How to save 40,000 women a year from having unnecessary Anti-D / RhoGAM

Let’s start at the beginning…

A bit of context…

It is now more than fifty years since some countries introduced a policy wherein Anti-D (known in the USA as RhoGAM) is offered to rhesus negative women who have given birth to a rhesus positive baby.

In that time, a number of related developments also occurred, and we began to offer Anti-D in other situations as well.

One of the most controversial of these was the recommendation in some areas of the world that all rhesus negative women should be routinely offered Anti-D once or twice (depending on the local policy) during their pregnancy.

But people knew from the outset this meant that we would be giving a lot of unnecessary Anti-D.

Explaining unnecessary Anti-D

The reason that Anti-D is often given unnecessarily is that many of these women’s unborn babies will not be rhesus positive. Some will be rhesus negative. There is no chance of sensitisation (the process that Anti-D is given to prevent) if the baby is rhesus negative.

When we offer Anti-D to any pregnant women, both they and their baby are taking on the small but significant risks associated with being given a blood product, but without there being any chance of benefit. (In fact, the Anti-D doesn’t physically benefit the mother or the baby in the womb. It’s for the possible benefit of a possible future baby. But that’s another blog post.)

But when it’s offered to a pregnant woman whose unborn baby is rhesus negative, then there is no possible benefit to anybody.

Ever.

Except, in countries where this is a commercial product, those who benefit from the sale and administration of Anti-D.

How did the controversy come about?

A couple of decades ago, some maternity care systems brought in the policy of offering Anti-D in pregnancy because it was thought that a small number of women might be experiencing something called ‘silent sensitisation.’

But I need to go back a step to explain what that means.

Anti-D is given in the hope of preventing a problem called sensitisation. Before routine Anti-D was a thing, it was only offered in pregnancy when a woman had experienced a potentially sensitising event. That’s basically a situation where it might be possible for a bit of the baby’s blood to enter its mother’s bloodstream. This would be something like a bump to her abdomen, or an invasive medical procedure.

Silent sensitisation and antenatal Anti-D

But a few women became sensitised even when there hadn’t been an obvious sensitising event recorded in the notes.

There could be several reasons for this, and in some cases it might be administrative or professional error. (In fact, I think that professional error is much more of an issue than people want to admit, which I discuss in my book, if you’d like to know more).

Some professionals argued that these ‘mystery’ cases of sensitisation could be prevented if all women were offered Anti-D during pregnancy. There were a lot of debates about this at the time (which I was involved in – it’s important to declare my bias, and I spoke out against this becoming a routine offer), but those in favour of offering Anti-D in pregnancy succeeded in making this a routine offer in many high-income countries.

The argument against routine antenatal Anti-D

In brief, the argument against antenatal Anti-D (and, again, loads more detail in my book) include that:

1. The chance of silent sensitisation is low. This raises questions about the justifiability of routine Anti-D in pregnancy, especially where there are potential side effects and risks for both mum and baby.

2. There isn’t nearly enough research about how Anti-D may affect the unborn baby. When Anti-D is warranted, it can save the lives of future babies. But we need to consider the health of the current baby too, especially as the theoretical future baby who the Anti-D is being given to protect may not ever exist.

3. Many of the women who receive routine antenatal Anti-D do not need it. That’s because they are carrying a rhesus negative baby. And the problem that Anti-D is given to prevent simply wouldn’t happen for these women. That’s why the issue of unnecessary Anti-D needs discussion.

The numbers

In the UK, 40,000 women a year fall into this last category, of those who will never benefit from antenatal Anti-D because they are carrying a rhesus negative baby.

That’s a third of all rhesus negative women (Finning et al 2008).

This figure will vary in other countries because the percentage of people who carry the rhesus factor varies according to ancestry.

But in simple terms, about 40,000 women in the UK each year receive unnecessary Anti-D.

They are given a medicine made from blood that they do not need.

But there’s a solution – at least for some

Here’s the really frustrating part.

We have a way of finding out which women are carrying a rhesus negative baby, so that we can make sure they aren’t offered unnecessary Anti-D.

That’s because there now exists a highly accurate test which shows whether the unborn baby is rhesus positive or rhesus negative.

Back in 2008, Finning et al‘s (2008) study confirmed that this test was feasible and that the false negative rate was extremely low, at 0.2%. This has been further confirmed in a 2014 study by Manzanares et al, and I’ve added links to even more recent data below.

No test can be right all the time but, partly because the chance of silent sensitisation is also very low, this test is really close.

In fact, if a rhesus negative woman has this test, is told that her baby is rhesus negative and decides not to have routine antenatal Anti-D as a result, her chances of becoming sensitised are only one in 86,000.

When we take into account the fact that Anti-D itself is not 100% effective (although it is close), it is little wonder that countries such as Denmark and The Netherlands quickly began to offer this test to all rhesus negative pregnant women.

The bottom line

The bottom line is that antenatal testing of a baby’s rhesus status significantly reduces the number of women who are offered unnecessary Anti-D.

Yes, those who are carrying a rhesus positive baby still need to weigh up the pros and cons of the decision.

But it removes the decision and worry entirely for a good proportion of rhesus negative women.

In some areas, for instance in parts of the UK and Australia, the test for a baby’s rhesus status is carried out as part of a NIPT test. There are still a few things that could be ironed out, because some women would like to know their baby’s rhesus status without having the rest of a NIPT test, but it’s an option. In other areas, this testing is not yet available. Sadly, as with induction of labour, it’s another postcode lottery.

More research confirms this

The issues have been debated in the literature for a number of years. For instance, the economic argument that the testing is not economically justified Szczepura et al (2011) was often set against the claim that it may be unethical not to offer this test to all rhesus negative woman (Kent et al 2014).

But the debate has moved on. More recent studies have confirmed the benefits of offering antenatal testing for baby’s rhesus status, and this test is increasingly offered in practice.

Here are a few examples.

A study by de Haas et al (2016) The results confirmed that, “…fetal RHD testing in week 27 of pregnancy as part of a national antenatal screening programme is highly reliable and can be used to target both antenatal and postnatal anti-D immunoglobulin use”.

Laboratory-based research by Vivanti et al (2016) also further confirmed the accuracy of this test.

In 2017, a study carried out in Finland provided more evidence on targeting anti-D. In this study, the blood test was performed at 24-26 weeks of pregnancy. Of the 10,814 women who had their blood tested over a period of two years, only one false negative and seven false positive results were reported.

In 2024, Moise wrote in the American Journal of Obstetrics and Gynecology, calling for fetal rhesus status testing to become a reality across the USA.

He pointed out that, “The manufacturer of RhoGAM® has recently announced a national shortage.”

This is not the first time that countries have experienced a shortage of RhoGam/Anti-D, and it makes this issue even more pertinent.

Moise (2024) also cites the realiability of the testing:

“Given the current availability of reliable cfDNA assays for determining the RHD status of the fetus, the time has come to implement this strategy to triage the antenatal use of Rhesus immune globulin in the U.S.”

How to find out more

As I have said, this is a frustrating situation for some women and families because of the postcode lottery that exists in this area.

If you’d like to know more about unnecessary Anti-D or, in fact, anything else relating to Anti-D, my book is called Anti-D Explained. It has been written to help women and families understand the issues and the evidence.

I also recommend connecting with local midwives, birth workers and pregnant women and families in your area, to find out what the options are.

It is sometimes possible to source private testing, if you can afford it, or to request testing even if this is not routinely offered.

The key is to get informed, so you can make the decisions that are right for you.

Here’s where you can find out more from me on this topic:

Anti-D Explained

Anti-D resources

References

Finning K, Martin P, Summers J et al (2008).  Effect of high throughput RHD typing of fetal DNA in maternal plasma on use of anti-RhD immunoglobulin in RhD negative pregnant women: prospective feasibility study. BMJ 2008;336:816.

de Haas et al (2016). Sensitivity of fetal RHD screening for safe guidance of targeted anti-D immunoglobulin prophylaxis: prospective cohort study of a nationwide programme in the Netherlands. BMJ 355 doi: http://dx.doi.org/10.1136/bmj.i5789

Kent J, Farrell A-M and Soothill P (2014).  Routine administration of Anti-D: the ethical case for offering pregnant women fetal RHD genotyping and a review of policy and practice. BMC Pregnancy and Childbirth 2014,14:87 doi:10.1186/1471-2393-14-87.

Manzanares S, Entrala C, Sanchez-Gila M et al (2014).  Noninvasive Fetal RhD Status Determination in Early Pregnancy. Fetal Diagnosis and Therapy 35(1): 7-12.

Moise KJ (2024). The use of free DNA for fetal RHD genotyping in the Rh negative pregnant patient – the time has come. American Journal of Obstetrics and Gynecology. doi.org/10.1016/j.ajog.2024.08.017

Szczepura A, Osipenko L, Freeman K (2011).  A new fetal RHD genotyping test: Costs and benefits of mass testing to target antenatal anti-D prophylaxis in England and Wales. BMC Pregnancy and Childbirth 2011, 11:5  doi:10.1186/1471-2393-11-5.

Vivanti A et al (2016). Diagnostic accuracy of fetal rhesus D genotyping using cell-free fetal DNA during the first trimester of pregnancy. AJOG 215(5): 606.e1–606.e5

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