Rhogam Anti-D - A review of the evidence

I find the Rhogam arguments very interesting. I was thinking earlier that I should do a post about what it means to have a negative blood type during pregnancy and what the rhogam shot does.  Rhogam is blood from someone else. They still often make them with mercury. Each Rhogam shot contains the antibodies of several different donors pooled together which increases the liklihood of viruses slipping through undetected to the RhoGam recipient. It is virtually impossible to test and screen out all the various viruses that could be present in the donor blood! I am sure there's people in the medical community who don’t know what it’s all about! If you should questioned the nurse who gave a woman the shot  it would be beyond her scope of understanding. I think everybody should read Anti-D in Midwifery: Panacea or Paradox by Sara Wickham.

In the US in 1960's, Rh disease caused about 10,000 perinatal deaths each year, plus uncounted miscarriages. It's rare now, but only because of the conscientious use of Rhogam to keep women from becoming sensitized, and the aging of the pre-rhogam women out of their fertile years. It is common knowledge that every person has a blood type identified as either “O”, “A”, “B”, or “AB”. In addition to this primary blood type, a person’s blood is either Rh positive or Rh negative. This is known as the Rh factor. The Rh factor refers to a protein that may or may not be found on the surface of an individual’s red blood cells. A person who has this protein present in her blood is Rh positive and a person who does not is Rh negative.

Here is the argument: RH- blood does not like RH+ blood. If RH- blood comes in contact with enough RH+ blood, the RH- blood will begin producing antibodies to fight off the RH+ blood because it sees it as a foreign and dangerous invader. It is a natural response like an immunity response. If an RH- woman is pregnant with an RH- baby, everything is wonderful and honky dory. If both the mother and father are RH-, then the baby will also be RH-, however, physcians may very well treat the pregnancy with the assumption that the baby is RH+ anyway, on the chance that the mother may have been messing around, etc. In some European countries, they do not give the rhogam shot at all during pregnancy unless there is trauma that could increase the risks of blood interaction  eg. such as a car accident. In those countries, they give the rhogam shot after delivery

The rhogam shot puts antibodies into your blood stream letting the RH- blood know there is no need to produce antibodies, because they are already there (from the shot).  Sara Wickham's book on the topic is a great start. Here is her article that I like to share with you.  While the postnatal administration of anti-D immunoglobulin to rhesus negative woman who have given birth to a rhesus positive baby has been considered by many as an acceptable and beneficial routine intervention for the last thirty years, the question of whether it is appropriate to offer routine antenatal administration of this product has been hotly debated for almost as long. There is little question that women who experience potentially sensitising events in pregnancy should be given appropriate information and offered this as an option. Rather, the debate concerns the issue of so-called 'silent' feto-maternal transfusion - the existence (or otherwise) of which phenomena forms part of the basis for arguments in favour of routine antenatal prophylaxis.

The debate surrounding the routine administration of anti-D during pregnancy began in 1969, when Zipursky and Israels suggested that antenatal anti-D administration may prove to reduce the rate of sensitisation. Bowman and Pollock (1978) followed this up with the specific recommendation that anti-D should be administered to all rhesus negative women at 28 weeks to prevent sensitisation in pregnancy. The debate continued throughout the 1980s and 1990's, with opinions divided between those who saw antenatal anti-D as a wholly beneficial intervention, which would save babies, and those who urged caution for a variety of reasons. Antenatal anti-D has been offered routinely in some countries, including the USA and Germany, for a number of years. Yet Britain's first active discussion of the debate occurred in 1997, when a consensus conference decided to recommend routine antenatal administration in the UK; an issue which is currently being debated on practical, professional and political levels.

Why Offer Antenatal Anti-D?
Proponents of routine antenatal administration base their arguments around evidence that suggests that current protocols for the administration of anti-D do not prevent all cases of isoimmunization. They feel that routine antenatal administration is the best way forward in moving closer to one hundred per cent protection from isoimmunization. For example, Hughes et al (1994) carried out research in Scotland, and concluded that, in 53 of the 80 babies with rhesus disease, this had been caused by the failure of the current guidelines to protect against maternal isoimmunization.

The effectiveness of the antenatal anti-D programme in Derbyshire - where women having their first baby are already offered antenatal anti-D at 28 and 34 weeks of pregnancy - was evaluated by Mayne et al (1997), who showed a fall in the mean overall sensitisation rate from 1.12 per cent in 1988-91 (before the onset of the antenatal programme) to 0.28 per cent in 1993-95. Another research study by McSweeney et al (1998) not only provides evidence in support of antenatal administration, but also highlights part of the argument against this. While these researchers estimate that over 80 per cent of women who became isoimmunized might not have experienced this had they been offered antenatal anti-D, they also found that professionals failed to offer anti-D in 48 per cent of cases where women experienced potential sensitising events in the antenatal period. This is one of the strongest arguments against the administration of routine antenatal anti-D.

The fact that most of the studies of this nature that are cited in support of routine antenatal anti-D are retrospective proves problematic. The use of women's case notes in such research is known to cause difficulties; many aspects of care are not always well documented by professionals and this can lead to bias in the results of the study. For instance, if a clinician had not documented the occurrence of a potentially sensitising event, or perhaps not even asked the woman about these, then it would look as if the woman had experienced silent fetomaternal haemorrhage if she then became isoimmunized.
Much of the evidence cited in this area, although interesting and useful in other ways, does not look at the effectiveness of antenatal anti-D in the light of prospective, randomised controlled trials. Only two antenatal anti-D trials of any real size and quality have been conducted - although it should be noted that neither of these was single or double blinded.

 Lee and Rawlinson (1995) gave women in the treatment group two doses of 50 micrograms (250 international units) of anti-D at 28 and 34 weeks, and showed no statistically significant difference between their outcomes and women in the group who had not received antenatal anti-D. However, researchers in Huchet et al's (1987) study gave a larger dose of anti-D (500 international units) at 28 and 34 weeks and showed a clear reduction in the incidence of isoimmunization at between two and twelve months, although no data which considered subsequent pregnancy in those women were available. In response to this data, Cochrane reviewers concluded that there was still a need for consideration of other issues, such as cost and supply of anti-D (Crowther and Kierse 1999). Of course, we should bear in mind that, even if we feel that the evidence shows antenatal anti-D administration to be effective, this does not necessarily mean it is necessary or beneficial for all women; this is another issue entirely.

Is there Evidence for Caution?
There are two main arguments against the routine administration of antenatal anti-D; although cost is a major issue, this will not be considered here - discussion of this can be found in Wickham (2001). The first of these arguments concerns the difficulty there exists with trying to establish how effective antenatal anti-D would be when there are still questions and problems regarding the current program of routine postnatal administration and antenatal administration in response to a potentially sensitising event. Ghosh and Murphy's (1994) Scottish study showed that just over 30 per cent of women who had experienced an antenatal sensitising event had not been offered anti-D. Tovey (1983) showed that 22 per cent of the women in his study became sensitised as a result of 'failure of administration' and Howard et al (1997) also propose that closer adherence to the 1991 recommendations might further reduce the incidence of isoimmunization. Their study found that only 20 per cent of women who had experienced abdominal trauma had been offered anti-D and only 95 per cent adherence to the recommendations in the area of postnatal administration.

Clearly, it is not helpful to begin an antenatal programme if a proportion of the women who are becoming sensitised during pregnancy are facing this as a result of professional failure to offer anti-D after a potentially sensitising event. Rather than subjecting all women to antenatal anti-D because some clinicians fail to offer this to the women that really need it, we need to consider how this trend can be reversed. We also need to establish how may women are becoming sensitised as a result of failure to implement the current guidelines, and not include these woman in figures which are being used to promote the uptake of routine antenatal prophylaxis.

It is not just midwifery and obstetric departments which are failing to offer anti-D. Huggon and Watson (1993) sampled 29 women who arrived in accident and emergency departments following a threatened miscarriage. Only eight women were tested to establish their blood group on admission and none of those women who were rhesus negative were offered anti-D. Gilling-Smith et al (1997) built on this small-scale study and researched 88 accident and emergency units, which treated women who experienced bleeding in early pregnancy. Seventy seven of these failed to administer anti-D when this was appropriate, and 37 per cent reported not even having access to Kleihauer testing to determine whether a woman had experienced a larger bleed than would be covered by the standard dose.

What are the Risks?
The second argument against routine antenatal anti-D concerns the potential risks of this, both to the woman and to her unborn baby (who will not herself benefit from this - anti-D effectively being a protective measure for her siblings). The fact that there has been no research investigating the effects of anti-D on the unborn child is one of the factors of concern to those currently calling for caution (Gaskin 1989, Coombes 1999). Gaskin (1989) cites several potential risk factors where babies are exposed to anti-D, including immune system compromise and potential problems during later reproduction for rhesus negative baby girls exposed to anti-D in utero.

Two further potential risks of antenatal anti-D are discussed in the medical literature; this does not, however, mean that these are the only possible risks; there may be others not yet predicted. The first risk is that of augmentation; or enhanced anti-D immunisation (Urbaniak 1998), where a woman who is given passive anti-D during the antenatal period could, upon exposure to rhesus positive cells (via transplacental haemorrhage) mount a primary immune response to these.

The second concern is the effect of passive anti-D on the unborn baby. There has been no systematic study, which looks at the short and long-term side effects of anti-D in babies (Urbaniak 1998). Although Gaskin's (1989) evidence concerning immune system compromise seems to have been ignored, other risks to the baby have been discussed in the literature. Some of these concern the fact that about ten per cent of the anti-D given to the mother will cross the placenta to the baby (Hughes-Jones et al 1971, Urbaniak 1998). Studies have shown that this causes a proportion of babies to test positive for antiglobulins (via a direct Coombs test) after they are born (Tovey et al 1983, Bowman and Pollock 1978, Herman et al 1984). The few studies which have looked at this have suggested that, while babies may suffer some anaemia, this does not require treatment in the immediate postnatal period.

Although Romm (1999) points out that the manufacturers of anti-D clearly state that this should not be given to babies, no-one has considered the question of whether there are long term consequences of this. It should be remembered that unborn babies will also be exposed to the risks which women face, such as that of virus transmission (Wickham 2000). This can only be exacerbated by the fact that the optimal dose of antenatal anti-D is not known; women and babies may be exposed to more of this product than they need.

Debating the Issues
In 1997, a Consensus Conference was held so that a group of experts could determine national recommendations for antenatal anti-D administration. These experts gathered to assess the evidence, including many of the studies here and make recommendations to the Royal College of Obstetricians and Gynaecologists and the Royal College of Physicians of Edinburgh. This group included haematologists, obstetricians, general practitioners and even a medical journalist. Significantly, a number of groups were not represented; no consumer-focused childbirth organisations or childbearing women were invited for their opinions, and there was no clinical midwifery representation on the group. This may seem undemocratic to some, as it is women who receive the product and usually midwives who inform them of the issues and administer it.

In relation to current failures of implementation, the conference noted their concern that; 'there is abundant evidence that the recommendations are not being fully applied.' (Urbaniak 1998: 1). They did not, however, feel that this issue warranted further investigation before making the decision to recommend routine antenatal anti-D. Another recommendation concerned the suggestion that, 'information leaflets concerning the recommendations should be given to RhD negative women and their partners'. This may be an issue which the midwifery profession needs to debate in relation to informed choice and the need for balanced information; the vast majority of the information leaflets currently available - mostly donated by the pharmaceutical companies producing anti-D - are biased towards women's acceptance of anti-D rather than the facilitation of informed choice. If more midwives became involved in the process of writing and evaluating this kind of information, women may have more of a foundation upon which to make their choices.

Where do we go from here?
The Royal College of Midwives (RCM 1999) and the UKCC (Coombes 1999) have raised concerns about the guidelines advocating the use of anti-D in the antenatal period; specifically the lack of testing of the product for routine use and the lack of sound evidence which suggests that antenatal administration is beneficial. Coombes (1999) is also among those who have highlighted the fact that around 40 per cent of the 100,000 or so women who would receive antenatal anti-D each year in the UK would be carrying rhesus negative babies, and therefore would have received this unnecessarily. Should paternal blood testing be one of the options which women should be offered at this time? Women who are pregnant with their last child are also among those who would not benefit from antenatal anti-D. Should it become routine practice for midwives to discuss these issues with women in relation to their personal need for anti-D?

Many questions remain in this area, which suggest the need for midwives to become more involved in this debate. Is there enough sound evidence to support the routine antenatal administration of anti-D, or should midwives - as women's advocates - be concerned about this prospect? How can the issues be addressed and the remaining questions answered in such a way that we know that the options we are offering women are beneficial rather than harmful and based on what is truly optimal for those women rather than being deemed necessary as a result of our own failures in other areas? More than ever, midwives need to be able to explain and discuss the evidence with the women who face this decision. Whatever recommendations are put in place, either locally or nationally, women have a right to make their own informed choices and midwives have a duty to enable these choices to be freely made.


Source: Sara Wickham

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