The patient has had two term pregnancies with normal outcomes and one pregnancy that ended in a third trimester fetal death. During the first pregnancy, the patient received RHIG at 28 weeks gestation without a problem. However, after delivery she received a post-partum injection of RHIG, which was followed by swelling, redness, and itching at the injection site and the development of a lump the size of a marble. During the second pregnancy, the patient received RHIG at 28 weeks gestation and postpartum, and each injection was associated with increasingly severe local reactions. During the third pregnancy she underwent amniocentesis to confirm/refute a positive blood screening test suggesting that her fetus might have Down syndrome. Following the amniocentesis she received RHIG and then developed a "large welt" (6-8 inches) with itching, redness, and swelling of inguinal lymph nodes. The patient was given Benadryl that she took for two days; the local reaction took nearly 1.5 weeks to subside. The fetus was found to be Rh negative; consequently, she did not receive RHIG at the beginning of the third trimester nor postpartum. Unfortunately, this pregnancy ended with a stillbirth (said to be nuchal cord but may be unexplained). The patient was then referred to an allergist for evaluation. Skin testing to RHIG was positive at a dilution of 1:100. The patient was then referred to the inquiring physician's institution for management of a fourth pregnancy. The inquiring physician considered the possibility that the patient was reacting to either thimerosal preservative or to latex on the end of the RHIG vial's plunger. However, checking drug lot numbers with the manufacturer revealed that she reacted to RHIG preparations produced after both the addition of thimerosal and the use of latex were eliminated. Furthermore, subsequent skin testing with an IV preparation of RHIG, a product always devoid of these materials, was equivalently positive at full strength. Interestingly, the patient developed skin discoloration at the sites of injection and skin testing. IgA deficiency (and then a reaction to IgA in the drugs) was also considered, but testing revealed that the patient was not IgA deficient. To the inquiring physician's knowledge, a deficiency of particular IgG subtypes was not determined. So, the basis for this patient's reaction to IM and IV preparations of RHIG is still unknown.

The options at this point that are being considered by the OB/Gyn team are as follows:

1. Attempt to desensitize the patient by giving her small but increasing doses of WinRho (up to the full dose of 1500 IU, which is equivalent to 300 micrograms) and then give her a dose of WinRho following her amniocentesis.
2. Perform the amniocentesis and, if "clean", not give the patient any RHIG because of the following considerations: her husband is heterozygous and the fetus may not be Rh-positive; by avoiding the placenta during the amniocentesis procedure, the probability of sensitization is probably much less than 1%; and the patient claims that this will be her last pregnancy.

In any event, molecular testing will be performed on the amniotic fluid to genotype the fetus to determine if Rh-immune globulin might be needed at 28 weeks and at delivery.

The following responses were received.

ADDENDA Sept. 1, 2003

1. A colleague in Minnesota comments that this interesting case does not mention whether the patient was tested for anti-IgA antibodies. The Minnesota colleague is of the opinion that even if the patient is not IgA deficient (as mentioned in the case history), the absence of a deficiency does not mean that the patient might not have a so-called "limited specificity" anti-IgA antibody. The Minnesota colleague recommends that the patient be tested for anti-IgA antibodies.

ADDENDA Sept. 2, 2003

2. A colleague in the Southern USA wonders if this interesting case of local reactions to RHIG has been evaluated to determine if the reactions are limited to a particular formulation of RHIG. He comments that it was not clear to him that the patient was evaluated against RHIG from different manufacturers to see if that variable made a difference.

3. In response to the Southern USA colleague's query (see ADDENDUM #2 above), the colleague who initially reported the case states that the skin tests were positive against both an IM formulation of RHIG (manufacturer #1) and an IV formulation (manufacturer #2). Furthermore, the colleague who reported this case states that these formulations were made by different manufacturers. Thus, the reporting colleague believes that these two formulations are subject to different manufacturer-specific processes and possibly even donor pools. The reporting colleague also believes that the preparation made by manufacturer #2 for IV use undergoes considerable purification (more so than what occurs for the IM injection formulation that is produced by manufacturer #1). Therefore, the reporting colleague believes that his laboratory has evaluated preparations of RHIG that were sufficiently different from each other, yet each formulation has been associated with findings that are suggestive of some type of allergic reaction.

ADDENDA Sept. 4, 2003

4. Dr. Girish N. Vyas of UC San Francisco (attribution used with permission) reports (verbatim) "The commentary by the Minneapolis colleague is pertinent to anti-IgA of limited specificity as a possible cause of allergic reactions to RHIG in the subject patient. The first three cases of anti-IgA of limited specificity occurring in patients with normal IgA levels and history of repeated transfusion reactions to IgA-containing blood products were characterized by 'urticaria or anaphylactoid symptoms' ⁽¹⁾. In one of the three patients the etiology of transfusion reactions caused by anti-IgA of limited specificity was experimentally established by safe transfusion of plasma lacking IgA (aIgA), and transfusion of IgA-containing normal plasma provoking a non-fatal anaphylactoid reaction with an acute drop in level of circulating complement ⁽¹⁾. The complement-activating IgG antibodies specific for one of the IgA1 myeloma proteins failed to define an allotype of IgA1. However, the discovery of the first allotype of human IgA, now termed A2m(1), was enabled by investigation of another female patient who had no history of transfusion but suffered an anaphylactoid transfusion reaction due to anti-IgA of limited specificity ⁽²⁾. Intrauterine exposure to her son's A2m(1) allotype, inherited from his father, was attributed to induce her anti-A2m(1), while the possibility of her being immunized during her intrauterine life to maternal IgA could not be excluded as her mother was deceased ⁽³⁾. Since this fundamental discovery four more cases of anti-A2m(1) associated with anaphylactoid, allergic and serum sickness-like syndrome have been annotated by us ⁽⁴⁾. Notably, uncommon Caucasians negative for A2m(1) tend to get sensitized to the allotype and suffer from allergic/anaphylactoid reactions associated with A2m(1) antibodies ⁽⁴⁾. Although we can test the serum for anti-A2m(1) in the subject patient reacting to RHIG, the American Red Cross Reference Laboratory in Philadelphia provides service for anti-IgA testing using both IgA1 and IgA2 paraproteins."

References:

⁽¹⁾ Vyas GN, Perkins HA, Fudenberg HH. Anaphylactoid transfusion reactions associated with anti-IgA. Lancet 1968; ii:312-5.

⁽²⁾ Vyas GN, Fudenberg HH. Am(1), the first genetic marker of human IgA globulin. Proc Natl Acad Sci USA, 1969; 64:1211-6.

⁽³⁾ Vyas GN, Levin AS, Fudenberg HH. Intra-uterine isoimmunization caused by maternal IgA crossing the placenta. Nature 1970; 225:275-6.

⁽⁴⁾ Vyas GN, Perkins HA. Transfusion 1976; 16:289-90."

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