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Haemolytic disease of the newborn can result from Rhesus incompatibility in utero. In this disease an Rh- mother becomes exposed to the antigens of an Rh+ foetus by fetomaternal haemorrhage causing her to mount an immune response against the D antigen. In her second pregnancy, repeat exposure to the D antigen activates memory cells causing a large production of IgG Anti-D antibodies that cross the placenta adhering to foetal red blood cells, which are then destroyed.

To prevent this, Rh- mothers are normally given exogenous Anti-D at 28 and 34 weeks gestation or after any sensitising event. The aim of this treatment as I understand it is to 'mop up' any D antigen in the maternal bloodstream, covering it in exogenous antigen so the mother's immune system does not mount its own response.

I had previously assumed that these exogenous antibodies would be IgM to avoid them crossing the placenta, however looking at the summaries of product characteristics for some of the common preparations I see that "at least 95%" of protein content other than albumin is IgG. I then wondered if the exogenous antibodies had a much reduced half life, however the half life is "about 3-4 weeks."

Why does the exogenous IgG not cause haemolytic disease of the newborn in the exact same way that endogenous IgG would in a previously exposed woman who had not had prophylaxis? Is it dose-dependent or am I missing something entirely?

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I've had a difficult time getting anything definitive to support my answer to your specific question of safety, however, I thought I'd go out on a limb and give you my understanding. A recent review of what is known about this can be found at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2809506/

I think you are on the right track with your 'dose-dependence' hypothesis. This is exactly what the makers of RhoGAM suggest, saying that the amount of antibody administered at 28 weeks into the pregnancy is sufficient to block any Rh antigen on Red Blood Cells that escape into the mother's blood, but insufficient to cross the placenta and be a problem. At this time the child will be large enough that any RhoGAM that does cross the placenta will not kill enough Red Blood Cells to harm the child.

Mom gets another dose of antibody after the delivery in order to ensure thorough coverage of antigen that results from mixing of blood at that time, however this dose is not a problem as the baby has already left the mother.

By the way, the rationale for the antenatal dose is that post-partum administration alone failed to prevent sero-conversion in almost 2% of Rh- women, putatively due to transplacental hemorrhaging.

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  • $\begingroup$ That's an excellent article, thank you. I had wondered if they used primarily IgG2 to reduce placental transmission but this is not the case (the article indicating IgG1 and IgG3). If a 125 unit dose can neutralise only 1.25 ml of D+ve blood and not all of it crosses the placenta then this is likely to be an insignificant dose to cause harm. I assume this could cause harm with a greater number of repeated doses after sensitising events but I think this is sufficient evidence to say that it is indeed a dose dependent phenomenon. Thanks! $\endgroup$
    – Rory M
    Commented Jul 12, 2015 at 10:40
  • $\begingroup$ I think this just isn't really the kind of thing that can be explored in a dose escalation trial (at least not in humans) and it would be meaningless to try to extrapolate from any other species. $\endgroup$
    – johntreml
    Commented Jul 12, 2015 at 23:15
  • $\begingroup$ From the most up-to-date article I can find on the D-GAM treatment, IgG1 is primarily used, followed by IgG2. To be precise: 64.3% IgG1, 29.0% IgG2, 6.2% IgG3, 0.5% IgG4 $\endgroup$
    – Astrid_Redfern
    Commented Nov 19, 2020 at 20:02
  • $\begingroup$ Another treatment for this is Rhophylac. In this case, we have: 84.1% IgG1, 7.6% IgG2, 9.1% IgG3, 1.0% IgG4 $\endgroup$
    – Astrid_Redfern
    Commented Nov 19, 2020 at 20:09
  • $\begingroup$ Where you say "insufficient to cross the placenta and be a problem" - the review paper you link to actually makes this clearer. It explains that some of it can cross the placenta, but not enough to endanger the newborn. $\endgroup$
    – Astrid_Redfern
    Commented Nov 19, 2020 at 20:26

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