A transfusion medicine physician in Tel Aviv, Israel, wonders how colleagues manage pregnancies that are complicated by non-D alloantibodies that have clinically-significant specificities. In particular, for which antibodies (if any) are titers relevant? Is transcranial doppler being used (more) routinely and as an alternative to amniocentesis?

The following comments have been received.

ADDENDA May 4, 2006

1. Dr. Kenneth Moise, Upjohn Distinguished Professor of Obstetrics and Gynecology at the University of North Carolina at Chapel Hill (attribution used with permission) reports that in his experience, many centers typically use a similar "critical titer" that they would employ in the RhD alloimmunized pregnancy to begin fetal testing when they are faced with anti-red cell antibodies other than anti-D. The critical titer value varies with institution and ranges between 16 and 64. The notable exception to this is Kell (K1) alloimmunization where a critical titer of 8 is routinely used. Dr. Moise adds that the peak systolic velocity of the middle cerebral artery has proven useful for the detection of fetal anemia in cases of maternal alloimmunization to non-RhD antibodies. He has observed that many centers now employ this as the first line of testing instead of serial amniocentesis for OD450 analysis.

ADDENDA May 8, 2006

2. A Biomedical Scientist working for the UK National Blood Service reports that for non-D/c alloantibodies (except anti-K, see below) they use a titration method to assess antibody strength. Titers for non-D/c antibodies below 32 are not seen as clinically significant. Titers for non-D/c antibodies of 32 and above are considered clinically significant. The first titer is usually done at 12 weeks gestation and repeated at 28-32 weeks. The repeat sample is tested in parallel with the previous sample (frozen archive). What they are looking for is a rise in the titer, which would indicate a possible further fetal-maternal bleed and stimulation of the mother's immune response. In their opinion, it is unlikely that non-D/c antibodies would require intervention before birth. Advice to the clinic is to monitor the pregnancy (the MCA doppler has been shown to be very effective in the UK), and to check the newborn's direct antiglobulin test at birth and to monitor the newborn's hemoglobin and bilirubin following birth. As stated above, the exception to the aforementioned strategy is anti-K. Their guidelines state that anti-K can cause severe HDN regardless of titer. If the partner (or fetus) is known to be K+ they titrate every 4 weeks to 28 weeks gestation and then every 2 weeks until birth.

3. Dr. Dennis Goldfinger, an extremely experienced transfusion medicine physician who practices at Cedars-Sinai Medical Center in Los Angeles (attribution used with permission) reports that in his experience the majority of non-D antibodies which are said to be capable of causing clinically important HDN rarely do so, even though these antibodies may produce serious hemolytic transfusion reactions. The two most important exceptions, in his opinion, are anti-c and anti-K. Anti-K is particularly important, since the antibody suppresses RBC production in the marrow in addition to causing hemolysis in the blood, so is potentially devastating and can cause very early fetal demise, before there is any opportunity for medical intervention. He believes that following the fetus with Doppler studies is the most sensible approach, particularly for the vast majority of antibodies which rarely cause significant HDN. He adds that the use of titers is OK and most useful when there is a substantial rise, which might justify more invasive diagnostic studies. All-in-all, in his opinion, non-anti-D HDN is a most uncommon complication of pregnancy and justifies the dictum of "first do no harm."

ADDENDA May 17, 2006

4. In the experience of Dr. Jeffrey Greenspoon, a practicing obstetrician/gynecologist in Los Angeles (attribution used with permission), while antibody titers to the D antigen are useful as a threshold to begin or evaluate for intervention, the antibody titer to other antigens is not relied upon in his everyday practice. He has never been in an institution or group that relied on the antibody titer for any paternal antigen which is capable of causing severe erythroblastosis (other than the D antigen) to make management decisions. All fetuses had surveillance using ultrasound. He adds that since the year 2000, Giancarlo Mari and his associates revolutionized fetal surveillance for isoimmunization with his observations of the fetal middle cerebral artery the peak systolic flow velocity (MAC-PSV). (N Engl J Med. 2000 Jan 6;342(1):9-14). In Dr. Greenspoon's opinion, the advantage to using the MCA-PSV is that it is non-invasive. Alloimmunization due to Rhesus antigen(s), Kell, Parvovirus, and other causes have been studied. The MCA-PSV also is useful after one or two intra-uterine transfusions. The optimal interval for surveillance may be weekly for most cases. As always, a team involving the maternal-fetal specialist, the blood bank, the ultrasonography group, neonatologists, and nursing provide better care than isolated specialists working alone. A weekly or bi-weekly conference to discuss all fetal/neonatal cases is useful in obtaining input, reaching consensus on management, planning the best time for procedures (cordocentesis and intra-vascular transfusion of the fetus) and events (delivery) for the entire team of providers.

ADDENDA Aug. 15, 2006

5. A physician in Virginia asks how colleagues manage a pregnant patient who has a warm autoantibody (with or without evidence of autoimmune hemolytic anemia). He acknowledges having reviewed relevant sections of the book by Drs. Petz and Garratty entitled "Immune Hemolytic Anemias", [Churchill Livingstone, Philadelphia, 2nd edition, 2004. chapter 9, page 345], as well as additional references including: Issitt, PD and DJ Anstee, Applied Blood Group Serology, Montgomery Scientific Press, Durham, 4th edition, 1998, pages 971 and 972; Williamson, TD et al, A maternal warm-reactive autoantibody presenting as a positive direct antiglobulin test in a neonate, Immunohematology 13: 6, 1997, as well as the links to information at:

• Lakasing L, Williamson C. Obstetric complications due to autoantibodies. Best Pract Res Clin Endocrinol Metab. 2005 Mar;19(1):149-75. Best Pract Res Clin Endocrinol Metab. 2005 Mar;19(1):149-75.
• Tincani A, et al. Autoimmunity and pregnancy: autoantibodies and pregnancy in rheumatic diseases. Ann N Y Acad Sci. 2006 Jun;1069:346-52.
• Lee LA. Transient autoimmunity related to maternal autoantibodies: neonatal lupus. Autoimmun Rev. 2005 Apr;4(4):207-13. Epub 2004 Dec 8.
• Dorner I, etal. Combined maternal erythrocyte autosensitization and materno-fetal Jk incompatibility. Transfusion. 1974 May-Jun;14(3):212-9.

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Ira A. Shulman, MD
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