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gagpinks

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Interesting case!!

We have ANC patient whose blood group is O Rh D negative and  antibody screen was negative at 28 weeks so she has been given Prophylaxis anti D at 28 weeks. She attend A&E due to sensitizing event at 32 weeks. Her antibody screen positive due to prophylaxis anti-D but strength of the reaction was 4+  by IAT so we sent sample to reference lab for quantification report came back with 1.1 iu/ml and within 3 days its gone up to 4.1iu/ ml. 

So do we still have to rely on strength of the reaction in conjunction with new guidelines. ?

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Did she have anymore anti-D Ig after the sensitising event?  I would have thought the increase in quant would be due to that, or she could have started making immune anti-D if she wasn't given any/enough following the bleed.  I've moved from a reference lab to a hospital and I've never been keen on looking at the strength of reaction to basically have a guess if it is prophylaxis.   The clearance or lack of clearance of Anti-D Ig is down to the individuals immune system.

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She has been given routine dose  at 28 weeks and she had sensitizing event at 32 weeks and this why we received G/S and she is been issued another dose on same day. Sample was taken before anti-D was given so that's strength of reaction wasn't due to recent dose.

 

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21 hours ago, gagpinks said:

Interesting case!!

We have ANC patient whose blood group is O Rh D negative and  antibody screen was negative at 28 weeks so she has been given Prophylaxis anti D at 28 weeks. She attend A&E due to sensitizing event at 32 weeks. Her antibody screen positive due to prophylaxis anti-D but strength of the reaction was 4+  by IAT so we sent sample to reference lab for quantification report came back with 1.1 iu/ml and within 3 days its gone up to 4.1iu/ ml. 

So do we still have to rely on strength of the reaction in conjunction with new guidelines. ?

Hi gagpinks,

Sorry to be a bit late on this one, but I have been marking some IBMS HSD papers, whilst I am off on sick leave, and got a bit engrossed in what I have been doing.

This is not only an interesting case, but is also a very rare case.

If you read either the RCOG Green Top Guideline 65 (The Management of Women with Red Cell Antibodies in Pregnancy) or the recent BCSH Guideline (Guideline for blood grouping and red cell antibody testing in pregnancy) you will see that any antibody produced de novo after 28 weeks of gestation is not usually considered to be clinically significant in terms of causing a clinically significant haemolytic disease of the foetus and newborn.  That having been said, both of the anti-D levels you quote (1.1 IUmL-1 and 4.1 IUmL-1) would be regarded as immune in nature, rather than as a result of anti-D immunoglobulin prophylaxis.  Equally, however, if you read the work of the late, great Prof Patrick Mollison (quoted in the latest edition of Klein HG and Anstee DJ, Mollison's Blood Transfusion in Clinical Medicine) you will see that the production of a de novo red blood cell antibody (primary immunisation, including anti-D) almost never happens so quickly.  Indeed, in most cases it takes weeks, and sometimes months (and multiple challenges to the immune system) to produce the antibody.

All that having been said, it is well known that there are three kinds of individuals that exist in terms of ability to produce (or not) red cell antibodies.  There are a small number who are known as "non-responders", and these individuals seem not to be able to produce an immune alloantibody (as opposed to an isoantibody, such as anti-A and/or anti-B), however many times their immune system is challenged by an antigen that they lack.  Then there are the large number of people who make antibodies after several challenges to their immune system, and after a long time (weeks or months) - the normal responders.  Lastly, there are a small number of individuals (known as super-responders) who tend to make antibodies after a very small challenge to their immune system (the great Ed Synder gave a wonderful lecture at a BBTS ASM some years ago, when he described such individuals as being able to produce an antibody after a virtual transfusion - as he put it, you show them a photograph of a red cell that expresses an antigen that they do not themselves express, and BANG, there is the antibody!).  BUT, although such individuals have been known about for many, many years, they do not appear in the literature as having produced a de novo antibody within a time quicker than normal.

All of the above verbiage, therefore, suggests to me that this is a secondary immune response, rather than a primary response.  Now, PLEASE realise that by saying this I am in no way suggesting that you (or your colleagues) have "missed" an antibody that should have been detected earlier.  What I mean by this is that the anti-D from a previous primary response may well have been there, but may well have been so weak that it would not have been detected by IAT, but only by the use of enzyme-treated red cells, and possibly by the use of an IAT using enzyme-treated red cells.  In other words, by an enzyme technique, which would not have been used for your antibody screening red cell testing (this is where the very rare bit of your case comes in).

You may well say to me that this is the woman's first pregnancy and that she has never been transfused, but there are cases in the literature where a woman has been pregnant, and had a spontaneous abortion or miscarriage without her actually knowing that she was pregnant in the first place, and this could be the cause of the primary immunisation, and this may be such a case.  Alternatively, she may have previously had a transfusion that she does not remember (maybe she was under GA), which involved the transfusion of a unit of blood that was Partial D.  Who knows?

 

20 hours ago, A little lab lost said:

Did she have anymore anti-D Ig after the sensitising event?  I would have thought the increase in quant would be due to that, or she could have started making immune anti-D if she wasn't given any/enough following the bleed.  I've moved from a reference lab to a hospital and I've never been keen on looking at the strength of reaction to basically have a guess if it is prophylaxis.   The clearance or lack of clearance of Anti-D Ig is down to the individuals immune system.

To go on with my lengthy answer (sorry about this, but all of my friends and colleagues say I love the sound of my own voice), experiments have been performed that show the parentral introduction of anti-D immunoglobulin into the circulation of volunteer D Negative individuals has resulted in levels of anti-D well below the threshold of 1.0 IUmL-1, which we used to use as the limit for this prophylaxis, but that, unless the woman was of particularly small stature, rarely rose above 0.5 IUmL-1.  These results were after several doses of more than 1500 IU of anti-D, not just standard doses, so a level of 4.1 IUmL-1 in this woman is most unlikely to be as a result of further doses of anti-D immunoglobulin prophylaxis.

The strength of reaction is not, I can assure both of you, a way of telling whether or not an anti-D is as the result of the administration of anti-D immunoglobulin or a genuine immune anti-D!  Having worked as the Reference Service Manager in an area of London that contained four hospitals that each had specialist foetal medicine units (all of which "imported" women from other hospitals, when the women had high levels of alloantibodies in pregnancy), I can assure you that a woman with an anti-D level in the thousands of IUmL-1 will often give quite weak results (vis-a-vis agglutination, as opposed to quantification or titre), because the D antigen sites of the test red cells are "swamped" by the number of IgG anti-D molecules.

I agree with you 100% A little lab lost, that the clearance of anti-D immunoglobulin is, within reason, "person specific".

19 hours ago, gagpinks said:

She has been given routine dose  at 28 weeks and she had sensitizing event at 32 weeks and this why we received G/S and she is been issued another dose on same day. Sample was taken before anti-D was given so that's strength of reaction wasn't due to recent dose.

 

Having said all of the above, I would strongly advise you gagpinks, to monitor this woman's anti-D levels every two weeks until delivery and would request (out of pure nosiness) that, after delivery, you post the results of her final pre-natal anti-D levels on here, and the outcome of the pregnancy.  Would you mind?

 

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Sure Malcolm I will! !

Malcolm and little lab my point here is that we could have  easily missed out   this case if we would have not checked the strength of reactions because her antibody screen was negative at 28 weeks and proph D was given 4 weeks ago. This was my special interest so I have performed in house titre which was 1: 512 so when we got result back  from ref lab we were not convinced and   so we sendt second sample for confirmation and where we got 4.1 iu/ml.  I don't know whether you have seen my previous post where I asked USA friends what is the correlation between titre and quantification.? 

Edited by gagpinks
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Hi gagpinks,

No, I would NEVER trust just the strength of reaction for reasons given above (that is, that there can be so much anti-D in the circulation that many, if not all, of the D antigens expressed on the reagent red cells can be blocked or "swamped").

 

In my opinion (and it is only MY opinion, others may well disagree - and legitimately so), this is not just an interesting case, but also a very unusual case, in that I am still convinced that the anti-D you are detecting is the result of a secondary immunisation, rather than a primary immunisation - not just because of the short time between an apparent sensitising event, but also with the speed the antibody concentration rose to 4.1 IUmL-1 (again, see my earlier comments as to why the anti-D may not have been detected).  It is this that makes the case so very unusual, as anti-D from a primary immunisation can usually be detected very easily, whereas, for example, an anti-Jka becomes undetectable by standard serological methods quite often.

I did see your other comment, but, to be honest, I doubt if many of our friends and colleagues in the USA will know the answer (as, I think I am correct in saying, they do not use quantification for anti-D at all), and, without going back in time (by reading early editions of Mollison, for example) I doubt if too many people in the UK would know the answer either, as we so rarely use titration for anti-D in pregnancy.  There are, however, a few isolated places that do titrate anti-D in pregnancy, and I think I am correct in saying that one of these is The William Harvey Hospital in Kent (contact their lead Biomedical Scientist Susan Mitchell-Townsend).

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My point here is that we could have  easily missed out   this case if we would have not Noticed the strength of reactions because her antibody screen was negative at 28 weeks so proph D was given as a routine RADDP at 28 weeks.  But when she came at 32 weeks her antibody screen was strong positive . 

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9 hours ago, gagpinks said:

My point here is that we could have  easily missed out   this case if we would have not Noticed the strength of reactions because her antibody screen was negative at 28 weeks so proph D was given as a routine RADDP at 28 weeks.  But when she came at 32 weeks her antibody screen was strong positive . 

Yes, I agree that, in this particular case, you could have missed the immune anti-D gagpinks, BUT, as I have said several times throughout this thread, this is a very unusual case.  I am no statistician, and so I would not like to say that it is 1 in a million or something like that, but I will say that it is 1 in an awful lot and, because of the rarity of such a case, I would also say that, if a cost/benefit study was to be performed, to see if there should be any changes to the BCSH or RCOG Guidelines with regard to when to test the women's plasma during pregnancy, the answer would be that the Guidelines would not change, as so few cases would be detected, compared with the cost of being able to detect such cases.  So, yes, in this case if you had not noticed the strength of reaction, the immune anti-D may not have been detected, and it may have resulted in a baby affected by the anti-D, but one cannot change general Guidelines using such unusual cases.

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1 hour ago, galvania said:

This is maybe a silly question, but I presume you have checked that the antibody she has made herself (as opposed to the proph) really is an anti-D and not an anti-G....

I may be wrong Anna, but I cannot remember gagpinks saying that there was a potential anti-C being in the plasma, as well as an anti-D (which would have been expected, if the antibody specificity was actually an anti-G), but, if that were to be the case, as the sample was sent to an NHSBT Reference Laboratory, any sample from a pregnant lady that appears to contain an anti-C+D is tested to ensure that it is not actually an anti-G.  On a cost/benefit argument, I can't say that this won my vote(!), but that is, nevertheless, the case.

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On 07/10/2016 at 6:19 PM, Malcolm Needs said:

that, after delivery, you post the results of her final pre-natal anti-D levels on here, and the outcome of the pregnancy.  Would you mind?

Hi Malcolm 

The woman   has delivered the baby at 35 weeks by planned C section. Her final quantification level is 6.1 iu/ml. 

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41 minutes ago, gagpinks said:

The woman has delivered the baby at 35 weeks by planned C section. Her final quantification level is 6.1 iu/ml. 

Thanks very much for that gagpinks, but I would really like to know about the health of the baby.  I would be prepared to "stick my neck out" and say that, at most, the baby probably needed a little phototherapy as a result of an anti-D level of 6.1 IUmL-1 so late in pregnancy, although there may be a small chance of physiological anaemia (as opposed to either immune anaemia or iatrogenic anaemia) due to the prematurity of the baby - albeit, planned prematurity.

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17 hours ago, Malcolm Needs said:

Thanks very much for that gagpinks, but I would really like to know about the health of the baby.  I would be prepared to "stick my neck out" and say that, at most, the baby probably needed a little phototherapy as a result of an anti-D level of 6.1 IUmL-1 so late in pregnancy, although there may be a small chance of physiological anaemia (as opposed to either immune anaemia or iatrogenic anaemia) due to the prematurity of the baby - albeit, planned prematurity.

Hi

Sorry for late reply.  Patient has known for placenta acreta so we are not sure the reason for c-section. (due to clinical condition or rising antibody level)

Baby's DAT is positive (obviously ) and Hb is 175 g/L and bilirubin is elevated to 89 umol/L . Baby is on phototherapy, no blood required so far. 

Thanks

 

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Placenta accreta, in itself, is probably the reason for the C-section, and the condition being present in the first place suggests that this is not the woman's first pregnancy (although this is by no means true in all cases), and this may explain the apparent (and probable) secondary immunisation.  One symptom of Placenta accreta is also PV haemorrhage and, even if this was a silent event, it would also add weight to the theory of a secondary immune response.

As far as the baby is concerned, that is what I would have expected.

Thanks for that gagpinks.  A very interesting case.  Keep us informed of any further developments, if you wouldn't mind.

Edited by Malcolm Needs
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Hi

Malcolm just wondering what is advisable in terms of follow up care for those neonates born to mothers with antibodies with the potential to cause HDFN. Some of these babies are born well but may deteriorate later. How long should we be concerned about haemolysis persisting post nataly for example with anti-D or anti-c. Also should we be less concerned with neonates born to mothers with a lower quantification? We are advised by RCI that pregnancy should not continue beyond term but this seems to be at odds with what is advised in BCSH and RCOG guidelines which advise that these babies should be delivered at 37 weeks.  

 

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I am not certain that the RCI "canned comments" say that the pregnancy should not continue beyond term, unless they have been changed very recently.  If they do say that, then they most certainly should not!  The RCI Department of the NHSBT has no business telling the Obstetricians how to look after their patients (even the NHSBT Medical Consultants will only give guarded advice), particularly as RCI will not have seen the patient (there may be a medical reason why the pregnancy should be allowed to beyond term) and are not medically qualified.  Certainly, most of the reports that go out to hospitals in the laboratory where I work (for another 11 days - when I retire - Yippee!!!!!!!!) are electronically signed by Biomedical Scientists and not by Medical Doctors.

Turning back to your other questions, again, how long you follow up a baby like this is really up to the Obstetrician/Neonatologist, however, in the case of two different babies (at quite different times, although both, strangely enough from a couple of hospitals in Kent that are quite close to one another), we followed the baby for several weeks afterwards, as they continued to require top-up transfusions.  These cases were both unusual, in that the anti-D in the mother's circulation were both above 100 IUmL-1, both required an IUT to be given during the pregnancy, and both required double exchange transfusions at birth.  Of course, this meant that the baby was not stimulated to produce it's own red cells for some time, but those that were produced were immediately destroyed by the maternal anti-D still in the baby's circulation.  I must stress, however, that such cases are very rare, and we were just unlikely to have two of them fairly close together.

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