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.
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.
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.
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.
Preveo: Ante Begonja
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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.
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.
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.
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.
24. (("follow up" or follow-up) adj (study or studies or assessment)).tw.
25. (observational adj (study or studies)).tw.
28. ((single or double* or triple* or treb*) and (blind* or mask*)).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.
39. (study adj3 aim*).ab.
40. "our study".ab.
45. (multicentre or multicenter or multi-centre or multi-center).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*
Haffkine Bio-Pharmaceutical Corporation Ltd
Link Medical Products Pty Ltd
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.
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.