Intervention Review

You have free access to this content

Post-exposure passive immunisation for preventing measles

  1. Megan K Young1,*,
  2. Graeme R Nimmo2,
  3. Allan W Cripps3,
  4. Mark A Jones4

Editorial Group: Cochrane Acute Respiratory Infections Group

Published Online: 1 APR 2014

Assessed as up-to-date: 14 AUG 2013

DOI: 10.1002/14651858.CD010056.pub2


How to Cite

Young MK, Nimmo GR, Cripps AW, Jones MA. Post-exposure passive immunisation for preventing measles. Cochrane Database of Systematic Reviews 2014, Issue 4. Art. No.: CD010056. DOI: 10.1002/14651858.CD010056.pub2.

Author Information

  1. 1

    Griffith University, School of Medicine, Griffith Health Institute, Meadowbrook, Queensland, Australia

  2. 2

    Pathology Queensland, Department of Microbiology, Brisbane, Queensland, Australia

  3. 3

    Griffith University, Griffith Health, Gold Coast, Queensland, Australia

  4. 4

    The University of Queensland, School of Population Health, Brisbane, Queensland, Australia

*Megan K Young, School of Medicine, Griffith Health Institute, Griffith University, University Drive, Meadowbrook, Queensland, 4121, Australia. megan.young@griffith.edu.au.

Publication History

  1. Publication Status: New
  2. Published Online: 1 APR 2014

SEARCH

 
Characteristics of included studies [ordered by study ID]
Berkovich 1963

MethodsNon-RCT undertaken in December 1961


ParticipantsTuberculous patients housed together in a children's ward of a New York hospital, USA and exposed to a symptomatic case of measles on the ward. Age and gender not reported


Interventions1. Commercially produced gamma globulin of 512 neutralising measles titre intramuscularly at 0.1 ml/pound of body weight

2. Ender's live measles virus vaccine and same lot of commercially produced gamma globulin at 0.02 ml/pound body weight intramuscularly at separate sites


OutcomesCases of measles


Total length of follow up20 days


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)High riskNot randomised

Allocation concealment (selection bias)High riskThose with parental consent received live virus vaccine while those without consent for the vaccine received gamma globulin only

Blinding of participants and personnel (performance bias)
All outcomes
Low riskThe nature of both interventions is not subject to variation due to performance

Blinding of outcome assessment (detection bias)
Cases of measles
Unclear riskNot clear who assessed the participants for signs of measles and no standard definition of measles was reported

Incomplete outcome data (attrition bias)
All outcomes
Low riskAll participants accounted for in the results

Selective reporting (reporting bias)Low riskNo outcomes specified that were not reported

ConfoundingHigh riskNo measurement of or control for potential confounders

Cockburn 1950

MethodsRCT undertaken in early 1949


ParticipantsChildren aged between 6 and 60 months of age who attended or resided at child care institutions in England and Scotland. Around 5% were under the age of 1 year. Just over half the participants were male


Interventions1. 225 mg to 450 mg of freeze-dried gamma globulin dissolved in 3 ml to 6 ml of sterile, distilled water immediately before intramuscular injection

2. 5 ml adult serum containing 0.5% phenol or reconstituted dried plasma intramuscularly


OutcomesCases of measles

Complications due to measles

Adverse events


Total length of follow up21 days


NotesAdverse events not specified as an outcome in the methods but reported for both groups collectively: "Apart from transient limb stiffness lasting one or two hours in a few cases, no local reactions were observed in the globulin or adult-serum groups. One child in the globulin group developed, three days after inoculation, an urticarial rash which disappeared in twenty-four hours" (pg 735)


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskA person who was not giving the injections provided for each study locality a list of pairs of letters, "G" for gamma globulin and "A" for adult serum. The order in which the letters appeared in the pair was determined by "random sampling numbers". No further information was reported on how numbers were generated

Allocation concealment (selection bias)High riskPerson giving injections made a list of all eligible consenting contacts, dividing them into groups according to predefined "intimacy of exposure" levels. Within each subgroup participants were listed in order of increasing age. From the top of the list, those in each pair were then allocated based on the letter list. Once used, the pair of letters was crossed off the list

Blinding of participants and personnel (performance bias)
All outcomes
Low riskThe nature of the interventions means they are not subject to variation due to performance

Blinding of outcome assessment (detection bias)
Cases of measles
Low riskThe details of the intervention were recorded and then filed away, with subsequent clinical observations recorded on a separate sheet (pg 733). While the doctors who gave the injections were the assessors of the outcomes, the authors tested recall of which child had which intervention in a preliminary study and "it was practically impossible for the observer to remember after inoculating the children whether a particular child had been given gamma globulin or adult serum"

Blinding of outcome assessment (detection bias)
Complications from measles
Low riskAs with cases of measles outcome

Blinding of outcome assessment (detection bias)
Adverse events
Low riskAs with cases of measles outcome

Incomplete outcome data (attrition bias)
All outcomes
Low riskNo loss to follow-up apparent. Each child was observed for 21 days at the child care institutions. If the child was absent, they were visited at their home. If no cases of measles occurred in the contacts within 21 days, the trial at that institution was closed

Selective reporting (reporting bias)Low riskNo outcomes specified that were not reported

Degkwitz 1920

MethodsNon-RCT. Year study undertaken not known


ParticipantsChildren aged 8 months to 13.5 years, exposed to measles in a hospital in Germany


Interventions1. Convalescent serum administered on day 4 after exposure, 3 ml versus 2.5 ml as control

2. Convalescent serum 6 ml to 7 ml administered on day 6 after exposure versus day 7 after exposure as control


OutcomesMeasles cases


Total length of follow upNot reported


NotesArticle in German - assessment based on translation form information


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)High riskNot randomised

Allocation concealment (selection bias)High riskNot randomised. Not reported how participants were allocated to groups

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 measles
Unclear riskNot clear who assessed the participants for signs of measles and no standard definition of measles was reported

Incomplete outcome data (attrition bias)
All outcomes
Low riskAll participants accounted for in the results

Selective reporting (reporting bias)Low riskNo outcomes specified that were not reported

ConfoundingHigh riskNo measurement of or control for potential confounders

Endo 2001

MethodsNon-RCT undertaken in 1999 to 2000


ParticipantsSusceptible infants and toddlers in Japan, of average age 1.5 years, who had close contact with someone with measles and whose parents consented to participate in the study. 24 boys and 9 girls were enrolled


InterventionsIntramuscular immunoglobulin 0.33 ml/kg within 5 days of exposure. 4 different lots of commercially obtained immunoglobulins were used. The concentrations of measles-specific antibody in each were: 16 IU/ml, 33 IU/ml, 40 IU/ml, 45 IU/ml


OutcomesCases of measles


Total length of follow up14 days


NotesAdverse events not reported


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)High riskNot randomised

Allocation concealment (selection bias)High riskNot randomised. It is not reported how participants were allocated to the different lots of immunoglobulin

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 measles
Unclear riskParents were asked to report fever or rash over the 2 weeks subsequent to intervention. Upon report, a physician examined the child to confirm the diagnosis. It is not reported whether the physician was aware of which lot of IG was administered

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskIt is not clear whether those parents who did not report illness of their child were actively followed up although the results suggest follow-up was complete

Selective reporting (reporting bias)Low riskNo outcomes specified that were not reported

ConfoundingHigh riskComparison is made between the 9 children with clinical measles and the 24 children without clinical measles over the follow-up period in terms of age, body weight, interval between exposure and intervention, dose of IG in ml/kg and measles-specific antibody titre, suggesting no difference in these characteristics between the 2 groups apart from the mean measles-specific antibody titre administered. There is no control for confounding according to lot of IG administered

Glyn-Jones 1972

MethodsQuasi-RCT undertaken in 1968 to 1969


ParticipantsSusceptible children aged 6 to 35 months admitted to the paediatric unit at Mpilo Hospital in Zimbabwe ('Rhodesia' at the time of the study) who were alive the day after admission


Interventions1. Human immune globulin 2 ml intramuscularly on the day after admission, repeated at 3-weekly intervals until discharge

2. No treatment

3. Measles vaccine, 1 dose intramuscularly on the day after admission


OutcomesCases of measles

Deaths due to measles

Complications from measles

Adverse events - measles vaccine reactions


Total length of follow upAt least 2 weeks after discharge from hospital


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)High riskAssigned sequentially according to admission order

Allocation concealment (selection bias)Unclear riskTreatment group assigned by author's colleague and given to senior ward nurses who administered the treatment (pg 4). Unclear if the colleague was involved in the care of the participants

Blinding of participants and personnel (performance bias)
All outcomes
Low riskThe nature of the interventions means they are not subject to variation due to performance

Blinding of outcome assessment (detection bias)
Cases of measles
Low riskAll assessment of participants carried out by author who was not aware of group allocation

Blinding of outcome assessment (detection bias)
Complications from measles
Low riskAll assessment of participants carried out by author who was not aware of group allocation

Blinding of outcome assessment (detection bias)
Deaths due to measles
Low riskAll assessment of participants carried out by author who was not aware of group allocation

Blinding of outcome assessment (detection bias)
Adverse events
Low riskAll assessment of participants carried out by author who was not aware of group allocation

Incomplete outcome data (attrition bias)
All outcomes
High riskAll participants accounted for in results. Loss to follow-up very similar across groups but exceeded 20%

Selective reporting (reporting bias)Low riskNo outcomes specified that were not reported

Hartley 1948

MethodsNon-RCT undertaken in 1943


ParticipantsSusceptible children aged 0 to 10+ years exposed to 'an undoubted case' of measles in their home or child care institution or hospital ward in England or Scotland


Interventions1. Gamma globulin manufactured in the USA by Cohn cold ethanol fractionation and administered intramuscularly in doses of 1.2 ml or less, 1.5 ml to 2 ml and 2.5 ml or more

2. Reconstituted dried human convalescent serum (single batch) intramuscularly in doses of 2.5 ml, 3.3 ml to 3.5 ml and 5 ml or more


OutcomesCases of measles


Total length of follow up3 weeks post-intervention


NotesAdverse reactions not specified as an outcome in the methods; very poorly reported and not specific for this cohort: "no untoward results were noted" (pg 43); "no local or general reactions followed the injection of gamma-globulin"


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)High riskNot randomised

Allocation concealment (selection bias)High riskNot randomised. Not reported how contacts were allocated to intervention group

Blinding of participants and personnel (performance bias)
All outcomes
Low riskThe nature of the interventions means they are not subject to variation due to performance

Blinding of outcome assessment (detection bias)
Cases of measles
Unclear riskNot reported who assessed the participants for signs of measles and measles is not defined for the purposes of the study

Incomplete outcome data (attrition bias)
All outcomes
Low riskAll participants accounted for in the results

Selective reporting (reporting bias)Low riskNo outcomes specified in the methods that were not reported

ConfoundingHigh riskDid not dose according to weight and did not account for 'high risk' of illness or other comorbidity. Restricted based on time between exposure and intervention and stratified by dose of gamma globulin/serum, age and place of exposure

Morales 1930

MethodsQuasi-RCT undertaken in 1928 to 1929


ParticipantsSusceptible children aged 6 months to 15 years old in Porto Rico exposed to a household case of measles


Interventions1. "Injection" of 4 ml to 6 ml pooled convalescent serum obtained from the 5th to 10th day of convalescence

2. "Injection" of 10 ml to 40 ml pooled serum from adult donors with a history of measles between 1 and 10 years ago

3. No treatment


OutcomesCases of measles

Complications due to measles

Deaths due to measles

Adverse events


Total length of follow up8 weeks following exposure


NotesAdverse events very poorly reported: "Among more than 500 who received injections of serum, only 2 children showed reactions; they had slight fever, accompanied by an urticarial rash" (pg 1218)


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)High risk"Every third child was regarded as a control and received no treatment, while each of the remainder received an injection of either convalescent or immune serum" (pg 1216)

Allocation concealment (selection bias)High riskNot reported who allocated participants to groups or whether the person allocating had any knowledge of participant characteristics

Blinding of participants and personnel (performance bias)
All outcomes
Low riskThe nature of the interventions means they are not subject to variation due to performance

Blinding of outcome assessment (detection bias)
Cases of measles
Unclear riskInspectors visited the participants at home at regular intervals and reported illness to one author who then visited the participant immediately to determine the cause of illness. Not reported whether the author was blinded to intervention group

Blinding of outcome assessment (detection bias)
Complications from measles
Unclear riskNo definition of complications from measles is reported for the purposes of study. Not reported who assessed participants for complications or whether they were blind to intervention group

Blinding of outcome assessment (detection bias)
Deaths due to measles
Unclear riskUnclear whether the author who confirmed measles diagnosis was blind to intervention status. Unclear whether the deaths reported are only those felt to be connected to measles or all deaths

Blinding of outcome assessment (detection bias)
Adverse events
Unclear riskInspectors visited the participants at home at regular intervals and reported illness to one author who then visited the participant immediately to determine the cause of illness. Not reported whether the author was blinded to intervention 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

Ordman 1944

MethodsNon-RCT undertaken in 1942 to 1943


ParticipantsSusceptible children 6 months of age and older living in Boston, USA exposed to a household member with measles


Interventions1. Single batch of gamma globulin prepared by Cohn cold ethanol fractionation 2 ml to 5 ml IM in the gluteal region

2. No treatment


OutcomesCases of measles

Complications due to measles


Total length of follow up3 weeks after intervention


NotesAdverse reactions not specified as an outcome in the methods, poorly reported and not specific for this cohort. "No severe reactions have been observed in the several hundred individuals inoculated with it. In less than 5 per cent of these, mild reactions occurred. With a single exception, the reactions consisted of a slight feeling of stiffness in the muscle injected or a little local erythema and induration. In one case, the individual had a rise in temperature to 102°F 2 days after inoculation but no other systemic or local manifestation. Whether or not this febrile reaction was due to the globulin cannot be stated" (pg 547)


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)High riskNot randomised

Allocation concealment (selection bias)High risk"When there were 2 or more susceptible contacts in a family, they were divided into 2 groups composed of persons as nearly alike as possible with respect to age and degree of exposure. Children over 15 years of age were placed in the control group" (pg 542)

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 measles
Unclear riskFamily was visited by one of the authors at each follow-up. Not reported whether assessors were different to those who had given the interventions or whether they were blinded to intervention group

Blinding of outcome assessment (detection bias)
Complications from measles
Unclear riskAs for cases of measles outcome

Incomplete outcome data (attrition bias)
All outcomes
Low riskAll participants accounted for in results

Selective reporting (reporting bias)Low riskNo outcomes specified in the methods that were not reported

ConfoundingHigh riskAdjusted dose to age as in methodological protocol but no other measurement or control for confounding

Salomon 1923

MethodsNon-RCT. Year study undertaken not reported


ParticipantsChildren aged older than 3 months in a hospital in Germany


Interventions1. Convalescent serum (dose not reported)

2. Adult serum 10 ml to 15 ml

3. No treatment


OutcomesMeasles cases

Death due to measles


Total length of follow upNot reported


NotesArticle in German. Assessment based on translation form information


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)High riskNot randomised

Allocation concealment (selection bias)High riskNot randomised. Interventions administered sequentially in blocks of time according to availability

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 measles
Unclear riskNot clear who assessed the participants for signs of measles and no standard definition of measles was reported

Blinding of outcome assessment (detection bias)
Deaths due to measles
Unclear riskNot clear who assessed the participants regarding death due to measles or whether they were blind to group allocation

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

ConfoundingHigh riskNo measurement of or control for potential confounders

Sheppeard 2009

MethodsNon-RCT undertaken in 2006


ParticipantsSusceptible contacts (aged 6 months to 40+ years) of confirmed cases of measles notified to New South Wales public health units


Interventions1. MMR if within 3 days of exposure

2. Normal human immunoglobulin (gamma globulin) within 7 days of exposure, 0.2 ml/kg up to 15 ml

3. No treatment


OutcomesCases of measles


Total length of follow upPassive surveillance until 2 incubation periods after the last notified case


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)High riskNot randomised

Allocation concealment (selection bias)High riskNot randomised. Allocation determined by length of time from exposure at point of contact with participant

Blinding of participants and personnel (performance bias)
All outcomes
Low riskThe nature of the interventions means they are not subject to variation due to performance

Blinding of outcome assessment (detection bias)
Cases of measles
Low riskCase of measles defined for the purposes of the study, criteria objective and likely assessed by other than the authors

Incomplete outcome data (attrition bias)
All outcomes
High riskFollow-up by passive surveillance

Selective reporting (reporting bias)Low riskNo outcomes specified that were not reported

ConfoundingHigh riskNo control of potential confounders. Measured setting of exposure only

Stillerman 1944

MethodsNon-RCT undertaken in 1938-1941


ParticipantsHealthy, susceptible children living in New York city, USA, aged 6 months to 15 years who were exposed to a family member in their household who had been diagnosed with measles


Interventions1. Pooled convalescent serum (collected from adolescents and adults up to 4 months after the onset of measles) 5 ml to 20 ml administered IM into the upper outer aspect of the buttock or the thigh

2. No treatment


OutcomesCases of measles

Complications from measles


Total length of follow upUp to 23 days after exposure


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)High riskNot randomised

Allocation concealment (selection bias)High riskNot randomised. Not reported how participants were allocated to groups

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 measles
Unclear riskNot reported who assessed participants for measles or whether they were blind to group allocation

Blinding of outcome assessment (detection bias)
Complications from measles
High riskComplications only reported for intervention group. Control only followed up until rash onset if they became ill

Incomplete outcome data (attrition bias)
All outcomes
Low riskAll participants accounted for in results for cases of measles

Selective reporting (reporting bias)Low riskNo outcomes specified that were not reported

ConfoundingHigh riskRestricted against 'high-risk' contacts in terms of comorbidity. Measured most prespecified confounders but only undertook univariate analyses. Did not dose according to weight

Toomey 1926

MethodsNon-RCT undertaken in 1925


ParticipantsCohort of susceptible 'children' exposed on the same hospital ward in the 2 days prior. Age and gender not reported


Interventions1. Convalescent serum (obtained 8 days after the rash began to disappear) 2.5 ml to 5 ml administered intramuscularly

2. No treatment


OutcomesCases of measles


Total length of follow up60 days


NotesSome children had a second exposure

Adverse reactions not specified as an outcome in the methods, poorly reported and not specific for this cohort. "There was no local reaction to the injection. In most instances there was a rise in temperature of from 1 to 1.5C, beginning within twenty-four hours after the injection and lasting rarely longer than twenty-four hours. In six susceptible subjects, diarrhea was noted" (pg 401)


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)High riskNot randomised

Allocation concealment (selection bias)High riskNot randomised. Not reported how participants allocated to groups

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 measles
Unclear riskNot reported who assessed participants for signs of measles or whether they were blind to group allocation; no standard definition of measles was reported

Incomplete outcome data (attrition bias)
All outcomes
Low riskFollow-up of all patients while on the ward and at 60 days

Selective reporting (reporting bias)High riskReport contains case series data for which adverse events were reported but this outcome not reported in relation to this cohort

ConfoundingHigh riskNo measurement of or control for potential confounders

Wesselhoeft 1928

MethodsNon-RCT undertaken in 1928


ParticipantsSusceptible children exposed to measles in the diptheria and scarlet fever wings of a hospital in Boston, USA. Age and gender not reported


Interventions1. Convalescent serum (collected from older children and adults) 5 ml administered intramuscularly

2. No treatment


OutcomesCases of measles

Complications due to measles

Deaths due to measles


Total length of follow upNot reported


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)High riskNot randomised

Allocation concealment (selection bias)High riskNot randomised. Not reported how participants were allocated to groups

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 measles
Unclear riskNot reported who assessed participants for signs of measles or whether they were blind to group allocation and no standard definition of measles was reported

Blinding of outcome assessment (detection bias)
Complications from measles
Unclear riskNot reported who assessed participants for complications due to measles or whether they were blind to group allocation

Blinding of outcome assessment (detection bias)
Deaths due to measles
Unclear riskNot reported who assessed participants regarding death due to measles or whether they were blind to group allocation

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

ConfoundingHigh riskNo measurement of or control for potential confounders

 
Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion

Barenberg 1930Unclear whether all participants were exposed

Benson 1927Intervention and control groups not recruited over similar and overlapping time periods

Blackfan 1923Unclear whether all participants were susceptible

Christensen 1953Unclear whether all controls were susceptible and placental and plasma globulin were combined as one intervention (results for each not separable)

Gunn 1928No definable control group for intervention of relevance

Haas 1926Unclear whether all controls were susceptible

Karelitz 1938Unclear whether all participants susceptible

King 1991Retrospective cohort study

Kingsbury 1927Unclear whether all participants exposed and unclear whether all susceptible

Laning 1935Immunoglobulin used was derived from placentas

LeBlanc 2012Communication from author that study was retrospective

Lempriere 1939Unclear whether all participants were exposed

McGuinness 1943Unclear whether control group were comparable and unclear whether all were susceptible

Monnet 1954Intervention and control groups not recruited over similar and overlapping time periods

Rivera 1991Unable to contact study author for further details. Review authors agreed retrospective study from published details

Weaver 1924Unclear whether controls came from the same exposed population as the intervention group

Zingher 1924Unclear whether all were susceptible

 
Comparison 1. Immunoglobulin versus no treatment

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Measles cases7Risk Ratio (M-H, Fixed, 95% CI)Totals not selected

 2 Measles cases7Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    2.1 Quasi-RCTs
1696Risk Ratio (M-H, Fixed, 95% CI)0.38 [0.32, 0.45]

    2.2 Cohort type studies
61575Risk Ratio (M-H, Fixed, 95% CI)0.52 [0.48, 0.57]

    2.3 Included infants < 6 months of age
1194Risk Ratio (M-H, Fixed, 95% CI)0.46 [0.38, 0.56]

    2.4 Did not include infants < 6 months of age
52001Risk Ratio (M-H, Fixed, 95% CI)0.49 [0.45, 0.54]

    2.5 Convalescent serum
51140Risk Ratio (M-H, Fixed, 95% CI)0.49 [0.44, 0.54]

    2.6 Adult serum
2586Risk Ratio (M-H, Fixed, 95% CI)0.52 [0.45, 0.59]

    2.7 Gamma globulin
2545Risk Ratio (M-H, Fixed, 95% CI)0.17 [0.08, 0.36]

 3 Measles cases6Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    3.1 Convalescent serum
3301Risk Ratio (M-H, Fixed, 95% CI)0.21 [0.15, 0.29]

    3.2 Adult serum
2586Risk Ratio (M-H, Fixed, 95% CI)0.52 [0.45, 0.59]

    3.3 Gamma globulin
2545Risk Ratio (M-H, Fixed, 95% CI)0.17 [0.08, 0.36]

 4 Mortality due to measles3893Risk Ratio (M-H, Fixed, 95% CI)0.24 [0.13, 0.44]

 5 Complications due to measles3832Risk Ratio (M-H, Fixed, 95% CI)0.18 [0.05, 0.60]

 
Comparison 2. Gamma globulin versus serum

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Measles cases2702Risk Ratio (M-H, Fixed, 95% CI)0.56 [0.46, 0.69]

 
Summary of findings for the main comparison. Immunoglobulin compared to no treatment for preventing measles

Immunoglobulin compared to no treatment for preventing measles

Patient or population: susceptible people exposed to measles
Settings: community and hospitals
Intervention: immunoglobulin
Comparison: no treatment

OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of participants
(studies)
Quality of the evidence
(GRADE)
Comments

Assumed riskCorresponding risk

No treatmentImmunoglobulin

Measles cases - convalescent serumStudy populationRR 0.21
(0.15 to 0.29)
301
(3 studies)
⊕⊕⊕⊝
moderate1,2,3,4,5,6

862 per 1000181 per 1000
(129 to 250)

Moderate

1000 per 1000210 per 1000
(150 to 290)

Measles cases - adult serumStudy populationRR 0.52
(0.45 to 0.59)
586
(2 studies)
⊕⊕⊕⊝
moderate3,5,7,8,9

860 per 1000447 per 1000
(387 to 507)

Moderate

907 per 1000472 per 1000
(408 to 535)

Measles cases - gamma globulinStudy populationRR 0.17
(0.08 to 0.36)
545
(2 studies)
⊕⊕⊕⊝
moderate4,5,10,11,12

110 per 100019 per 1000
(9 to 40)

Moderate

402 per 100068 per 1000
(32 to 145)

Mortality due to measlesStudy populationRR 0.24
(0.13 to 0.44)
893
(3 studies)
⊕⊕⊕⊕
high3,5,7

142 per 100034 per 1000
(18 to 62)

Moderate

40 per 100010 per 1000
(5 to 18)

Complications due to measlesStudy populationRR 0.18
(0.05 to 0.6)
832
(3 studies)
⊕⊕⊕⊝
moderate3,4,5,7

52 per 10009 per 1000
(3 to 31)

Moderate

71 per 100013 per 1000
(4 to 43)

Adverse eventsStudy populationNot estimable0
(0)
See commentAdverse events were poorly reported or not measured in all but one study comparing immunoglobulins and no treatment. No serious adverse events were reported.13

See commentSee comment

Moderate


*The basis for the assumed risk is the median control group risk across studies. 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.

 1Downgraded one level for risk of bias. We pooled one quasi-randomised trial and two cohort studies to give this estimate. Two further cohort studies also assessed convalescent serum versus no treatment for the prevention of measles. These latter studies had heterogenous results that may have resulted from differences in methodology and so were not included. We rated no studies at high risk of measurement bias, but lack of information about blinding and assessment of the outcome typically resulted in unclear risk. While any uncontrolled confounding would have decreased the effect size, measurement bias may have increased the effect size and so warrants a downgrade in quality here.
2Downgraded one level for inconsistency. The two cohort studies that assessed convalescent serum versus no treatment, which were left out of this pooled estimate, had heterogenous results, although still indicated a significant benefit of this intervention.
3Publication bias strongly suspected. The studies in this analysis were all published in the first half of the 20th century. Not as many journals existed and reporting standards were not as rigorous. It is very likely that many small studies were not published.
4Upgraded for very large effect size. The effect size was very large and reasonably precise.
5Upgraded as plausible confounding would reduce the demonstrated effect.
6Upgraded for dose-response gradient. Convalescent serum was one subgroup of three in an analysis that examined the effect of an approximation of dose on the results. An apparent dose response could be seen across the three subgroups.
7Downgraded one level for risk of bias. We pooled one quasi-randomised trial and two cohort studies to give this estimate. We rated no study at high risk of measurement bias, but lack of information about blinding and assessment of the outcome typically resulted in unclear risk. While any uncontrolled confounding would have decreased the effect size, measurement bias may have increased the effect size and so warrants a downgrade in quality here.
8Upgraded for large effect size. The effect size was large and precise.
9Upgraded for dose-response gradient. Adult serum was one subgroup of three in an analysis that examined the effect of an approximation of dose on the results. An apparent dose response could be seen across the three subgroups.
10Downgraded two levels for risk of bias. Both of the studies contributing to this estimate were cohort studies. Any uncontrolled confounding would have decreased the effect size. We rated measurement bias as unclear for one study and this may have increased the effect size in this case. We rated measurement bias as low risk for the other study, but attrition bias was high risk for that study. Overall, a downgrading of two levels is warranted.
11Publication bias strongly suspected. Although one study in the analysis of this subgroup was published recently, the other was published in the first half of the 20th century. Not as many journals existed and reporting standards were not as rigorous at that time. It is very likely that many small studies were not published.
12Upgraded for dose-response gradient. Gamma globulin was one subgroup of three in an analysis that examined the effect of an approximation of dose on the results. An apparent dose response could be seen across the three subgroups.
13One study recording 'vaccine reactions' reported 'fever and rash' at rates of 5% in the gamma globulin group, 4% in the vaccine group and 1% in the no treatment group. The differences between groups were not statistically significant. This study reported loss to follow-up exceeding 20%.
 
Summary of findings 2. Gamma globulin compared to serum for preventing measles

Gamma globulin compared to serum for preventing measles

Patient or population: susceptible children exposed to measles
Settings: community and hospitals
Intervention: gamma globulin
Comparison: serum

OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of participants
(studies)
Quality of the evidence
(GRADE)
Comments

Assumed riskCorresponding risk

SerumGamma globulin

Measles casesStudy populationRR 0.56
(0.46 to 0.69)
702
(2 studies)
⊕⊕⊕⊕
high1,2,3,4,5

464 per 1000260 per 1000
(214 to 320)

Moderate

554 per 1000310 per 1000
(255 to 382)

Mortality due to measlesStudy populationNot estimable0
(0)
See commentMortality was not measured in the studies comparing gamma globulin and serum

See commentSee comment

Moderate


Complications due to measlesStudy populationNot estimable0
(0)
See commentComplications were not measured by one of the two studies comparing gamma globulin and serum. RCT results favoured gamma globulin (RR 0.41, 95% CI 0.08 to 2.07).

See commentSee comment

Moderate


Adverse eventsStudy populationNot estimable0
(0)
See commentAdverse events were not specified as a measured outcome by the studies comparing gamma globulin and serum. Reporting was poor and the results are not amenable to meta-analysis.

See commentSee comment

Moderate


*The basis for the assumed risk is the median control group risk across studies. 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; RCT: randomised controlled trial; 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.

 1Not downgraded for risk of bias. One of the studies contributing to this estimate is a randomised controlled trial, the other is a cohort study. Any uncontrolled confounding would have decreased the effect size. Measurement bias was low-risk for the RCT and unclear for the cohort study. Overall, the downgrade of quality already applied for including cohort studies is all that is warranted.
2Publication bias strongly suspected. Both studies were published in the first half of the 20th century. Not as many journals existed and reporting standards were not as rigorous. It is likely that many small studies would not have been published.
3Upgraded for large effect size. Effect size is large and precise.
4Upgraded as plausible confounding would reduce the demonstrated effect.
5Upgraded for dose-response gradient. Two doses of gamma globulin were used by the RCT. The higher dose was a smaller group and the confidence intervals overlap with that of the lower dose from this study, but the estimates of effect are consistent with a dose response.