Addenda: Aug. 3 & 24, 2009

Antibody titer testing on pregnant women when the patient has an antibody known to possibly cause hemolytic disease of the newborn/fetus (HDN/F)

A Transfusion Service Supervisor in California reports that his laboratory performs antibody titer testing on pregnant women when the patient has an antibody known to possibly cause hemolytic disease of the newborn/fetus (HDN/F). He was asked by a staff physician what antibody titer would cause concern for a developing fetus, and what change in titer from a previous result would “send up a red flag" indicating that intervention might required.

Upon being referred to the following discussions (see below), the inquiring colleague said: “I appreciate the references regarding antibody titers during pregnancy. They were of much help in making some changes to my procedure”.

• Antibody titer studies in pregnant women at risk for bearing an infant with hemolytic disease of the newborn
• Indications to perform a titer when anti-D is detected in a patient who has received Rh Immune Globulin
• Management of a pregnant woman who may have native anti-D, but has also received an antepartum dose of RhIG

The following comments have been submitted in response.

ADDENDA August 3, 2009

1. According to W. John Judd, FIBMS, MIBiol, Emeritus Professor of the Department of Pathology at the University of Michigan (attribution used with permission), historically, titration of potentially significant blood group antibodies encountered in pregnancy was done to limit the use of amniocentesis. A critical titer of 16/32 was established, as mentioned in the discussion "Antibody titer studies in pregnant women at risk for bearing an infant with hemolytic disease of the newborn"; when the antibody titer reached or exceeded this value, the extent of hemolytic disease was monitored by measuring the bilirubin level (DeltaOD450) in amniotic fluid. It is important to note that all the "critical titer" data involved pregnancies affected with anti-D. However, the same value is often applied to other antibodies capable of causing HDN/F. The major exception being antibodies to Kell-system antigens, where the extent of hemolytic disease is monitored by high-resolution ultrasound and measurement of middle-cerebral arterial flow by Doppler (MCAD). For all other potentially significant antibodies, it is recommended that the obstetricians be contacted prior to performing titers and asked how they propose to use the data. Indeed, the management of the alloimmunized pregnancy by measurement of bilirubin in amniotic fluid has largely if not completely been replaced by use of ultrasound and MCAD studies. To limit the use of these procedures, an anti-D titer of 8 or higher may be used (per obstetricians at the University of Michigan).

ADDENDA August 24, 2009

2. According to George Garratty, PhD, FRCPath., Scientific Director at the American Red Cross Blood Services in Southern California, although the "critical titer" of anti-D has been commonly used, up to the last few years, he has always felt that it had little value as it was routinely applied. It was first described by a group that had data relating titers to the predictive value in their institution. From all we have learned about predicting the clinical significance of alloantibodies, it is clear that titers do not measure quantity of antibody well, and that quantity of antibody is only one of many factors (e.g., subclass, efficiency of macrophages system in individual patients) that can reflect the ability of the antibody to cause significant RBC destruction. There are even more factors involved in hemolytic disease of the fetus and newborn (HDFN) [e.g., efficiency of placental transfer from mother to baby, inhibitory affects of antigen (e.g., ABH, HLA) on tissue and other cells in fetus]. Thus, for a hospital that has no data of its own on correlation of titer results and severity, it makes little sense to use another institution's level (titer). Others have published similar opinions (see Gall and Miller, Rh isoimmunization: a 24 year experience at Duke University Medical Center, Am J Obstet Gynecol 1981;140:902-8;and van Dijk et al, Red cell antibodies in pregnancy: there is no 'critical titre'. Transfus Med 1995;4:199-202). All of this relates to using it for anti-D. Dr. Garratty knows of no comparable data on antibodies other than anti-D. Thus, he would suggest that using "critical" titers for antibodies other than anti-D is a very unscientific approach on which to base decisions on using invasive approaches (e.g., amniocentesis) on the mother. The good news is that the better obstetrical practices are using a non-invasive Doppler ultrasound method (peak systolic velocity of the middle cerebral artery) instead of "critical" titer. He adds: "If this is not available, before obstetricians make decisions on "critical titer" for antibodies other than anti-D, I would point out to them data showing how unusual it is for such antibodies to cause HDFN that needs treatment. Bowman [Hemolytic disease of the newborn. In, Immunobiology of Transfusion Medicine. Garratty, G (ed) New York: Dekker, 1994, pp 553-95] showed that only 51% of D+ babies , born with a positive DAT, to a D– mother with anti-D, needed treatment, and that only 26% (range 12-50%) of babies born with a positive DAT, due to antibodies other than anti-D, e.g., anti-c, -E, -C, Kell, Duffy and S antibodies, needed treatment. In a large study from the Netherlands, Koelewijn et al (Effect of screening for red cell antibodies, other than anti-D, to detect hemolytic disease of the fetus and newborn: a population study in the Netherlands. Transfusion 2008;48:941-52), showed severe HDFN requiring intrauterine and/or exchange transfusions for antibodies other than anti-D were 3.7% of fetuses at risk (antigen+), and 11.6% for anti-K; 8.5% for anti-c; and 1.1% for anti-E; and none with antibodies other than Rh and Kell. Having said the above, unfortunately, the last Education Bulletin on Rh from ACOG, in 2006, still contains the 8-32 'critical titer' values and suggests this can be applied to all antibodies except Kell!" To answer the doctor’s question about rises in antibody titer is just as difficult to answer. If the maternal antibody is titrated in parallel with the last sample, then any rise in titer should be of interest; there is no magical correlation with a certain number of tubes difference and clinical significance; it only indicates a need to monitor the mother/fetus carefully.

Submit comments to the e-Network Forum at enetworkforum@cbbsweb.org

Ira A. Shulman, MD
CBBS e-Network Forum Senior Editor & Moderator

W. Tait Stevens, MD
CBBS e-Network Forum Editor & Moderator

Elizabeth M. St. Lezin, MD
CBBS e-Network Forum Associate Editor & Moderator