Anti-D in pregnancy: how we haven’t moved on…

The first Cochrane review of the research relating to the administration of Anti-D during pregnancy was undertaken in 1996.

Nearly twenty years later, September 2015 saw the publication of the latest update. During that time, however, the only changes were to the format, as the Cochrane Collaboration has updated their approach to the presentation of information. No relevant new trials had been published, and the reviewers’ conclusions haven’t really changed.

That’s still the case today.

Here are the results of that first review, which was published in the online Cochrane database in 1999:

 

“Two average to poor-quality trials, involving over 4500 women, compared anti-D prophylaxis with no treatment. When women received anti-D at 28 and 34 weeks’ gestation, relative risk (RR) of immunisation during pregnancy was 0.42 (95% confidence interval (CI) 0.15 to 1.17); after the birth of a Rh-positive infant the RR was 0.42 (95% CI 0.15 to 1.17); and within 12 months after birth of a Rh-positive infant the RR was 0.41 (95% CI 0.16 to 1.04). While none of these differences were statistically significant, the risk difference (RD) between anti-D and no treatment was significant (RD -0.01, 95% CI -0.01 to 0.00) suggesting reduced incidence of immunisation after anti-D prophylaxis.

In the higher dose trial (100 µg; 500 international units (IU) anti-D), there was a nonsignificant reduction in immunisation at two to 12 months following birth of a Rh-positive infant in women who had received anti-D (RR 0.14, 95% CI 0.02 to 1.15). However, women receiving anti-D were significantly less likely to register a positive Kleihauer test (which detects fetal cells in maternal blood) in pregnancy (RR 0.60, 95% CI 0.41 to 0.88) and at the birth of a Rh-positive infant (RR 0.60, 95% CI 0.46 to 0.79). No data were available for the risk of Rhesus D alloimmunisation in a subsequent pregnancy. No differences were seen for neonatal jaundice.” (Crowther and Middleton 1999)

 

Unclear results

In other words, although the trials seem to show some benefit to routine antenatal Anti-D, this is not equivocal. The studies are of average to poor quality and some significant questions and wider issues remain unanswered and undiscussed. So you might think that we would do one of two things.

(a) Do more and better designed scientific research trials to get some better evidence, and/or

(b) Delay offering routine antenatal Anti-D until we have some better evidence.

As you may know, and as I discuss at length in Anti-D Explained, this isn’t what happened.

 

Why evidence matters

Getting better evidence seems especially important given that:

(1) Anti-D is manufactured from blood. This makes it even more worthy of our respect and care than usual. Medicines made from blood can carry viruses, lead to serious allergic reactions and cause other notable problems.

(2) Very few rhesus negative pregnant women would be affected. The risk is very low, even for those carrying a rhesus positive baby.

(3) A proportion of rhesus negative women are carrying a rhesus negative baby. They aren’t at ANY risk of isoimmunisation. We can now offer a test for this, as I’ll explain below. But it’s not offered everywhere, and it doesn’t solve the problem for everyone.

(4) There is evidence that a good part of the problem could be solved another way. That is, if Anti-D was offered at appropriate times and in response to potentially sensitising events. More in Anti-D Explained.

(5) We haven’t carried out much work looking into the potential risks and side effects of Anti-D. This applies both to the mother and her current baby. That’s really important, because neither of them directly physically benefit from its administration. Neither have we explored the wider issues and ramifications of this more fully. Again, more in my book.

 

But it’s offered anyway

In practice, and despite these factors, many systems of maternity care offer antenatal Anti-D to all rhesus negative pregnant women. Not all of these women want it, of course, but many do. I have lectured widely on this topic and this has led me to understand one thing very well. Many of the people offering antenatal Anti-D to women would love to be able to explain the pros and cons. But they don’t feel able to do so. Sometimes this is because they don’t have the time. But some also lack the confidence to go against the party line.

And yet, as the authors’ conclusions from the Cochrane review show, we still don’t have good evidence that this intervention is effective or helpful. And many concerns and questions remain.

 

Existing studies do not provide conclusive evidence that the use of anti-D during pregnancy benefits either mother or baby in terms of incidence of Rhesus D alloimmunisation during the pregnancy or postpartum, or the incidence of neonatal morbidity (jaundice) (low to very low quality evidence). However women receiving anti-D may be less likely to register a positive Kleihauer test in pregnancy and at the birth of a Rh-positive infant (low quality evidence). Fewer women who receive anti-D during pregnancy may have Rhesus D antibodies in a subsequent pregnancy, with benefits for the baby, however this needs to be tested in studies of robust design. (McBain et al 2015)

 

The risk problem (again)

Antenatal Anti-D is one of those pregnancy and birth interventions often offered without full information but within a context painted in shades of fear and risk. This is really unhelpful for women and families.

We have moved on in one way. We can now offer testing, though this only helps those women who are found to be carrying rhesus negative babies. But I’ve written about that in a couple of blog posts, if you’re interested. How to save 40,000 women a year from having an unnecessary blood product  and Yet more evidence to help women avoid unnecessary Anti-D.

This still leaves a lot of uncertainty for a lot of women and families, however.

If you’d like to explore this topic further, you might like to read my book, Anti-D Explained.

 

Finally, here’s the link to the latest version of the Cochrane review if you’d like to read it in full.

Crowther CA, Middleton P. Anti-D administration in pregnancy for preventing Rhesus alloimmunisation. Cochrane Database of Systematic Reviews, Issue 2. DOI: 10.1002/14651858.CD000020

McBain RD, Crowther CA, Middleton P (2015).  Anti-D administration in pregnancy for preventing Rhesus alloimmunisation.  Article first published online: 3 Sep 2015. DOI: 10.1002/14651858.CD000020.pub3

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