]/lim
#1.4 rubella:ab,ti OR rubeole:ab,ti AND [embase]/lim
#1.3 'rubella virus'/de AND [embase]/lim
#1.2 'congenital rubella syndrome'/de AND [embase]/lim
#1.1 'rubella'/de AND [embase]/lim

Appendix 3. CINAHL (Ebsco) search strategy

S12 S4 AND S11 76
S11 S5 OR S6 OR S7 OR S8 OR S9 OR S10 9,435
S10 TI ((post exposur* or post-exposur* or postexposur*) N2 (prophyla* or prevent* or immuni*)) OR AB ((post exposur* or post-exposur* or postexposur*) N2 (prophyla* or prevent* or immuni*)) 438
S9 (MH "Postexposure Follow-Up") 987
S8 TI (passiv* N2 (immuni* or antibody transfer* or prophyla*)) OR AB (passiv* N2 (immuni* or antibody transfer* or prophyla*)) 75
S7 TI (gammaglobulin* or gamma-globulin* or gamma globulin*) OR AB (gammaglobulin* or gamma-globulin* or gamma globulin*) 73
S6 TI (immunoglobulin* or immuno-globulin* or immun* globulin*) OR AB (immunoglobulin* or immuno-globulin* or immun* globulin*) 3,511
S5 (MH "Immunoglobulins+") 6,621
S4 S1 OR S2 OR S3 1,096
S3 TI german measles OR AB german measles 11
S2 TI (rubella or rubeole) OR AB (rubella or rubeole) 886
S1 (MH "Rubella+") 582

Appendix 4. LILACS (BIREME) search strategy

(mh:rubella OR mh:c02.782.930.700.700* OR rubella OR rubéola OR "german measles" OR "Sarampión Alemán" OR "Sarampo Alemão") AND (mh:immunoglobulins OR mh:d12.776.124.486.485* OR mh:d12.776.124.790.651* OR mh:d12.776.377.715.548* OR inmunoglobulinas OR imunoglobulinas OR "immune globulins" OR "Globulinas Inmunes" OR "Globulinas Inmunitárias" OR "Globulinas Imunitárias" OR "Globulinas Imunes" OR immunglobulin* OR gamma globulin* OR "gama-Globulinas" OR "Immunization, Passive" OR mh:e02.095.465.425.400.330* OR mh:e05.478.550.520* OR "Passive Antibody Transfer" OR "Passive Transfer of Immunity" OR serotherapy OR "Traslado de Anticuerpo Pasivo" OR "Traslado Pasivo de Inmunidad" OR seroterapia OR "Inmunoterapia Pasiva" OR "Transferência Passiva de Anticorpos" OR "Transferência Passiva de Imunidade" OR soroterapia OR mh:"Post-Exposure Prophylaxis" OR "Profilaxis Post-Exposición" OR "Profilaxia Pós-Exposição") AND db:("LILACS")

Appendix 5. Web of Science (Thomson Reuters) search strategy

# 6 521

#5 AND #1

Databases=SCI-EXPANDED, CPCI-S Timespan=All years

# 5 138,097

#4 OR #3 OR #2

Databases=SCI-EXPANDED, CPCI-S Timespan=All years

# 4 1,770

Topic=(("post exposur*" or post-exposur* or postexposur*) NEAR/2 (prophyla* or prevent* or immuni*))

Databases=SCI-EXPANDED, CPCI-S Timespan=All years

# 3 4,580

Topic=((passiv* NEAR/2 (immuni* or "antibody transfer*" or prophyla*)))

Databases=SCI-EXPANDED, CPCI-S Timespan=All years

# 2 133,257

Topic=(immunoglobulin* or "immuno-globulin*" or (immun* NEAR/1 globulin*)) OR Topic=(gammaglobulin* or "gamma-globulin*" or "gamma globulin*")

Databases=SCI-EXPANDED, CPCI-S Timespan=All years

# 1 8,883

Topic=(rubella or rubeole or "german measles")

Databases=SCI-EXPANDED, CPCI-S Timespan=All years

Appendix 6. MEDLINE and EMBASE filter for study type

The Cochrane Highly Sensitive Search Strategy for identifying randomised trials (Lefebvre 2011) was used for the initial search in the MEDLINE database. The MEDLINE search was then repeated replacing the randomised trial filter with the following filter (adapted from filters for non-randomised studies provided by the Cochrane Effective Practice and Organisation of Care Group and the Cochrane Public Health Group and these publicly available filters: BMJ Clinical Evidence 2012; Furlan 2006; SIGN 2012; University of Texas 2012) to identify non-randomised prospective intervention studies (not before and after and not time series studies). These two searches were combined to give the search results for MEDLINE. This process was repeated for the EMBASE database, adapting the filter as needed.

1. exp Cohort Studies/
2. Epidemiologic Studies/
3. Intervention Studies/
4. Evaluation Studies/
5. Program Evaluation/
6. Random Allocation/
7. Clinical Trial/
8. Single-Blind Method/
9. Double-Blind Method/
10. Control Groups/
11. Pilot Projects/
12. controlled clinical trial.pt.
13. clinical trial.pt.
14. comparative study.pt.
15. multicenter study.pt.
16. evaluation studies.pt.
17. Comparative Study/
18. Multicenter Study/
19. Follow-Up Studies/
20. Prospective Studies/
21. (cohort adj (study or studies)).tw.
22. cohort analy*.tw.
23. cohort*.tw.
24. (("follow up" or follow-up) adj (study or studies or assessment)).tw.
25. (observational adj (study or studies)).tw.
26. longitudinal.tw.
27. prospective.tw.
28. ((single or double* or triple* or treb*) and (blind* or mask*)).tw.
29. trial*.tw.
30. placebo.tw.
31. groups.tw.
32. ("pre test" or pretest or pre-intervention or preintervention or "pre intervention" or "post test" or posttest or post-intervention or postintervention or "post intervention").tw.
33. (pre adj5 post).tw.
34. ((evaluat* or intervention or interventional or treatment) and (control or controlled or study or studies or program* or comparison or comparative or "usual care")).tw.
35. ((intervention or interventional or process or program) adj8 (evaluat* or effect* or outcome*)).tw.
36. (program or programme or secondary analyse*).tw.
37. (quasi-experiment* or Quasiexperiment* or "quasi random*" or quasirandom* or "quasi control*" or quasi control* or ((quasi* or experimental) adj3 (method* or study or studies or trial or design*))).tw.
38. random*.tw.
39. (study adj3 aim*).ab.
40. "our study".ab.
41. multivariate.ab.
42. compared.ab.
43. intervention*.ti.
44. pilot.ti.
45. (multicentre or multicenter or multi-centre or multi-center).ti.
46. controlled.ti.
47. (rat or rats or cow or cows or chicken* or horse or horses or mice or mouse or bovine or animal*).ti.
48. exp animals/ not humans.sh.
49. (or/1-46) not (47 or 48)

Appendix 7. Glossary

antibody - any of a large number of proteins that are produced by specialised cells of the immune system. Also called immunoglobulin.

congenital - existing at or dating from birth; acquired during development in the uterus.

encephalitis - inflammation of the brain.

epidemic - an outbreak; suddenly and greatly increased numbers of cases of disease.

foetal - pertaining to a developing human, usually from two months after conception to birth.

gamma-globulins - IgG; a subclass of immunoglobulins.

gestation - pregnancy; the period of development from the time of conception until birth.

glaucoma - eye disease characterised by an increase in pressure inside the eye resulting in defects in the field of vision.

hepatosplenomegaly - abnormal enlargement of the liver and the spleen.

IG - human immune globulin; a blood product; a protein fraction of blood rich in antibodies.

IgG - gamma-globulins; a subclass of immunoglobulins.

IgM - a subclass of immunoglobulins usually produced first in an immune response prior to IgG.

immunoglobulin - any of a large number of proteins produced by specialised cells of the immune system. Also called antibodies.

incidence - the rate of occurrence of new cases of a particular disease within a population.

intramuscular - into or within a muscle.

meningoencephalitis - inflammation of the brain and tissue covering the brain and spinal cord.

microcephaly - abnormal smallness of the head resulting from failure of brain growth.

passive immunisation - the transfer of antibodies from donor to recipient.

pigmentary retinopathy - a disease where excessive pigment is produced by cells at the back of the eye leading to blindness.

plasma - the fluid remaining after the cells are removed from blood.

polyclonal - produced by different cells (as opposed to monoclonal - produced by the same cell).

purpura - purplish discolouration resulting from bleeding into the skin.

radiolucent bone disease - bones that appear abnormal on x-ray as they allow the x-rays to pass through them.

seroconversion - the change of a serological test from negative to positive indicating the development of antibodies.

serological testing - a blood test that detects the presence of antibodies to a particular protein molecule (e.g. a virus particle).

serum - the fluid remaining after clotting factors (certain proteins and other molecules) have been removed from plasma by clot formation.

susceptible - capable of being infected.

titre - a measure of the concentration of a specific antibody in a sample of serum.

viraemia - the presence of viruses in the blood.

Appendix 8. Companies manufacturing immunoglobulin products contacted for unpublished studies

Bayer Healthcare Pharmaceuticals

BDI Pharma (a business unit of Baxter Healthcare corporation)

Bio Products Laboratory*

CSL Behring*

Grifols*

Haffkine Bio-Pharmaceutical Corporation Ltd

Kedrion Biopharma

LFB Biotechnologies

Link Medical Products Pty Ltd

Mirren*

Octapharma*

Sanofi Aventis*

Taj Pharmaceuticals Limited

Companies contacted using details available publicly on their websites in October 2012.

*Companies that responded indicated with an asterisk.

Appendix 9. Published national public health guidelines on rubella control where reference list was searched

Australian Technical Advisory Group on Immunisation. The Australian Immunisation Handbook 10th edition. Canberra: Commonwealth of Australia; 2013.

Australian Technical Advisory Group on Immunisation. The Australian Immunisation Handbook. 9th edition. Canberra: Australian Government, 2008.

Centers for Disease Control and Prevention. Control and prevention of rubella: evaluation and management of suspected outbreaks, rubella in pregnant women, and surveillance for congenital rubella syndrome. MMWR - Morbidity and Mortality Weekly Report 2001;50(RR12):1-23.

Centers for Disease Control and Prevention. Measles, mumps, and rubella - vaccine use and strategies for elimination of measles, rubella and congenital rubella syndrome and control of mumps: Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR - Morbidity and Mortality Weekly Report 1998;47(RR8):1-57.

Dontigny L, Arsenault MY, Martel MJ, Clinical Practice Obstetrics Committee. Rubella in Pregnancy - Society of Obstetricians and Gynaecologists of Canada Clinical Practice Guideline. Journal of Obstetrics and Gynaecology Canada 2008; 30(2): 152-8.

HPA Rash Guidance Working Group. Guidance on Viral Rash in Pregnancy. London: Health Protection Agency; 2011.

Immunisation Department. Rubella. Immunoglobulin Handbook. UK: Health Protection Agency; 2009.

McLean H, Redd S, Abernathy E, Icenogle J, Wallace G. Chapter 14: Rubella In VPD Surveillance Manual 5th Edition. Atlanta: Centers for Disease Control and Prevention; 2012.

McLean H, Redd S, Abernathy E, Icenogle J, Wallace G. Chapter 15: Congenital rubella syndrome In VPD Surveillance Manual 5th Edition. Atlanta: Centers for Disease Control and Prevention; 2012.

Ministry of Health. Chapter 12: Rubella in Immunisation Handbook 2011. Wellington: Ministry of Health; 2011. Available at: http://www.health.govt.nz/publication/immunisation-handbook-2011. Accessed 3 January 2012.

Morgan-Capner P, Crowcroft NS, PHLS Joint Working Party of the Advisory Committees of Virology and Vaccines and Immunisation. Guidelines on the management of and exposure to, rash illness in pregnancy (including consideration of relevant antibody screening programmes in pregnancy). Communicable Disease and Public Health 2002; 5(1): 59-71.

New South Wales Health. Control Guideline: Rubella. Sydney: NSW government; 2004. Available at: http://www.health.nsw.gov.au/factsheets/guideline/rubella.html. Accessed 29 Dec 2011.

Public Health Agency of Canada. Canadian Immunization Guide. Part 4, Active Vaccines: Rubella Vaccine. Last modified 30 Nov 2012. Available at: http://www.phac-aspc.gc.ca/publicat/cig-gci/p04-rube-eng.php#other Accessed 4 November 2013.

Queensland Health. Rubella: Queensland Health Guidelines for Public Health Units. Brisbane: Queensland Government; 2010. Available at: http://www.health.qld.gov.au/cdcg/index/rubella.asp Accessed 2 November 2013.

Reef S, Redd S, Abernathy E, Icenogle J. Chapter 14: Rubella In VPD Surveillance Manual 4th Edition. Atlanta: Centers for Disease Control and Prevention; 2008.

Reef S, Redd S. Chapter 15: Congenital rubella syndrome. In VPD Surveillance Manual 4th Edition. Atlanta: Centers for Disease Control and Prevention; 2008.

UK Department of Health. Chapter 28: Rubella - file replaced 14 December 2010. Immunisation against infectious disease - "The Green Book" - 2006 updated edition. UK: Department of Health; 2010.

Victorian Department of Health. Infectious diseases epidemiology and surveillance: Rubella (German measles). Melbourne: Department of Health, Victoria, Australia; 2007. Available at: http://ideas.health.vic.gov.au/bluebook/rubella.asp. Accessed 29 December 2011.

Contributions of authors

Dr Megan Young drafted the protocol.
Prof Allan Cripps, Prof Graeme Nimmo and Prof Mieke van Driel reviewed and edited the draft for intellectual content.
Dr Megan Young (MY) and Prof Graeme Nimmo (GN) obtained copies of the studies and selected studies for inclusion in the review. 
MY and Prof Allan Cripps (AC) extracted the data and assessed the risk of bias in the studies.
MY entered the data. 
Prof Mieke van Driel (MVD) and MY analysed the data and interpreted the analysis. 
All authors completed the final review.

Declarations of interest

Dr Megan Young is a public health physician in Queensland, Australia who is involved in the public health management of rubella. She is undertaking a PhD examining the effectiveness and efficiency of passive immunisation with IG for the public health management of communicable diseases and is collaborating with staff of CSL Biotherapies, Australia on a study related to the review topic. She receives no financial benefits from CSL or any other pharmaceutical company.
Prof Allan Cripps has been a consultant to Probiotec Pty Ltd, has received grant funding for a clinical trial on probiotics from Danisco, and holds stock of Bioxyne. None of these activities relate to the current review. He is Dr Megan Young's PhD supervisor.
Prof Graeme Nimmo has been a sponsored speaker for bioMerieux P/L, has served on advisory boards for Wyeth, Pfizer and AstraZeneca, and has co-ordinated a study for Quotient Bioresearch. He is Dr Megan Young's PhD supervisor.
Prof Mieke van Driel has no known conflicts of interest.

Sources of support

Internal sources

  • Griffith University, Australia.

    In-kind employee time

  • University of Queensland, Australia.

    In-kind employee time

  • Queensland Health, Australia.

    In-kind employee time

External sources

  • No sources of support supplied

Differences between protocol and review

We found several studies where the design was a controlled clinical trial (with exposure to rubella virus controlled by the investigators) but the method of allocation of participants to groups was not reported. We found an alternative report of one of these studies that indicated that participants were assigned to groups randomly. We therefore included such studies and undertook sensitivity analysis by gradually removing them from the analysis firstly in order of the magnitude of the effect estimate (largest to smallest) and then separately in order of the size of the trial (largest to smallest).

A number of the studies assessed participant susceptibility by means of history only and up to 50% of rubella infections are asymptomatic, therefore we undertook sensitivity analysis by excluding those studies using only history of rubella as the means of assessing susceptibility.

Given variability among the studies with respect to the time between exposure and intervention and the dose of immunoglobulins administered, and that these factors are most likely to impact on effectiveness, we conducted a post hoc meta-analysis that considered both simultaneously. We subgrouped studies according to estimated dose and then removed studies where the intervention was administered up to eight to 28 days after exposure.

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Anderson 1953a

MethodsRCT
ParticipantsFemale university students (sample size 24) aged 18 to 26 from Victoria, Australia, with no history of rubella, exposed artificially with virus obtained from rubella sufferers and processed to a solution of 500 Oxford units per millilitre. The viral solution was administered to the volunteers by atomised spray into the throat (0.1 ml) and dropped into each nostril during inhalation (0.1 ml)
Interventions70 hours after exposure, 4 ml (0.03 to 0.04 ml/lb) gamma-globulin (rubella antibody titre not reported) IM versus no intervention
Outcomes

Rubella cases diagnosed after examination by 2 physicians

Follow-up duration: 21 days plus

NotesFunding: intervention product supplied by Red Cross Blood Transfusion Service and CSL, Australia
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNot reported
Allocation concealment (selection bias)Unclear riskNot reported
Blinding of participants and personnel (performance bias)
All outcomes
Low riskThe nature of the intervention means it is not subject to variation due to performance
Blinding of outcome assessment (detection bias)
Cases of rubella
High riskBlinding not reported. Outcome assessed subjectively
Incomplete outcome data (attrition bias)
All outcomes
Low riskAll participants accounted for in results
Selective reporting (reporting bias)Low riskNo outcomes specified that were not reported

Anderson 1953b

MethodsRCT
ParticipantsAdolescent boys (sample size 91) aged 15 to 18 years from Victoria, Australia with no history of rubella living together with other boys diagnosed with rubella in the preceding 4 days
InterventionsOn day 5 since the first case was diagnosed, 4 ml gamma-globulin (rubella antibody titre not reported) IM versus 4 ml normal saline IM
Outcomes

Rubella cases diagnosed by a physician

Follow-up duration: 21 days plus

NotesFunding: intervention product supplied by Red Cross Blood Transfusion Service and CSL, Australia
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNot reported
Allocation concealment (selection bias)Unclear riskNot reported
Blinding of participants and personnel (performance bias)
All outcomes
Low riskThe nature of the intervention means it is not subject to variation due to performance
Blinding of outcome assessment (detection bias)
Cases of rubella
Low riskParticipants and outcome assessors blinded: "Both the globulin and the saline were given by the same physicians and the boys had no knowledge of which they received. From May 19 to June 3 the 91 boys were inspected daily by one of the authors (SGA), who at the time of inspection did not know who had received saline and who globulin" p184
Incomplete outcome data (attrition bias)
All outcomes
Low riskAll participants accounted for in results
Selective reporting (reporting bias)Low riskNo outcomes specified that were not reported

Doege 1967

MethodsRCT
ParticipantsResidents (sample size 17) aged 3 to 19 with rubella antibody neutralisation titres < 1:4 who lived in 1 wing of an institution for mentally handicapped people in Seattle, USA where diagnosed cases also resided
Interventions3 weeks after the first case and 6 days after the most recent case in the wing was diagnosed, 0.5 ml per unit bodyweight (unit not specified) 'poliomyelitis immune globulin' with rubella neutralisation titre 1:300 IM versus no intervention
Outcomes

Rubella cases: clinical signs, virus isolates from oropharyngeal or nasopharyngeal swabs, change in rubella neutralisation titre

Follow-up duration: 3 months

Notes

Data were presented in the publication on a wider range of participants but we have included only those the authors determined to be susceptible to rubella (which the authors based on rubella neutralisation titre < 1:4)

Funding: intervention product supplied by Parke, Davis & Co, Detroit. Study supported by US Public Health Service infectious diseases training grant

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskMeans of random sequence generation not reported. Of 47 participants randomised from 1 wing, we have included only the 17 deemed by the authors as susceptible
Allocation concealment (selection bias)Unclear riskNot reported
Blinding of participants and personnel (performance bias)
All outcomes
Low riskThe nature of the intervention means it is not subject to variation due to performance
Blinding of outcome assessment (detection bias)
Cases of rubella
Low riskVirus isolation and serology measures objective. Participants with "suspicious rashes" were examined by one of the authors who was blind to group allocation: "Children of both wings were observed by competent nurses and attending physicians and persons with suspicious rashes were examined by one of us (TCD) without knowledge of their group" p105
Incomplete outcome data (attrition bias)
All outcomes
Low riskAll participants accounted for in results
Selective reporting (reporting bias)Low riskNo outcomes specified that were not reported

Green 1965a

MethodsControlled clinical trial with unclear randomisation
ParticipantsMentally handicapped children (sample size 13) aged 1 to 10 years residing at an institution on Staten Island, USA, with rubella neutralisation titres at baseline < 1:4 who were living with a child with clinical rubella after that child's artificial infection
Interventions24 hours after the appearance of rash on the infected child, 0.15 ml/lb of gamma-globulin with rubella neutralising titre of 1:32 IM versus no intervention
Outcomes

Rubella cases: significant neutralising antibody titre rise +/- clinical signs +/- virus isolation from serum or pharynx

Follow-up: 53 days

NotesFunding: grant from the National Institute of Allergy and Infectious Diseases, US Public Health Service and a contract with the US Army Medical Research and Development Command, Office of the Surgeon General
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskMeans of allocation to groups not reported
Allocation concealment (selection bias)Unclear riskMeans of allocation to groups not reported
Blinding of participants and personnel (performance bias)
All outcomes
Low riskThe nature of the intervention means it is not subject to variation due to performance
Blinding of outcome assessment (detection bias)
Cases of rubella
Low riskNo blinding reported but outcome measured objectively using serology
Incomplete outcome data (attrition bias)
All outcomes
Low riskAll participants accounted for in the results regarding the outcome rubella cases
Selective reporting (reporting bias)High riskViraemia outcome presented for 5 intervention and 5 control participants only of all participants in Green 1965a, b, and c. Results of swab/serum virus isolation for other participants not reported

Green 1965b

MethodsControlled clinical trial with unclear randomisation
ParticipantsMentally handicapped children (sample size 10) aged 1 to 10 years residing at an institution on Staten Island, USA, with rubella neutralisation titres at baseline < 1:4 who were living with a child with clinical rubella from onset of rash on that child
Interventions24 hours after initial exposure to the child with rash, 0.2 ml/lb of gamma-globulin with rubella neutralising titre 1:64 IM versus no intervention
Outcomes

Rubella cases: significant neutralising antibody titre rise +/- clinical signs +/- virus isolation from serum or pharynx

Follow-up: 53 days

NotesFunding: grant from the National Institute of Allergy and Infectious Diseases, US Public Health Service and a contract with the US Army Medical Research and Development Command, Office of the Surgeon General
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskMeans of allocation to groups not reported
Allocation concealment (selection bias)Unclear riskMeans of allocation to groups not reported
Blinding of participants and personnel (performance bias)
All outcomes
Low riskThe nature of the intervention means it is not subject to variation due to performance
Blinding of outcome assessment (detection bias)
Cases of rubella
Low riskNo blinding reported but outcome measured objectively using serology
Incomplete outcome data (attrition bias)
All outcomes
Low riskAll participants accounted for in the results regarding the outcome rubella cases
Selective reporting (reporting bias)High riskViraemia outcome presented for 5 intervention and 5 control participants only of all participants in Green 1965a, b and c. Results of swab/serum virus isolation for other participants not reported

Green 1965c

MethodsControlled clinical trial with unclear randomisation
ParticipantsMentally handicapped children (sample size 11) aged 1 to 10 years residing at an institution on Staten Island, USA, with rubella neutralisation titres at baseline < 1:4 who had brief contact (30 minutes but included 'intimate oral contact') with 2 children on the first day of their rubella rash
InterventionsAt a time (not reported) after exposure, 0.2 ml/lb gamma-globulin with rubella neutralising titre 1:64 IM versus no intervention
Outcomes

Rubella cases: significant neutralising antibody titre rise +/- clinical signs +/- virus isolation from serum or pharynx

Follow-up: 53 days

NotesFunding: grant from the National Institute of Allergy and Infectious Diseases, US Public Health Service and a contract with the US Army Medical Research and Development Command, Office of the Surgeon General
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskMeans of allocation to groups not reported
Allocation concealment (selection bias)Unclear riskMeans of allocation to groups not reported
Blinding of participants and personnel (performance bias)
All outcomes
Low riskThe nature of the intervention means it is not subject to variation due to performance
Blinding of outcome assessment (detection bias)
Cases of rubella
Low riskNo blinding reported but outcome measured objectively using serology
Incomplete outcome data (attrition bias)
All outcomes
Low riskAll participants accounted for in the results regarding the outcome rubella cases
Selective reporting (reporting bias)High riskViraemia outcome presented for 5 intervention and 5 control participants only of all participants in Green 1965a, b and c. Results of swab/serum virus isolation for other participants not reported

Martin du Pan 1972

MethodsControlled clinical trial with unclear randomisation
ParticipantsUniversity student volunteers (sample size 7) from Geneva, Switzerland with no history of rubella and no rubella antibody at baseline on hemagglutinin inhibition (HI) testing, who were infected by intranasal administration of 1 ml solution containing 10 000 TCID50 (median tissue culture infective dose) rubella viruses of attenuated Brown strain
Interventions5 days after infection, 30 ml to 60 ml of gamma-globulin with 1:1000 rubella titre by HI diluted in 200 ml saline IV versus no intervention
Outcomes

Rubella cases: significant rise in rubella serum titre by HI +/- clinical signs

Follow-up: 6 weeks

NotesFunding: no source reported
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskMeans of allocation to groups not reported
Allocation concealment (selection bias)Unclear riskMeans of allocation to groups not reported
Blinding of participants and personnel (performance bias)
All outcomes
Low riskThe nature of the intervention means it is not subject to variation due to performance
Blinding of outcome assessment (detection bias)
Cases of rubella
Low riskNo blinding reported but outcome measured objectively using serology
Incomplete outcome data (attrition bias)
All outcomes
Low riskAll participants accounted for in results
Selective reporting (reporting bias)Low riskNo outcomes specified that were not reported

McCallin 1972

MethodsRCT
ParticipantsWomen (sample size 41) registering at an antenatal clinic in Hawaii, USA who were fewer than 9 weeks pregnant, had no rubella antibody at baseline based on HI testing and self reported exposure to rubella during the first trimester of pregnancy
InterventionsOn enrolment, 20 ml gamma-globulin with rubella HI titre 1:512 IM versus 20 ml gamma-globulin with rubella HI titre 1:64
Outcomes

Maternal rubella cases: seroconversion by HI. Follow-up: 2 months

CRS: means of examination not reported. Infants "followed up for minimum 6 months and up to 3 years" p187

Notes

Publication reports on a 3rd study group given no intervention but this group was not randomly assigned

Funding: no source reported

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNot reported
Allocation concealment (selection bias)Unclear riskNot reported
Blinding of participants and personnel (performance bias)
All outcomes
Low riskThe nature of the intervention means it is not subject to variation due to performance
Blinding of outcome assessment (detection bias)
Cases of rubella
Low riskNo blinding reported but outcome measured objectively using serology
Blinding of outcome assessment (detection bias)
Cases of congenital rubella syndrome
Unclear riskNo blinding reported. No reported definition of congenital rubella syndrome, no details on the means of examination of infants in each group, no reported average length of follow-up according to group
Incomplete outcome data (attrition bias)
All outcomes
Low riskAll participants accounted for in results
Selective reporting (reporting bias)Low riskNo outcomes specified that were not reported

McDonald 1963

MethodsRCT
ParticipantsChildren (sample size 179) (age not further defined) in 5 wards in a hospital in London, UK with no past history of rubella who were "exposed to infection" p416
InterventionsAt a time (not reported) after exposure, 250 mg gamma-globulin from 1 of 46 different batches (rubella antibody titre not reported) versus no intervention
Outcomes

Rubella cases: outcome criteria not reported

Excluded 'cases' from results where illness onset was within 3 days of the intervention time

Follow-up: 35 days

Notes

Main portion of the publication reports on a case series, which is not a study design included in the review

Funding: no source reported

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNot reported
Allocation concealment (selection bias)Unclear riskNot reported
Blinding of participants and personnel (performance bias)
All outcomes
Low riskThe nature of the intervention means it is not subject to variation due to performance
Blinding of outcome assessment (detection bias)
Cases of rubella
High riskBlinding not reported. No mention of blood testing or other investigation for infection. Outcome likely to have been assessed subjectively
Incomplete outcome data (attrition bias)
All outcomes
Low riskAll participants accounted for in results
Selective reporting (reporting bias)Low riskNo outcomes specified that were not reported although report was brief

Petersen 1978

MethodsControlled clinical trial with unclear randomisation
ParticipantsMedical student volunteers (sample size 16) in Germany with a mean age of 25 years who had no rubella antibody at baseline based on HI testing and were infected by administration of 0.25 ml of 1500 GKID50 (median tissue culture infective dose) rubella virus suspension into each nostril
Interventions24 hours after exposure, 15 ml of gamma-globulin with rubella HI titre 1:2560 IM (intervention group had had 20 ml IM of same 6 weeks earlier) versus no intervention
Outcomes

Rubella cases: seroconversion as measured by HI +/- virus isolation +/- clinical signs

Follow-up: 8 weeks

NotesFunding: no source reported
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskMeans of allocation to groups not reported
Allocation concealment (selection bias)Unclear riskMeans of allocation to groups not reported
Blinding of participants and personnel (performance bias)
All outcomes
Low riskThe nature of the intervention means it is not subject to variation due to performance
Blinding of outcome assessment (detection bias)
Cases of rubella
Low riskNo blinding reported but outcome measured objectively using serology
Incomplete outcome data (attrition bias)
All outcomes
Low riskAll participants accounted for in results
Selective reporting (reporting bias)Low riskNo outcomes specified that were not reported

Schiff 1969a

MethodsRCT
ParticipantsAdult male (sample size 10) (age not further defined) inmates of a correctional institution in Ohio, USA with no rubella neutralising antibody titre at baseline who were infected by dripping 0.5 ml of 100 TCID50 Gilchrist strain virus solution into each nostril after roughing the posterior pharynx with a cotton swab
Interventions

24 hours after exposure, 20 ml (0.12 ml/lb to 0.15 ml/lb) of gamma-globulin (called immune globulin in the publications) with rubella neutralisation titre of 1024 to 4096*/0.1 ml IM versus saline 20 ml IM

*(gamma-globulin original batch titre 4096/0.1 ml but on retesting after 3 years in storage titre was 1024/0.1 ml - unclear at what time in relation to testing of titre the study used the batch)

Outcomes

Rubella cases: seroconversion by neutralisation +/- virus isolation +/- clinical signs

Follow-up: 42 days

NotesFunding: the 'National Foundation' and a 'Career Research Development Award from the National Institutes of Health'
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNot reported
Allocation concealment (selection bias)Unclear riskNot reported
Blinding of participants and personnel (performance bias)
All outcomes
Low riskThe nature of the intervention means it is not subject to variation due to performance
Blinding of outcome assessment (detection bias)
Cases of rubella
Low riskNo blinding reported but outcome measured objectively using serology
Incomplete outcome data (attrition bias)
All outcomes
Low riskAll participants accounted for in results
Selective reporting (reporting bias)Low riskNo outcomes specified that were not reported

Schiff 1969b

  1. a

    CRS: congenital rubella syndrome
    HI: hemagglutinin inhibition
    IM: intramuscular
    IV: intravenous
    RCT: randomised controlled trial

MethodsRCT
ParticipantsAdult male (sample size 11) (age not further defined) inmates of a correctional institution in Ohio, USA with no rubella HI titre at baseline who were infected by dripping 0.5 ml of 100 TCID50 Gilchrist strain virus solution into each nostril after roughing the posterior pharynx with a cotton swab
Interventions24 hours after exposure, 20 ml of gamma-globulin (called immune globulin in the publications) with rubella neutralisation titre of 256/0.1 ml IM versus saline 20 ml IM
Outcomes

Rubella cases: seroconversion by HI +/- virus isolation +/- clinical signs

Follow-up: 42 days

NotesFunding: the 'National Foundation' and a 'Career Research Development Award from the National Institutes of Health'
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNot reported
Allocation concealment (selection bias)Unclear riskNot reported
Blinding of participants and personnel (performance bias)
All outcomes
Low riskThe nature of the intervention means it is not subject to variation due to performance
Blinding of outcome assessment (detection bias)
Cases of rubella
Low riskNo blinding reported but outcome measured objectively using serology
Incomplete outcome data (attrition bias)
All outcomes
Low riskAll participants accounted for in results
Selective reporting (reporting bias)Low riskNo outcomes specified that were not reported

Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion
  1. a

    RCT: randomised controlled trial

Adams 1997No immunoglobulin administered
Alyswort 1971Case study
Andre 1980Letter - no primary study
Anon 1970Letter - no primary study
Anon 1975Question and answer - no primary study
Anon 1977No immunoglobulin administered
Anon 1993Does not appear to be a RCT or quasi-RCT. Immunoglobulin given prior to vaccination. Outcome was seroconversion in relation to vaccine
Aurousse 1973No comparison group
Badillet 1967No comparison group
Balsamo 1963No immunoglobulin administered
Banatvala 2004Review
Barenberg 1942No comparison group
Bass 1949Participant susceptibility not known by investigators
Beasley 1969No immunoglobulin administered
Bradstreet 1978Laboratory study. No immunoglobulin administered
Brody 1965Descriptive study. No immunoglobulin administered
Budai 1970No comparison group
Carne 1973Descriptive study. No immunoglobulin administered
CDC 1964Descriptive study. No immunoglobulin administered
CDC 1978Case study
CDC 1979Descriptive study. No immunoglobulin administered
CDC 1980Descriptive study. No immunoglobulin administered
CDC 1981aReview
CDC 1981bReview
CDC 1981cCase series
CDC 1983Descriptive study. No immunoglobulin administered
CDC 1986No exposure - vaccination only. No immunoglobulin administered
Clarke 1975Laboratory study
Connolly 1984Descriptive study. No immunoglobulin administered
Cradock-Watson 1973Symptomatic participants. No immunoglobulin administered
Cradock-Watson 1976Participants were infants with suspected or confirmed congenital rubella syndrome
Craig 1999No comparison group
D'Agaro 2010Outbreak description. No intervention
Darbois 1974No comparison group. No immunoglobulin administered
DMPS 1973Descriptive study. No intervention
Dudgeon 1974Letter - no primary study
Fliegel 1982No immunoglobulin administered
Forrest 1971No immunoglobulin administered
Forrest 1973Case study
Forrest 1974Retrospective examination of cases
Frank 1969Discussion at a conference/seminar - no primary study
Freestone 1972Review
Furukawa 1970No immunoglobulin administered
Geursen 1982Review
Gilberto 1988Review
Giles 1965Case series
Giraldi 2009Symptomatic participants. No immunoglobulins administered
Gladstone 1981No immunoglobulin administered
Goetz 1974Question and answer - no primary study
Grayston 1959Participants not identified as susceptible
Greaves 1982Review
Greenberg 1947Review. Some details of a primary study by the authors regarding rubella, but participants not identified as susceptible
Hahne 2009No immunoglobulin administered
Haire 1970Case series
Happe 1984No comparison group
Hillenbrand 1956Descriptive study. No immunoglobulin administered
Horstmann 1965Descriptive study. No immunoglobulin administered
Horstmann 1971Review
Houser 1958Immunoglobulin given pre-exposure
Huntley 1969Examination of infant immunoglobulin levels
Hutchinson 1967No comparison group
Jackson 1993No immunoglobulins administered
Just 1969Conference proceedings on the vaccine
Kabat 1963Review
Karchmer 1969No exposure. No immunoglobulin administered
Karthikeyan 2012Case study
Korns 1952Participant susceptibility not known by investigators
Krugman 1954Review
Krugman 1958Laboratory study. No immunoglobulin administered
Krugman 1963Review
Krugman 1970Letter - no primary study
Lamprecht 1982Descriptive study. No immunoglobulin administered
Lock 1961Retrospective study
Lundstrom 1953No comparison group
Lundstrom 1956Review
Lundstrom 1961aNo comparison group. Second group given 'pooled gamma-globulin' but this was derived from retroplacental blood
Lundstrom 1961bParticipants symptomatic
Lundstrom 1962No comparison group
Lundstrom 1965Review
Lundstrom 1969Discussion session at a conference. No primary study
Luthardt 1974No exposure
Macrae 1968Outcome was rubella cases and allocation to groups not random or quasi-random
Macrae 1970No comparison group
Magath 1957Editorial
Marshall 1976Review
Martin 1999Descriptive study. No immunoglobulin administered
Martin du Pan 1969No exposure. No comparison group
Martin du Pan 1971No comparison group
Matsen 1970No immunoglobulin administered
McDonald 1967No comparison group
McLorinan 1949No comparison group
McLorinan 1950No comparison group
Mele 1949Not a RCT/quasi-RCT. Allocation based on availability of gamma-globulin
Mellinger 1995Retrospective study
Miller 1967Participant susceptibility not known by investigators
Millian 1971Laboratory assessment of gamma-globulin
Morgan 1950Report - no primary study
Neumann-Haefelin 1975Not a RCT. Allocation based on organisation aspects and willingness of participants
Peckham 1974aParticipants symptomatic/diagnosed with rubella
Peckham 1974bLetter - no primary study
Petersen 1982No exposure - vaccination only
Plotinsky 2007Case study
Polk 1980Descriptive study. No immunoglobulin administered
Pollock 1970Secondhand account of several primary studies
Reid 1967Review
Sanchez 2010Case study
Sandow 1978Review
Schiff 1965aRetrospective study. No comparison group
Schiff 1965bNot all participants susceptible. No immunoglobulin administered
Schiff 1966Review
Schiff 1969cNo immunoglobulin administered
Seglenieks 1974Topic of study not rubella
Seth 1972Seroprevalence study
Sever 1965aNot all participants susceptible and cannot separate results for those who were
Sever 1965bDescriptive study. No immunoglobulin administered
Skinner 1961Review
Spiteri 2008Descriptive study. No immunoglobulin administered
Stokes 1947Review - topic not rubella
Strassburg 1981No immunoglobulin administered
Strauss 1980No immunoglobulin administered. Vaccine only
Urquhart 1978No exposure - vaccine only
Vaheri 1972Review regarding vaccination
Ward 1956Participant susceptibility not known by investigators
Watson 1969No immunoglobulin administered
WHO 2000Review
WHO 2002Descriptive study. No immunoglobulin administered

Ancillary