Routine antenatal anti-D prophylaxis for RhD-negative women: a systematic review and economic evaluation

Article history

The research reported in this issue of the journal was commissioned and funded by the HTA Programme on behalf of NICE as project number 07/05/01. The protocol was agreed in August 2007. The assessment report began editorial review in November 2007 and was accepted for publication in June 2008. The authors have been wholly responsible for all data collection, analysis and interpretation, and for writing up their work. The HTA editors and publisher have tried to ensure the accuracy of the authors’ report and would like to thank the referees for their constructive comments on the draft document. However, they do not accept liability for damages or losses arising from material published in this report.

Declared competing interests of authors

None.

Copyright statement

© 2009 Queen’s Printer and Controller of HMSO. This monograph may be freely reproduced for the purposes of private research and study and may be included in professional journals provided that suitable acknowledgement is made and the reproduction is not associated with any form of advertising. Applications for commercial reproduction should be addressed to: NCCHTA, Alpha House, Enterprise Road, Southampton Science Park, Chilworth, Southampton SO16 7NS, UK.

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Description of health problem

Human blood is classified according to two main systems: the ABO system and the Rhesus (Rh) system. The Rh system consists of several related proteins, the most important of which is called the Rhesus D (RhD) antigen. People who have this antigen on their red blood cells are said to be RhD positive, whereas those who do not are said to be RhD negative. Both ABO and Rh blood types are inherited characteristics and therefore a fetus may inherit a blood type from its father which differs from that of its mother.

Haemolytic disease of the newborn (HDN) is a haemolytic anaemia that affects the fetus or neonate. It results from the transplacental passage of antibodies created by the mother and directed against fetal red cell antigens inherited from the father. Over 90% of all cases of clinically significant HDN affect RhD-positive infants born to RhD-negative mothers.

Current service provision

It is current national guidance that RAADP be offered to all non-sensitised pregnant women who are RhD negative. The clinician responsible for the prenatal care of a non-sensitised RhD-negative woman should enable her to make an informed choice about treatment taking into account circumstances under which such prophylaxis would not be necessary (for instance, if the woman has opted to be sterilised after the birth of her baby or is otherwise certain that she will not have another child after her current pregnancy, or if she is in a stable relationship with the father of the child and he is known or found to be RhD negative). Use of RAADP should not be affected by use of prophylactic anti-D for a potential sensitising event earlier in the same pregnancy. 87

It is also current standard practice in the UK to give 500 IU of intramuscular anti-D immunoglobulin within 72 hours of delivery to all RhD-negative pregnant women who deliver RhD-positive infants and who are not already sensitised. 88 This dose will cover a TPH of at least 4 ml of fetal red cells (i.e. 99% of all TPHs). 10 The size of any FMH is routinely estimated and further anti-D given if indicated. Any event during pregnancy with the potential to cause sensitisation should also prompt assessment of FMH and administration of anti-D within 72 hours. Such events include chorion villus sampling, (late) miscarriage, termination of pregnancy, amniocentesis, abdominal trauma, antepartum haemorrhage and external cephalic version.

There is some uncertainty about the current uptake of RAADP in England and Wales. It has not been universally adopted: in their submission,89 the Royal College of Physicians and Royal College of Pathologists state that, in 2005, a survey of 328 UK maternity units found that only 75% were offering RAADP; of these, 81% were using the two-dose regimen. They also refer to a recent postal survey of 233 hospital transfusion laboratories which found that, of the 173 laboratories (75%) which responded, only 155 (90%) had fully implemented RAADP. There are no data on the level of uptake in terms of the number of RhD-negative pregnant women in those centres that have implemented RAADP who actually receive RAADP. 90

The Royal Colleges of Physicians and Pathologists also refer to anecdotal evidence that many centres are changing from a two-dose to a single-dose regimen, presumably for logistic reasons and perhaps also in the hope of increasing compliance. 89 The Bio Products Laboratory (BPL) submission91 indicates that 55% of hospitals that have implemented RAADP are currently using D-Gam 500 IU in a two-dose regimen, whereas Behring92 state that 71 centres in England and Wales are currently using a single 1500-IU dose of Rhophylac.

Description of technology under assessment

The technology under assessment is RAADP for non-sensitised pregnant women who are RhD negative. Prophylactic anti-D, whether antenatal or postpartum, can only suppress primary RhD immunisation; it has no effect in women who have already developed anti-D, however weak,10 and therefore should not be given to such women.

The half-life of prophylactic anti-D is approximately 3 weeks; it can be detected by serological tests for several weeks, by the indirect antiglobulin test (IAT) for around 8 weeks, and by more sensitive techniques for up to 12 weeks (exceptionally, for several months). 80

RAADP may take the form of either two doses of at least 500 IU of anti-D immunoglobulin, the first at 28 weeks’ and the second at 34 weeks’ gestation, or a single dose of at least 1500 IU at 28 weeks (1500 IU of Rhophylac is sufficient anti-D to neutralise the sensitising potential of approximately 15 ml of RhD-positive red blood cells93). In theory, if prophylactic anti-D has a half-life of up to 12 weeks, a two-dose regimen will provide greater protection in late pregnancy. The British Committee for Standards in Haematology supports the use of the two-dose regimen recommended in the previous NICE guidance and notes that more evidence is required to establish the comparative efficacy of a single dose of 1500 IU at 28 weeks. 94

RAADP is additional to any antenatal anti-D prophylaxis (AADP) offered in response to a potential sensitising event, and postpartum anti-D prophylaxis is still required within 72 hours of delivery if the infant is RhD positive.

When the original assessment of RAADP was undertaken on behalf of NICE by Chilcott et al. in 2001,1 only two products were licensed for use in the UK. These products, manufactured by BPL and Baxter Healthcare, were both two-dose regimens. Since then two additional products have been licensed for UK use; these products, manufactured by CSL Behring and Baxter BioScience, are both single-dose regimens (for details see Summary of product characteristics). This updated assessment has been prompted by the availability of these single-dose products, as well as by the wish to reflect potential changes in the management of sensitised pregnancies, rather than by any significant change in the evidence base relating to the efficacy of RAAPD.

As noted above, it is current national guidance that RAADP be offered to all non-sensitised pregnant women who are RhD negative. Prenatal identification of the fetus’s RhD blood group would enable RAADP to be targeted only to those non-sensitised RhD-negative women pregnant with RhD-positive infants. This approach has not previously been possible because identification of the blood group of the fetus used to require a sample of fetal cells, obtained using invasive procedures (amniocentesis or chorion villus biopsy), which themselves carry the risk of FMH and consequent sensitisation or, in women who have already undergone silent sensitisation, boosting of the maternal immune response,95 in addition to an 0.5–1.0% risk of spontaneous abortion. 96 However, recent technological developments have made it possible to predict the fetal RhD genotype non-invasively by polymerase chain reaction (PCR) using fetal DNA present in the mother’s plasma. 95 In principle, this technology permits the screening of all non-sensitised RhD-negative pregnant women to enable antenatal prophylaxis to be targeted only to those carrying RhD-positive fetuses. However, to be feasible in practice the test results must yield no false negatives (i.e. cases in which the fetus appears to be RhD negative but is actually RhD positive), and this level of accuracy does not yet appear to have been achieved. 96 (The existence of false positives is less important, as it simply means that, as in current practice, a RhD-negative woman carrying a RhD-negative fetus will be given unnecessary prophylaxis. 96) Moreover, targeted antenatal prophylaxis would only be possible if it was demonstrated that the test was reliable when undertaken before 28 weeks’ gestation. This has yet to be achieved. However, in their submission,89 the Royal College of Physicians and Royal College of Pathologists anticipate that a test which has 99% accuracy at 15+ weeks’ gestation will become routinely available within 12–24 months, that the costs of implementation will not be prohibitive, and that the advantages in terms of the reduced use of anti-D (for potential sensitising events as well as for RAADP) will be significant. However, were such a test to be routinely used it would still be necessary to use anti-D in compliance with the current guidelines either in the absence of test results or if the results were equivocal, as well as in cases in which the fetus is confirmed to be RhD positive. 91

In most cases it is likely that RAADP is administered by midwives based in the community and/or antenatal clinic. Side effects (short-term discomfort at the injection site and, very rarely, anaphylaxis) are rare and do not necessitate monitoring of recipients other than by extending the clinical audit process to include RAADP. However, as with other blood products, scrupulous record keeping is essential to be able to link individual women with specific batches of anti-D. This is important both because of the risk of infection transmission and because of the importance of traceability for the interpretation of blood tests if a blood transfusion is needed at a later date. 89

Decision problem

The decision problem has been specified as follows.

Overall aims and objectives of assessment

The review has the following aims:

• to evaluate the clinical effectiveness of anti-D for RhD-negative pregnant women, in any licensed regimen, in terms of a reduction in the incidence of sensitisation (alloimmunisation) in RhD-negative women delivered of RhD-positive infants, a reduction in the incidence of HDN, survival of the child, disability of the child, and health-related quality of life of the child and parents (if relevant evidence is available)

• to evaluate the adverse effect profile

• to estimate the incremental cost-effectiveness of different dosing regimens and different methods of administration of anti-D prophylaxis

• to identify key areas for primary research

• to estimate the possible overall cost in England and Wales.

Methods for reviewing effectiveness

Results

Quantity and quality of research available

Quantity of research available

The original systematic review carried out on behalf of NICE1 was not limited to specific licensed anti-D dosage regimens. It identified 11 studies comparing an intervention group receiving RAADP with a control group (see Table 9 for details). However, only eight of these studies met the inclusion criteria for the current review by stating that they used one of the currently licensed regimens. These were:

• the studies by Huchet et al. ,125 MacKenzie et al. ,126 Mayne et al. 127 and Tovey et al. ,128 which used two doses of 500 IU at 28 and 34 weeks’ gestation

• the study by Bowman et al. ,129 which used two doses of 1500 IU at 28 and 34 weeks’ gestation

• the 1978130 and 1987131 studies by Bowman and Pollock and the study by Trolle,132 which used a single dose of 1500 IU at 28 weeks’ gestation.

TABLE 9 - Characteristics of studies included in the previous review1

i.m., intramuscularly; i.v., intravenously; RCT, randomised controlled trial.

In describing participants as primigravidae or primiparae, the wording used by the original authors has been followed. Because women may not always reveal details of previous pregnancies, information on parity is likely to be the more reliable.

Studies that meet the inclusion criteria for the current review.

Study	Study type	Date and location of intervention	Date and location of control	Patient selectiona	Specific product (production method) and route of administration	Dosage and administration schedule
bBowman et al. 1978129	Prospective study, historical/geographical controls	December 1968–August 1976, Winnipeg, Canada	March 1967–December 1974, Manitoba, Canada	Primigravidae	Rho(D) immune globulin (Cohn method), Connaught Laboratories, Toronto; i.m.131	2 × 1500 IU, 28 and 34 weeks
bBowman and Pollock 1978130	Prospective study, historical controls	March 1976–June 1977, Manitoba, Canada	March 1967–December 1974, Manitoba, Canada	Primigravidae and unsensitised multigravidae	Rho(D) immune globulin (Cohn method), Connaught Laboratories, Toronto; i.m.	1500 IU, 28 weeks
bBowman and Pollock 1987131	Retrospective study, historical controls	June 1977–February 1986, Manitoba, Canada	March 1967–December 1974, Manitoba, Canada	Primigravidae and unsensitised multigravidae	RhIG-IV (WinRho) (ion exchange), Winnipeg Rh Institute; usually i.m. but could be i.v.	1500 IU, 28 weeks
Hermann et al. 1984134	Prospective study, historical controls	Not stated, Växjö, Sweden	1968–77, Växjö, Sweden	Primigravidae and unsensitised multigravidae	Rhesonativ, KabiVitrum AB, Sweden; i.m.	1250 IU, 32–34 weeks
bHuchet et al. 1987125	Quasi-RCT	January 1983–June 1984, Paris	January 1983–June 1984, Paris	Primigravidae	Product not specified; i.m.	2 × 500 IU, 28 and 34 weeks
Lee and Rawlinson 1995135	RCT	Not stated, UK	Not stated, UK	Primigravidae	Not specified	2 × 250 IU, 28 and 34 weeks
bMacKenzie et al. 1999126	Community intervention trial (controlled before-and-after study)	1990–6, Oxfordshire	1990–6, Northants	Primiparae	Not specified	2 × 500 IU, 28 and 34 weeks
bMayne et al. 1997127	Retrospective before-and-after study	1993–5, southern Derbyshire	1988–90, southern Derbyshire	Primiparae	Not specified	2 × 500 IU, 28 and 34 weeks
Parsons et al. 1998136	Retrospective survey, geographical controls	1988–95, Nova Scotia	1988–95, Scotland	Not stated	Not specified	One dose, 28 weeks
bTovey et al. 1983128	Prospective study, historical controls	1980–1, Yorkshire	1978–9, Yorkshire	Primigravidae	Not specified	2 × 500 IU, 28 and 34 weeks
bTrolle 1989132	Prospective study, historical controls	1980–5, Kolding, Denmark	1972–7, Kolding, Denmark	Primigravidae and unsensitised multigravidae	Not specified	1500 IU, 28 weeks

An article by Thornton et al. 133 was also included as it presented follow-up data relating to the study by Tovey et al. ,128 studying the safety and efficacy of antenatal prophylaxis by examining obstetric data relating to women in that trial in their first and subsequent pregnancies. There was agreement between the first and second reviewers in relation to study selection and validity.

The updated searches identified four additional papers that related to relevant studies of clinical effectiveness (see Table 10 for summary). Only one of these related to a study that was not included in our previous review. This was the relatively recent RCT by MacKenzie et al. 100 comparing intravenous with intramuscular Rhophylac. A conference abstract by MacKenzie et al. 137 related to the 1999 community intervention study by MacKenzie et al. ;126 it did not present any additional data. A further two papers by Bowman14,101 related to a clinical trial of WinRho whose results were combined with those of the subsequent service programme of RAADP with WinRho in Bowman and Pollock’s 1987 analysis of failures of intravenous anti-D. 131 As the clinical trial effectively takes the form of a case series compared with the control group reported in the 1978 study of Bowman et al. 129 there seems no reason to differentiate between the trial and the service programme components of the 1987 study, and therefore the results reported by Bowman et al. in 198014 and by Bowman in 1982101 have been considered as interim results in relation to the 1987 study.

TABLE 10 - Additional papers relating to relevant studies of clinical effectiveness identified by the update searches

Paper	Status
MacKenzie et al. 2004100	Included as a new independent study
MacKenzie et al. 1998137	Included as relating to a previously included study (MacKenzie et al. 1999125)
Bowman et al. 198014	Included as relating to a previously included study (Bowman and Pollock 1987131)
Bowman 1982101	Included as relating to a previously included study (Bowman and Pollock 1987131)

It was not possible to read an additional, potentially relevant study by Eklund and Nevanlinna,138 as it was published in Finnish and had no English abstract. However, as it was published in 1971 it seems highly likely that it dealt with postpartum rather than antenatal prophylaxis. Similarly, it was not possible to obtain a potentially relevant paper by Potron et al. ,139 but because this was published in 1973 it seems likely that it too would have dealt with postpartum rather than antenatal prophylaxis. Finally, we were unable to find any further information regarding a proposed multicentre trial of monoclonal anti-D,140 and understand that the principal investigator is now deceased.

A population study by Koelewijn141 of the effect of the introduction of RAADP in the Netherlands did not meet our inclusion criteria as it used a single dose of only 1000 IU of anti-D at 30 weeks’ gestation.

Thus, the electronic literature searches identified 670 potentially relevant references, 12 of which referred to eight relevant studies of clinical effectiveness. Only one reference related to a study that had not been included in our earlier review (Figure 1). For details of excluded studies, including those included in the previous review, see Appendix 3.

FIGURE 1.

Assessment of clinical effectiveness: summary of study selection and exclusion.

The updated searches did not identify the 1978 study of Bowman and Pollock,130 which was identified by the searches for our earlier review;1 this brought the total number of included studies to nine. A summary of the 1977 McMaster Conference on the prevention of RhD immunisation142 was identified from a citation. This included brief summaries of the results of three unpublished studies of RAADP. Two of these studies, the Australian and Hamilton studies, did not meet our inclusion criteria because, although both were said to use a two-dose regimen, the actual dose was not specified. These studies do not appear to have been published elsewhere and attempts to obtain fuller reports from the investigators have been unsuccessful. The third, Swedish study was excluded because it used a single unspecified dose at 34 weeks’ gestation; it appears to represent an interim analysis of the study published in 1984 by Hermann et al. ,134 included in our previous review,1 which used a dose of 1250 IU. A study of alloimmunisation following RAADP in north-east Scotland143 was subsequently drawn to our attention; this could not be included because it identified sensitised women as a proportion of all RhD-negative women who had received RAADP and was therefore not comparable with the included studies, which identified them as a proportion of only those RhD-negative women who had subsequently been delivered of RhD-positive infants.

An additional study, described by Baxter Healthcare as pivotal, appeared to have been completed by 1993 but was still unpublished in 2005. 119 This used intravenous anti-D (WinRho SD) according to three regimens, only one of which (2 × 1200 IU) is currently licensed:

• 1 × 600 IU (at 28 weeks)

• 1 × 1200 IU (at 28 weeks)

• 2 × 1200 IU (at 28 and 34 weeks).

There appears to have been no untreated control group, although reference is made to the expected level of sensitisation. Follow-up was very poor: of 806 RhD-negative women delivered of an RhD-positive infant, only 325 (40%) were tested 6 months after delivery for evidence of sensitisation. For these reasons this study was not felt to meet our inclusion criteria.

In summary, we identified only one relevant study that was not included in our earlier review. This was the RCT by MacKenzie et al. 100

Quality of included research

Overall, the quality of included research was not high. We identified only one true RCT, that by MacKenzie et al. 100 This used a computer-generated randomisation schedule but did not state how treatment allocation was concealed. The randomised comparison was between the same dose of Rhophylac (1 × 1500 IU) given intravenously and intramuscularly. However, the study was not powered to demonstrate a difference in efficacy between these two administration routes as the sample size had been calculated to test the null hypothesis that Rhophylac was inferior to currently marketed anti-D products in terms of the number of sensitisations. In other words, the sample size had been calculated not to compare one of the two randomised groups with the other but to compare the pooled results of the two randomised groups with the pooled results of the earlier studies, whose populations differed from the study population chronologically and in most cases also geographically.

A quasi-RCT by Huchet et al. 125 used year of birth to allocate participants to treatment groups (those born in odd years forming the intervention group and those in even years the control group); it compared two 500-IU doses of anti-D with no treatment.

Because of the shortage of RCTs comparing a currently licensed dose of anti-D with no treatment, all relevant non-randomised studies were retained for further consideration. They are:

• a community intervention trial (controlled before-and-after study) by MacKenzie et al. 126

• a retrospective before-and-after study by Mayne et al. 127

• five non-randomised studies with historical or geographical controls. 128–132

Many of these studies were poorly designed. The greatest concerns relate to the comparability of the intervention and control groups: although the larger non-randomised studies are probably large enough to ensure comparability in terms of potential confounding factors such as ABO blood group distribution and maternal age, the use in a number of studies of non-contemporary or geographically distant controls raises the issue of possible differences in clinical care other than the use of RAADP (see further below). The use of intention to treat analysis is also important in assessing the impact of a programme of RAADP. The lack of blinding is less problematic given the objective nature of the main outcome measure (the presence/absence of anti-D). Table 11 contains a summary of study quality based on the comparability of the control groups and the use of intention to treat analysis; more detailed comments on study quality are presented in Appendix 4.

TABLE 11 - Characteristics of included studies

i.m., intramuscularly; ITT, intention to treat; i.v., intravenously; RCT, randomised controlled trial.

In describing participants as primigravidae or primiparae the wording used by the original authors has been followed. Because women may not always reveal details of previous pregnancies, information on parity is likely to be the more reliable.

Study	Study type	Study quality	ITT analysis	Date and location of intervention	Date and location of control	Patient selectiona	Number of RhD– women in intervention group delivered of RhD+ infant	Specific product (production method) and route of administration	Dosage and administration schedule	Source of funding
Bowman et al. 1978129	Prospective study, historical/geographical controls	Poor	No	December 1968–August 1976, Winnipeg, Canada	March 1967–December 1974, Manitoba, Canada	Primigravidae	1357	Rho(D) immune globulin (Cohn method), Connaught Laboratories, Toronto; i.m.131	2 × 1500 IU, 28 and 34 weeks	National Health and Medical Research Council of Canada
Bowman and Pollock 1978130	Prospective study, historical controls	Fair	No	March 1976–June 1977, Manitoba, Canada	March 1967–December 1974, Manitoba, Canada	Primigravidae and unsensitised multigravidae	1804	Rho(D) immune globulin (Cohn method), Connaught Laboratories, Toronto; i.m.	1500 IU, 28 weeks	Not stated
Bowman and Pollock 1987131	Retrospective study, historical controls	Poor	No	June 1977–February 1986, Manitoba, Canada	March 1967–December 1974, Manitoba, Canada	Primigravidae and unsensitised multigravidae	9303	RhIG-IV (WinRho) (ion exchange), Winnipeg Rh Institute; usually i.m. but could be i.v.	1500 IU, 28 weeks	Not stated
Huchet et al. 1987125	Quasi-RCT	Good	Yes	January 1983–June 1984, Paris	January 1983–June 1984, Paris	Primiparae (not all of whom were primigravidae)	599	Product not specified; i.m.	2 × 500 IU, 28 and 34 weeks	Not stated
MacKenzie et al. 1999126	Community intervention trial (controlled before-and-after study)	Good	Yes	1990–6, Oxfordshire	1990–6, Northants	Primiparae	3320	Product and route of administration not specified	2 × 500 IU, 28 and 34 weeks	Bio Products Laboratories
MacKenzie et al. 2004100	Open-label RCT; results presented as uncontrolled study	Poor	No	Date not specified, UK and US	i.m. controls contemporary with i.v. intervention; no untreated controls, UK and US	Unselected (primigravidae 28.5%)	270 (figure includes those receiving i.v. and i.m. Rhophylac)	Rhophylac i.v. vs i.m.	1 × 1500 IU, 28 weeks	Chiltern International
Mayne et al. 1997127	Retrospective before-and-after study	Fair	Yes	1993–5, southern Derbyshire	1988–90, southern Derbyshire	Primiparae	1425	Product and route of administration not specified	2 × 500 IU, 28 and 34 weeks	Bio Products Laboratories
Tovey et al. 1983128	Prospective study, historical controls	Fair	Yes	1980–1, Yorkshire	1978–9, Yorkshire	Primigravidae	1238	Product and route of administration not specified	2 × 500 IU, 28 and 34 weeks	Not stated
Trolle 1989132	Prospective study, historical controls	Poor	No	1980–5, Kolding, Denmark	1972–7, Kolding, Denmark	Primigravidae and unsensitised multigravidae	346	Product and route of administration not specified	1500 IU, 28 weeks	Not stated

The studies vary in terms of their patient selection criteria and dosage regimens. Five studies125–129 recruited their intervention group from primigravidae. Four of these studies126–129 recorded data relating to these women in subsequent pregnancies. Bowman et al. ,129 MacKenzie et al. 126 and Mayne et al. 127 did this to assess the prevalence of sensitisation arising from the first pregnancy; only the study by Tovey et al. 128,133 also provided data relating to the incidence of sensitisation resulting from subsequent RhD-positive pregnancies in which RAADP was not provided.

The studies by Bowman and Pollock,130,131 MacKenzie et al. 100 and Trolle132 recruited both primigravidae and unsensitised multigravidae. In MacKenzie et al. 100 almost three-quarters (71.5%) of the participants had been pregnant before and, of these, 81.9% had received anti-D in a previous pregnancy; as noted in the later section on critical review and synthesis of information, this may offer some degree of protection in subsequent pregnancies and may therefore have affected the study results.

As noted above, the 2004 study by MacKenzie et al. 100 compared RAADP using the same anti-D preparation (Rhophylac) administered intravenously and intramuscularly. The remaining studies compared RAADP with no RAADP; none used placebo. Four studies125–128 used 500 IU at 28 and 34 weeks’ gestation, one129 used 1500 IU at 28 and 24 weeks, and four100,130–132 used a single dose of 1500 IU at 28 weeks.

It was originally stated that studies would be included in the review only if they used the specific licensed interventions, as follows:

• D-Gam 500 IU or Partobulin SDF 1000–1650 IU given intramuscularly at weeks 28 and 34 of pregnancy

• Rhophylac 1500 IU given as a single dose intramuscularly or intravenously at week 28 of pregnancy

• WinRho SDF 1500 IU given as a single dose intramuscularly or intravenously at week 28 of pregnancy.

However, only two studies met this criterion: the 1987 study by Bowman and Pollock,131 which used WinRho, and the 2004 study by MacKenzie et al. ,100 which used Rhophylac. In their 1978 studies, Bowman et al. 129 and Bowman and Pollock130 used anti-D prepared by the Connaught laboratories using the Cohn method. The remaining studies did not specify what product was used, and some did not even state the route of administration (see Table 11). Consequently, the review has not been limited to studies which stated that they used one of the specific varieties of anti-D listed above.

All of the included studies with the exception of that by Bowman and Pollock in 1978130 stated that women in both the intervention and control groups who were delivered of RhD-positive infants received postpartum anti-D. It seems highly likely that this was also the case in that study.

Only three of the included studies had contemporary controls: the RCT by MacKenzie et al. ,100 the quasi-RCT by Huchet et al. 125 and the community intervention trial by MacKenzie et al. 126 The 1978 study by Bowman et al. 129 purported to be a community intervention trial with contemporary controls. However, it in fact combined the results for a contemporary control group with the results for a geographically contiguous group of women during an overlapping but not identical time period (JM Bowman, 2001, personal communication). As preintervention data were not provided for the two groups it is not clear to what extent they were actually comparable. Because the intervention group was a city population and the control group was derived in the main from a largely rural population, they may have differed in relation to key variables such as rates of Caesarean section and other invasive procedures. They certainly differed in that the intervention group included only women who for all of their pregnancies were treated in accordance with the trial protocol, whereas the reported control group included women who had had previous pregnancies. Although these pregnancies appeared not to have resulted in alloimmunisation, they may in some cases have resulted in silent sensitisation, thus potentially elevating the alloimmunisation rate in the control group and exaggerating the effectiveness of RAADP.

It has been suggested that, because the antiglobulin tests formerly used to identify maternal anti-D are less sensitive than more recent assays, studies using controls that antedate the intervention group by several years are likely to underestimate the true incidence of alloimmunisation in the control group and therefore the degree of protection provided by AADP. 15 However, the community intervention trial by MacKenzie et al. 126 used a retrospective analysis of prospectively collected data to demonstrate the baseline comparability of the two communities compared in the prospective study in terms of rates of alloimmunisation. It also demonstrated that the rate of sensitisation in the control group fell substantially over time, although the reduction was not as great as in the intervention group. This change over time in the control group is presumably due to changes in obstetric practice, possibly including a more comprehensive use of anti-D following potential sensitising events; it suggests that studies which use historical controls may overestimate, rather than underestimate, the degree of protection provided by RAADP when compared with current good practice.

Although most TPHs large enough to cause sensitisation occur in the last trimester, some women become sensitised before the 28th week. However, Trolle132 excluded women who were sensitised between the first antibody screen test in the first trimester and the 28th week from the intervention group but apparently not from the control group. Moreover, in this study, 38.8% of women in the control group had received more than 1 µl of fetal blood, compared with only 7.9% in the intervention group (p < 0.001). The study results are therefore likely to be biased in favour of the intervention.

The studies also vary in terms of the time at which they collected data on sensitisation. The true rate of sensitisation is greater than that identified by the presence of anti-D at, or 6 months following, delivery (see Chapter 1, Aetiology, pathology and prognosis). However, only two of the included studies – the 1999 study by MacKenzie et al. 126 and the study by Mayne et al. 127 – provided data on the number of women found to be sensitised during a subsequent pregnancy. Moreover, these data also underestimate the true rate of sensitisation because, although they include women in whom silent sensitisation did not become identifiable until a subsequent pregnancy, they exclude those women who did not undergo a subsequent pregnancy.

Assessment of effectiveness

Critical review and synthesis of information

As noted earlier (see Quality of included research), the studies reviewed here vary in terms of the administration schedule and doses of anti-D, and the primary outcome measures used, as well as in their choice of study design and use of intention to treat analysis. The clinically important outcome measure in relation to RAADP is the number of RhD-negative women delivered of a RhD-positive baby who are found to be sensitised during a subsequent RhD-positive pregnancy, although this will underestimate the total number of sensitised women as it will not take into account those who do not go on to become pregnant again. Only two studies, those by MacKenzie et al. 126 and Mayne et al. ,127 took this as their primary end point; both were community-based studies and therefore their results included women who in fact did not receive RAADP in their first pregnancy. However, two studies that did not take it as their primary end point, the studies by Bowman et al. 129 and Tovey et al. ,128 also included information on the number of RhD-negative women delivered of RhD-positive infants in either the intervention or the control group who were found to be sensitised during a subsequent RhD-positive pregnancy (Table 12).

TABLE 12 - Summary of trial results: women found to be sensitised in a subsequent pregnancy as a result of a previous pregnancy, by total anti-D dose

CI, confidence interval; n, number of RhD-negative women in the trial group undergoing subsequent pregnancy following a RhD-positive pregnancy; r, number of sensitised RhD-negative women in the trial group.

For comparability with other studies this figure excludes 11 women who developed antibodies in a previous pregnancy but were retained in the study.

Study	Study design	Dosage	Anti-D prophylaxis group			Control group
			n	r	% Sensitised (95% CI)	n	r	% Sensitised (95% CI)
Bowman et al. 1978129	Prospective study, historical/geographical controls	2 × 1500 IU (28 and 34 weeks) (initially at 34 weeks only)	343	0	0.0 (0.0–0.0)	No data
MacKenzie et al. 1999126	Community intervention trial	2 × 500 IU (28 and 34 weeks)	3320	12	0.4 (0.2–0.6)	3146	26	0.8 (0.5–1.1)
Mayne et al. 1997127	Before-and-after study	2 × 500 IU (28 and 34 weeks)	1425	4	0.3 (0.0–0.6)	1426	16	1.1 (0.6–1.7)
Tovey et al. 1983128	Prospective study, historical controls	2 × 500 IU(28 and 34 weeks)	325	2	0.6 (–0.2 to 1.5)	582	11a	1.9 (0.8–3.0)

As noted in the previous section on quantity and quality of research available, MacKenzie et al. 126 found a fall over time in the number of women in the control group who were found to be sensitised during a subsequent RhD-positive pregnancy. This change, which was not statistically significant, may have been due to the growth of good practice in the delivery of anti-D, both postpartum and antenatally, in response to potential sensitising events, and this may also have affected the intervention group; it was stated that it was not due to the use of antenatal prophylaxis in some women in the control group. Thus, Mayne et al. 127 noted that the introduction of a programme of RAADP was associated with an increase in requests for anti-D following vaginal bleeding or antepartum haemorrhage: they conjectured that this was due to heightened awareness of anti-D among midwives and community doctors, and that it may therefore have contributed to reducing the overall sensitisation rate in women receiving RAADP.

Other outcome measures used in the studies are sensitisation during pregnancy or within 3 days of delivery, and sensitisation at postnatal follow-up. Data relating to sensitisation at these different dates are tabulated in Appendix 5. As these figures differ, an attempt is made in Table 13 to estimate the total number of sensitised women in each study. As none of the included studies presents the total number of women found to be sensitised at either delivery or 6-month follow-up, with the exception of the studies by MacKenzie et al. 126 and Mayne et al. ,127 which present sensitisation rates during the subsequent pregnancy, the figures in Table 13 are likely to underestimate the true prevalence of sensitisation at 6 months because the extent of overlap between women with demonstrable antibodies at delivery and at follow-up is not clear. Moreover, all of the studies are likely to underestimate the numbers of women who would be found to be sensitised were they to become pregnant again, either because they did not measure that outcome and thus did not take into account the phenomenon of silent sensitisation or because, in the case of the studies by MacKenzie and Mayne, they could not identify those women who were sensitised but did not become pregnant again.

TABLE 13 - Summary of trial results: overall percentage of women sensitised, including silent sensitisation (authors’ figures), by total anti-D dose

CI, confidence interval; n, number of RhD-negative women in the trial group delivered of RhD-positive babies; r, number of sensitised RhD-negative women in the trial group; RCT, randomised controlled trial.

153 received only one dose, at 28 or 34 weeks.

Data from Thornton et al. 133

Study	Study design	Dosage	Patient Selection	Anti-D prophylaxis group			Control group
				n	r	% Sensitised, including silent sensitisation (95% CI)	n	r	% Sensitised, including silent sensitisation (95% CI)
Bowman et al. 1978129	Prospective study, historical/geographical controls	2 × 1500 IU (28 and 34 weeks) (initially at 34 weeks only)	Primigravidae	1357a	1	0.1 (–0.1 to 0.3)	2768	45	1.6 (1.2–2.1)
Bowman and Pollock 1978130	Prospective study, historical controls	1 × 1500 IU (28 weeks)	Unselected	1804	5	0.3 (0.0–0.5)	3533	62	1.8 (1.3–2.2)
Bowman and Pollock 1987131	Retrospective study, historical controls	1 × 1500 IU (28 weeks)	Unselected	9303	25	0.3 (0.2–0.4)	3533	62	1.8 (1.3–2.2)
Trolle 1989132	Prospective study, historical controls	1 × 1500 IU (28 weeks)	Unselected	346	0	0.0 (0.0–0.0)	354	6	1.7 (0.4–3.0)
MacKenzie et al. 2004100	Open-label RCT; results presented as uncontrolled study	1 × 1500 IU (28 weeks)	Unselected	248 (per protocol population)	0	0.0 (0.0–0.0)	–	–	–
Huchet et al. 1987125	Quasi-RCT	2 × 500 IU (28 and 34 weeks)	Primiparae	461	0	0.0 (0.0–0.0)	454	4	0.9 (0.0–1.7)
			Multiparae	138	1	0.7 (–0.7 to 2.1)	136	3	2.2 (–0.3 to 4.7)
			Unselected	599	1	0.2 (–0.2 to 0.5)	590	7	1.2 (0.3–2.1)
MacKenzie et al. 1999126	Community intervention trial	2 × 500 IU (28 and 34 weeks)	Primiparae	3320	12	0.4 (0.2–0.6)	3146	26	0.8 (0.5–1.1)
Mayne et al. 1997127	Before-and-after study	2 × 500 IU (28 and 34 weeks)	Primiparae	1425	4	0.3 (0.0–0.6)	1426	16	1.1 (0.6–1.7)
Tovey et al. 1983128	Prospective study, historical controls	2 × 500 IU (28 and 34 weeks)	First pregnancy	1238	4b	0.3 (0.0–0.6)	2000	19b	1.0 (0.5–1.4)
			Second pregnancy	604b	1b	0.2 (–0.2 to 0.5)	582	9b	1.5 (0.5–2.5)
			Third pregnancies	2037b	6b	0.3 (0.1–0.5)	2721b	32b	1.2 (0.8–1.6)

Comparability of results

The studies vary in the results that they present. Six studies – the study by Bowman et al. ,129 the two studies by Bowman and Pollock130,131 and the studies by Huchet et al. ,125 Tovey et al. 128 and Trolle132 – report in effect the aggregated results of treating individual women. Although Bowman and Pollock130 set out to describe the results of providing RAADP on a Canadian province-wide basis, they in fact only present the results for those women who actually received RAADP (stated to be only 89% of those at risk). In addition, as noted above, Trolle132 screened women for antibodies before inclusion and gave no indication of the numbers who were excluded from the study on this basis.

Studies that only include data relating to women known both to have received the intervention and to have received it before sensitisation will provide an indication of the clinical effectiveness of RAADP but will overestimate its efficacy in non-trial conditions. Efficacy can only be indicated by community studies that demonstrate the likely reduction in sensitisation rates achievable in practice by offering the intervention in a geographical area and including all women in that area in an intention to-treat analysis. Only two studies were of this nature, those by MacKenzie et al. 126 and Mayne et al. 127 MacKenzie et al. 126 gave prophylaxis to all non-sensitised pregnant RhD-negative nulliparae, and reported the results in terms of the number of those women found to be sensitised in their second continuing pregnancy. Mayne et al. 127 gave prophylaxis to primigravidae and women with no living children, but presented the results for all women ‘at risk’ (i.e. all RhD-negative women delivered of RhD-positive babies having a subsequent pregnancy), thus indicating the overall efficacy of the programme, which in its second and subsequent years was said to reach most RhD-negative primiparae in the area.

It would therefore not be surprising if the results obtained by before-and-after studies differed from those of the other studies, as only the before-and-after studies included a number of untreated women in the intervention group. Moreover, as noted above, they report the effect of a policy of RAADP in primigravidae on sensitisation in subsequent pregnancies, and the number of women found to be sensitised at this point could theoretically also include women sensitised early in their second rather than in their first pregnancy.

Finally, there were some discrepancies between the studies in terms of the inclusion or exclusion from the reported results of cases of apparent sensitisation in women who received RAADP. For comparability with the before-and-after studies, Table 14 displays the overall numbers of sensitised women including, where possible, any stated to have been excluded from the authors’ analyses. Table 15 provides details of the numbers of women excluded from the authors’ analyses, and the reasons for this, together with further information relating to the women sensitised despite being in the intervention groups, i.e. potential failures of protection.

TABLE 14 - Summary of trial results: comparison with no treatment: overall percentage of women sensitised, including silent sensitisation, by total anti-D dose, including, where possible, women excluded from published analyses for various reasonsa (see Table 16)

CI, confidence interval; n, number of RhD-negative women in the trial group delivered of RhD-positive babies; r, number of sensitised RhD-negative women in the trial group; RCT, randomised controlled trial.

Information on numbers excluded from published analyses not available for Huchet and Trolle studies.

153 received only one dose, at 28 or 34 weeks.

Data from Thornton et al. 133

Study	Study design	Dosage	Patient selection	Anti-D prophylaxis group			Control group
				n	r	% Sensitised, including silent sensitisation (95% CI)	n	r	% sensitised, including silent sensitisation (95% CI)
Bowman et al. 1978129	Prospective study, historical/geographical controls	2 × 1500 IU (28 and 34 weeks) (initially at 34 weeks only)	Primigravidae	1357b	1	0.1 (–0.1 to 0.3)	2768	45	1.6 (1.2–2.1)
Bowman and Pollock 1978130	Prospective study, historical controls	1 × 1500 IU (28 weeks)	Unselected	1806	11	0.6 (0.3–1.0)	3533	62	1.8 (1.3–2.2)
Bowman and Pollock 1987131	Retrospective study, historical controls	1 × 1500 IU (28 weeks)	Unselected	9295	30	0.3 (0.2–0.4)	3533	62	1.8 (1.3–2.2)
Trolle 1989132	Prospective study, historical controls	1 × 1500 IU (28 weeks)	Unselected	346	0	0.0 (0.0–0.0)	354	6	1.7 (0.4–3.0)
Huchet et al. 1987125	Quasi-RCT	2 × 500 IU (28 and 34 weeks)	Primiparae	461	0	0.0 (0.0–0.0)	454	4	0.9 (0.0–1.7)
			Multiparae	138	1	0.7 (–0.7 to 2.1)	136	3	2.2 (–0.3–4.7)
			Unselected	599	1	0.2 (–0.2 to 0.5)	590	7	1.2 (0.3–2.1)
MacKenzie et al. 1999126	Community intervention trial	2 × 500 IU (28 and 34 weeks)	Primiparae	3320	12	0.4 (0.2–0.6)	3146	26	0.8 (0.5–1.1)
Mayne et al. 1997127	Before-and-after study	2 × 500 IU (28 and 34 weeks)	Primiparae	1425	4	0.3 (0.0–0.6)	1426	16	1.1 (0.6–1.7)
Tovey et al. 1983128	Prospective study, historical controls	2 × 500 IU (28 and 34 weeks)	First pregnancy	1238	4c	0.3 (0.0–0.6)	2000	19c	1.0 (0.5–1.4)
			Second pregnancy	604c	1c	0.2 (–0.2 to 0.5)	582	9c	1.5 (0.5–2.5)
			All pregnancies	2037c	6c	0.3 (0.1–0.5)	2721c	32c	1.2 (0.8–1.6)

TABLE 15 - Women sensitised in intervention groups

When two figures are provided, the first figure is the number of sensitised women included in the authors’ analyses and the second figure is the number of sensitised women excluded from these analyses.

Study	Number of sensitised women in intervention groupa	Comments
Bowman et al. 1978129	1, unspecified number	Considered by the investigators probably to be a case of passive RhD antibody persisting at 6 months after delivery; as the woman was lost to follow-up at 9 months it was not possible to establish whether it still existed at that point. In the first 6 months of the study an unspecified number of women were sensitised before 34 weeks; these were not included in the analysis
Bowman and Pollock 1978130	5, 6	Two women were sensitised before 28 weeks; one multigravida may have undergone silent sensitisation as a result of an earlier abortion when no anti-D was given or may have been sensitised before receiving prophylaxis at 29 weeks in the current pregnancy; and two more multigravidae may either have undergone silent sensitisation in a previous pregnancy or may represent failures of prophylaxis. In addition, two primigravidae appeared to have been sensitised before what they stated was their first pregnancy; three multigravidae appeared to have undergone silent sensitisation by an earlier pregnancy; and one had received an RhD-positive blood transfusion: these were all excluded from the analysis
Bowman and Pollock 1987131	25, 5	13 failures of prophylaxis; four women in whom sensitisation could be due either to failure of prophylaxis or to failure to treat following a previous abortion or delivery; five women sensitised by 28 weeks in current pregnancy; and three women sensitised by 28 weeks who possibly underwent silent sensitisation in an earlier pregnancy. In addition, five women who appeared to have undergone silent sensitisation in a previous pregnancy were excluded from the analysis
Huchet et al. 1987125	1	Apparently a failure of prophylaxis – the woman in question had received anti-D during a previous pregnancy, which was terminated for therapeutic reasons
MacKenzie et al. 1999126	12	Six women were delivered of their first pregnancy outside Oxfordshire: four certainly and two possibly did not receive antenatal prophylaxis during that first pregnancy; one woman had undergone a potential sensitising event at 18 weeks for which anti-D may not have been given; one woman, who delivered at 37 weeks, had undergone a large fetomaternal haemorrhage, probably at 35 weeks (routine prophylaxis had been given at 29 and 35 weeks); and four women had received prophylaxis at 28 and 34 weeks and did not appear to have suffered an incident likely to provoke a fetomaternal haemorrhage
Mayne et al. 1997127	4	Three women had previously delivered in places where routine antenatal prophylaxis was unlikely; one had not received prophylaxis during her first pregnancy despite the existence of a programme of RAADP
Tovey et al. 1983128	5	All seem due to failures of prophylaxis, although two women sensitised during their first pregnancy had low but persisting levels of antibodies, which might possibly be rare ‘naturally occurring’ anti-D
Trolle 1989132	0, unspecified number	An unspecified number of women who had been sensitised by 28 weeks were excluded from the study

The 2004 study by MacKenzie et al. 100 found no difference in efficacy or safety between Rhophylac administered intravenously and Rhophylac administered intramuscularly. However, this does not prove that there was no difference, as the study was not powered to identify such a difference, even though this was the randomised comparison.

The studies were broadly comparable in terms of the percentage of women in the control groups who were sensitised: this ranged from 1.2–1.8% in unselected groups, 0.8–1.6% in primiparae and 1.4–2.2% in multiparae (see Table 14). MacKenzie et al. 126 found an unexpected, and statistically non-significant, reduction in the number of cases observed in the control arm between the two study periods, from 1.3% in 1980–6 to 0.8% in 1990–6.

In all studies the proportion of women who were sensitised was lower in the intervention arm than in the control arm. However, the difference between sensitisation rates in the intervention and control arms varied between studies. As might be expected, this difference was particularly small, at 0.4–0.7%, in the before-and-after studies by MacKenzie et al. 126 and Mayne et al. 127 as their intention to treat analyses will have included women who had not received RAADP.

Meta-analysis of clinical effectiveness

In our earlier review we conducted meta-analysis on three groups of studies using the overall results presented in Table 14, which include, where possible, women excluded from the authors’ analyses:

• Group 1: the four studies that used a dosage regimen of 500 IU at 28 weeks and 34 weeks and reported results for primigravidae – Huchet et al. ,125 MacKenzie et al. ,126 Mayne et al. 127 and Tovey et al. 128

• Group 2: the three studies that used a dosage regimen of 1500 IU at 28 weeks – the two studies by Bowman and Pollock130,131 and that by Trolle. 132 These studies included both primigravidae and multigravidae.

• Group 3: the two community-based UK studies that used a dosage regimen of 500 IU at 28 weeks and 34 weeks and reported results for primigravidae – MacKenzie et al. 126 and Mayne et al. 127

As the current systematic review identified no additional studies comparing RAADP with no treatment, we present the results of these meta-analyses again here. On the basis of face validity, visual examination of the absolute trial results, individual odds ratios within trials and results of the meta-analyses (Table 16), the trials show a remarkable consistency in results, even between dosage regimens. Consequently, the results of the meta-analysis of group 3 trials are deemed to give a representative reflection of the actual effectiveness of RAADP and these figures are used in the economic evaluation.

TABLE 16 - Results of the meta-analysis

CI, confidence interval.

	Group 1	Group 2	Group 3
Test for heterogeneity (p-value)	0.812	0.940	0.976
Odds ratio of sensitisation with antenatal prophylaxis (95% CI)	0.33 (0.20–0.55)	0.20 (0.13–0.29)	0.37 (0.21–0.65)
Sensitisation rate of control group (95% CI)	0.89% (0.21–1.56%)	1.60% (0.37–2.83%)	0.95% (0.18%–1.71%)
Sensitisation rate of antenatal prophylaxis group using meta-analysis (95% CI)	0.30% (0.22–0.38%)	0.34% (0.28–0.40%)	0.35% (0.29–0.40%)

Sensitisation rates for the conventional management groups were calculated by applying to each study the average of the sensitisation event probabilities estimated in the logistic regression model. Within group 2, the 1987 study by Bowman and Pollock131 used the same control arm results as the 1978 study by the same authors. 130 To prevent double counting, which would have a significant effect on the overall results because of the size of the studies, the two studies were combined into a three-arm study within the meta-analysis, consisting of two treatment arms and one control arm.

The results of the meta-analyses are shown in Table 16 and Figures 2–4.

FIGURE 2.

Group 1: 2 × 500 IU in RhD-negative primigravidae. Note: number of women in intervention group in brackets.

FIGURE 3.

Group 2: 1 × 1500 IU in unselected RhD-negative women. Note: number of women in intervention group in brackets.

FIGURE 4.

Group 3: 2 × 500 IU in RhD-negative primigravidae. Note: number of women in intervention group in brackets.

Comparison of dosage regimens

Pooling the data from those studies that used one dose of 1500 IU at 28 weeks (group 2) produced a point estimate for sensitisation in the RAADP group of 0.34%. In comparison, the study by Bowman et al. ,129 which used two doses of 1500 IU at 28 and 34 weeks, reported a rate of 0.1%. Although this suggests that, as one might expect, two doses of 1500 IU are more effective than one, there are no trials that directly compare these two regimens.

In theory, two doses of 500 IU at 28 and 34 weeks should also be more effective than a single dose of 1500 IU at 28 weeks, as they would result in a slightly higher residual anti-D at term. 15 Pooling the data from those studies that used two doses of 500 IU at 28 and 34 weeks yields a point estimate for sensitisation in the RAADP group of 0.30%, marginally lower than that for a single dose of 1500 IU (0.34%). However, because the sensitisation rate in the control groups was lower in the studies using two doses of 500 IU than in all of the other studies, the point estimate of the odds ratio for one dose of 1500 IU at 28 weeks is lower (0.20; i.e. more effective) than that for two doses of 500 IU (0.33). For both the odds ratios and the point estimates of the sensitisation rates the 95% confidence intervals of the estimates overlap, implying that the differences are not statistically significant.

Compliance

Only one of the included studies, the 1999 study by MacKenzie et al. ,126 examined the extent to which comprehensive prophylaxis was achieved. This study found that, of a sample of eligible women delivered in the John Radcliffe Hospital, Oxford, during 1992–6, only 89% received the first dose of a two-dose regimen, only 76% received both doses and only 29% received both doses at the correct gestation. This audit was later extended to include the years 1997–2003. 122 During the latter period 90% of women received the first dose and 79% both doses. Although these modest improvements were not statistically significant, in the later period the timing of both injections had improved significantly. Despite this improvement in compliance there was estimated to be no reduction in the sensitisation rate among women who had delivered their first baby in the Oxford district and who would have been eligible for RAADP during that pregnancy.

Longer-term outcomes

Bowman et al. 129 provided information on the clinical outcomes of 17 subsequent RhD-positive pregnancies in the 62 sensitised women in the study’s control group. Seven of the 17 infants (41%) required treatment related to HDN (Table 17).

TABLE 17 - Clinical outcomes of RhD-positive pregnancies in sensitised women129

The Coombs’ test measures the presence of antibodies on the surface of red blood cells. It may be measured directly in the infant or indirectly in the mother.

Outcome	Number of pregnancies (%)
Fetal and exchange transfusion required	2 (12%)
Exchange transfusion and early delivery required	3 (18%)
Phototherapy required	2 (12%)
Direct Coombs’ test positivea – treatment not required	5 (29%)
Direct Coombs’ test negative – unaffected	5 (29%)

In the study by Tovey et al. 128 anti-D antibodies were identified during their first pregnancy in 18 women in the control group: 14 of their infants (78%) were mildly affected, two (11%) were moderately affected, requiring exchange transfusion, one died for reasons other than RhD HDN and one was RhD negative. Between them these 18 women, and one other woman in the control group in whom the antibody had been detected before her first pregnancy, went on to have 11 further pregnancies: five (45%) of these infants were mildly affected, two (18%) were moderately affected and one was severely affected (requiring six exchange transfusions).

Thornton et al. 133 studied the effect of RAADP given only in the first pregnancy on sensitisation rates in subsequent pregnancies. This was a follow-up to the study by Tovey et al. 128 and reports on the same cohorts of women. Thornton et al. 133 found that only one woman who had received RAADP in her first pregnancy produced anti-D antibodies in her second pregnancy, none produced anti-D antibodies in the third pregnancy and only one produced anti-D antibodies in the fourth pregnancy (Table 18). Overall, sensitisation occurred in six women in the treatment group and in 32 women in the control group. No explanation was proposed as to why prophylaxis provided in the first pregnancy should appear to confer benefits in subsequent pregnancies.

TABLE 18 - Anti-D antibody detected in first and subsequent pregnancies of RhD-negative women delivered of an RhD-positive infant (RAADP given to the treatment group in the first pregnancy only)133

First pregnancy		Second pregnancy		Third pregnancy		Fourth pregnancy
Treatment group (n = 1234)	Control group (n = 1881)	Treatment group (n = 604)	Control group (n = 582)	Treatment group (n = 167)	Control group (n = 121)	Treatment group (n = 32)	Control group (n = 18)
4 (0.32%)	19 (1%)	1 (0.17%)	9 (1.5%)	0 (0%)	3 (2.5%)	1 (3.1%)	1 (5.5%)

More recently, a retrospective longitudinal observational study carried out by MacKenzie et al. 144 compared the rate of RhD sensitisation following the implementation of a policy of restricted prophylaxis, in which RAADP was offered to all non-sensitised RhD-negative pregnant women with no living children booked for confinement in the Oxford Health District, with that predicted by mathematical modelling following a policy of universal prophylaxis, in which RAADP would be offered to all RhD-negative pregnant women irrespective of parity. This study also found that the policy of restricted prophylaxis provided continuing protection in subsequent pregnancies.

Thornton et al. 133 provided data relating to preterm deliveries, birth weights and perinatal deaths in both the first and second pregnancy, and abortions in the second pregnancy, in RhD-negative women who, following RAADP in their first pregnancy, had delivered a RhD-positive baby in that first pregnancy. These data were compared with those relating to untreated RhD-negative women who gave birth to RhD-positive babies in their first pregnancy and to RhD-positive mothers who were comparable except for the RhD status. No significant differences were observed either in terms of these outcomes or in terms of maternal hypertension and proteinuria in the first, second and third pregnancies. 133

ABO compatibility

As noted in Chapter 1 (see Aetiology, pathology and prognosis), in approximately 20% of pregnancies in RhD-negative women the mother and fetus have different ABO blood groups. Sensitisation is less common when mother and baby are ABO incompatible. This is demonstrated by information from the control group of the study by Bowman et al. 129 (Table 19).

TABLE 19 - ABO compatibility and incidence of sensitisation in RhD-negative women not treated with routine antenatal anti-D prophylaxis129

CI, confidence interval; n, number of deliveries of RhD-positive babies to RhD-negative women; r, number of sensitised RhD-negative women.

ABO compatibility	n	r	% Sensitised (95% CI)
Primigravidae	2768	45	1.6 (1.2–2.1)
Compatible	2257	44	1.9 (1.4–2.5)
Incompatible	511	1	0.2 (–0.2 to 0.6)
Multigravidae	765	17	2.2 (1.2–3.3)
Compatible	602	14	2.3 (1.4–3.5)
Incompatible	163	3	1.8 (–0.2 to 3.9)

Summary of clinical effectiveness

In the eight studies that compared RAADP with no prophylaxis, RAADP was given to, or available for, RhD-negative women undergoing a total of around 19,719 pregnancies that resulted in RhD-positive babies. Of these pregnancies, 65 (0.33%) resulted in sensitisation. The control groups for these studies (six groups in all, as all three studies by Bowman used the same control population) included a total of 11,049 pregnancies in women at risk of RhD sensitisation that resulted in RhD-positive babies: 136 of these pregnancies (1.2%) resulted in sensitisation.

The largest study, by Bowman and Pollock,131 accounts for nearly half of the total number of pregnancies in which RAADP was given or available. However, its design is relatively weak, comparing women who received RAADP between 1977 and 1986 with controls from the same geographical area during the period 1967–74.

Overall, it would appear that of the 65 pregnancies in the intervention groups that were reported to have resulted in sensitisation (including silent sensitisation):

• 29 represented possible or probable failures of treatment (i.e. cases in which sensitisation occurred despite appropriate administration of anti-D)

• at least 19 represented probable or possible logistic failures (i.e. instances in which, in the absence of any recognised sensitising event, sensitisation preceded the administration of prophylaxis or in which prophylaxis was not administered despite the existence of a policy of antenatal prophylaxis)

• 12 were sensitised as a result of a previous delivery in a place where routine antenatal prophylaxis was either certainly or probably not provided.

Overall, therefore, the number of eligible pregnancies that resulted in sensitisation despite antenatal prophylaxis would appear to be as low as 29/19,719 (0.15%; 95% CI 0.1–0.2%). This figure would rise to a maximum of 48/19,719 (0.24%; 95% CI 0.2–1.3%) with the inclusion of logistic failures of prophylaxis – women sensitised either before the date at which the first dose of antenatal prophylaxis would have been administered or following failure to administer either routine prophylaxis or prophylaxis following a potential sensitising event.

The best indication of the likely efficacy of a programme of routine AADP in England and Wales comes from the two non-randomised community-based studies by MacKenzie et al. 126 and Mayne et al. 127 The pooled results of these two studies suggest that, compared with no RAADP, such a programme may reduce the sensitisation rate from 0.95% to 0.35%. This gives an odds ratio for the risk of sensitisation of 0.37, and an absolute reduction in risk of sensitisation in RhD-negative mothers at risk (i.e. carrying a RhD-positive child) of 0.6%. The number of such women needed to treat (NNT) to avoid one case of sensitisation is 1/0.006, which is 166. However, in the absence of a programme of non-invasive fetal genotyping a RhD-negative woman will not know if she is carrying a RhD-positive child; in fact, only 60% of them will be, making the overall NNT = 10/6 × 166 = 278.

Further, a woman will only benefit clinically if she has an RhD-positive infant and she would have been sensitised and she goes on to have a further infant who is also RhD positive. It is the avoidance of HDN in that infant which constitutes the clinical benefit.

In Chapter 1 (see Significance for the NHS) we estimated that currently, were there no programme of RAADP, approximately 650 RhD-negative women a year would be sensitised antenatally and that subsequent pregnancies in these women would lead to around 31 fetal or neonatal losses per year. Avoidance of sensitisation can be expected to avoid fetal loss in 4.8% of cases (this takes into account the fact that women who become immunised during a first pregnancy may be ‘high responders’ who produce a vigorous response to a small FMH). An estimate of the overall NNT to avoid a fetal or neonatal loss in a subsequent pregnancy is therefore 278/0.048 = 5790.

Adverse events

No serious adverse events related to the administration of RAADP were reported by any of the studies included in the review of clinical effectiveness. MacKenzie et al. 100 reported a few cases of mild pain, soreness or itching at the injection site following administration of Rhophylac. Bowman et al. 100 reported mild adverse reactions (marked flushing and mild chest discomfort that disappeared within 30 seconds without the use of medication) in two out of 3733 women given WinRho either antenatally or postpartum; they both received WinRho from a lot containing unacceptable levels of moisture and aggregated IgG.

The study by MacKenzie et al. 100 was unique in screening for blood group alloantibodies and viral markers both before RAADP and 6 months after the last administration of anti-D. Anti-C was identified in the sera of three women who had received intravenous Rhophylac. In terms of viral markers two women seroconverted for hepatitis A virus antibodies, three for cytomegalovirus and one for anti-HBc (hepatitis B core antigen); for these women the route of Rhophylac administration was not specified but the investigators considered it unlikely that any of the observed seroconversions were related to Rhophylac; one of the seroconversions for hepatitis A virus followed immunisation for international travel. Moreover, as the investigators acknowledge, the note for guidance from the Committee for Proprietary Medicinal Products145 on the clinical investigation of human anti-D immunoglobulin for intravenous and/or intramuscular use states that, because of the effectiveness of procedures to control potential viral contamination, ‘it is no longer considered appropriate to use clinical trials to investigate viral safety with regard to enveloped viruses’, and that, although these procedures may be of limited value against non-enveloped viruses such as hepatitis A and parvovirus B19, ‘the safety of the products with respect to non-enveloped viruses cannot currently be adequately evaluated in clinical studies’.

In 2006, 77 adverse events relating to the administration of anti-D for all indications were reported to the SHOT (Serious Hazards of Transfusion) Committee. All involved lack of communication and poor documentation. The nature of the majority of these incidents is not specified. However, it was stated that 13 women with immune anti-D received treatment with anti-D immunoglobulin, although not necessarily as part of RAADP. 89 This is a particular cause for concern because it implies a failure to identify a pregnant woman as sensitised, which can in turn lead to failure to monitor immune antibodies during pregnancy, with the risk of adverse outcomes if the fetus is affected by HDN.

Discussion

All of the evidence indicates that RAADP reduces the incidence of sensitisation. In assessing the impact of a programme of RAADP the most relevant studies are those by MacKenzie et al. 126 and Mayne et al. 127 These are community-based studies with high external validity as they demonstrate the effectiveness of RAADP in real life in the UK rather than under trial conditions and as measured by the most clinically relevant outcome measure, the number of women found to be sensitised in a subsequent pregnancy. Meta-analysis of the data from these studies indicates that the introduction of such a programme is associated with a fall of 0.6% (from 0.95% to 0.35%) in the number of women found in a subsequent pregnancy to be sensitised, an odds ratio of 0.37 (95% CI 0.21–0.65).

However, although the implementation of a programme of RAADP should lead to a significant fall in the residual numbers of women becoming sensitised, some women continue to become sensitised. There are five possible reasons for continuing cases of sensitisation:

• failure to recognise potential sensitising events in pregnancy as such and to treat them appropriately

• failure to assess the extent of FMH adequately

• failure to comply with postpartum prophylaxis guidelines

• refusal of RAADP by the mother

• failure to implement RAADP by some trusts and incomplete adherence to advice (i.e. poor compliance with the second dose).

Before the introduction of RAADP there was not universal adherence to UK guidelines, particularly with respect to administration of anti-D following potentially sensitising events in pregnancy. An audit of anti-D sensitisation carried out in Yorkshire between 1988 and 1991146 found that the guidelines were followed fully in only 52% (30/58) of possible sensitising events for which full data were available. In Scotland an audit found that, in 1992, anti-D was given in only 70% (195/280) of recorded antenatal events which should have resulted in its administration. 147 A questionnaire survey published in 1994 found that many A&E departments in England and Wales were not adequately prepared for treating with anti-D women bleeding in early pregnancy and were not following the guidelines so to do. 148 A retrospective study of 922 RhD-negative women delivered in Merseyside in 1994 found that, in 39% (158/396) of potentially sensitising events, the guideline recommendations were not recorded as having been followed. 149 In an audit of singleton pregnancies delivered in nine hospitals within a hundred-mile radius of Manchester between 1 August 1994 and 31 July 1995, anti-D was recorded as being administered after 79% (478/602) of potentially sensitising events overall, but administration rates in the individual hospitals ranged from 58% to 96%. 150 In 1998 an audit of 3274 RhD-negative women in Northern Ireland found that anti-D was given after only 44% (117/264) of potentially sensitising events that occurred before, and 58% (184/319) of those that occurred after, 20 weeks’ gestation. However, in some cases this was because the women themselves had not sought advice from maternity care staff within 72 hours of the event. 151

The evidence suggests closer adherence to the guidelines for postpartum administration. Appropriate postnatal prophylaxis was given in 95% of cases (497/520) in Merseyside in 1994149 and in 98% of cases (1820/1852) in Northern Ireland in 1998. 151

It should be noted that the above studies were all carried out in the 1990s. Although more recent evidence has not been found it is possible that compliance with guidance relating to the administration of anti-D following potentially sensitising events in pregnancy may have improved following the introduction of RAADP and the consequent raising of awareness of the importance of antenatal prophylaxis. Probably only a minority of the current cases of sensitisation are attributable to failure to comply with current established UK guidelines relating to either postpartum prophylaxis or prophylaxis in response to potential sensitising events. Nevertheless, these observations inevitably raise the question of whether sensitisation rates cannot be further reduced by stricter adherence to these guidelines rather than by offering RAADP to all RhD-negative pregnant women who are not already sensitised.

There is no evidence to suggest that RAADP is associated with adverse effects of any consequence for either mother or child other than the possibility of transmission of bloodborne infections; this is minimised by the safeguards built into the modern manufacturing process.

Systematic review of existing cost-effectiveness evidence

A systematic review of economic evaluations was carried out using the search criteria and databases set out within the clinical effectiveness section (see Chapter 3, Identification of studies); the only variation from this was that the study design was defined as economic evaluations. A total of 11 papers (nine different studies) were identified by the systematic searches (Figure 5); eight of these studies were included in the RAADP assessment report for NICE in 2001,155 later published as a NICE Health Technology Assessment report. 1 These were the studies by Adams et al. ,156 Baskett and Parsons,157 Lim et al. ,158 Mackenzie et al. ,126 Selinger,159 Torrance and Zipursky,160 Tovey et al. 128 and Vick et al. 161,162 Two of these studies126,128 were also included as studies of clinical effectiveness. Only one additional economic evaluation was identified by the updated searches. This was the previous RAADP NICE Health Technology Assessment by Chilcott et al. carried out in 2001. 1

FIGURE 5.

Assessment of cost-effectiveness: summary of study selection and exclusion.

Because of the variability between the studies a quality assessment has not formally been carried out. However, the following sections of this report present an overview of the nine included economic evaluations. The description of eight of the studies presented here has been taken from the previous anti-D Health Technology Assessment by Chilcott et al. carried out in 20011 for the NICE appraisal of RAADP. Of the nine studies included in the review, five evaluations used UK costs, but only the studies by Vick et al. 161,162 and Chilcott et al. 1 describe a detailed modelling evaluation that appears to be applicable to the UK NHS. Four of the studies are over 20 years old and an additional three of the studies are over 10 years old; hence, caution should be taken if comparing these results with those of the model presented here. The economic evaluations included in the review cover a range of RAADP regimens, as summarised in Table 20.

Independent economic assessment

There were no new health economic models provided within the manufacturers’ submissions for this assessment report. The independent economic model that was developed in 2001 for the NICE RAADP appraisal87 has been modified to incorporate recent additional evidence identified for this review. This review reassesses the use of 500 IU and 1250 IU of anti-D at 28 and 34 weeks’ gestation and, in addition, evaluates the use of a single dose of 1500 IU of anti-D at 28 weeks’ gestation. Although coverage of RAADP is currently approximately 90%,89 these regimens are evaluated against no RAADP to enable the assessment of all interventions against the same comparator and to enable a reassessment of the cost-effectiveness of RAADP against no RAADP. Within this assessment, in an attempt to improve upon the cost per QALY analysis, we have also revisited the assumptions around valuation of fetal loss and quality of life of those who suffer from developmental problems. Population parameters, costs and current statistics such as average life expectancy and the probability associated with having subsequent children have also been updated within this assessment.

Results

Results of the deterministic analysis

The incremental cost-effectiveness outcomes associated with RAADP for RhD-negative primigravidae and for all RhD-negative women are shown in Tables 27 and 28 respectively.

TABLE 27 - Incremental cost-effectiveness outcomes associated with RAADP for RhD-negative primigravidae versus no RAADP

LYG, life-year gained; QALY, quality-adjusted life-year.

The baseline values are the absolute totals.

Anti-D dose	Total additional cost	Number of sensitisations avoided	Number of affected pregnancies avoided	Number of fetal losses avoided	LYG	QALYs gained	Cost per sensitisation avoided	Cost per affected pregnancy avoided	Cost per fetal loss avoided	Cost per LYG	Cost per QALY gained
Baseline valuea	£1,796,546	630	353	14	2,878,648	2,533,240
2 × 500 IU (D-Gam)	£2,360,604	162	150	6	250	207	£14,561	£15,783	£394,580	£9457	£11,384
2 × 1250 IU (Partobulin)	£3,081,262	162	150	6	250	207	£19,006	£20,602	£515,040	£12,344	£14,859
1 × 1500 IU (Rhophylac)	£1,797,590	162	150	6	250	207	£11,088	£12,019	£300,471	£7201	£8669
1 × 1500 IU (WinRho)	£13,823,575	162	150	6	250	207	£85,267	£92,426	£2,310,641	£55,378	£66,661

TABLE 28 - Incremental cost-effectiveness outcomes associated with RAADP for all RhD-negative women versus primigravidae

LYG, life-year gained; QALY, quality-adjusted life-year.

Anti-D dose	Total cost	Number of sensitisations avoided	Number of affected pregnancies avoided	Number of fetal losses avoided	LYG	QALYs gained	Cost per sensitisation avoided	Cost per affected pregnancy avoided	Cost per fetal loss avoided	Cost per LYG	Cost per QALY gained
2 × 500 IU (D-Gam)	£2,645,120	233	72	3	120	100	£11,358	£36,679	£916,982	£21,977	£26,455
2 × 1250 IU (Partobulin)	£3,457,346	233	72	3	120	100	£14,846	£47,942	£1,198,556	£28,725	£34,578
1 × 1500 IU (Rhophylac)	£2,010,568	233	72	3	120	100	£8634	£27,880	£697,002	£16,705	£20,108
1 × 1500 IU (WinRho)	£15,564,594	233	72	3	120	100	£66,836	£215,831	£5,395,767	£129,317	£155,666

The model results show that WinRho RAADP would not be considered cost-effective in comparison with the other regimens of RAADP. Excluding WinRho, for all other regimens of RAADP given to RhD-negative primigravidae versus no RAADP, the cost per sensitisation avoided and the cost per affected pregnancy avoided are estimated to be between £11,000 and £21,000. The cost per fetal loss avoided is estimated to be between £300,000 and £515,000. These high estimates are due to the low proportion of fetal losses occurring as a result of HDN within a group of pregnant RhD-negative women.

RAADP given to all RhD-negative women is expected to decrease the number of sensitisations, the number of affected pregnancies and the number of fetal losses, but it is also expected to increase costs. Therefore, giving RAADP to RhD-negative primigravidae and multigravidae compared with giving RAADP to RhD-negative primigravidae only results in a cost per sensitisation avoided of between £8000 and £15,000 and a cost per affected pregnancy avoided of between £28,000 and £48,000 for all regimens of RAADP excluding WinRho. The cost per fetal loss avoided is estimated to be between £697,000 and £1.2 million.

Giving RAADP to RhD-negative primigravidae compared with no RAADP results in a cost per LYG of between £7000 and £12,000 for all RAADP regimens excluding WinRho. For RAADP given to RhD-negative primigravidae and multigravidae versus RhD-negative primigravidae only, the cost per LYG is estimated to be between £17,000 and £29,000. The cost per QALY gained as a result of RAADP given to RhD-negative primigravidae versus no RAADP is between £9000 and £15,000 for all RAADP regimens apart from the one-dose regimen of 1500 IU of WinRho, which has a cost per QALY gained of around £67,000. For RhD-negative primigravidae and multigravidae compared with primigravidae only, the cost per QALY gained as a result of RAADP is between £20,000 and £35,000 for all anti-D products, again with the exception of 1500 IU of WinRho, which has a cost per QALY gained of around £156,000. As described previously, any comparisons between the different regimens of RAADP should be considered with caution given the variability in actual prices paid by hospitals for anti-D.

Results of the subgroup analysis

Ethnic minorities in England and Wales are less likely to be RhD negative and hence the absolute number of women requiring routine anti-D is expected to be smaller for these subgroups; however, the impact per person is expected to increase if we assume that the father is of the same ethnicity. For example, considering Asian, West African and Chinese people, the model predicts that, although the proportionate number of sensitisations, affected pregnancies and fetal losses will be lower in these ethnic minorities than in the Caucasian population, the cost per sensitisation, cost per affected pregnancy and cost per fetal loss will also be lower. Consequently, the cost-effectiveness ratio is estimated to be slightly better for ethnic minorities. Because the efficacy of each of the RAADP regimens is assumed to be the same within the model, the impact of changes in the proportion of people who are RhD negative is expected to have the same relative impact across the different regimens. Therefore, these results are presented in terms of a 500-IU dose of anti-D (D-Gam) at 28 and 34 weeks’ gestation (Table 29).

TABLE 29 - Incremental cost-effectiveness results for different ethnicities

LYG, life-year gained; QALY, quality-adjusted life-year.

The baseline values are the absolute totals.

Ethnicity (% RhD negative)a	Total additional cost	Number of sensitisations avoided	Number of affected pregnancies avoided	Number of fetal losses avoided	LYG	QALYs gained	Cost per sensitisation avoided	Cost per affected pregnancy avoided	Cost per fetal loss avoided	Cost per LYG	Cost per QALY gained
Baseline Caucasian (16%)	£1,796,546	630	353	14.1	2,878,648	2,533,240
RhD-negative Caucasian primigravidae	£2,360,604	162	150	6	250	207	£14,561	£15,783	£394,580	£9457	£11,384
All RhD-negative Caucasian women	£2,645,120	233	72	3	120	100	£11,358	£36,679	£916,982	£21,977	£26,455
Baseline Asian (9%)	£1,073,357	375	216	8.64	1,619,211	1,424,923
RhD-negative Asian primigravidae	£1,302,875	99	93	4	154	128	£13,188	£14,080	£352,012	£8436	£10,155
All RhD-negative Asian women	£1,473,105	136	43	2	72	60	£10,797	£34,316	£857,902	£20,561	£24,750
Baseline West African (5%)	£615,566	215	125	5.0	899,553	791,617
RhD-negative West African primigravidae	£715,875	57	54	2	90	75	£12,494	£13,226	£330,651	£7925	£9539
All RhD-negative West African women	£814,149	77	25	1	41	34	£10,525	£33,158	£828,949	£19,867	£23,915
Baseline Chinese (1%)	£126,868	44	26	1.0	179,909	158,322
RhD-negative Chinese primigravidae	£141,583	12	11	0	19	16	£11,856	£12,445	£311,116	£7456	£8976
All RhD-negative Chinese women	£162,045	16	5	0	8	7	£10,284	£32,119	£802,986	£19,245	£23,166

Results of the one-way sensitivity analysis

Several key uncertain parameters within the model (see Sensitivity analysis) have been explored within a one-way sensitivity analysis to assess the robustness of the model. Because the only difference modelled between the RAADP regimens is the price of the drug, each of the model parameters would be expected to have a similar impact upon the cost-effectiveness ratio independent of the RAADP regimen of anti-D. Therefore, these results are presented in Table 30 in terms of a 500-IU dose of anti-D (D-Gam) at 28 and 34 weeks’ gestation to avoid unnecessary repetition.

TABLE 30 - Results of the one-way sensitivity analysis

LB, lower bound; QALY, quality-adjusted life-year; QoL, quality of life; RAADP, routine antenatal anti-D prophylaxis; UB, upper bound.

Parameter		Parameter value	Cost per QALY gained
			Primigravidae	Multigravidae
Base case			£11,384	£26,455
Odds ratio for sensitisation rate of RAADP	Base case	0.37
	LB	0.21	£8551	£19,836
	UB	0.65	£22,571	£52,596
Base-case sensitisation rate	Base case	0.95%
	LB	0.18%	£70,452	£164,801
	UB	1.71%	£5255	£12,090
Proportion of heterozygous males	Base case	55%
	LB	35%	£8497	£19,463
	UB	75%	£15,817	£37,279
Fetal loss rate per woman at risk	Base case	4%
	LB	2%	£17,378	£40,396
	UB	6%	£8466	£19,669
Cost of anti-D administration per dose	Base case	£5
	LB	£1	£9646	£22,393
	UB	£9	£13,121	£30,516
Cost of management of sensitisation	Base case	£2885
	LB	£1513	£12,458	£29,215
	UB	£4257	£10,310	£23,694
Rate of major developmental problems	Base case	3%
	LB	1%	£14,180	£32,705
	UB	5%	£9469	£22,176
Yearly cost of major developmental problems	Base case	£458
	LB	£78	£11,559	£26,614
	UB	£1532	£10,886	£26,005
Life expectancy for people with major developmental problems	Base case	60
	LB	40	£11,077	£25,704
	UB	79	£11,556	£26,879
QoL of people with major developmental problems	Base case	0.42
	LB	0.36	£11,029	£25,630
	UB	0.48	£11,762	£27,334
Percentage of births outside marriage with same father	Base case	50%
	LB	26%	£11,193	£25,662
	UB	74%	£11,581	£27,281

The one-way sensitivity analysis suggests that changing many of the model assumptions has only a small impact upon the incremental cost-effectiveness ratio (ICER). The parameters that have the greatest impact upon the ICER are the base-case sensitisation rate and the odds ratio for the sensitisation rate associated with RAADP. If the base-case sensitisation rate was lower than predicted, anti-D would have a lower absolute effect and hence the cost per QALY gained would increase. At a base-case sensitisation rate of 0.18% (the lower 95% confidence interval), the cost per QALY gained for providing RAADP to all RhD-negative pregnant women is estimated to be around £162,000. At a base-case sensitisation rate of 0.95%, increasing the odds ratio for the sensitisation of RAADP in comparison with no RAADP to its upper 95% confidence interval of 0.65 gives a cost per QALY gained of around £50,000 for RAADP given to all RhD-negative women.

Decreasing the fetal loss rate as a result of HDN from 4% to 2% would increase the cost per QALY gained by around £8000 to £34,000. Decreasing the impact of HDN in any way will increase the ICER to some extent as RAADP will then have less of an impact in terms of efficacy. However, different assumptions around the quality of life and cost of people with major developmental problems do not affect the ICER substantially, increasing it by around £1000 and £3000 respectively. Similarly, different assumptions around the costs of anti-D administration and the management of sensitisation do not have a big impact upon the ICER.

Threshold analysis of the valuation of a fetal loss

Because the valuation of a fetal loss is subjective, according to how the individual may value the QALYs lost associated with the fetus and the QALYs lost by the parent(s), a threshold analysis has been carried out to investigate the impact of different valuations associated with fetal loss. The results are presented in Table 31.

TABLE 31 - Implied quality-adjusted life-year differential per fetal loss avoided

		Threshold
		£20K	£25K	£30K	£35K	£40K	£45K	£50K
RAADP given to RhD-negative primigravidae versus no RAADP	D-Gam	17	13	10	8	6	5	4
	Partobulin	24	18	14	12	9	8	7
	Rhophylac	12	8	6	5	3	3	2
RAADP given to all RhD-negative women versus primigravidae	D-Gam	36	26	20	16	13	10	8
	Partobulin	50	38	30	24	20	16	14
	Rhophylac	25	18	13	10	7	5	4

These results show that RAADP given to RhD-negative primigravidae compared with no RAADP would be considered cost-effective at a threshold of £30,000 per QALY gained if a fetal loss is assumed to be worth 10, 14 and 6 QALYs lost for D-Gam, Partobulin and Rhophylac respectively. Similarly, RAADP given to all RhD-negative women compared with RhD-negative primigravidae only would be considered cost-effective at a threshold of £30,000 per QALY gained if a fetal loss is assumed to be worth 20, 30 and 13 QALYs lost for D-Gam, Partobulin and Rhophylac respectively. These QALY losses are a combination of both the parental QALYs lost and those QALYs lost as a result of the death of the fetus itself. As a lifetime lost with a life expectancy of 79 years is equal to 24 QALYs after discounting, Partobulin would be considered cost-effective for all RhD-negative women compared with RhD-negative primigravidae at a threshold of £30,000 per QALY gained if the loss of a fetus was assumed to be equal to the loss of a life with average lifetime expectancy and six QALYs lost by the parent(s).

Threshold analysis of the cost of anti-D

Because the listed price of anti-D in the BNF116 may be different from the actual cost of the drug, a threshold analysis has been carried out. This analysis evaluates the estimated price of anti-D in order for it to be cost-effective at a range of thresholds. The results are presented in Figure 6 below.

FIGURE 6.

Cost per quality-adjusted life-year (QALY) gained based on cost of anti-D and its administration per person.

This shows that, at a cost per QALY gained of £30,000, RAADP given to all RhD-negative women compared with RAADP given to primigravidae only would be considered cost-effective at a cost of £76. However, because the results presented here include an administration cost of £5 per dose, a two-dose regimen of RAADP would be considered cost-effective at a cost of £33 per dose [(£33 × 2) + £10 = £76] whereas, at this threshold, a one-dose regimen would be considered cost-effective at a cost of £71 per dose (£71 + £5 = £76).

Results of the probabilistic sensitivity analysis

The results of the probabilistic sensitivity analysis for RAADP given to primigravidae versus no RAADP and RAADP given to primigravidae and multigravidae versus primigravidae only in terms of LYG and QALYs gained are shown in Tables 32 and 33 respectively.

TABLE 32 - Results of probabilistic sensitivity analysis – RAADP given to RhD-negative primigravidae versus no RAADP

LYG, life-years gained; QALY, quality-adjusted life-year.

The baseline values are the absolute totals.

Anti-D regimen	Total additional cost	LYG	QALYs gained	Cost per LYG	Cost per QALY gained
Base case: no RAADPa	£1,788,704	2,878,650	2,532,262
D-Gam: 2 × 500 IU	£2,361,850	250	208	£9434	£11,347
Partobulin: 2 × 1250 IU	£3,082,766	251	208	£12,305	£14,821
Rhophylac: 1 × 1500 IU	£1,798,655	250	208	£7184	£8634
WinRho: 1 × 1500 IU	£13,825,342	250	208	£55,281	£66,446

TABLE 33 - Results of probabilistic sensitivity analysis – RAADP given to all RhD-negative women versus primigravidae only

LYG, life-years gained; QALY, quality-adjusted life-year.

Anti-D regimen	Total additional cost	LYG	QALYs gained	Cost per LYG	Cost per QALY gained
D-Gam: 2 × 500 IU	£2,645,112	121	101	£21,871	£26,306
Partobulin: 2 × 1250 IU	£3,457,481	121	100	£28,633	£34,409
Rhophylac: 1 × 1500 IU	£2,010,281	121	101	£16,610	£19,977
WinRho: 1 × 1500 IU	£15,564,912	121	101	£128,746	£154,758

The results of the probabilistic sensitivity analysis closely match those of the deterministic analysis. Any slight difference in the efficacy of each of the RAADP regimens is due to the stochastic nature of the analysis. After taking into account the uncertainty associated with the model parameters, each of the RAADP regimens with the exception of WinRho has an ICER that is between £9000 and £15,000 per QALY gained for RAADP given to RhD-negative primigravidae versus no RAADP, and between £20,000 and £34,000 per QALY gained for RAADP given to primigravidae and multigravidae compared with primigravidae only. WinRho has a cost per QALY gained of around £66,000 for RAADP given to primigravidae versus no RAADP and around £155,000 for RAADP given to all RhD-negative women versus RhD-negative primigravidae only.

Figure 7 presents cost-effectiveness acceptability curves for each of the regimens of RAADP versus no RAADP and each other. These curves describe the probability that each of the regimens of RAADP and no RAADP have a cost per QALY ratio that is better than a given willingness to pay threshold (λ).

FIGURE 7.

Cost-effectiveness acceptability curves (CEACs).

Figure 7 suggests that, at a threshold of £30,000 per QALY gained, it is more likely to be cost-effective to give RAADP to all RhD-negative pregnant women than to not provide RAADP or to provide RAADP to primigravidae only. Because the model assumes that the efficacy of the different anti-D regimens is the same, the cheaper regimens of anti-D are estimated to be more cost-effective. Therefore, based on the BNF drug prices,116 one dose of 1500 IU of Rhophylac at 28 weeks’ gestation is most likely to be cost-effective (around 40% probability) followed by two doses of 500 IU of D-Gam (around 25% probability) and two doses of 1250 IU of Partobulin (around 10% probability) at 28 and 34 weeks’ gestation. The comparison of cost-effectiveness between these three RAADP regimens should be interpreted with caution because of the variability in actual prices paid by hospitals for anti-D. The probability that any of the regimens of RAADP (excluding WinRho) given to all RhD-negative pregnant women is cost-effective at a threshold of £30,000 compared with RAADP given to RhD-negative primigravidae or providing no RAADP is around 70%. One dose of 1500 IU of WinRho is not likely to be considered cost-effective at any threshold because it is substantially more expensive and because of the availability of its comparators.

Statement of principal findings

All of the evidence indicates that RAADP reduces the incidence of sensitisation. In assessing the impact of the introduction of a programme of RAADP the most relevant studies are those by MacKenzie et al. 126 and Mayne et al. 127 Meta-analysis of the data from these studies indicates that the introduction of such a programme is associated with a fall of 0.6% (from 0.95% to 0.35%) in the number of women found in a subsequent pregnancy to be sensitised, an odds ratio of 0.37 (95% CI 0.21–0.65). These are community-based studies with high external validity as they demonstrate the effectiveness of RAADP in real life in the UK rather than under trial conditions and as measured by the most clinically relevant outcome measure, the number of women found to be sensitised in a subsequent pregnancy.

Although some instances of sensitisation are inevitable, others can be avoided (namely those attributable to failure to provide prophylaxis when appropriate despite the existence of a policy of RAADP). However, the avoidance of such cases will require careful adherence to guidelines. Further, a woman will only benefit clinically if she has an RhD-positive infant and she would have been sensitised and she goes on to have a further infant who is also RhD positive. It is the avoidance of HDN in that infant which constitutes the clinical benefit of RAADP.

No head-to-head studies have been undertaken that compare a one-dose with a two-dose regimen of RAADP, and the studies reviewed above do not provide any evidence to suggest that two 500-IU or 1250-IU doses of anti-D at 28 and 34 weeks’ gestation are more or less effective than a single dose of 1500 IU of anti-D at 28–30 weeks’ gestation. However, the Royal College of Nursing has expressed concern that a single dose given at 30 weeks (as is possible under the licensed indication for Rhophylac) will clearly not provide protection against an FMH at 28 weeks and may be insufficient to provide protection against an FMH at 39 weeks. 123 Several other arguments in addition to clinical effectiveness have been put forward to support the use of one or other regimen; these relate to compliance and safety. However, there is no published evidence that demonstrates any such differences. It could also be argued that the regimen that uses least anti-D, and places least demand on plasma donors, has an advantage.

There is no evidence to suggest that RAADP is associated with adverse effects of any consequence for either mother or child other than the possibility of transmission of bloodborne infections; this risk is minimised by the safeguards built into the modern manufacturing process.

The economic analysis of RAADP is based on the model developed for the 2002 NICE RAADP appraisal. 88 However, as well as considering the cost-effectiveness of the two-dose regimens, D-Gam and Partobulin, this assessment also evaluates the use of the one-dose regimens, Rhophylac and WinRho. Of the nine studies identified within the cost-effectiveness review, only those by Vick et al. 161,162 and Chilcott et al. 1,164 describe a detailed modelling study that appears to be applicable to the UK NHS. Furthermore, no new mathematical models were provided within the manufacturers’ submissions for the appraisal. The health economic model developed by the assessment group suggests that the cost per QALY gained of RAADP given to RhD-negative primigravidae versus no RAADP is between £9000 and £15,000, and of RAADP given to all RhD-negative women rather than RhD-negative primigravidae only is between £20,000 and £35,000, depending on the RAADP regimen (excluding WinRho). However, as the actual prices paid by hospitals vary, the cost-effectiveness in practice may be better than that presented here. The one-dose regimen of 1500 IU of WinRho is estimated to have a cost per QALY gained above £60,000. The cost-effectiveness of RAADP improves slightly for ethnic minorities in England and Wales.

Strengths and limitations of the assessment

This assessment report reviews the work carried out for the NICE RAADP appraisal from 2002;87 despite further research being recommended within the original report, no additional evidence was identified to be used within the analysis in terms of either clinical effectiveness or cost-effectiveness. Therefore, both the clinical effectiveness and cost-effectiveness are based largely on data taken from the 1990s. However, the clinical effectiveness of anti-D is based on two large community-based UK studies with high external validity. There is no comparative evidence available regarding the efficacy of different RAADP regimens, and therefore the economic comparison of the different regimens is dependent on price only. However, the model of cost-effectiveness is reasonably robust to changes in the parameter values and, hence, at a threshold of £35,000 it is likely that D-Gam, Partobulin and Rhophylac RAADP given to all RhD-negative pregnant women will be cost-effective.

Uncertainties

The key uncertainties associated with the assessment of RAADP are:

• the efficacy of different dosing regimens of RAADP

• the quality of life of children suffering from HDN and of their parents (including parents of stillborn children)

• the incidence rate of outcomes as a result of HDN

• the costs associated with HDN in terms of the management of sensitisation and the management of people with developmental problems over their lifetime.

Other relevant factors

Problems have been encountered in the past in relation to the availability of anti-D. If such problems are likely to be encountered in the future then an argument can be made for those strategies that minimise the volume of plasma required. These include:

• the use of a two-dose 500-IU D-Gam regimen, as this uses two-thirds of the quantity of anti-D used by the single-dose regimen

• the use of the ion-exchange chromatography method of preparation, as this retains 30–40% more anti-D than the Cohn method.

Since the NICE guidance was issued in 2002, rates of compliance with RAADP seem to have increased. 89 However, although the implementation of a programme of RAADP should lead to a significant fall in the residual numbers of women affected, some women continue to become sensitised despite the existence of such a programme. There are five possible reasons for continuing cases of sensitisation:

• the failure to recognise potential sensitising events in pregnancy as such and to treat them appropriately

• the failure to assess the extent of FMH adequately

• the failure to comply with postpartum prophylaxis guidelines

• the refusal of RAADP by the mother

• the failure to implement RAADP by some trusts and incomplete adherence to advice (i.e. poor compliance with the second dose).

Consideration of these issues is required.

The Royal College of Nursing123 suggests that Section 1.2 of the NICE Technology Appraisal No. 4187 presents some practical difficulties for midwives as ‘in addition to the sensitivities of discussing paternity, there are difficulties associated with an institution assuming that the father is indeed RhD-negative as reported without having this confirmed by internal testing’. Other practical concerns have been raised with regards to the certainty with which a woman may know that she is not going to have another child. These issues were not considered in a subgroup analysis as planned because of their feasibility in practice.

Finally, non-invasive fetal genotyping has not yet been demonstrated to be sufficiently accurate to enable its use to target provision of RAADP only to those non-sensitised RhD-negative women pregnant with RhD-positive infants. However, a test that is sufficiently accurate at an early enough gestational date may become available in the next few years.

About ScHARR

The School of Health and Related Research (ScHARR) is one of the four Schools that comprise the Faculty of Medicine at the University of Sheffield. ScHARR brings together a wide range of medical- and health-related disciplines including public health, general practice, mental health, epidemiology, health economics, management sciences, medical statistics, operational research and information science. It includes the Sheffield unit of the Trent RDSU, which is funded by NIHR to facilitate high-quality health services research and capacity development.

The ScHARR Technology Assessment Group (ScHARR-TAG) synthesises research on the effectiveness and cost-effectiveness of health-care interventions for the NIHR HTA Programme on behalf of a range of policy-makers, including the National Institute for Health and Clinical Excellence. ScHARR-TAG is part of a wider collaboration of six units from other regions. The other units are Southampton Health Technology Assessment Centre (SHTAC), University of Southampton; Aberdeen Health Technology Assessment Group (Aberdeen HTA Group), University of Aberdeen; Liverpool Reviews and Implementation Group (LRiG), University of Liverpool; Peninsula Technology Assessment Group (PenTAG), University of Exeter; NHS Centre for Reviews and Dissemination, University of York; and West Midlands Health Technology Assessment Collaboration (WMHTAC), University of Birmingham.

Contribution of authors

H Pilgrim was the review lead and undertook the cost-effectiveness review. M Lloyd-Jones undertook the clinical effectiveness review. A Rees conducted the literature searches.

Disclaimers

The views expressed in this publication are those of the authors and not necessarily those of the HTA Programme or the Department of Health.

Health Technology Assessment reports published to date

1. Home parenteral nutrition: a systematic review.

   By Richards DM, Deeks JJ, Sheldon TA, Shaffer JL.

2. Diagnosis, management and screening of early localised prostate cancer.

   A review by Selley S, Donovan J, Faulkner A, Coast J, Gillatt D.

3. The diagnosis, management, treatment and costs of prostate cancer in England and Wales.

   A review by Chamberlain J, Melia J, Moss S, Brown J.

4. Screening for fragile X syndrome.

   A review by Murray J, Cuckle H, Taylor G, Hewison J.

5. A review of near patient testing in primary care.

   By Hobbs FDR, Delaney BC, Fitzmaurice DA, Wilson S, Hyde CJ, Thorpe GH, et al.

6. Systematic review of outpatient services for chronic pain control.

   By McQuay HJ, Moore RA, Eccleston C, Morley S, de C Williams AC.

7. Neonatal screening for inborn errors of metabolism: cost, yield and outcome.

   A review by Pollitt RJ, Green A, McCabe CJ, Booth A, Cooper NJ, Leonard JV, et al.

8. Preschool vision screening.

   A review by Snowdon SK, Stewart-Brown SL.

9. Implications of socio-cultural contexts for the ethics of clinical trials.

   A review by Ashcroft RE, Chadwick DW, Clark SRL, Edwards RHT, Frith L, Hutton JL.

10. A critical review of the role of neonatal hearing screening in the detection of congenital hearing impairment.

    By Davis A, Bamford J, Wilson I, Ramkalawan T, Forshaw M, Wright S.

11. Newborn screening for inborn errors of metabolism: a systematic review.

    By Seymour CA, Thomason MJ, Chalmers RA, Addison GM, Bain MD, Cockburn F, et al.

12. Routine preoperative testing: a systematic review of the evidence.

    By Munro J, Booth A, Nicholl J.

13. Systematic review of the effectiveness of laxatives in the elderly.

    By Petticrew M, Watt I, Sheldon T.

14. When and how to assess fast-changing technologies: a comparative study of medical applications of four generic technologies.

    A review by Mowatt G, Bower DJ, Brebner JA, Cairns JA, Grant AM, McKee L.

1. Antenatal screening for Down’s syndrome.

   A review by Wald NJ, Kennard A, Hackshaw A, McGuire A.

2. Screening for ovarian cancer: a systematic review.

   By Bell R, Petticrew M, Luengo S, Sheldon TA.

3. Consensus development methods, and their use in clinical guideline development.

   A review by Murphy MK, Black NA, Lamping DL, McKee CM, Sanderson CFB, Askham J, et al.

4. A cost–utility analysis of interferon beta for multiple sclerosis.

   By Parkin D, McNamee P, Jacoby A, Miller P, Thomas S, Bates D.

5. Effectiveness and efficiency of methods of dialysis therapy for end-stage renal disease: systematic reviews.

   By MacLeod A, Grant A, Donaldson C, Khan I, Campbell M, Daly C, et al.

6. Effectiveness of hip prostheses in primary total hip replacement: a critical review of evidence and an economic model.

   By Faulkner A, Kennedy LG, Baxter K, Donovan J, Wilkinson M, Bevan G.

7. Antimicrobial prophylaxis in colorectal surgery: a systematic review of randomised controlled trials.

   By Song F, Glenny AM.

8. Bone marrow and peripheral blood stem cell transplantation for malignancy.

   A review by Johnson PWM, Simnett SJ, Sweetenham JW, Morgan GJ, Stewart LA.

9. Screening for speech and language delay: a systematic review of the literature.

   By Law J, Boyle J, Harris F, Harkness A, Nye C.

10. Resource allocation for chronic stable angina: a systematic review of effectiveness, costs and cost-effectiveness of alternative interventions.

    By Sculpher MJ, Petticrew M, Kelland JL, Elliott RA, Holdright DR, Buxton MJ.

11. Detection, adherence and control of hypertension for the prevention of stroke: a systematic review.

    By Ebrahim S.

12. Postoperative analgesia and vomiting, with special reference to day-case surgery: a systematic review.

    By McQuay HJ, Moore RA.

13. Choosing between randomised and nonrandomised studies: a systematic review.

    By Britton A, McKee M, Black N, McPherson K, Sanderson C, Bain C.

14. Evaluating patient-based outcome measures for use in clinical trials.

    A review by Fitzpatrick R, Davey C, Buxton MJ, Jones DR.

15. Ethical issues in the design and conduct of randomised controlled trials.

    A review by Edwards SJL, Lilford RJ, Braunholtz DA, Jackson JC, Hewison J, Thornton J.

16. Qualitative research methods in health technology assessment: a review of the literature.

    By Murphy E, Dingwall R, Greatbatch D, Parker S, Watson P.

17. The costs and benefits of paramedic skills in pre-hospital trauma care.

    By Nicholl J, Hughes S, Dixon S, Turner J, Yates D.

18. Systematic review of endoscopic ultrasound in gastro-oesophageal cancer.

    By Harris KM, Kelly S, Berry E, Hutton J, Roderick P, Cullingworth J, et al.

19. Systematic reviews of trials and other studies.

    By Sutton AJ, Abrams KR, Jones DR, Sheldon TA, Song F.

20. Primary total hip replacement surgery: a systematic review of outcomes and modelling of cost-effectiveness associated with different prostheses.

    A review by Fitzpatrick R, Shortall E, Sculpher M, Murray D, Morris R, Lodge M, et al.

1. Informed decision making: an annotated bibliography and systematic review.

   By Bekker H, Thornton JG, Airey CM, Connelly JB, Hewison J, Robinson MB, et al.

2. Handling uncertainty when performing economic evaluation of healthcare interventions.

   A review by Briggs AH, Gray AM.

3. The role of expectancies in the placebo effect and their use in the delivery of health care: a systematic review.

   By Crow R, Gage H, Hampson S, Hart J, Kimber A, Thomas H.

4. A randomised controlled trial of different approaches to universal antenatal HIV testing: uptake and acceptability. Annex: Antenatal HIV testing – assessment of a routine voluntary approach.

   By Simpson WM, Johnstone FD, Boyd FM, Goldberg DJ, Hart GJ, Gormley SM, et al.

5. Methods for evaluating area-wide and organisation-based interventions in health and health care: a systematic review.

   By Ukoumunne OC, Gulliford MC, Chinn S, Sterne JAC, Burney PGJ.

6. Assessing the costs of healthcare technologies in clinical trials.

   A review by Johnston K, Buxton MJ, Jones DR, Fitzpatrick R.

7. Cooperatives and their primary care emergency centres: organisation and impact.

   By Hallam L, Henthorne K.

8. Screening for cystic fibrosis.

   A review by Murray J, Cuckle H, Taylor G, Littlewood J, Hewison J.

9. A review of the use of health status measures in economic evaluation.

   By Brazier J, Deverill M, Green C, Harper R, Booth A.

10. Methods for the analysis of quality-of-life and survival data in health technology assessment.

    A review by Billingham LJ, Abrams KR, Jones DR.

11. Antenatal and neonatal haemoglobinopathy screening in the UK: review and economic analysis.

    By Zeuner D, Ades AE, Karnon J, Brown J, Dezateux C, Anionwu EN.

12. Assessing the quality of reports of randomised trials: implications for the conduct of meta-analyses.

    A review by Moher D, Cook DJ, Jadad AR, Tugwell P, Moher M, Jones A, et al.

13. ‘Early warning systems’ for identifying new healthcare technologies.

    By Robert G, Stevens A, Gabbay J.

14. A systematic review of the role of human papillomavirus testing within a cervical screening programme.

    By Cuzick J, Sasieni P, Davies P, Adams J, Normand C, Frater A, et al.

15. Near patient testing in diabetes clinics: appraising the costs and outcomes.

    By Grieve R, Beech R, Vincent J, Mazurkiewicz J.

16. Positron emission tomography: establishing priorities for health technology assessment.

    A review by Robert G, Milne R.

17. The debridement of chronic wounds: a systematic review.

    By Bradley M, Cullum N, Sheldon T.

18. Systematic reviews of wound care management: (2) Dressings and topical agents used in the healing of chronic wounds.

    By Bradley M, Cullum N, Nelson EA, Petticrew M, Sheldon T, Torgerson D.

19. A systematic literature review of spiral and electron beam computed tomography: with particular reference to clinical applications in hepatic lesions, pulmonary embolus and coronary artery disease.

    By Berry E, Kelly S, Hutton J, Harris KM, Roderick P, Boyce JC, et al.

20. What role for statins? A review and economic model.

    By Ebrahim S, Davey Smith G, McCabe C, Payne N, Pickin M, Sheldon TA, et al.

21. Factors that limit the quality, number and progress of randomised controlled trials.

    A review by Prescott RJ, Counsell CE, Gillespie WJ, Grant AM, Russell IT, Kiauka S, et al.

22. Antimicrobial prophylaxis in total hip replacement: a systematic review.

    By Glenny AM, Song F.

23. Health promoting schools and health promotion in schools: two systematic reviews.

    By Lister-Sharp D, Chapman S, Stewart-Brown S, Sowden A.

24. Economic evaluation of a primary care-based education programme for patients with osteoarthritis of the knee.

    A review by Lord J, Victor C, Littlejohns P, Ross FM, Axford JS.

1. The estimation of marginal time preference in a UK-wide sample (TEMPUS) project.

   A review by Cairns JA, van der Pol MM.

2. Geriatric rehabilitation following fractures in older people: a systematic review.

   By Cameron I, Crotty M, Currie C, Finnegan T, Gillespie L, Gillespie W, et al.

3. Screening for sickle cell disease and thalassaemia: a systematic review with supplementary research.

   By Davies SC, Cronin E, Gill M, Greengross P, Hickman M, Normand C.

4. Community provision of hearing aids and related audiology services.

   A review by Reeves DJ, Alborz A, Hickson FS, Bamford JM.

5. False-negative results in screening programmes: systematic review of impact and implications.

   By Petticrew MP, Sowden AJ, Lister-Sharp D, Wright K.

6. Costs and benefits of community postnatal support workers: a randomised controlled trial.

   By Morrell CJ, Spiby H, Stewart P, Walters S, Morgan A.

7. Implantable contraceptives (subdermal implants and hormonally impregnated intrauterine systems) versus other forms of reversible contraceptives: two systematic reviews to assess relative effectiveness, acceptability, tolerability and cost-effectiveness.

   By French RS, Cowan FM, Mansour DJA, Morris S, Procter T, Hughes D, et al.

8. An introduction to statistical methods for health technology assessment.

   A review by White SJ, Ashby D, Brown PJ.

9. Disease-modifying drugs for multiple sclerosis: a rapid and systematic review.

   By Clegg A, Bryant J, Milne R.

10. Publication and related biases.

    A review by Song F, Eastwood AJ, Gilbody S, Duley L, Sutton AJ.

11. Cost and outcome implications of the organisation of vascular services.

    By Michaels J, Brazier J, Palfreyman S, Shackley P, Slack R.

12. Monitoring blood glucose control in diabetes mellitus: a systematic review.

    By Coster S, Gulliford MC, Seed PT, Powrie JK, Swaminathan R.

13. The effectiveness of domiciliary health visiting: a systematic review of international studies and a selective review of the British literature.

    By Elkan R, Kendrick D, Hewitt M, Robinson JJA, Tolley K, Blair M, et al.

14. The determinants of screening uptake and interventions for increasing uptake: a systematic review.

    By Jepson R, Clegg A, Forbes C, Lewis R, Sowden A, Kleijnen J.

15. The effectiveness and cost-effectiveness of prophylactic removal of wisdom teeth.

    A rapid review by Song F, O’Meara S, Wilson P, Golder S, Kleijnen J.

16. Ultrasound screening in pregnancy: a systematic review of the clinical effectiveness, cost-effectiveness and women’s views.

    By Bricker L, Garcia J, Henderson J, Mugford M, Neilson J, Roberts T, et al.

17. A rapid and systematic review of the effectiveness and cost-effectiveness of the taxanes used in the treatment of advanced breast and ovarian cancer.

    By Lister-Sharp D, McDonagh MS, Khan KS, Kleijnen J.

18. Liquid-based cytology in cervical screening: a rapid and systematic review.

    By Payne N, Chilcott J, McGoogan E.

19. Randomised controlled trial of non-directive counselling, cognitive–behaviour therapy and usual general practitioner care in the management of depression as well as mixed anxiety and depression in primary care.

    By King M, Sibbald B, Ward E, Bower P, Lloyd M, Gabbay M, et al.

20. Routine referral for radiography of patients presenting with low back pain: is patients’ outcome influenced by GPs’ referral for plain radiography?

    By Kerry S, Hilton S, Patel S, Dundas D, Rink E, Lord J.

21. Systematic reviews of wound care management: (3) antimicrobial agents for chronic wounds; (4) diabetic foot ulceration.

    By O’Meara S, Cullum N, Majid M, Sheldon T.

22. Using routine data to complement and enhance the results of randomised controlled trials.

    By Lewsey JD, Leyland AH, Murray GD, Boddy FA.

23. Coronary artery stents in the treatment of ischaemic heart disease: a rapid and systematic review.

    By Meads C, Cummins C, Jolly K, Stevens A, Burls A, Hyde C.

24. Outcome measures for adult critical care: a systematic review.

    By Hayes JA, Black NA, Jenkinson C, Young JD, Rowan KM, Daly K, et al.

25. A systematic review to evaluate the effectiveness of interventions to promote the initiation of breastfeeding.

    By Fairbank L, O’Meara S, Renfrew MJ, Woolridge M, Sowden AJ, Lister-Sharp D.

26. Implantable cardioverter defibrillators: arrhythmias. A rapid and systematic review.

    By Parkes J, Bryant J, Milne R.

27. Treatments for fatigue in multiple sclerosis: a rapid and systematic review.

    By Brañas P, Jordan R, Fry-Smith A, Burls A, Hyde C.

28. Early asthma prophylaxis, natural history, skeletal development and economy (EASE): a pilot randomised controlled trial.

    By Baxter-Jones ADG, Helms PJ, Russell G, Grant A, Ross S, Cairns JA, et al.

29. Screening for hypercholesterolaemia versus case finding for familial hypercholesterolaemia: a systematic review and cost-effectiveness analysis.

    By Marks D, Wonderling D, Thorogood M, Lambert H, Humphries SE, Neil HAW.

30. A rapid and systematic review of the clinical effectiveness and cost-effectiveness of glycoprotein IIb/IIIa antagonists in the medical management of unstable angina.

    By McDonagh MS, Bachmann LM, Golder S, Kleijnen J, ter Riet G.

31. A randomised controlled trial of prehospital intravenous fluid replacement therapy in serious trauma.

    By Turner J, Nicholl J, Webber L, Cox H, Dixon S, Yates D.

32. Intrathecal pumps for giving opioids in chronic pain: a systematic review.

    By Williams JE, Louw G, Towlerton G.

33. Combination therapy (interferon alfa and ribavirin) in the treatment of chronic hepatitis C: a rapid and systematic review.

    By Shepherd J, Waugh N, Hewitson P.

34. A systematic review of comparisons of effect sizes derived from randomised and non-randomised studies.

    By MacLehose RR, Reeves BC, Harvey IM, Sheldon TA, Russell IT, Black AMS.

35. Intravascular ultrasound-guided interventions in coronary artery disease: a systematic literature review, with decision-analytic modelling, of outcomes and cost-effectiveness.

    By Berry E, Kelly S, Hutton J, Lindsay HSJ, Blaxill JM, Evans JA, et al.

36. A randomised controlled trial to evaluate the effectiveness and cost-effectiveness of counselling patients with chronic depression.

    By Simpson S, Corney R, Fitzgerald P, Beecham J.

37. Systematic review of treatments for atopic eczema.

    By Hoare C, Li Wan Po A, Williams H.

38. Bayesian methods in health technology assessment: a review.

    By Spiegelhalter DJ, Myles JP, Jones DR, Abrams KR.

39. The management of dyspepsia: a systematic review.

    By Delaney B, Moayyedi P, Deeks J, Innes M, Soo S, Barton P, et al.

40. A systematic review of treatments for severe psoriasis.

    By Griffiths CEM, Clark CM, Chalmers RJG, Li Wan Po A, Williams HC.

1. Clinical and cost-effectiveness of donepezil, rivastigmine and galantamine for Alzheimer’s disease: a rapid and systematic review.

   By Clegg A, Bryant J, Nicholson T, McIntyre L, De Broe S, Gerard K, et al.

2. The clinical effectiveness and cost-effectiveness of riluzole for motor neurone disease: a rapid and systematic review.

   By Stewart A, Sandercock J, Bryan S, Hyde C, Barton PM, Fry-Smith A, et al.

3. Equity and the economic evaluation of healthcare.

   By Sassi F, Archard L, Le Grand J.

4. Quality-of-life measures in chronic diseases of childhood.

   By Eiser C, Morse R.

5. Eliciting public preferences for healthcare: a systematic review of techniques.

   By Ryan M, Scott DA, Reeves C, Bate A, van Teijlingen ER, Russell EM, et al.

6. General health status measures for people with cognitive impairment: learning disability and acquired brain injury.

   By Riemsma RP, Forbes CA, Glanville JM, Eastwood AJ, Kleijnen J.

7. An assessment of screening strategies for fragile X syndrome in the UK.

   By Pembrey ME, Barnicoat AJ, Carmichael B, Bobrow M, Turner G.

8. Issues in methodological research: perspectives from researchers and commissioners.

   By Lilford RJ, Richardson A, Stevens A, Fitzpatrick R, Edwards S, Rock F, et al.

9. Systematic reviews of wound care management: (5) beds; (6) compression; (7) laser therapy, therapeutic ultrasound, electrotherapy and electromagnetic therapy.

   By Cullum N, Nelson EA, Flemming K, Sheldon T.

10. Effects of educational and psychosocial interventions for adolescents with diabetes mellitus: a systematic review.

    By Hampson SE, Skinner TC, Hart J, Storey L, Gage H, Foxcroft D, et al.

11. Effectiveness of autologous chondrocyte transplantation for hyaline cartilage defects in knees: a rapid and systematic review.

    By Jobanputra P, Parry D, Fry-Smith A, Burls A.

12. Statistical assessment of the learning curves of health technologies.

    By Ramsay CR, Grant AM, Wallace SA, Garthwaite PH, Monk AF, Russell IT.

13. The effectiveness and cost-effectiveness of temozolomide for the treatment of recurrent malignant glioma: a rapid and systematic review.

    By Dinnes J, Cave C, Huang S, Major K, Milne R.

14. A rapid and systematic review of the clinical effectiveness and cost-effectiveness of debriding agents in treating surgical wounds healing by secondary intention.

    By Lewis R, Whiting P, ter Riet G, O’Meara S, Glanville J.

15. Home treatment for mental health problems: a systematic review.

    By Burns T, Knapp M, Catty J, Healey A, Henderson J, Watt H, et al.

16. How to develop cost-conscious guidelines.

    By Eccles M, Mason J.

17. The role of specialist nurses in multiple sclerosis: a rapid and systematic review.

    By De Broe S, Christopher F, Waugh N.

18. A rapid and systematic review of the clinical effectiveness and cost-effectiveness of orlistat in the management of obesity.

    By O’Meara S, Riemsma R, Shirran L, Mather L, ter Riet G.

19. The clinical effectiveness and cost-effectiveness of pioglitazone for type 2 diabetes mellitus: a rapid and systematic review.

    By Chilcott J, Wight J, Lloyd Jones M, Tappenden P.

20. Extended scope of nursing practice: a multicentre randomised controlled trial of appropriately trained nurses and preregistration house officers in preoperative assessment in elective general surgery.

    By Kinley H, Czoski-Murray C, George S, McCabe C, Primrose J, Reilly C, et al.

21. Systematic reviews of the effectiveness of day care for people with severe mental disorders: (1) Acute day hospital versus admission; (2) Vocational rehabilitation; (3) Day hospital versus outpatient care.

    By Marshall M, Crowther R, Almaraz- Serrano A, Creed F, Sledge W, Kluiter H, et al.

22. The measurement and monitoring of surgical adverse events.

    By Bruce J, Russell EM, Mollison J, Krukowski ZH.

23. Action research: a systematic review and guidance for assessment.

    By Waterman H, Tillen D, Dickson R, de Koning K.

24. A rapid and systematic review of the clinical effectiveness and cost-effectiveness of gemcitabine for the treatment of pancreatic cancer.

    By Ward S, Morris E, Bansback N, Calvert N, Crellin A, Forman D, et al.

25. A rapid and systematic review of the evidence for the clinical effectiveness and cost-effectiveness of irinotecan, oxaliplatin and raltitrexed for the treatment of advanced colorectal cancer.

    By Lloyd Jones M, Hummel S, Bansback N, Orr B, Seymour M.

26. Comparison of the effectiveness of inhaler devices in asthma and chronic obstructive airways disease: a systematic review of the literature.

    By Brocklebank D, Ram F, Wright J, Barry P, Cates C, Davies L, et al.

27. The cost-effectiveness of magnetic resonance imaging for investigation of the knee joint.

    By Bryan S, Weatherburn G, Bungay H, Hatrick C, Salas C, Parry D, et al.

28. A rapid and systematic review of the clinical effectiveness and cost-effectiveness of topotecan for ovarian cancer.

    By Forbes C, Shirran L, Bagnall A-M, Duffy S, ter Riet G.

29. Superseded by a report published in a later volume.

30. The role of radiography in primary care patients with low back pain of at least 6 weeks duration: a randomised (unblinded) controlled trial.

    By Kendrick D, Fielding K, Bentley E, Miller P, Kerslake R, Pringle M.

31. Design and use of questionnaires: a review of best practice applicable to surveys of health service staff and patients.

    By McColl E, Jacoby A, Thomas L, Soutter J, Bamford C, Steen N, et al.

32. A rapid and systematic review of the clinical effectiveness and cost-effectiveness of paclitaxel, docetaxel, gemcitabine and vinorelbine in non-small-cell lung cancer.

    By Clegg A, Scott DA, Sidhu M, Hewitson P, Waugh N.

33. Subgroup analyses in randomised controlled trials: quantifying the risks of false-positives and false-negatives.

    By Brookes ST, Whitley E, Peters TJ, Mulheran PA, Egger M, Davey Smith G.

34. Depot antipsychotic medication in the treatment of patients with schizophrenia: (1) Meta-review; (2) Patient and nurse attitudes.

    By David AS, Adams C.

35. A systematic review of controlled trials of the effectiveness and cost-effectiveness of brief psychological treatments for depression.

    By Churchill R, Hunot V, Corney R, Knapp M, McGuire H, Tylee A, et al.

36. Cost analysis of child health surveillance.

    By Sanderson D, Wright D, Acton C, Duree D.

1. A study of the methods used to select review criteria for clinical audit.

   By Hearnshaw H, Harker R, Cheater F, Baker R, Grimshaw G.

2. Fludarabine as second-line therapy for B cell chronic lymphocytic leukaemia: a technology assessment.

   By Hyde C, Wake B, Bryan S, Barton P, Fry-Smith A, Davenport C, et al.

3. Rituximab as third-line treatment for refractory or recurrent Stage III or IV follicular non-Hodgkin’s lymphoma: a systematic review and economic evaluation.

   By Wake B, Hyde C, Bryan S, Barton P, Song F, Fry-Smith A, et al.

4. A systematic review of discharge arrangements for older people.

   By Parker SG, Peet SM, McPherson A, Cannaby AM, Baker R, Wilson A, et al.

5. The clinical effectiveness and cost-effectiveness of inhaler devices used in the routine management of chronic asthma in older children: a systematic review and economic evaluation.

   By Peters J, Stevenson M, Beverley C, Lim J, Smith S.

6. The clinical effectiveness and cost-effectiveness of sibutramine in the management of obesity: a technology assessment.

   By O’Meara S, Riemsma R, Shirran L, Mather L, ter Riet G.

7. The cost-effectiveness of magnetic resonance angiography for carotid artery stenosis and peripheral vascular disease: a systematic review.

   By Berry E, Kelly S, Westwood ME, Davies LM, Gough MJ, Bamford JM, et al.

8. Promoting physical activity in South Asian Muslim women through ‘exercise on prescription’.

   By Carroll B, Ali N, Azam N.

9. Zanamivir for the treatment of influenza in adults: a systematic review and economic evaluation.

   By Burls A, Clark W, Stewart T, Preston C, Bryan S, Jefferson T, et al.

10. A review of the natural history and epidemiology of multiple sclerosis: implications for resource allocation and health economic models.

    By Richards RG, Sampson FC, Beard SM, Tappenden P.

11. Screening for gestational diabetes: a systematic review and economic evaluation.

    By Scott DA, Loveman E, McIntyre L, Waugh N.

12. The clinical effectiveness and cost-effectiveness of surgery for people with morbid obesity: a systematic review and economic evaluation.

    By Clegg AJ, Colquitt J, Sidhu MK, Royle P, Loveman E, Walker A.

13. The clinical effectiveness of trastuzumab for breast cancer: a systematic review.

    By Lewis R, Bagnall A-M, Forbes C, Shirran E, Duffy S, Kleijnen J, et al.

14. The clinical effectiveness and cost-effectiveness of vinorelbine for breast cancer: a systematic review and economic evaluation.

    By Lewis R, Bagnall A-M, King S, Woolacott N, Forbes C, Shirran L, et al.

15. A systematic review of the effectiveness and cost-effectiveness of metal-on-metal hip resurfacing arthroplasty for treatment of hip disease.

    By Vale L, Wyness L, McCormack K, McKenzie L, Brazzelli M, Stearns SC.

16. The clinical effectiveness and cost-effectiveness of bupropion and nicotine replacement therapy for smoking cessation: a systematic review and economic evaluation.

    By Woolacott NF, Jones L, Forbes CA, Mather LC, Sowden AJ, Song FJ, et al.

17. A systematic review of effectiveness and economic evaluation of new drug treatments for juvenile idiopathic arthritis: etanercept.

    By Cummins C, Connock M, Fry-Smith A, Burls A.

18. Clinical effectiveness and cost-effectiveness of growth hormone in children: a systematic review and economic evaluation.

    By Bryant J, Cave C, Mihaylova B, Chase D, McIntyre L, Gerard K, et al.

19. Clinical effectiveness and cost-effectiveness of growth hormone in adults in relation to impact on quality of life: a systematic review and economic evaluation.

    By Bryant J, Loveman E, Chase D, Mihaylova B, Cave C, Gerard K, et al.

20. Clinical medication review by a pharmacist of patients on repeat prescriptions in general practice: a randomised controlled trial.

    By Zermansky AG, Petty DR, Raynor DK, Lowe CJ, Freementle N, Vail A.

21. The effectiveness of infliximab and etanercept for the treatment of rheumatoid arthritis: a systematic review and economic evaluation.

    By Jobanputra P, Barton P, Bryan S, Burls A.

22. A systematic review and economic evaluation of computerised cognitive behaviour therapy for depression and anxiety.

    By Kaltenthaler E, Shackley P, Stevens K, Beverley C, Parry G, Chilcott J.

23. A systematic review and economic evaluation of pegylated liposomal doxorubicin hydrochloride for ovarian cancer.

    By Forbes C, Wilby J, Richardson G, Sculpher M, Mather L, Reimsma R.

24. A systematic review of the effectiveness of interventions based on a stages-of-change approach to promote individual behaviour change.

    By Riemsma RP, Pattenden J, Bridle C, Sowden AJ, Mather L, Watt IS, et al.

25. A systematic review update of the clinical effectiveness and cost-effectiveness of glycoprotein IIb/IIIa antagonists.

    By Robinson M, Ginnelly L, Sculpher M, Jones L, Riemsma R, Palmer S, et al.

26. A systematic review of the effectiveness, cost-effectiveness and barriers to implementation of thrombolytic and neuroprotective therapy for acute ischaemic stroke in the NHS.

    By Sandercock P, Berge E, Dennis M, Forbes J, Hand P, Kwan J, et al.

27. A randomised controlled crossover trial of nurse practitioner versus doctor-led outpatient care in a bronchiectasis clinic.

    By Caine N, Sharples LD, Hollingworth W, French J, Keogan M, Exley A, et al.

28. Clinical effectiveness and cost – consequences of selective serotonin reuptake inhibitors in the treatment of sex offenders.

    By Adi Y, Ashcroft D, Browne K, Beech A, Fry-Smith A, Hyde C.

29. Treatment of established osteoporosis: a systematic review and cost–utility analysis.

    By Kanis JA, Brazier JE, Stevenson M, Calvert NW, Lloyd Jones M.

30. Which anaesthetic agents are cost-effective in day surgery? Literature review, national survey of practice and randomised controlled trial.

    By Elliott RA Payne K, Moore JK, Davies LM, Harper NJN, St Leger AS, et al.

31. Screening for hepatitis C among injecting drug users and in genitourinary medicine clinics: systematic reviews of effectiveness, modelling study and national survey of current practice.

    By Stein K, Dalziel K, Walker A, McIntyre L, Jenkins B, Horne J, et al.

32. The measurement of satisfaction with healthcare: implications for practice from a systematic review of the literature.

    By Crow R, Gage H, Hampson S, Hart J, Kimber A, Storey L, et al.

33. The effectiveness and cost-effectiveness of imatinib in chronic myeloid leukaemia: a systematic review.

    By Garside R, Round A, Dalziel K, Stein K, Royle R.

34. A comparative study of hypertonic saline, daily and alternate-day rhDNase in children with cystic fibrosis.

    By Suri R, Wallis C, Bush A, Thompson S, Normand C, Flather M, et al.

35. A systematic review of the costs and effectiveness of different models of paediatric home care.

    By Parker G, Bhakta P, Lovett CA, Paisley S, Olsen R, Turner D, et al.

1. How important are comprehensive literature searches and the assessment of trial quality in systematic reviews? Empirical study.

   By Egger M, Jüni P, Bartlett C, Holenstein F, Sterne J.

2. Systematic review of the effectiveness and cost-effectiveness, and economic evaluation, of home versus hospital or satellite unit haemodialysis for people with end-stage renal failure.

   By Mowatt G, Vale L, Perez J, Wyness L, Fraser C, MacLeod A, et al.

3. Systematic review and economic evaluation of the effectiveness of infliximab for the treatment of Crohn’s disease.

   By Clark W, Raftery J, Barton P, Song F, Fry-Smith A, Burls A.

4. A review of the clinical effectiveness and cost-effectiveness of routine anti-D prophylaxis for pregnant women who are rhesus negative.

   By Chilcott J, Lloyd Jones M, Wight J, Forman K, Wray J, Beverley C, et al.

5. Systematic review and evaluation of the use of tumour markers in paediatric oncology: Ewing’s sarcoma and neuroblastoma.

   By Riley RD, Burchill SA, Abrams KR, Heney D, Lambert PC, Jones DR, et al.

6. The cost-effectiveness of screening for Helicobacter pylori to reduce mortality and morbidity from gastric cancer and peptic ulcer disease: a discrete-event simulation model.

   By Roderick P, Davies R, Raftery J, Crabbe D, Pearce R, Bhandari P, et al.

7. The clinical effectiveness and cost-effectiveness of routine dental checks: a systematic review and economic evaluation.

   By Davenport C, Elley K, Salas C, Taylor-Weetman CL, Fry-Smith A, Bryan S, et al.

8. A multicentre randomised controlled trial assessing the costs and benefits of using structured information and analysis of women’s preferences in the management of menorrhagia.

   By Kennedy ADM, Sculpher MJ, Coulter A, Dwyer N, Rees M, Horsley S, et al.

9. Clinical effectiveness and cost–utility of photodynamic therapy for wet age-related macular degeneration: a systematic review and economic evaluation.

   By Meads C, Salas C, Roberts T, Moore D, Fry-Smith A, Hyde C.

10. Evaluation of molecular tests for prenatal diagnosis of chromosome abnormalities.

    By Grimshaw GM, Szczepura A, Hultén M, MacDonald F, Nevin NC, Sutton F, et al.

11. First and second trimester antenatal screening for Down’s syndrome: the results of the Serum, Urine and Ultrasound Screening Study (SURUSS).

    By Wald NJ, Rodeck C, Hackshaw AK, Walters J, Chitty L, Mackinson AM.

12. The effectiveness and cost-effectiveness of ultrasound locating devices for central venous access: a systematic review and economic evaluation.

    By Calvert N, Hind D, McWilliams RG, Thomas SM, Beverley C, Davidson A.

13. A systematic review of atypical antipsychotics in schizophrenia.

    By Bagnall A-M, Jones L, Lewis R, Ginnelly L, Glanville J, Torgerson D, et al.

14. Prostate Testing for Cancer and Treatment (ProtecT) feasibility study.

    By Donovan J, Hamdy F, Neal D, Peters T, Oliver S, Brindle L, et al.

15. Early thrombolysis for the treatment of acute myocardial infarction: a systematic review and economic evaluation.

    By Boland A, Dundar Y, Bagust A, Haycox A, Hill R, Mujica Mota R, et al.

16. Screening for fragile X syndrome: a literature review and modelling.

    By Song FJ, Barton P, Sleightholme V, Yao GL, Fry-Smith A.

17. Systematic review of endoscopic sinus surgery for nasal polyps.

    By Dalziel K, Stein K, Round A, Garside R, Royle P.

18. Towards efficient guidelines: how to monitor guideline use in primary care.

    By Hutchinson A, McIntosh A, Cox S, Gilbert C.

19. Effectiveness and cost-effectiveness of acute hospital-based spinal cord injuries services: systematic review.

    By Bagnall A-M, Jones L, Richardson G, Duffy S, Riemsma R.

20. Prioritisation of health technology assessment. The PATHS model: methods and case studies.

    By Townsend J, Buxton M, Harper G.

21. Systematic review of the clinical effectiveness and cost-effectiveness of tension-free vaginal tape for treatment of urinary stress incontinence.

    By Cody J, Wyness L, Wallace S, Glazener C, Kilonzo M, Stearns S, et al.

22. The clinical and cost-effectiveness of patient education models for diabetes: a systematic review and economic evaluation.

    By Loveman E, Cave C, Green C, Royle P, Dunn N, Waugh N.

23. The role of modelling in prioritising and planning clinical trials.

    By Chilcott J, Brennan A, Booth A, Karnon J, Tappenden P.

24. Cost–benefit evaluation of routine influenza immunisation in people 65–74 years of age.

    By Allsup S, Gosney M, Haycox A, Regan M.

25. The clinical and cost-effectiveness of pulsatile machine perfusion versus cold storage of kidneys for transplantation retrieved from heart-beating and non-heart-beating donors.

    By Wight J, Chilcott J, Holmes M, Brewer N.

26. Can randomised trials rely on existing electronic data? A feasibility study to explore the value of routine data in health technology assessment.

    By Williams JG, Cheung WY, Cohen DR, Hutchings HA, Longo MF, Russell IT.

27. Evaluating non-randomised intervention studies.

    By Deeks JJ, Dinnes J, D’Amico R, Sowden AJ, Sakarovitch C, Song F, et al.

28. A randomised controlled trial to assess the impact of a package comprising a patient-orientated, evidence-based self- help guidebook and patient-centred consultations on disease management and satisfaction in inflammatory bowel disease.

    By Kennedy A, Nelson E, Reeves D, Richardson G, Roberts C, Robinson A, et al.

29. The effectiveness of diagnostic tests for the assessment of shoulder pain due to soft tissue disorders: a systematic review.

    By Dinnes J, Loveman E, McIntyre L, Waugh N.

30. The value of digital imaging in diabetic retinopathy.

    By Sharp PF, Olson J, Strachan F, Hipwell J, Ludbrook A, O’Donnell M, et al.

31. Lowering blood pressure to prevent myocardial infarction and stroke: a new preventive strategy.

    By Law M, Wald N, Morris J.

32. Clinical and cost-effectiveness of capecitabine and tegafur with uracil for the treatment of metastatic colorectal cancer: systematic review and economic evaluation.

    By Ward S, Kaltenthaler E, Cowan J, Brewer N.

33. Clinical and cost-effectiveness of new and emerging technologies for early localised prostate cancer: a systematic review.

    By Hummel S, Paisley S, Morgan A, Currie E, Brewer N.

34. Literature searching for clinical and cost-effectiveness studies used in health technology assessment reports carried out for the National Institute for Clinical Excellence appraisal system.

    By Royle P, Waugh N.

35. Systematic review and economic decision modelling for the prevention and treatment of influenza A and B.

    By Turner D, Wailoo A, Nicholson K, Cooper N, Sutton A, Abrams K.

36. A randomised controlled trial to evaluate the clinical and cost-effectiveness of Hickman line insertions in adult cancer patients by nurses.

    By Boland A, Haycox A, Bagust A, Fitzsimmons L.

37. Redesigning postnatal care: a randomised controlled trial of protocol-based midwifery-led care focused on individual women’s physical and psychological health needs.

    By MacArthur C, Winter HR, Bick DE, Lilford RJ, Lancashire RJ, Knowles H, et al.

38. Estimating implied rates of discount in healthcare decision-making.

    By West RR, McNabb R, Thompson AGH, Sheldon TA, Grimley Evans J.

39. Systematic review of isolation policies in the hospital management of methicillin-resistant Staphylococcus aureus: a review of the literature with epidemiological and economic modelling.

    By Cooper BS, Stone SP, Kibbler CC, Cookson BD, Roberts JA, Medley GF, et al.

40. Treatments for spasticity and pain in multiple sclerosis: a systematic review.

    By Beard S, Hunn A, Wight J.

41. The inclusion of reports of randomised trials published in languages other than English in systematic reviews.

    By Moher D, Pham B, Lawson ML, Klassen TP.

42. The impact of screening on future health-promoting behaviours and health beliefs: a systematic review.

    By Bankhead CR, Brett J, Bukach C, Webster P, Stewart-Brown S, Munafo M, et al.

1. What is the best imaging strategy for acute stroke?

   By Wardlaw JM, Keir SL, Seymour J, Lewis S, Sandercock PAG, Dennis MS, et al.

2. Systematic review and modelling of the investigation of acute and chronic chest pain presenting in primary care.

   By Mant J, McManus RJ, Oakes RAL, Delaney BC, Barton PM, Deeks JJ, et al.

3. The effectiveness and cost-effectiveness of microwave and thermal balloon endometrial ablation for heavy menstrual bleeding: a systematic review and economic modelling.

   By Garside R, Stein K, Wyatt K, Round A, Price A.

4. A systematic review of the role of bisphosphonates in metastatic disease.

   By Ross JR, Saunders Y, Edmonds PM, Patel S, Wonderling D, Normand C, et al.

5. Systematic review of the clinical effectiveness and cost-effectiveness of capecitabine (Xeloda^®) for locally advanced and/or metastatic breast cancer.

   By Jones L, Hawkins N, Westwood M, Wright K, Richardson G, Riemsma R.

6. Effectiveness and efficiency of guideline dissemination and implementation strategies.

   By Grimshaw JM, Thomas RE, MacLennan G, Fraser C, Ramsay CR, Vale L, et al.

7. Clinical effectiveness and costs of the Sugarbaker procedure for the treatment of pseudomyxoma peritonei.

   By Bryant J, Clegg AJ, Sidhu MK, Brodin H, Royle P, Davidson P.

8. Psychological treatment for insomnia in the regulation of long-term hypnotic drug use.

   By Morgan K, Dixon S, Mathers N, Thompson J, Tomeny M.

9. Improving the evaluation of therapeutic interventions in multiple sclerosis: development of a patient-based measure of outcome.

   By Hobart JC, Riazi A, Lamping DL, Fitzpatrick R, Thompson AJ.

10. A systematic review and economic evaluation of magnetic resonance cholangiopancreatography compared with diagnostic endoscopic retrograde cholangiopancreatography.

    By Kaltenthaler E, Bravo Vergel Y, Chilcott J, Thomas S, Blakeborough T, Walters SJ, et al.

11. The use of modelling to evaluate new drugs for patients with a chronic condition: the case of antibodies against tumour necrosis factor in rheumatoid arthritis.

    By Barton P, Jobanputra P, Wilson J, Bryan S, Burls A.

12. Clinical effectiveness and cost-effectiveness of neonatal screening for inborn errors of metabolism using tandem mass spectrometry: a systematic review.

    By Pandor A, Eastham J, Beverley C, Chilcott J, Paisley S.

13. Clinical effectiveness and cost-effectiveness of pioglitazone and rosiglitazone in the treatment of type 2 diabetes: a systematic review and economic evaluation.

    By Czoski-Murray C, Warren E, Chilcott J, Beverley C, Psyllaki MA, Cowan J.

14. Routine examination of the newborn: the EMREN study. Evaluation of an extension of the midwife role including a randomised controlled trial of appropriately trained midwives and paediatric senior house officers.

    By Townsend J, Wolke D, Hayes J, Davé S, Rogers C, Bloomfield L, et al.

15. Involving consumers in research and development agenda setting for the NHS: developing an evidence-based approach.

    By Oliver S, Clarke-Jones L, Rees R, Milne R, Buchanan P, Gabbay J, et al.

16. A multi-centre randomised controlled trial of minimally invasive direct coronary bypass grafting versus percutaneous transluminal coronary angioplasty with stenting for proximal stenosis of the left anterior descending coronary artery.

    By Reeves BC, Angelini GD, Bryan AJ, Taylor FC, Cripps T, Spyt TJ, et al.

17. Does early magnetic resonance imaging influence management or improve outcome in patients referred to secondary care with low back pain? A pragmatic randomised controlled trial.

    By Gilbert FJ, Grant AM, Gillan MGC, Vale L, Scott NW, Campbell MK, et al.

18. The clinical and cost-effectiveness of anakinra for the treatment of rheumatoid arthritis in adults: a systematic review and economic analysis.

    By Clark W, Jobanputra P, Barton P, Burls A.

19. A rapid and systematic review and economic evaluation of the clinical and cost-effectiveness of newer drugs for treatment of mania associated with bipolar affective disorder.

    By Bridle C, Palmer S, Bagnall A-M, Darba J, Duffy S, Sculpher M, et al.

20. Liquid-based cytology in cervical screening: an updated rapid and systematic review and economic analysis.

    By Karnon J, Peters J, Platt J, Chilcott J, McGoogan E, Brewer N.

21. Systematic review of the long-term effects and economic consequences of treatments for obesity and implications for health improvement.

    By Avenell A, Broom J, Brown TJ, Poobalan A, Aucott L, Stearns SC, et al.

22. Autoantibody testing in children with newly diagnosed type 1 diabetes mellitus.

    By Dretzke J, Cummins C, Sandercock J, Fry-Smith A, Barrett T, Burls A.

23. Clinical effectiveness and cost-effectiveness of prehospital intravenous fluids in trauma patients.

    By Dretzke J, Sandercock J, Bayliss S, Burls A.

24. Newer hypnotic drugs for the short-term management of insomnia: a systematic review and economic evaluation.

    By Dündar Y, Boland A, Strobl J, Dodd S, Haycox A, Bagust A, et al.

25. Development and validation of methods for assessing the quality of diagnostic accuracy studies.

    By Whiting P, Rutjes AWS, Dinnes J, Reitsma JB, Bossuyt PMM, Kleijnen J.

26. EVALUATE hysterectomy trial: a multicentre randomised trial comparing abdominal, vaginal and laparoscopic methods of hysterectomy.

    By Garry R, Fountain J, Brown J, Manca A, Mason S, Sculpher M, et al.

27. Methods for expected value of information analysis in complex health economic models: developments on the health economics of interferon-β and glatiramer acetate for multiple sclerosis.

    By Tappenden P, Chilcott JB, Eggington S, Oakley J, McCabe C.

28. Effectiveness and cost-effectiveness of imatinib for first-line treatment of chronic myeloid leukaemia in chronic phase: a systematic review and economic analysis.

    By Dalziel K, Round A, Stein K, Garside R, Price A.

29. VenUS I: a randomised controlled trial of two types of bandage for treating venous leg ulcers.

    By Iglesias C, Nelson EA, Cullum NA, Torgerson DJ, on behalf of the VenUS Team.

30. Systematic review of the effectiveness and cost-effectiveness, and economic evaluation, of myocardial perfusion scintigraphy for the diagnosis and management of angina and myocardial infarction.

    By Mowatt G, Vale L, Brazzelli M, Hernandez R, Murray A, Scott N, et al.

31. A pilot study on the use of decision theory and value of information analysis as part of the NHS Health Technology Assessment programme.

    By Claxton K, Ginnelly L, Sculpher M, Philips Z, Palmer S.

32. The Social Support and Family Health Study: a randomised controlled trial and economic evaluation of two alternative forms of postnatal support for mothers living in disadvantaged inner-city areas.

    By Wiggins M, Oakley A, Roberts I, Turner H, Rajan L, Austerberry H, et al.

33. Psychosocial aspects of genetic screening of pregnant women and newborns: a systematic review.

    By Green JM, Hewison J, Bekker HL, Bryant, Cuckle HS.

34. Evaluation of abnormal uterine bleeding: comparison of three outpatient procedures within cohorts defined by age and menopausal status.

    By Critchley HOD, Warner P, Lee AJ, Brechin S, Guise J, Graham B.

35. Coronary artery stents: a rapid systematic review and economic evaluation.

    By Hill R, Bagust A, Bakhai A, Dickson R, Dündar Y, Haycox A, et al.

36. Review of guidelines for good practice in decision-analytic modelling in health technology assessment.

    By Philips Z, Ginnelly L, Sculpher M, Claxton K, Golder S, Riemsma R, et al.

37. Rituximab (MabThera^®) for aggressive non-Hodgkin’s lymphoma: systematic review and economic evaluation.

    By Knight C, Hind D, Brewer N, Abbott V.

38. Clinical effectiveness and cost-effectiveness of clopidogrel and modified-release dipyridamole in the secondary prevention of occlusive vascular events: a systematic review and economic evaluation.

    By Jones L, Griffin S, Palmer S, Main C, Orton V, Sculpher M, et al.

39. Pegylated interferon α-2a and -2b in combination with ribavirin in the treatment of chronic hepatitis C: a systematic review and economic evaluation.

    By Shepherd J, Brodin H, Cave C, Waugh N, Price A, Gabbay J.

40. Clopidogrel used in combination with aspirin compared with aspirin alone in the treatment of non-ST-segment- elevation acute coronary syndromes: a systematic review and economic evaluation.

    By Main C, Palmer S, Griffin S, Jones L, Orton V, Sculpher M, et al.

41. Provision, uptake and cost of cardiac rehabilitation programmes: improving services to under-represented groups.

    By Beswick AD, Rees K, Griebsch I, Taylor FC, Burke M, West RR, et al.

42. Involving South Asian patients in clinical trials.

    By Hussain-Gambles M, Leese B, Atkin K, Brown J, Mason S, Tovey P.

43. Clinical and cost-effectiveness of continuous subcutaneous insulin infusion for diabetes.

    By Colquitt JL, Green C, Sidhu MK, Hartwell D, Waugh N.

44. Identification and assessment of ongoing trials in health technology assessment reviews.

    By Song FJ, Fry-Smith A, Davenport C, Bayliss S, Adi Y, Wilson JS, et al.

45. Systematic review and economic evaluation of a long-acting insulin analogue, insulin glargine

    By Warren E, Weatherley-Jones E, Chilcott J, Beverley C.

46. Supplementation of a home-based exercise programme with a class-based programme for people with osteoarthritis of the knees: a randomised controlled trial and health economic analysis.

    By McCarthy CJ, Mills PM, Pullen R, Richardson G, Hawkins N, Roberts CR, et al.

47. Clinical and cost-effectiveness of once-daily versus more frequent use of same potency topical corticosteroids for atopic eczema: a systematic review and economic evaluation.

    By Green C, Colquitt JL, Kirby J, Davidson P, Payne E.

48. Acupuncture of chronic headache disorders in primary care: randomised controlled trial and economic analysis.

    By Vickers AJ, Rees RW, Zollman CE, McCarney R, Smith CM, Ellis N, et al.

49. Generalisability in economic evaluation studies in healthcare: a review and case studies.

    By Sculpher MJ, Pang FS, Manca A, Drummond MF, Golder S, Urdahl H, et al.

50. Virtual outreach: a randomised controlled trial and economic evaluation of joint teleconferenced medical consultations.

    By Wallace P, Barber J, Clayton W, Currell R, Fleming K, Garner P, et al.

1. Randomised controlled multiple treatment comparison to provide a cost-effectiveness rationale for the selection of antimicrobial therapy in acne.

   By Ozolins M, Eady EA, Avery A, Cunliffe WJ, O’Neill C, Simpson NB, et al.

2. Do the findings of case series studies vary significantly according to methodological characteristics?

   By Dalziel K, Round A, Stein K, Garside R, Castelnuovo E, Payne L.

3. Improving the referral process for familial breast cancer genetic counselling: findings of three randomised controlled trials of two interventions.

   By Wilson BJ, Torrance N, Mollison J, Wordsworth S, Gray JR, Haites NE, et al.

4. Randomised evaluation of alternative electrosurgical modalities to treat bladder outflow obstruction in men with benign prostatic hyperplasia.

   By Fowler C, McAllister W, Plail R, Karim O, Yang Q.

5. A pragmatic randomised controlled trial of the cost-effectiveness of palliative therapies for patients with inoperable oesophageal cancer.

   By Shenfine J, McNamee P, Steen N, Bond J, Griffin SM.

6. Impact of computer-aided detection prompts on the sensitivity and specificity of screening mammography.

   By Taylor P, Champness J, Given- Wilson R, Johnston K, Potts H.

7. Issues in data monitoring and interim analysis of trials.

   By Grant AM, Altman DG, Babiker AB, Campbell MK, Clemens FJ, Darbyshire JH, et al.

8. Lay public’s understanding of equipoise and randomisation in randomised controlled trials.

   By Robinson EJ, Kerr CEP, Stevens AJ, Lilford RJ, Braunholtz DA, Edwards SJ, et al.

9. Clinical and cost-effectiveness of electroconvulsive therapy for depressive illness, schizophrenia, catatonia and mania: systematic reviews and economic modelling studies.

   By Greenhalgh J, Knight C, Hind D, Beverley C, Walters S.

10. Measurement of health-related quality of life for people with dementia: development of a new instrument (DEMQOL) and an evaluation of current methodology.

    By Smith SC, Lamping DL, Banerjee S, Harwood R, Foley B, Smith P, et al.

11. Clinical effectiveness and cost-effectiveness of drotrecogin alfa (activated) (Xigris^®) for the treatment of severe sepsis in adults: a systematic review and economic evaluation.

    By Green C, Dinnes J, Takeda A, Shepherd J, Hartwell D, Cave C, et al.

12. A methodological review of how heterogeneity has been examined in systematic reviews of diagnostic test accuracy.

    By Dinnes J, Deeks J, Kirby J, Roderick P.

13. Cervical screening programmes: can automation help? Evidence from systematic reviews, an economic analysis and a simulation modelling exercise applied to the UK.

    By Willis BH, Barton P, Pearmain P, Bryan S, Hyde C.

14. Laparoscopic surgery for inguinal hernia repair: systematic review of effectiveness and economic evaluation.

    By McCormack K, Wake B, Perez J, Fraser C, Cook J, McIntosh E, et al.

15. Clinical effectiveness, tolerability and cost-effectiveness of newer drugs for epilepsy in adults: a systematic review and economic evaluation.

    By Wilby J, Kainth A, Hawkins N, Epstein D, McIntosh H, McDaid C, et al.

16. A randomised controlled trial to compare the cost-effectiveness of tricyclic antidepressants, selective serotonin reuptake inhibitors and lofepramine.

    By Peveler R, Kendrick T, Buxton M, Longworth L, Baldwin D, Moore M, et al.

17. Clinical effectiveness and cost-effectiveness of immediate angioplasty for acute myocardial infarction: systematic review and economic evaluation.

    By Hartwell D, Colquitt J, Loveman E, Clegg AJ, Brodin H, Waugh N, et al.

18. A randomised controlled comparison of alternative strategies in stroke care.

    By Kalra L, Evans A, Perez I, Knapp M, Swift C, Donaldson N.

19. The investigation and analysis of critical incidents and adverse events in healthcare.

    By Woloshynowych M, Rogers S, Taylor-Adams S, Vincent C.

20. Potential use of routine databases in health technology assessment.

    By Raftery J, Roderick P, Stevens A.

21. Clinical and cost-effectiveness of newer immunosuppressive regimens in renal transplantation: a systematic review and modelling study.

    By Woodroffe R, Yao GL, Meads C, Bayliss S, Ready A, Raftery J, et al.

22. A systematic review and economic evaluation of alendronate, etidronate, risedronate, raloxifene and teriparatide for the prevention and treatment of postmenopausal osteoporosis.

    By Stevenson M, Lloyd Jones M, De Nigris E, Brewer N, Davis S, Oakley J.

23. A systematic review to examine the impact of psycho-educational interventions on health outcomes and costs in adults and children with difficult asthma.

    By Smith JR, Mugford M, Holland R, Candy B, Noble MJ, Harrison BDW, et al.

24. An evaluation of the costs, effectiveness and quality of renal replacement therapy provision in renal satellite units in England and Wales.

    By Roderick P, Nicholson T, Armitage A, Mehta R, Mullee M, Gerard K, et al.

25. Imatinib for the treatment of patients with unresectable and/or metastatic gastrointestinal stromal tumours: systematic review and economic evaluation.

    By Wilson J, Connock M, Song F, Yao G, Fry-Smith A, Raftery J, et al.

26. Indirect comparisons of competing interventions.

    By Glenny AM, Altman DG, Song F, Sakarovitch C, Deeks JJ, D’Amico R, et al.

27. Cost-effectiveness of alternative strategies for the initial medical management of non-ST elevation acute coronary syndrome: systematic review and decision-analytical modelling.

    By Robinson M, Palmer S, Sculpher M, Philips Z, Ginnelly L, Bowens A, et al.

28. Outcomes of electrically stimulated gracilis neosphincter surgery.

    By Tillin T, Chambers M, Feldman R.

29. The effectiveness and cost-effectiveness of pimecrolimus and tacrolimus for atopic eczema: a systematic review and economic evaluation.

    By Garside R, Stein K, Castelnuovo E, Pitt M, Ashcroft D, Dimmock P, et al.

30. Systematic review on urine albumin testing for early detection of diabetic complications.

    By Newman DJ, Mattock MB, Dawnay ABS, Kerry S, McGuire A, Yaqoob M, et al.

31. Randomised controlled trial of the cost-effectiveness of water-based therapy for lower limb osteoarthritis.

    By Cochrane T, Davey RC, Matthes Edwards SM.

32. Longer term clinical and economic benefits of offering acupuncture care to patients with chronic low back pain.

    By Thomas KJ, MacPherson H, Ratcliffe J, Thorpe L, Brazier J, Campbell M, et al.

33. Cost-effectiveness and safety of epidural steroids in the management of sciatica.

    By Price C, Arden N, Coglan L, Rogers P.

34. The British Rheumatoid Outcome Study Group (BROSG) randomised controlled trial to compare the effectiveness and cost-effectiveness of aggressive versus symptomatic therapy in established rheumatoid arthritis.

    By Symmons D, Tricker K, Roberts C, Davies L, Dawes P, Scott DL.

35. Conceptual framework and systematic review of the effects of participants’ and professionals’ preferences in randomised controlled trials.

    By King M, Nazareth I, Lampe F, Bower P, Chandler M, Morou M, et al.

36. The clinical and cost-effectiveness of implantable cardioverter defibrillators: a systematic review.

    By Bryant J, Brodin H, Loveman E, Payne E, Clegg A.

37. A trial of problem-solving by community mental health nurses for anxiety, depression and life difficulties among general practice patients. The CPN-GP study.

    By Kendrick T, Simons L, Mynors-Wallis L, Gray A, Lathlean J, Pickering R, et al.

38. The causes and effects of socio-demographic exclusions from clinical trials.

    By Bartlett C, Doyal L, Ebrahim S, Davey P, Bachmann M, Egger M, et al.

39. Is hydrotherapy cost-effective? A randomised controlled trial of combined hydrotherapy programmes compared with physiotherapy land techniques in children with juvenile idiopathic arthritis.

    By Epps H, Ginnelly L, Utley M, Southwood T, Gallivan S, Sculpher M, et al.

40. A randomised controlled trial and cost-effectiveness study of systematic screening (targeted and total population screening) versus routine practice for the detection of atrial fibrillation in people aged 65 and over. The SAFE study.

    By Hobbs FDR, Fitzmaurice DA, Mant J, Murray E, Jowett S, Bryan S, et al.

41. Displaced intracapsular hip fractures in fit, older people: a randomised comparison of reduction and fixation, bipolar hemiarthroplasty and total hip arthroplasty.

    By Keating JF, Grant A, Masson M, Scott NW, Forbes JF.

42. Long-term outcome of cognitive behaviour therapy clinical trials in central Scotland.

    By Durham RC, Chambers JA, Power KG, Sharp DM, Macdonald RR, Major KA, et al.

43. The effectiveness and cost-effectiveness of dual-chamber pacemakers compared with single-chamber pacemakers for bradycardia due to atrioventricular block or sick sinus syndrome: systematic review and economic evaluation.

    By Castelnuovo E, Stein K, Pitt M, Garside R, Payne E.

44. Newborn screening for congenital heart defects: a systematic review and cost-effectiveness analysis.

    By Knowles R, Griebsch I, Dezateux C, Brown J, Bull C, Wren C.

45. The clinical and cost-effectiveness of left ventricular assist devices for end-stage heart failure: a systematic review and economic evaluation.

    By Clegg AJ, Scott DA, Loveman E, Colquitt J, Hutchinson J, Royle P, et al.

46. The effectiveness of the Heidelberg Retina Tomograph and laser diagnostic glaucoma scanning system (GDx) in detecting and monitoring glaucoma.

    By Kwartz AJ, Henson DB, Harper RA, Spencer AF, McLeod D.

47. Clinical and cost-effectiveness of autologous chondrocyte implantation for cartilage defects in knee joints: systematic review and economic evaluation.

    By Clar C, Cummins E, McIntyre L, Thomas S, Lamb J, Bain L, et al.

48. Systematic review of effectiveness of different treatments for childhood retinoblastoma.

    By McDaid C, Hartley S, Bagnall A-M, Ritchie G, Light K, Riemsma R.

49. Towards evidence-based guidelines for the prevention of venous thromboembolism: systematic reviews of mechanical methods, oral anticoagulation, dextran and regional anaesthesia as thromboprophylaxis.

    By Roderick P, Ferris G, Wilson K, Halls H, Jackson D, Collins R, et al.

50. The effectiveness and cost-effectiveness of parent training/education programmes for the treatment of conduct disorder, including oppositional defiant disorder, in children.

    By Dretzke J, Frew E, Davenport C, Barlow J, Stewart-Brown S, Sandercock J, et al.

1. The clinical and cost-effectiveness of donepezil, rivastigmine, galantamine and memantine for Alzheimer’s disease.

   By Loveman E, Green C, Kirby J, Takeda A, Picot J, Payne E, et al.

2. FOOD: a multicentre randomised trial evaluating feeding policies in patients admitted to hospital with a recent stroke.

   By Dennis M, Lewis S, Cranswick G, Forbes J.

3. The clinical effectiveness and cost-effectiveness of computed tomography screening for lung cancer: systematic reviews.

   By Black C, Bagust A, Boland A, Walker S, McLeod C, De Verteuil R, et al.

4. A systematic review of the effectiveness and cost-effectiveness of neuroimaging assessments used to visualise the seizure focus in people with refractory epilepsy being considered for surgery.

   By Whiting P, Gupta R, Burch J, Mujica Mota RE, Wright K, Marson A, et al.

5. Comparison of conference abstracts and presentations with full-text articles in the health technology assessments of rapidly evolving technologies.

   By Dundar Y, Dodd S, Dickson R, Walley T, Haycox A, Williamson PR.

6. Systematic review and evaluation of methods of assessing urinary incontinence.

   By Martin JL, Williams KS, Abrams KR, Turner DA, Sutton AJ, Chapple C, et al.

7. The clinical effectiveness and cost-effectiveness of newer drugs for children with epilepsy. A systematic review.

   By Connock M, Frew E, Evans B-W, Bryan S, Cummins C, Fry-Smith A, et al.

8. Surveillance of Barrett’s oesophagus: exploring the uncertainty through systematic review, expert workshop and economic modelling.

   By Garside R, Pitt M, Somerville M, Stein K, Price A, Gilbert N.

9. Topotecan, pegylated liposomal doxorubicin hydrochloride and paclitaxel for second-line or subsequent treatment of advanced ovarian cancer: a systematic review and economic evaluation.

   By Main C, Bojke L, Griffin S, Norman G, Barbieri M, Mather L, et al.

10. Evaluation of molecular techniques in prediction and diagnosis of cytomegalovirus disease in immunocompromised patients.

    By Szczepura A, Westmoreland D, Vinogradova Y, Fox J, Clark M.

11. Screening for thrombophilia in high-risk situations: systematic review and cost-effectiveness analysis. The Thrombosis: Risk and Economic Assessment of Thrombophilia Screening (TREATS) study.

    By Wu O, Robertson L, Twaddle S, Lowe GDO, Clark P, Greaves M, et al.

12. A series of systematic reviews to inform a decision analysis for sampling and treating infected diabetic foot ulcers.

    By Nelson EA, O’Meara S, Craig D, Iglesias C, Golder S, Dalton J, et al.

13. Randomised clinical trial, observational study and assessment of cost-effectiveness of the treatment of varicose veins (REACTIV trial).

    By Michaels JA, Campbell WB, Brazier JE, MacIntyre JB, Palfreyman SJ, Ratcliffe J, et al.

14. The cost-effectiveness of screening for oral cancer in primary care.

    By Speight PM, Palmer S, Moles DR, Downer MC, Smith DH, Henriksson M, et al.

15. Measurement of the clinical and cost-effectiveness of non-invasive diagnostic testing strategies for deep vein thrombosis.

    By Goodacre S, Sampson F, Stevenson M, Wailoo A, Sutton A, Thomas S, et al.

16. Systematic review of the effectiveness and cost-effectiveness of HealOzone^® for the treatment of occlusal pit/fissure caries and root caries.

    By Brazzelli M, McKenzie L, Fielding S, Fraser C, Clarkson J, Kilonzo M, et al.

17. Randomised controlled trials of conventional antipsychotic versus new atypical drugs, and new atypical drugs versus clozapine, in people with schizophrenia responding poorly to, or intolerant of, current drug treatment.

    By Lewis SW, Davies L, Jones PB, Barnes TRE, Murray RM, Kerwin R, et al.

18. Diagnostic tests and algorithms used in the investigation of haematuria: systematic reviews and economic evaluation.

    By Rodgers M, Nixon J, Hempel S, Aho T, Kelly J, Neal D, et al.

19. Cognitive behavioural therapy in addition to antispasmodic therapy for irritable bowel syndrome in primary care: randomised controlled trial.

    By Kennedy TM, Chalder T, McCrone P, Darnley S, Knapp M, Jones RH, et al.

20. A systematic review of the clinical effectiveness and cost-effectiveness of enzyme replacement therapies for Fabry’s disease and mucopolysaccharidosis type 1.

    By Connock M, Juarez-Garcia A, Frew E, Mans A, Dretzke J, Fry-Smith A, et al.

21. Health benefits of antiviral therapy for mild chronic hepatitis C: randomised controlled trial and economic evaluation.

    By Wright M, Grieve R, Roberts J, Main J, Thomas HC, on behalf of the UK Mild Hepatitis C Trial Investigators.

22. Pressure relieving support surfaces: a randomised evaluation.

    By Nixon J, Nelson EA, Cranny G, Iglesias CP, Hawkins K, Cullum NA, et al.

23. A systematic review and economic model of the effectiveness and cost-effectiveness of methylphenidate, dexamfetamine and atomoxetine for the treatment of attention deficit hyperactivity disorder in children and adolescents.

    By King S, Griffin S, Hodges Z, Weatherly H, Asseburg C, Richardson G, et al.

24. The clinical effectiveness and cost-effectiveness of enzyme replacement therapy for Gaucher’s disease: a systematic review.

    By Connock M, Burls A, Frew E, Fry-Smith A, Juarez-Garcia A, McCabe C, et al.

25. Effectiveness and cost-effectiveness of salicylic acid and cryotherapy for cutaneous warts. An economic decision model.

    By Thomas KS, Keogh-Brown MR, Chalmers JR, Fordham RJ, Holland RC, Armstrong SJ, et al.

26. A systematic literature review of the effectiveness of non-pharmacological interventions to prevent wandering in dementia and evaluation of the ethical implications and acceptability of their use.

    By Robinson L, Hutchings D, Corner L, Beyer F, Dickinson H, Vanoli A, et al.

27. A review of the evidence on the effects and costs of implantable cardioverter defibrillator therapy in different patient groups, and modelling of cost-effectiveness and cost–utility for these groups in a UK context.

    By Buxton M, Caine N, Chase D, Connelly D, Grace A, Jackson C, et al.

28. Adefovir dipivoxil and pegylated interferon alfa-2a for the treatment of chronic hepatitis B: a systematic review and economic evaluation.

    By Shepherd J, Jones J, Takeda A, Davidson P, Price A.

29. An evaluation of the clinical and cost-effectiveness of pulmonary artery catheters in patient management in intensive care: a systematic review and a randomised controlled trial.

    By Harvey S, Stevens K, Harrison D, Young D, Brampton W, McCabe C, et al.

30. Accurate, practical and cost-effective assessment of carotid stenosis in the UK.

    By Wardlaw JM, Chappell FM, Stevenson M, De Nigris E, Thomas S, Gillard J, et al.

31. Etanercept and infliximab for the treatment of psoriatic arthritis: a systematic review and economic evaluation.

    By Woolacott N, Bravo Vergel Y, Hawkins N, Kainth A, Khadjesari Z, Misso K, et al.

32. The cost-effectiveness of testing for hepatitis C in former injecting drug users.

    By Castelnuovo E, Thompson-Coon J, Pitt M, Cramp M, Siebert U, Price A, et al.

33. Computerised cognitive behaviour therapy for depression and anxiety update: a systematic review and economic evaluation.

    By Kaltenthaler E, Brazier J, De Nigris E, Tumur I, Ferriter M, Beverley C, et al.

34. Cost-effectiveness of using prognostic information to select women with breast cancer for adjuvant systemic therapy.

    By Williams C, Brunskill S, Altman D, Briggs A, Campbell H, Clarke M, et al.

35. Psychological therapies including dialectical behaviour therapy for borderline personality disorder: a systematic review and preliminary economic evaluation.

    By Brazier J, Tumur I, Holmes M, Ferriter M, Parry G, Dent-Brown K, et al.

36. Clinical effectiveness and cost-effectiveness of tests for the diagnosis and investigation of urinary tract infection in children: a systematic review and economic model.

    By Whiting P, Westwood M, Bojke L, Palmer S, Richardson G, Cooper J, et al.

37. Cognitive behavioural therapy in chronic fatigue syndrome: a randomised controlled trial of an outpatient group programme.

    By O’Dowd H, Gladwell P, Rogers CA, Hollinghurst S, Gregory A.

38. A comparison of the cost-effectiveness of five strategies for the prevention of nonsteroidal anti-inflammatory drug-induced gastrointestinal toxicity: a systematic review with economic modelling.

    By Brown TJ, Hooper L, Elliott RA, Payne K, Webb R, Roberts C, et al.

39. The effectiveness and cost-effectiveness of computed tomography screening for coronary artery disease: systematic review.

    By Waugh N, Black C, Walker S, McIntyre L, Cummins E, Hillis G.

40. What are the clinical outcome and cost-effectiveness of endoscopy undertaken by nurses when compared with doctors? A Multi-Institution Nurse Endoscopy Trial (MINuET).

    By Williams J, Russell I, Durai D, Cheung W-Y, Farrin A, Bloor K, et al.

41. The clinical and cost-effectiveness of oxaliplatin and capecitabine for the adjuvant treatment of colon cancer: systematic review and economic evaluation.

    By Pandor A, Eggington S, Paisley S, Tappenden P, Sutcliffe P.

42. A systematic review of the effectiveness of adalimumab, etanercept and infliximab for the treatment of rheumatoid arthritis in adults and an economic evaluation of their cost-effectiveness.

    By Chen Y-F, Jobanputra P, Barton P, Jowett S, Bryan S, Clark W, et al.

43. Telemedicine in dermatology: a randomised controlled trial.

    By Bowns IR, Collins K, Walters SJ, McDonagh AJG.

44. Cost-effectiveness of cell salvage and alternative methods of minimising perioperative allogeneic blood transfusion: a systematic review and economic model.

    By Davies L, Brown TJ, Haynes S, Payne K, Elliott RA, McCollum C.

45. Clinical effectiveness and cost-effectiveness of laparoscopic surgery for colorectal cancer: systematic reviews and economic evaluation.

    By Murray A, Lourenco T, de Verteuil R, Hernandez R, Fraser C, McKinley A, et al.

46. Etanercept and efalizumab for the treatment of psoriasis: a systematic review.

    By Woolacott N, Hawkins N, Mason A, Kainth A, Khadjesari Z, Bravo Vergel Y, et al.

47. Systematic reviews of clinical decision tools for acute abdominal pain.

    By Liu JLY, Wyatt JC, Deeks JJ, Clamp S, Keen J, Verde P, et al.

48. Evaluation of the ventricular assist device programme in the UK.

    By Sharples L, Buxton M, Caine N, Cafferty F, Demiris N, Dyer M, et al.

49. A systematic review and economic model of the clinical and cost-effectiveness of immunosuppressive therapy for renal transplantation in children.

    By Yao G, Albon E, Adi Y, Milford D, Bayliss S, Ready A, et al.

50. Amniocentesis results: investigation of anxiety. The ARIA trial.

    By Hewison J, Nixon J, Fountain J, Cocks K, Jones C, Mason G, et al.

1. Pemetrexed disodium for the treatment of malignant pleural mesothelioma: a systematic review and economic evaluation.

   By Dundar Y, Bagust A, Dickson R, Dodd S, Green J, Haycox A, et al.

2. A systematic review and economic model of the clinical effectiveness and cost-effectiveness of docetaxel in combination with prednisone or prednisolone for the treatment of hormone-refractory metastatic prostate cancer.

   By Collins R, Fenwick E, Trowman R, Perard R, Norman G, Light K, et al.

3. A systematic review of rapid diagnostic tests for the detection of tuberculosis infection.

   By Dinnes J, Deeks J, Kunst H, Gibson A, Cummins E, Waugh N, et al.

4. The clinical effectiveness and cost-effectiveness of strontium ranelate for the prevention of osteoporotic fragility fractures in postmenopausal women.

   By Stevenson M, Davis S, Lloyd-Jones M, Beverley C.

5. A systematic review of quantitative and qualitative research on the role and effectiveness of written information available to patients about individual medicines.

   By Raynor DK, Blenkinsopp A, Knapp P, Grime J, Nicolson DJ, Pollock K, et al.

6. Oral naltrexone as a treatment for relapse prevention in formerly opioid-dependent drug users: a systematic review and economic evaluation.

   By Adi Y, Juarez-Garcia A, Wang D, Jowett S, Frew E, Day E, et al.

7. Glucocorticoid-induced osteoporosis: a systematic review and cost–utility analysis.

   By Kanis JA, Stevenson M, McCloskey EV, Davis S, Lloyd-Jones M.

8. Epidemiological, social, diagnostic and economic evaluation of population screening for genital chlamydial infection.

   By Low N, McCarthy A, Macleod J, Salisbury C, Campbell R, Roberts TE, et al.

9. Methadone and buprenorphine for the management of opioid dependence: a systematic review and economic evaluation.

   By Connock M, Juarez-Garcia A, Jowett S, Frew E, Liu Z, Taylor RJ, et al.

10. Exercise Evaluation Randomised Trial (EXERT): a randomised trial comparing GP referral for leisure centre-based exercise, community-based walking and advice only.

    By Isaacs AJ, Critchley JA, See Tai S, Buckingham K, Westley D, Harridge SDR, et al.

11. Interferon alfa (pegylated and non-pegylated) and ribavirin for the treatment of mild chronic hepatitis C: a systematic review and economic evaluation.

    By Shepherd J, Jones J, Hartwell D, Davidson P, Price A, Waugh N.

12. Systematic review and economic evaluation of bevacizumab and cetuximab for the treatment of metastatic colorectal cancer.

    By Tappenden P, Jones R, Paisley S, Carroll C.

13. A systematic review and economic evaluation of epoetin alfa, epoetin beta and darbepoetin alfa in anaemia associated with cancer, especially that attributable to cancer treatment.

    By Wilson J, Yao GL, Raftery J, Bohlius J, Brunskill S, Sandercock J, et al.

14. A systematic review and economic evaluation of statins for the prevention of coronary events.

    By Ward S, Lloyd Jones M, Pandor A, Holmes M, Ara R, Ryan A, et al.

15. A systematic review of the effectiveness and cost-effectiveness of different models of community-based respite care for frail older people and their carers.

    By Mason A, Weatherly H, Spilsbury K, Arksey H, Golder S, Adamson J, et al.

16. Additional therapy for young children with spastic cerebral palsy: a randomised controlled trial.

    By Weindling AM, Cunningham CC, Glenn SM, Edwards RT, Reeves DJ.

17. Screening for type 2 diabetes: literature review and economic modelling.

    By Waugh N, Scotland G, McNamee P, Gillett M, Brennan A, Goyder E, et al.

18. The effectiveness and cost-effectiveness of cinacalcet for secondary hyperparathyroidism in end-stage renal disease patients on dialysis: a systematic review and economic evaluation.

    By Garside R, Pitt M, Anderson R, Mealing S, Roome C, Snaith A, et al.

19. The clinical effectiveness and cost-effectiveness of gemcitabine for metastatic breast cancer: a systematic review and economic evaluation.

    By Takeda AL, Jones J, Loveman E, Tan SC, Clegg AJ.

20. A systematic review of duplex ultrasound, magnetic resonance angiography and computed tomography angiography for the diagnosis and assessment of symptomatic, lower limb peripheral arterial disease.

    By Collins R, Cranny G, Burch J, Aguiar-Ibáñez R, Craig D, Wright K, et al.

21. The clinical effectiveness and cost-effectiveness of treatments for children with idiopathic steroid-resistant nephrotic syndrome: a systematic review.

    By Colquitt JL, Kirby J, Green C, Cooper K, Trompeter RS.

22. A systematic review of the routine monitoring of growth in children of primary school age to identify growth-related conditions.

    By Fayter D, Nixon J, Hartley S, Rithalia A, Butler G, Rudolf M, et al.

23. Systematic review of the effectiveness of preventing and treating Staphylococcus aureus carriage in reducing peritoneal catheter-related infections.

    By McCormack K, Rabindranath K, Kilonzo M, Vale L, Fraser C, McIntyre L, et al.

24. The clinical effectiveness and cost of repetitive transcranial magnetic stimulation versus electroconvulsive therapy in severe depression: a multicentre pragmatic randomised controlled trial and economic analysis.

    By McLoughlin DM, Mogg A, Eranti S, Pluck G, Purvis R, Edwards D, et al.

25. A randomised controlled trial and economic evaluation of direct versus indirect and individual versus group modes of speech and language therapy for children with primary language impairment.

    By Boyle J, McCartney E, Forbes J, O’Hare A.

26. Hormonal therapies for early breast cancer: systematic review and economic evaluation.

    By Hind D, Ward S, De Nigris E, Simpson E, Carroll C, Wyld L.

27. Cardioprotection against the toxic effects of anthracyclines given to children with cancer: a systematic review.

    By Bryant J, Picot J, Levitt G, Sullivan I, Baxter L, Clegg A.

28. Adalimumab, etanercept and infliximab for the treatment of ankylosing spondylitis: a systematic review and economic evaluation.

    By McLeod C, Bagust A, Boland A, Dagenais P, Dickson R, Dundar Y, et al.

29. Prenatal screening and treatment strategies to prevent group B streptococcal and other bacterial infections in early infancy: cost-effectiveness and expected value of information analyses.

    By Colbourn T, Asseburg C, Bojke L, Philips Z, Claxton K, Ades AE, et al.

30. Clinical effectiveness and cost-effectiveness of bone morphogenetic proteins in the non-healing of fractures and spinal fusion: a systematic review.

    By Garrison KR, Donell S, Ryder J, Shemilt I, Mugford M, Harvey I, et al.

31. A randomised controlled trial of postoperative radiotherapy following breast-conserving surgery in a minimum-risk older population. The PRIME trial.

    By Prescott RJ, Kunkler IH, Williams LJ, King CC, Jack W, van der Pol M, et al.

32. Current practice, accuracy, effectiveness and cost-effectiveness of the school entry hearing screen.

    By Bamford J, Fortnum H, Bristow K, Smith J, Vamvakas G, Davies L, et al.

33. The clinical effectiveness and cost-effectiveness of inhaled insulin in diabetes mellitus: a systematic review and economic evaluation.

    By Black C, Cummins E, Royle P, Philip S, Waugh N.

34. Surveillance of cirrhosis for hepatocellular carcinoma: systematic review and economic analysis.

    By Thompson Coon J, Rogers G, Hewson P, Wright D, Anderson R, Cramp M, et al.

35. The Birmingham Rehabilitation Uptake Maximisation Study (BRUM). Homebased compared with hospital-based cardiac rehabilitation in a multi-ethnic population: cost-effectiveness and patient adherence.

    By Jolly K, Taylor R, Lip GYH, Greenfield S, Raftery J, Mant J, et al.

36. A systematic review of the clinical, public health and cost-effectiveness of rapid diagnostic tests for the detection and identification of bacterial intestinal pathogens in faeces and food.

    By Abubakar I, Irvine L, Aldus CF, Wyatt GM, Fordham R, Schelenz S, et al.

37. A randomised controlled trial examining the longer-term outcomes of standard versus new antiepileptic drugs. The SANAD trial.

    By Marson AG, Appleton R, Baker GA, Chadwick DW, Doughty J, Eaton B, et al.

38. Clinical effectiveness and cost-effectiveness of different models of managing long-term oral anti-coagulation therapy: a systematic review and economic modelling.

    By Connock M, Stevens C, Fry-Smith A, Jowett S, Fitzmaurice D, Moore D, et al.

39. A systematic review and economic model of the clinical effectiveness and cost-effectiveness of interventions for preventing relapse in people with bipolar disorder.

    By Soares-Weiser K, Bravo Vergel Y, Beynon S, Dunn G, Barbieri M, Duffy S, et al.

40. Taxanes for the adjuvant treatment of early breast cancer: systematic review and economic evaluation.

    By Ward S, Simpson E, Davis S, Hind D, Rees A, Wilkinson A.

41. The clinical effectiveness and cost-effectiveness of screening for open angle glaucoma: a systematic review and economic evaluation.

    By Burr JM, Mowatt G, Hernández R, Siddiqui MAR, Cook J, Lourenco T, et al.

42. Acceptability, benefit and costs of early screening for hearing disability: a study of potential screening tests and models.

    By Davis A, Smith P, Ferguson M, Stephens D, Gianopoulos I.

43. Contamination in trials of educational interventions.

    By Keogh-Brown MR, Bachmann MO, Shepstone L, Hewitt C, Howe A, Ramsay CR, et al.

44. Overview of the clinical effectiveness of positron emission tomography imaging in selected cancers.

    By Facey K, Bradbury I, Laking G, Payne E.

45. The effectiveness and cost-effectiveness of carmustine implants and temozolomide for the treatment of newly diagnosed high-grade glioma: a systematic review and economic evaluation.

    By Garside R, Pitt M, Anderson R, Rogers G, Dyer M, Mealing S, et al.

46. Drug-eluting stents: a systematic review and economic evaluation.

    By Hill RA, Boland A, Dickson R, Dündar Y, Haycox A, McLeod C, et al.

47. The clinical effectiveness and cost-effectiveness of cardiac resynchronisation (biventricular pacing) for heart failure: systematic review and economic model.

    By Fox M, Mealing S, Anderson R, Dean J, Stein K, Price A, et al.

48. Recruitment to randomised trials: strategies for trial enrolment and participation study. The STEPS study.

    By Campbell MK, Snowdon C, Francis D, Elbourne D, McDonald AM, Knight R, et al.

49. Cost-effectiveness of functional cardiac testing in the diagnosis and management of coronary artery disease: a randomised controlled trial. The CECaT trial.

    By Sharples L, Hughes V, Crean A, Dyer M, Buxton M, Goldsmith K, et al.

50. Evaluation of diagnostic tests when there is no gold standard. A review of methods.

    By Rutjes AWS, Reitsma JB, Coomarasamy A, Khan KS, Bossuyt PMM.

51. Systematic reviews of the clinical effectiveness and cost-effectiveness of proton pump inhibitors in acute upper gastrointestinal bleeding.

    By Leontiadis GI, Sreedharan A, Dorward S, Barton P, Delaney B, Howden CW, et al.

52. A review and critique of modelling in prioritising and designing screening programmes.

    By Karnon J, Goyder E, Tappenden P, McPhie S, Towers I, Brazier J, et al.

53. An assessment of the impact of the NHS Health Technology Assessment Programme.

    By Hanney S, Buxton M, Green C, Coulson D, Raftery J.

1. A systematic review and economic model of switching from nonglycopeptide to glycopeptide antibiotic prophylaxis for surgery.

   By Cranny G, Elliott R, Weatherly H, Chambers D, Hawkins N, Myers L, et al.

2. ‘Cut down to quit’ with nicotine replacement therapies in smoking cessation: a systematic review of effectiveness and economic analysis.

   By Wang D, Connock M, Barton P, Fry-Smith A, Aveyard P, Moore D.

3. A systematic review of the effectiveness of strategies for reducing fracture risk in children with juvenile idiopathic arthritis with additional data on long-term risk of fracture and cost of disease management.

   By Thornton J, Ashcroft D, O’Neill T, Elliott R, Adams J, Roberts C, et al.

4. Does befriending by trained lay workers improve psychological well-being and quality of life for carers of people with dementia, and at what cost? A randomised controlled trial.

   By Charlesworth G, Shepstone L, Wilson E, Thalanany M, Mugford M, Poland F.

5. A multi-centre retrospective cohort study comparing the efficacy, safety and cost-effectiveness of hysterectomy and uterine artery embolisation for the treatment of symptomatic uterine fibroids. The HOPEFUL study.

   By Hirst A, Dutton S, Wu O, Briggs A, Edwards C, Waldenmaier L, et al.

6. Methods of prediction and prevention of pre-eclampsia: systematic reviews of accuracy and effectiveness literature with economic modelling.

   By Meads CA, Cnossen JS, Meher S, Juarez-Garcia A, ter Riet G, Duley L, et al.

7. The use of economic evaluations in NHS decision-making: a review and empirical investigation.

   By Williams I, McIver S, Moore D, Bryan S.

8. Stapled haemorrhoidectomy (haemorrhoidopexy) for the treatment of haemorrhoids: a systematic review and economic evaluation.

   By Burch J, Epstein D, Baba-Akbari A, Weatherly H, Fox D, Golder S, et al.

9. The clinical effectiveness of diabetes education models for Type 2 diabetes: a systematic review.

   By Loveman E, Frampton GK, Clegg AJ.

10. Payment to healthcare professionals for patient recruitment to trials: systematic review and qualitative study.

    By Raftery J, Bryant J, Powell J, Kerr C, Hawker S.

11. Cyclooxygenase-2 selective non-steroidal anti-inflammatory drugs (etodolac, meloxicam, celecoxib, rofecoxib, etoricoxib, valdecoxib and lumiracoxib) for osteoarthritis and rheumatoid arthritis: a systematic review and economic evaluation.

    By Chen Y-F, Jobanputra P, Barton P, Bryan S, Fry-Smith A, Harris G, et al.

12. The clinical effectiveness and cost-effectiveness of central venous catheters treated with anti-infective agents in preventing bloodstream infections: a systematic review and economic evaluation.

    By Hockenhull JC, Dwan K, Boland A, Smith G, Bagust A, Dundar Y, et al.

13. Stepped treatment of older adults on laxatives. The STOOL trial.

    By Mihaylov S, Stark C, McColl E, Steen N, Vanoli A, Rubin G, et al.

14. A randomised controlled trial of cognitive behaviour therapy in adolescents with major depression treated by selective serotonin reuptake inhibitors. The ADAPT trial.

    By Goodyer IM, Dubicka B, Wilkinson P, Kelvin R, Roberts C, Byford S, et al.

15. The use of irinotecan, oxaliplatin and raltitrexed for the treatment of advanced colorectal cancer: systematic review and economic evaluation.

    By Hind D, Tappenden P, Tumur I, Eggington E, Sutcliffe P, Ryan A.

16. Ranibizumab and pegaptanib for the treatment of age-related macular degeneration: a systematic review and economic evaluation.

    By Colquitt JL, Jones J, Tan SC, Takeda A, Clegg AJ, Price A.

17. Systematic review of the clinical effectiveness and cost-effectiveness of 64-slice or higher computed tomography angiography as an alternative to invasive coronary angiography in the investigation of coronary artery disease.

    By Mowatt G, Cummins E, Waugh N, Walker S, Cook J, Jia X, et al.

18. Structural neuroimaging in psychosis: a systematic review and economic evaluation.

    By Albon E, Tsourapas A, Frew E, Davenport C, Oyebode F, Bayliss S, et al.

19. Systematic review and economic analysis of the comparative effectiveness of different inhaled corticosteroids and their usage with long-acting beta₂ agonists for the treatment of chronic asthma in adults and children aged 12 years and over.

    By Shepherd J, Rogers G, Anderson R, Main C, Thompson-Coon J, Hartwell D, et al.

20. Systematic review and economic analysis of the comparative effectiveness of different inhaled corticosteroids and their usage with long-acting beta₂ agonists for the treatment of chronic asthma in children under the age of 12 years.

    By Main C, Shepherd J, Anderson R, Rogers G, Thompson-Coon J, Liu Z, et al.

21. Ezetimibe for the treatment of hypercholesterolaemia: a systematic review and economic evaluation.

    By Ara R, Tumur I, Pandor A, Duenas A, Williams R, Wilkinson A, et al.

22. Topical or oral ibuprofen for chronic knee pain in older people. The TOIB study.

    By Underwood M, Ashby D, Carnes D, Castelnuovo E, Cross P, Harding G, et al.

23. A prospective randomised comparison of minor surgery in primary and secondary care. The MiSTIC trial.

    By George S, Pockney P, Primrose J, Smith H, Little P, Kinley H, et al.

24. A review and critical appraisal of measures of therapist–patient interactions in mental health settings.

    By Cahill J, Barkham M, Hardy G, Gilbody S, Richards D, Bower P, et al.

25. The clinical effectiveness and cost-effectiveness of screening programmes for amblyopia and strabismus in children up to the age of 4–5 years: a systematic review and economic evaluation.

    By Carlton J, Karnon J, Czoski-Murray C, Smith KJ, Marr J.

26. A systematic review of the clinical effectiveness and cost-effectiveness and economic modelling of minimal incision total hip replacement approaches in the management of arthritic disease of the hip.

    By de Verteuil R, Imamura M, Zhu S, Glazener C, Fraser C, Munro N, et al.

27. A preliminary model-based assessment of the cost–utility of a screening programme for early age-related macular degeneration.

    By Karnon J, Czoski-Murray C, Smith K, Brand C, Chakravarthy U, Davis S, et al.

28. Intravenous magnesium sulphate and sotalol for prevention of atrial fibrillation after coronary artery bypass surgery: a systematic review and economic evaluation.

    By Shepherd J, Jones J, Frampton GK, Tanajewski L, Turner D, Price A.

29. Absorbent products for urinary/faecal incontinence: a comparative evaluation of key product categories.

    By Fader M, Cottenden A, Getliffe K, Gage H, Clarke-O’Neill S, Jamieson K, et al.

30. A systematic review of repetitive functional task practice with modelling of resource use, costs and effectiveness.

    By French B, Leathley M, Sutton C, McAdam J, Thomas L, Forster A, et al.

31. The effectiveness and cost-effectivness of minimal access surgery amongst people with gastro-oesophageal reflux disease – a UK collaborative study. The reflux trial.

    By Grant A, Wileman S, Ramsay C, Bojke L, Epstein D, Sculpher M, et al.

32. Time to full publication of studies of anti-cancer medicines for breast cancer and the potential for publication bias: a short systematic review.

    By Takeda A, Loveman E, Harris P, Hartwell D, Welch K.

33. Performance of screening tests for child physical abuse in accident and emergency departments.

    By Woodman J, Pitt M, Wentz R, Taylor B, Hodes D, Gilbert RE.

34. Curative catheter ablation in atrial fibrillation and typical atrial flutter: systematic review and economic evaluation.

    By Rodgers M, McKenna C, Palmer S, Chambers D, Van Hout S, Golder S, et al.

35. Systematic review and economic modelling of effectiveness and cost utility of surgical treatments for men with benign prostatic enlargement.

    By Lourenco T, Armstrong N, N’Dow J, Nabi G, Deverill M, Pickard R, et al.

36. Immunoprophylaxis against respiratory syncytial virus (RSV) with palivizumab in children: a systematic review and economic evaluation.

    By Wang D, Cummins C, Bayliss S, Sandercock J, Burls A.

1. Deferasirox for the treatment of iron overload associated with regular blood transfusions (transfusional haemosiderosis) in patients suffering with chronic anaemia: a systematic review and economic evaluation.

   By McLeod C, Fleeman N, Kirkham J, Bagust A, Boland A, Chu P, et al.

2. Thrombophilia testing in people with venous thromboembolism: systematic review and cost-effectiveness analysis.

   By Simpson EL, Stevenson MD, Rawdin A, Papaioannou D.

3. Surgical procedures and non-surgical devices for the management of non-apnoeic snoring: a systematic review of clinical effects and associated treatment costs.

   By Main C, Liu Z, Welch K, Weiner G, Quentin Jones S, Stein K.

4. Continuous positive airway pressure devices for the treatment of obstructive sleep apnoea–hypopnoea syndrome: a systematic review and economic analysis.

   By McDaid C, Griffin S, Weatherly H, Durée K, van der Burgt M, van Hout S, Akers J, et al.

5. Use of classical and novel biomarkers as prognostic risk factors for localised prostate cancer: a systematic review.

   By Sutcliffe P, Hummel S, Simpson E, Young T, Rees A, Wilkinson A, et al.

6. The harmful health effects of recreational ecstasy: a systematic review of observational evidence.

   By Rogers G, Elston J, Garside R, Roome C, Taylor R, Younger P, et al.

7. Systematic review of the clinical effectiveness and cost-effectiveness of oesophageal Doppler monitoring in critically ill and high-risk surgical patients.

   By Mowatt G, Houston G, Hernández R, de Verteuil R, Fraser C, Cuthbertson B, et al.

8. The use of surrogate outcomes in model-based cost-effectiveness analyses: a survey of UK Health Technology Assessment reports.

   By Taylor RS, Elston J.

9. Controlling Hypertension and Hypotension Immediately Post Stroke (CHHIPS) – a randomised controlled trial.

   By Potter J, Mistri A, Brodie F, Chernova J, Wilson E, Jagger C, et al.

Health Technology Assessment Programme

1. Director, NIHR HTA Programme, Professor of Clinical Pharmacology, University of Liverpool

2. Director, Medical Care Research Unit, University of Sheffield