Abstract
Background
The development of Rhesus immunisation and its prophylactic use since the 1970s has meant that severe Rhesus D (RhD) alloimmunisation is now rarely seen.
Objectives
The objective of this systematic review was to assess the effects of giving anti‐D to Rhesus negative women, with no anti‐D antibodies, who had given birth to a Rhesus positive infant.
Search methods
We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (March 2010) and reference lists of relevant articles.
Selection criteria
Randomised trials in Rhesus negative women without antibodies who were given anti‐D immunoglobulin postpartum compared with no treatment or placebo.
Data collection and analysis
Assessments of inclusion criteria, trial quality and data extraction were done by each author independently. Initial analyses included all trials. Other analyses assessed the effect of trial quality, ABO compatibility and dose.
Main results
Six eligible trials compared postpartum anti‐D prophylaxis with no treatment or placebo. The trials involved over 10,000 women, but trial quality varied. Anti‐D lowered the incidence of RhD alloimmunisation six months after birth (risk ratio (RR) 0.04, 95% confidence interval (CI) 0.02 to 0.06), and in a subsequent pregnancy (RR 0.12, 95% CI 0.07 to 0.23). These benefits were seen regardless of the ABO status of the mother and baby, when anti‐D was given within 72 hours of birth. Higher doses (up to 200 micrograms) were more effective than lower doses (up to 50 micrograms) in preventing RhD alloimmunisation in a subsequent pregnancy.
Authors' conclusions
Anti‐D, given within 72 hours after childbirth, reduces the risk of RhD alloimmunisation in Rhesus negative women who have given birth to a Rhesus positive infant. However the evidence on the optimal dose is limited.
Plain language summary
Anti‐D administration after childbirth for preventing Rhesus alloimmunisation
Immunisation of Rhesus negative women with anti‐D after the birth of a Rhesus positive infant reduces the chances of developing Rhesus antibodies.
Mothers and babies may have incompatible blood characteristics (such as Rhesus positive babies and Rhesus negative mothers). After the birth of a Rhesus positive infant, Rhesus negative women are given an injection of anti‐D, which aims to prevent the women forming antibodies that would attack the red cells of a Rhesus positive baby in a future pregnancy. Such antibodies may make the baby anaemic and if severe enough can cause the baby to die. This review of six trials, involving over 10,000 women, found that anti‐D given to Rhesus negative women within 72 hours of giving birth to a Rhesus positive infant decreased the likelihood of the women developing Rhesus antibodies within six months of the birth and in their next pregnancy.
Background
Rhesus D (RhD) alloimmunisation leading to haemolytic disease of the fetus and newborn remained a major cause of perinatal mortality, morbidity, and long‐term disability until the 1970s. With the development of Rhesus immunoglobulin and its evaluation and then utilisation in clinical practice, severe RhD alloimmunisation is rarely seen today. The dramatic reduction in deaths from Rhesus haemolytic disease by the use of postpartum anti‐D immunoglobulin has been a major obstetrical achievement. Nevertheless Rhesus haemolytic disease is unlikely to disappear and is still a problem for women and their babies who are affected.
Over 100 years ago, Von Dungern (Von Dungern 1900) showed that active immunisation can be prevented in the presence of a passive antibody to a particular antigen. However, it was another 60 years before it was shown that sensitisation to Rhesus positive blood could be prevented by administering anti‐D antibody (Stern 1961). After this pioneering work, studies continued, mainly in the UK and North America (Clarke 1963; Freda 1964) culminating in the clinical trials of Rhesus prophylaxis after childbirth ‐ an international collaborative effort. With anti‐D being in short supply in some countries, it is important to be able to determine minimum effective doses (NHMRC 1999).
For trials of Rhesus prophylaxis during pregnancy, see the Cochrane review 'Anti‐D administration in pregnancy for preventing Rhesus alloimmunisation' (Crowther 1999).
Objectives
To assess the effects of giving anti‐D after birth to Rhesus negative women, with no anti‐D antibodies, who had given birth to a Rhesus positive infant.
Methods
Criteria for considering studies for this review
Types of studies
All published, unpublished, ongoing randomised and quasi‐randomised trials with reported data which assess outcomes in Rhesus negative women without antibodies, and their babies, who were given anti‐D immunoglobulin prophylaxis after birth, compared with Rhesus negative women without antibodies not given anti‐D, and their babies.
Types of participants
Rhesus negative women without anti‐D antibodies who gave birth to a Rhesus positive baby.
Types of interventions
Anti‐D immunoglobulin given after birth irrespective of parity, ABO compatibility, size of feto‐maternal haemorrhage, dose or timing.
Types of outcome measures
Primary outcomes
Main outcomes considered were subsequent development of Rhesus D alloimmunisation, maternal concerns and adverse effects of treatment, and neonatal morbidity in a subsequent pregnancy.
Search methods for identification of studies
Electronic searches
We searched the Cochrane Pregnancy and Childbirth Group’s Trials Register by contacting the Trials Search Co‐ordinator (March 2010).
The Cochrane Pregnancy and Childbirth Group’s Trials Register is maintained by the Trials Search Co‐ordinator and contains trials identified from:
quarterly searches of the Cochrane Central Register of Controlled Trials (CENTRAL);
weekly searches of MEDLINE;
handsearches of 30 journals and the proceedings of major conferences;
weekly current awareness alerts for a further 44 journals plus monthly BioMed Central email alerts.
Details of the search strategies for CENTRAL and MEDLINE, the list of handsearched journals and conference proceedings, and the list of journals reviewed via the current awareness service can be found in the ‘Specialized Register’ section within the editorial information about the Cochrane Pregnancy and Childbirth Group.
Trials identified through the searching activities described above are each assigned to a review topic (or topics). The Trials Search Co‐ordinator searches the register for each review using the topic list rather than keywords.
Searching other resources
We screened the reference lists of relevant papers.
We did not apply any language restrictions.
Data collection and analysis
Trials under consideration were evaluated for appropriateness for inclusion and methodological quality without consideration of their results. This was assessed separately by each author. There was no blinding of authorship. Included trial data were processed as described in the Cochrane Reviewers' Handbook (Clarke 2000).
Quality scores for concealment of allocation were assigned to each trial, using the criteria described in Clarke 2000: (A) adequate concealment of the allocation; (B) unclear whether adequate concealment of the allocation; (C) inadequate concealment of allocation (includes quasi‐randomised studies); (D) indicates the score was not assigned.
In addition, quality scores were assigned to each trial for completeness of follow up and blinding of outcome assessment as follows.
Completeness of follow up: (A) less than 3% of participants excluded; (B) 3% to 9.9% of participants excluded; (C) 10% to 19.9% of participants excluded; (D) 20% or more excluded.
For blinding of assessment of outcome: (A) double blind, neither investigator nor participant knew or were likely to guess the allocated treatment; (B) single blind, either the investigator or the participant knew the allocation. Or, the trial is described as double blind, but side effects of one or other treatment mean that it is likely that for a significant proportion (20% or more) of participants the allocation could be correctly identified; (C) no blinding, both investigator and participant knew (or were likely to guess) the allocated treatment.
Data were extracted independently by the two review authors and double entered. Discrepancies were resolved by discussion.
Descriptive data included authors, year of publication, setting, country, time span of the trial, use of placebo and type if used, dosage and timing of anti‐D, pre‐trial calculation of sample size and number randomised and analysed.
Categorical data were compared using risk ratios and 95% confidence intervals. Statistical heterogeneity between trials was tested for using the chi‐squared test with n (the number of trials contributing data) minus one degrees of freedom. With no significant heterogeneity (P > 0.10), data were pooled using a fixed‐effect model. If significant heterogeneity was found, the random‐effects model was used.
All eligible trials were included in the initial analysis and pre‐specified analyses have been carried out to evaluate the effects of ABO compatibility and dose. Sensitivity analysis assessed the effect of trial quality by excluding trials given a C or D rating for quality of treatment allocation.
Results
Description of studies
Six studies that involved over 10,000 women met the inclusion criteria (International 1966; Liverpool 1971; MRC 1974; Netherlands 1968; UK Baltimore 1965; Western Canada 1968). SeeCharacteristics of included studies for further detail. Four other studies were considered, but excluded from this review as detailed in the Characteristics of excluded studies table.
Both the dose of anti‐D used and the timing varied: (International 1966, 300 ug within 72 hours of birth with a higher dose of 4000 to 6000 ug for a small group of women in the early phase of the trial; Liverpool 1971, 200 ug within 36 hours of birth; MRC 1974, 20 ug, 50 ug, 100 ug, or 200 ug within 36 hours of birth; Netherlands 1968, 250 ug within 24 hours of birth; UK Baltimore 1965, 1000 ug or up to 5000 ug in Baltimore within 36 hours of birth; Western Canada 1968, 145 ug or 435 ug within 48 hours of birth).
Risk of bias in included studies
In three trials, the method of treatment allocation was unclear (International 1966; MRC 1974; Western Canada 1968), and quasi‐randomised in three trials (Liverpool 1971; Netherlands 1968; UK Baltimore 1965). A placebo was used in a subset of the International 1966 trial (Stenchever 1970; White 1970), although the other reports of this trial state that no placebo was used. Three trials report losses to follow up (about 10% for MRC 1974 and Netherlands 1968) and at least 11% (International 1966). Losses to follow up in the other trials are unknown. It is unclear whether blinding of assessment of outcome was achieved from any of the trial reports.
Effects of interventions
In all five trials of postpartum anti‐D prophylaxis versus no prophylaxis, Rhesus D (RhD) alloimmunisation was less common six months after birth in women who received anti‐D (risk ratio (RR) 0.04, 95% confidence interval (CI) 0.02 to 0.12, random‐effects model). In the four trials for which data were available, the administration of anti‐D immunoglobulin reduced the incidence of RhD alloimmunisation in a subsequent pregnancy, (RR 0.14, 95% CI 0.06 to 0.35, random‐effects model). These beneficial effects were seen regardless of the ABO status of mother and baby, when anti‐D is given within 72 hours of birth. Significant heterogeneity was detected between trials for these outcomes, but no reasons were found to explain this. Use of the random‐effects model made little change to the RR or 95% CIs.
In doses available for comparison, 200 ug (1000 international units (IU)) anti‐D and above, the risk of sensitisation at six months after delivery (RR 0.04, 95% CI 0.00 to 0.64) and in a subsequent pregnancy were reduced (RR 0.23, 95% CI 0.07 to 0.78), compared with no prophylaxis.
Sensitivity analyses, excluding the three trials given a C rating for quality of treatment allocation, did not alter the beneficial results seen.
The data on comparative doses show that up to 50 ug (250 IU) anti‐D compared with higher doses up to 200 ug (1000 IU) increased the risk of sensitisation in a subsequent pregnancy. No evidence was seen that a lower dose of 100 ug (500 IU) anti‐D was substantially less effective than a higher dose of 150 ug (750 IU) anti‐D, although the number of immunisations were few.
See summary of analyses tables.
Discussion
Prophylaxis with postpartum anti‐D immunoglobulin is effective in reducing the risk of sensitisation after pregnancy and in a subsequent pregnancy irrespective of the ABO status of mother and baby. From these trials, effective prophylaxis is shown when anti‐D is given within 72 hours of birth.
The evidence on the optimal amount of anti‐D to recommend for prophylaxis is limited. Recommendations in different countries will depend on the relative availability and costs of anti‐D, and the costs of laboratory assessments of the volume of feto‐maternal haemorrhage. In the UK, postnatal administration of at least 100 ug (500 IU) is recommended (RCOG), in Australia 125 ug (625 IU) (NHMRC 1999) and in the USA and parts of Europe 200 ug to 300 ug (1000 IU to 1500 IU). It is generally accepted that 25 ug (125 IU) anti‐D protects against 1 ml of fetal anti‐D cells or 2 ml of whole blood. Therefore, 100 ug (500 IU) should protect against a feto‐maternal haemorrhage of up to 8 ml and 300 ug anti‐D against a feto‐maternal haemorrhage of up to 30 ml of fetal blood. A feto‐maternal haemorrhage of 30 ml or more is uncommon but does occur in up to 0.6% of births (Zipursky 1977).
There is a paucity of information about the attitudes of women towards anti‐D prophylaxis and the health of infants in subsequent pregnancies. No adverse effects of the treatment are reported, though risks of rare adverse effects of sensitivity reactions and transmission of infectious diseases remain possible.
Authors' conclusions
Implications for practice.
Anti‐D, given within 72 hours after childbirth, reduces the risk of Rhesus D alloimmunisation in Rhesus negative women who have given birth to a Rhesus positive infant. The clear results of this review support the policy of giving anti‐D immunoglobulin prophylaxis within 72 hours (irrespective of ABO status) to all Rhesus negative women, without anti‐D antibodies, who give birth to a Rhesus positive baby or a baby whose Rhesus status cannot be determined.
Implications for research.
No further placebo controlled trials are warranted to establish the effectiveness of anti‐D given within 72 hours after birth.
As the evidence on the optimal amount of anti‐D to recommend for postpartum prophylaxis is limited, further good quality comparative trials would be appropriate. In particular, the cost‐effectiveness of smaller doses of anti‐D immunoglobulin, combined with screening for the degree of feto‐maternal haemorrhage and administering additional anti‐D as necessary, should be compared with the use of larger doses of anti‐D.
In further trials, the attitudes of women towards anti‐D prophylaxis and the health of infants born in subsequent pregnancies should be evaluated. Any adverse effects of the treatment, including sensitivity reactions and transmission of infectious diseases, should be documented.
What's new
| Date | Event | Description |
|---|---|---|
| 31 March 2010 | New search has been performed | Search updated. No new trials identified. |
History
Protocol first published: Issue 2, 1997 Review first published: Issue 2, 1997
| Date | Event | Description |
|---|---|---|
| 10 November 2008 | Amended | Corrected error in Plain Language Summary. Contact details updated. |
| 6 March 2008 | Amended | Converted to new review format. |
| 25 June 2007 | New search has been performed | Search updated. No new trials identified. |
| 10 November 2004 | New search has been performed | Search updated. No new trials identified. |
| 22 November 2000 | New search has been performed | Search updated. Minor editing to background, discussion and references. |
Acknowledgements
Professor Jack Gravenhorst compiled the first version of this review, and Professor Marc Keirse was a reviewer of the 'pre‐Cochrane' reviews. We also thank Lynn Hampson and Denise Atherton for their help with this update.
Data and analyses
Comparison 1. Anti‐D prophylaxis postpartum (overall, irrespective of ABO status).
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
|---|---|---|---|---|
| 1 Immunisation after 6 months | 5 | 7580 | Peto Odds Ratio (Peto, Fixed, 95% CI) | 0.08 [0.06, 0.11] |
| 2 Immunisation in subsequent pregnancy | 4 | 1071 | Peto Odds Ratio (Peto, Fixed, 95% CI) | 0.12 [0.07, 0.19] |
| 3 Health of infant in subsequent pregnancy | 0 | 0 | Peto Odds Ratio (Peto, Fixed, 95% CI) | 0.0 [0.0, 0.0] |
| 4 Adverse effects of treatment | 0 | 0 | Peto Odds Ratio (Peto, Fixed, 95% CI) | 0.0 [0.0, 0.0] |
1.1. Analysis.
Comparison 1 Anti‐D prophylaxis postpartum (overall, irrespective of ABO status), Outcome 1 Immunisation after 6 months.
1.2. Analysis.
Comparison 1 Anti‐D prophylaxis postpartum (overall, irrespective of ABO status), Outcome 2 Immunisation in subsequent pregnancy.
Comparison 2. Anti‐D prophylaxis postpartum (ABO compatible, irrespective of dose).
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
|---|---|---|---|---|
| 1 Immunisation after 6 months | 4 | 6918 | Peto Odds Ratio (Peto, Fixed, 95% CI) | 0.07 [0.05, 0.10] |
| 2 Immunisation in subsequent pregnancy | 4 | 1071 | Peto Odds Ratio (Peto, Fixed, 95% CI) | 0.12 [0.07, 0.19] |
2.1. Analysis.
Comparison 2 Anti‐D prophylaxis postpartum (ABO compatible, irrespective of dose), Outcome 1 Immunisation after 6 months.
2.2. Analysis.
Comparison 2 Anti‐D prophylaxis postpartum (ABO compatible, irrespective of dose), Outcome 2 Immunisation in subsequent pregnancy.
Comparison 3. Anti‐D prophylaxis postpartum, up to 200 ug versus no treatment.
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
|---|---|---|---|---|
| 1 Immunisation after 6 months | 1 | 715 | Peto Odds Ratio (Peto, Fixed, 95% CI) | 0.13 [0.04, 0.40] |
| 2 Immunisation at subsequent pregnancy | 1 | 255 | Peto Odds Ratio (Peto, Fixed, 95% CI) | 0.26 [0.10, 0.72] |
3.1. Analysis.
Comparison 3 Anti‐D prophylaxis postpartum, up to 200 ug versus no treatment, Outcome 1 Immunisation after 6 months.
3.2. Analysis.
Comparison 3 Anti‐D prophylaxis postpartum, up to 200 ug versus no treatment, Outcome 2 Immunisation at subsequent pregnancy.
Comparison 4. Anti‐D prophylaxis postpartum, up to 250 ug versus no treatment.
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
|---|---|---|---|---|
| 1 Immunisation after six months | 2 | 1377 | Peto Odds Ratio (Peto, Fixed, 95% CI) | 0.19 [0.09, 0.37] |
| 2 Immunisation at subsequent pregnancy | 1 | 255 | Peto Odds Ratio (Peto, Fixed, 95% CI) | 0.26 [0.10, 0.72] |
4.1. Analysis.
Comparison 4 Anti‐D prophylaxis postpartum, up to 250 ug versus no treatment, Outcome 1 Immunisation after six months.
4.2. Analysis.
Comparison 4 Anti‐D prophylaxis postpartum, up to 250 ug versus no treatment, Outcome 2 Immunisation at subsequent pregnancy.
Comparison 5. Anti‐D prophylaxis postpartum, up to 300 ug versus no treatment.
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
|---|---|---|---|---|
| 1 Immunisation after 6 months | 3 | 5936 | Peto Odds Ratio (Peto, Fixed, 95% CI) | 0.08 [0.05, 0.11] |
| 2 Immunisation at subsequent pregnancy | 2 | 872 | Peto Odds Ratio (Peto, Fixed, 95% CI) | 0.11 [0.06, 0.21] |
5.1. Analysis.
Comparison 5 Anti‐D prophylaxis postpartum, up to 300 ug versus no treatment, Outcome 1 Immunisation after 6 months.
5.2. Analysis.
Comparison 5 Anti‐D prophylaxis postpartum, up to 300 ug versus no treatment, Outcome 2 Immunisation at subsequent pregnancy.
Comparison 6. Anti‐D prophylaxis postpartum, 4000‐7000 ug versus no treatment.
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
|---|---|---|---|---|
| 1 Immunisation after 6 months | 2 | 584 | Peto Odds Ratio (Peto, Fixed, 95% CI) | 0.10 [0.04, 0.22] |
| 2 Immunisation at subsequent pregnancy | 1 | 16 | Peto Odds Ratio (Peto, Fixed, 95% CI) | 0.02 [0.00, 1.69] |
6.1. Analysis.
Comparison 6 Anti‐D prophylaxis postpartum, 4000‐7000 ug versus no treatment, Outcome 1 Immunisation after 6 months.
6.2. Analysis.
Comparison 6 Anti‐D prophylaxis postpartum, 4000‐7000 ug versus no treatment, Outcome 2 Immunisation at subsequent pregnancy.
Comparison 7. Dosage comparison, up to 50 ug versus more than 50 ug anti‐D.
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
|---|---|---|---|---|
| 1 Immunisation after 6 months | 1 | 1800 | Peto Odds Ratio (Peto, Fixed, 95% CI) | 3.36 [0.97, 11.63] |
| 2 Immunisation in subsequent pregnancy | 1 | 807 | Peto Odds Ratio (Peto, Fixed, 95% CI) | 2.53 [1.02, 6.27] |
7.1. Analysis.
Comparison 7 Dosage comparison, up to 50 ug versus more than 50 ug anti‐D, Outcome 1 Immunisation after 6 months.
7.2. Analysis.
Comparison 7 Dosage comparison, up to 50 ug versus more than 50 ug anti‐D, Outcome 2 Immunisation in subsequent pregnancy.
Comparison 8. Dosage comparison, up to 100 ug versus more than 100 ug anti‐D.
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
|---|---|---|---|---|
| 1 Immunisation after 6 months | 1 | 1800 | Peto Odds Ratio (Peto, Fixed, 95% CI) | 2.27 [0.55, 9.45] |
| 2 Immunisation in subsequent pregnancy | 1 | 807 | Peto Odds Ratio (Peto, Fixed, 95% CI) | 1.69 [0.60, 4.79] |
8.1. Analysis.
Comparison 8 Dosage comparison, up to 100 ug versus more than 100 ug anti‐D, Outcome 1 Immunisation after 6 months.
8.2. Analysis.
Comparison 8 Dosage comparison, up to 100 ug versus more than 100 ug anti‐D, Outcome 2 Immunisation in subsequent pregnancy.
Comparison 9. Dosage comparison, up to 150 ug versus more than 150 ug anti‐D.
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
|---|---|---|---|---|
| 1 Immunisation after 6 months | 2 | 3010 | Peto Odds Ratio (Peto, Fixed, 95% CI) | 2.27 [0.55, 9.45] |
| 2 Immunisation in subsequent pregnancy | 1 | 807 | Peto Odds Ratio (Peto, Fixed, 95% CI) | 1.69 [0.60, 4.79] |
9.1. Analysis.
Comparison 9 Dosage comparison, up to 150 ug versus more than 150 ug anti‐D, Outcome 1 Immunisation after 6 months.
9.2. Analysis.
Comparison 9 Dosage comparison, up to 150 ug versus more than 150 ug anti‐D, Outcome 2 Immunisation in subsequent pregnancy.
Characteristics of studies
Characteristics of included studies [ordered by study ID]
International 1966.
| Methods | 'Randomly allocated, although some degree of variation between centres, eg. 'admitted to either study or control group' which suggests that randomisation may not have been standard across all 43 centres. | |
| Participants | Over 3000 mothers; Rh negative, not immunised, any parity with infants who were Rh positive and ABO compatible with negative Coombs test. | |
| Interventions | At least 300 ug of anti‐D within 72 hours of delivery and a higher dose of 4000‐6000 ug for a small group of women recruited in the early phase of the trial. Most trial reports state no placebo was given, however in 2 reports (Stenchever 1970 and White 1970), the control group received 1 ml of gamma globulin without anti‐Rh antibody. | |
| Outcomes | Immunisation after 6 months. Immunisation at a subsequent pregnancy. | |
| Notes | This 43 centre trial was an exemplary international collaborative effort. However, there does seem to have been some variation in study quality between the centres. The final figures for immunisation after 6 months have been taken from White 1970 and the final figures for immunisation at a subsequent pregnancy have been taken from Schumacher 1971. Losses to follow up are not given for the overall trial, but an early study report showed losses to follow up of nearly 11%. | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Allocation concealment? | Unclear risk | B ‐ Unclear |
Liverpool 1971.
| Methods | Alternate treatment and control. | |
| Participants | 715 mothers; Rh negative, primiparous. Babies: Rh positive, ABO compatible, with less than 2 ml fetal/maternal bleed, 'low risk'. | |
| Interventions | 200 ug of anti‐D, mostly within 36 hours of delivery. Control: no treatment given. | |
| Outcomes | Immunisation after 6 months. Immunisation at a subsequent pregnancy. | |
| Notes | Losses to follow up not given. | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Allocation concealment? | High risk | C ‐ Inadequate |
MRC 1974.
| Methods | All women received anti‐D. Method of dose allocation was 'by coded serial number, assigned randomly'. | |
| Participants | 1800 mothers; Rh negative, no anti‐D, primiparous, married, white, no history of abortion or blood transfusion. Babies: Rh positive, ABO compatible. | |
| Interventions | 20, 50, 100 or 200 ug anti‐D within 36 hours of delivery. | |
| Outcomes | Immunisation after 6 months. Immunisation at a subsequent pregnancy. Infant health at the subsequent pregnancy (limited information). | |
| Notes | A total of 2000 doses were given, meaning a loss to follow up of 10%. | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Allocation concealment? | Unclear risk | B ‐ Unclear |
Netherlands 1968.
| Methods | 'Randomised by treating with anti‐D those with odd‐numbered birthdays.' | |
| Participants | 740 mothers; Rh negative, no anti‐D. Babies: Rh positive, irrespective of parity or ABO compatibility. | |
| Interventions | 250 ug of anti‐D within 24 hours of delivery. Controls were given no treatment. | |
| Outcomes | Immunisation after 4‐6 months. | |
| Notes | Figures for losses to follow up not given. Immunisation at a subsequent pregnancy was followed, but figures were only given for the treated group. | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Allocation concealment? | High risk | C ‐ Inadequate |
UK Baltimore 1965.
| Methods | Aimed for alternation, but reverted to days of the week and consecutive dosages. The researchers reported 'considerable upset' to their original methodology. | |
| Participants | 349 mothers; Rh negative, free of Rh antibodies, primiparous, ABO compatible with baby. Babies: Rh positive, feto‐maternal bleeds of greater than 0.2 ml, 'high risk'. | |
| Interventions | Treatment groups: 1000 ug (5 ml) of anti‐D within 36 hours of delivery or up to 5000 ug in Baltimore. Control group: untreated. | |
| Outcomes | Immunisation of mother after 6 months. Immunisation of mother after a subsequent pregnancy. | |
| Notes | No information given about losses to follow up. | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Allocation concealment? | High risk | C ‐ Inadequate |
Western Canada 1968.
| Methods | While the trial was 'intended to be random', this may not have been adhered to throughout the whole trial, eg. some mothers who refused treatment were used as controls. | |
| Participants | 444 mothers; Rh negative, no anti‐D, any parity. Babies: Rh positive, ABO compatible, negative Coombs test. | |
| Interventions | 145 ug or 435 ug of anti‐D vs untreated control. 145 ug vs 435 ug of anti‐D, within 48 hours of delivery. | |
| Outcomes | Immunisation after 6 months. | |
| Notes | Results from Saskatoon have not been included as this site did not use concurrent controls. Figures for losses to follow up were not given. | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Allocation concealment? | Unclear risk | B ‐ Unclear |
Rh: Rhesus vs: versus
Characteristics of excluded studies [ordered by study ID]
| Study | Reason for exclusion |
|---|---|
| Beer 1969 | Separate results not given for numbers of mothers immunised. Alternate allocation of treatment. |
| Hamilton 1967 | Historical controls; allocation of treatment not randomised. |
| Schneider 1966 | Cannot establish whether controls were used and there is no information on allocation of treatment. |
| Zipursky 1967 | No mention of how treatment groups were chosen; no mention of randomisation. |
Contributions of authors
Both review authors contributed to the development of the protocol, identification and selection of studies for inclusion, data extraction and preparation of the text of the review.
Sources of support
Internal sources
Discipline of Obstetrics and Gynaecology, The University of Adelaide, Australia.
Australasian Cochrane Centre, Australia.
External sources
No sources of support supplied
Declarations of interest
None known.
New search for studies and content updated (no change to conclusions)
References
References to studies included in this review
International 1966 {published data only}
- Ascari WQ, Allen AE, Baker WJ, Pollack W. Rho (D) immune globulin (human); evaluation in women at risk of Rh immunization. JAMA 1968;205(1):71‐4. [DOI] [PubMed] [Google Scholar]
- Ascari WQ, Levine, P, Pollack W. Incidence of maternal Rh immunization by ABO compatible and incompatible pregnancies. BMJ 1969;1:399‐401. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Bishop GJ, Krieger VI. One millilitre injections of Rho (D) immune globulin (human) in the prevention of Rh immunization: a further report on the clinical trial. Medical Journal of Australia 1969;2:171‐4. [PubMed] [Google Scholar]
- Bishop GJ, Krieger VI, Tait M, Walsh C. Clinical trial of one millilitre injections of Rho (D) immune globulin (human) in the prevention of Rh immunization: preliminary report. Medical Journal of Australia 1968;55:1122‐7. [PubMed] [Google Scholar]
- Bryant EC, Hart GD, Cairns D, Gamarra JA, Veber LL, Holland CG, et al. Clinical evaluation of Rho (D) immune globulin (human) in Canada. Canadian Medical Association Journal 1969;101:82‐3. [PMC free article] [PubMed] [Google Scholar]
- Freda VJ, Gorman JG, Pollack W. Rh factor: prevention of isoimmunization and clinical trial on mothers. Science 1966;151:828‐30. [DOI] [PubMed] [Google Scholar]
- Freda VJ, Gorman JG, Pollack W, Robertson JG, Jennings ER, Sullivan JF. Prevention of Rh isoimmunisation; progress report of the clinical trial in mothers. JAMA 1967;199:140‐4. [DOI] [PubMed] [Google Scholar]
- Jennings ER, Dibbern HH, Hodell FH, Monroe CH, Peckham NH, Sullivan JF, et al. Long Beach (California) experience with Rh immunoglobulin. Transfusion 1968;8(3):146‐7. [DOI] [PubMed] [Google Scholar]
- Pollack W, Gorman JG, Freda VJ, Ascari WQ, Allen AE, Baker WJ. Results of clinical trials of RhoGAM in women. Transfusion 1968;8(3):151‐3. [DOI] [PubMed] [Google Scholar]
- Robertson JG. Edinburgh (Scotland) experience with Rh immunoglobulin. Transfusion 1968;8(3):149‐50. [DOI] [PubMed] [Google Scholar]
- Robertson JG, Holmes CM. A clinical trial of anti‐Rho(D) immunoglobulin in the prevention of Rho(D) immunization. Journal of Obstetrics and Gynaecology of the British Commonwealth 1969;76:252‐9. [DOI] [PubMed] [Google Scholar]
- Schumacher GFB, Schneider J. Current problems in prophylactic treatment of Rh‐erythroblastosis; an invitational symposium. Journal of Reproductive Medicine 1971;6(5):232‐55. [PubMed] [Google Scholar]
- Stenchever MA, Davies IJ, Weisman R, Gross S. Rho(D) immune globulin: a double blind clinical trial. American Journal of Obstetrics and Gynecology 1970;106:316‐7. [DOI] [PubMed] [Google Scholar]
- White CA, Visscher RD, Visscher HC, Wade ME. Rho (D) immune prophylaxis. A double‐blind cooperative study. Obstetrics & Gynecology 1970;36:341‐6. [PubMed] [Google Scholar]
Liverpool 1971 {published data only}
- Woodrow JC, Clarke CA, McConnell RB, Towers SH, Donohoe WTA. Prevention of Rh‐haemolytic disease. Results of the Liverpool 'low‐risk' clinical trial. BMJ 1971;2:610‐2. [DOI] [PMC free article] [PubMed] [Google Scholar]
MRC 1974 {published data only}
- Medical Research Council. Controlled trial of various anti‐D dosages in suppression of Rh sensitization following pregnancy. BMJ 1974;2:75‐80. [PMC free article] [PubMed] [Google Scholar]
Netherlands 1968 {published data only}
- Dudok De Wit C, Borst‐Eilers E, Weerdt CM, Kloosterman GJ. Prevention of Rhesus immunisation. A controlled clinical trial with a comparatively low dose of anti‐D immunoglobulin. BMJ 1968;4:477‐9. [DOI] [PMC free article] [PubMed] [Google Scholar]
UK Baltimore 1965 {published data only}
- Clarke CA. Prophylaxis of Rhesus iso‐immunization. British Medical Bulletin 1968;24(1):3‐9. [Google Scholar]
- Clarke CA, Donohoe WTA, Durkin CM, Finn R, Lehane D, McConnell RB, et al. Prevention of Rh‐haemolytic disease: results of a clinical trial. A combined study from centres in England and Baltimore. BMJ 1966;2:907‐14. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Clarke CA, Donohoe WTA, Finn R, Lehane D, McConnell RB, Sheppard PM, et al. Prevention of Rh‐haemolytic disease: final results of the 'high risk' clinical trial. A combined study from centres in England and Baltimore. BMJ 1971;2:607‐9. [PMC free article] [PubMed] [Google Scholar]
- Clarke CA, Sheppard PM. Prevention of Rhesus haemolytic disease [letter]. Lancet 1965;2:343. [DOI] [PubMed] [Google Scholar]
- Finn R. Liverpool experience with Rh immunoglobulin. Transfusion 1968;8(3):148‐9. [DOI] [PubMed] [Google Scholar]
- Woodrow JC, Clarke CA, Donohoe WT, Finn R, McConnell RB, Sheppard PM, et al. Prevention of Rh‐haemolytic disease; a third report. BMJ 1965;1:279‐83. [DOI] [PMC free article] [PubMed] [Google Scholar]
Western Canada 1968 {published data only}
- Buchanan DI, Bell RE, Beck RP, Taylor WC. Use of different doses of anti‐Rh D in the prevention of Rh isoimmunisation. Lancet 1969;2:288‐90. [DOI] [PubMed] [Google Scholar]
- Chown B, Duff AM, James J, Nation E, Ellement M, Buchanan DI, et al. Prevention of primary Rh immunization: first report of the Western Canadian Trial, 1966‐1968. Canadian Medical Association Journal 1969;100:1021‐4. [PMC free article] [PubMed] [Google Scholar]
- Godel JC, Buchanan DI, Jarosch JM, McHugh M. Significance of Rh‐sensitization during pregnancy; its relation to a preventive programme. BMJ 1968;2:479‐82. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Schumacher GFB, Schneider J. Current problems in prophylactic treatment of Rh‐erythroblastosis: an invitational symposium. Journal of Reproductive Medicine 1971;6(5):232‐55. [PubMed] [Google Scholar]
References to studies excluded from this review
Beer 1969 {published data only}
- Beer AE. Fetal erythrocytes in maternal circulation of 155 Rh‐negative women. Obstetrics & Gynecology 1969;34:143‐50. [PubMed] [Google Scholar]
Hamilton 1967 {published data only}
- Hamilton EG. Prevention of Rh isoimmunization by injection of anti‐D antibody. Obstetrics & Gynecology 1967;30(6):812‐5. [PubMed] [Google Scholar]
Schneider 1966 {published data only}
- Schneider J, Preisler O. Prevention of Rh sensitization from fetomaternal microtransfusions. Obstetrics & Gynecology 1966;23(5):615‐21. [PubMed] [Google Scholar]
Zipursky 1967 {published data only}
- Zipursky A, Israels LG. The pathogenesis and prevention of Rh immunization. Canadian Medical Association Journal 1967;97(21):1245‐57. [PMC free article] [PubMed] [Google Scholar]
Additional references
Clarke 1963
- Clarke CA, Donohoe WTA, McConnell RB, Woodrow JC, Finn R, Krevans J, et al. Further experimental studies on the prevention of Rh haemolytic disease. BMJ 1963;1:929. [DOI] [PMC free article] [PubMed] [Google Scholar]
Clarke 2000
- Clarke M, Oxman AD, editors. Cochrane Reviewers’ Handbook 4.1 [updated June 2000]. In: Review Manager (RevMan) [Computer program]. Version 4.1. Oxford, England: The Cochrane Collaboration, 2000.
Crowther 1999
- Crowther CA, Middleton P. Anti‐D administration in pregnancy for preventing Rhesus alloimmunisation. Cochrane Database of Systematic Reviews 1999, Issue 2. [Art. No.: CD000020. DOI: 10.1002/14651858.CD000020] [DOI] [PubMed] [Google Scholar]
Freda 1964
- Freda VJ, Gorman JG, Pollack W. Successful prevention of experimental Rh‐sensitization in man with an anti‐Rh gammaglobulin antibody preparation. Transfusion 1964;4:26‐32. [DOI] [PubMed] [Google Scholar]
NHMRC 1999
- Australia. National Health and Medical Research Council. Guidelines on the prophylactic use of Rh D immunoglobulin (anti‐D) in obstetrics. www.nhmrc.health.gov.au/publicat/pdf/wh27.pdf (accessed 20 November 2000).
RCOG
- United Kingdom. Royal College of Obstetrics and Gynaecology. Use of Anti‐D immunoglobin for Rh prophylaxis. www.rcog.org.uk/guidelines/antid.html (accessed 20 November 2000).
Stenchever 1970
- Stenchever MA, Davies IJ, Weisman R, Gross S. Rho (D) immune globulin; a double blind clinical trial. American Journal of Obstetrics and Gynecology 1970;106:316‐7. [DOI] [PubMed] [Google Scholar]
Stern 1961
- Stern K, Goodman HS, Berger M. Experimental isoimmunisation to hemoantigens in man. Journal of Immunology 1961;87:189‐97. [Google Scholar]
Von Dungern 1900
- Dungern F. Beitrage zur immunitatslehr. Munchener Medizinische Wochenschrift 1900;47:677. [Google Scholar]
White 1970
- White CA, Visscher RD, Visscher HC, Wade ME. Rho (D) immune prophylaxis. A double‐blind cooperative study. Obstetrics & Gynecology 1970;36:341‐6. [PubMed] [Google Scholar]
Zipursky 1977
- Zipursky A. Rh hemolytic disease of the newborn ‐ the disease eradicated by immunology. Clinical Obstetrics and Gynecology 1977;20:759‐72. [DOI] [PubMed] [Google Scholar]
References to other published versions of this review
CDSR 1997
- Crowther C, Middleton P. Anti‐Rh‐D prophylaxis postpartum. In: Neilson JP, Crowther CA, Hodnett ED, Hofmeyr GJ, Keirse MJNC (eds) Pregnancy and Childbirth Module of The Cochrane Database of Systematic Reviews, [updated April 1997]. Available in The Cochrane Library [database on disk and CDROM]. The Cochrane Collaboration; Issue 2. Oxford: Update Software; 1997.
CDSR 1999
- Crowther C, Middleton P. Anti‐D administration after childbirth for preventing Rhesus alloimmunisation (Cochrane Review). The Cochrane Library 1999, Issue 2. [DOI] [PMC free article] [PubMed] [Google Scholar]
Crowther 1995a
- Crowther CA, Keirse MJNC. Anti‐Rh‐D prophylaxis postpartum (overall, irrespective of ABO status) [revised 05 October 1993]. In: Enkin MW, Keirse MJNC, Renfrew MJ, Neilson JP, Crowther C (eds) Pregnancy and Childbirth Module. In: The Cochrane Pregnancy and Childbirth Database [database on disk and CDROM]. The Cochrane Collaboration; Issue 2, Oxford: Update Software; 1995.
Crowther 1995b
- Crowther CA, Keirse MJNC. Anti‐Rh‐D prophylaxis postpartum <72 hours in ABO compatible cases [revised 05 October 1993]. In: Enkin MW, Keirse MJNC, Renfrew MJ, Neilson JP, Crowther C (eds) Pregnancy and Childbirth Module. In: The Cochrane Pregnancy and Childbirth Database [database on disk and CDROM]. The Cochrane Collaboration; Issue 2, Oxford: Update Software; 1995.
Crowther 1995c
- Crowther CA, Keirse MJNC. <301ug Anti‐Rh‐D postpartum vs higher doses [revised 05 October 1993]. In: Enkin MW, Keirse MJNC, Renfrew MJ, Neilson JP, Crowther C (eds) Pregnancy and Childbirth Module. In: The Cochrane Pregnancy and Childbirth Database [database on disk and CDROM]. The Cochrane Collaboration; Issue 2, Oxford: Update Software; 1995.
Crowther 1995d
- Crowther CA, Keirse MJNC. <200ug Anti‐Rh‐D postpartum vs higher doses [revised 16th November 1993]. In: Enkin MW, Keirse MJNC, Renfrew MJ, Neilson JP, Crowther C (eds) Pregnancy and Childbirth Module. In: The Cochrane Pregnancy and Childbirth Database [database on disk and CDROM]. The Cochrane Collaboration; Issue 2, Oxford: Update Software; 1995.