A colleague (location intentionally vague) reports that a hospital recently treated a pregnant Rh negative woman who presented during the third trimester because of spotting and contractions. She was admitted to the hospital and her obstetrician ordered 1 vial of RHIG for immunoprophylaxis. The woman did not exhibit anti-D or any other unexpected antibodies prior to the administration of the RHIG, but because the patient was beyond 28 weeks gestation, and because she was experiencing spotting, the order for RHIG automatically triggered the blood bank laboratory to perform a rosette test on the patient's blood sample (in accordance with local laboratory policy) to screen for a feto-maternal bleed, in the event that additional vials of RHIG might be necessary. The reporting colleague states that the rosette test was strongly positive, and that the laboratory reflexed to perform a Kleihauer-Betke test to quantify the size of a feto-maternal bleed. The Kleihauer-Betke test reportedly showed 4% fetal cells, which was interpreted as a feto-maternal bleed of ~200 mL. When presented with the aforementioned result, a debate ensued regarding the credibility of the Kleihauer-Betke test results, since the obstetrician allegedly felt that the fetus would be dead if a bleed of that size had really taken place. Consequently, the Kleihauer-Betke test was repeated, but the repeat test showed the same results. The obstetrician ordered an ultrasound, hemoglobin electrophoresis and consulted with two neonatologists at another hospital. No further RHIG was administered at that time. In the meantime, the mother's blood specimen was sent to a reference lab for flow cytometry to quantify the percentage of fetal cells. The reporting colleague states that the flow cytometry results showed 4% fetal cells. In addition, the hemoglobin electrophoresis reported showed 4% fetal hemoglobin. The obstetrician judged that the lab results were aberrant. Two weeks later the woman returned to the hospital in labor and a C-Section was performed. The mother's antibody screen was negative using LISS-AHG. The infant's hemoglobin level was reportedly 5.1 g/dL, and a transfusion of 100 mL of group O Rh negative leukocyte-reduced, CMV-negative, fresh, (less than 7 days old) RBCs was initiated. The baby was group O Rh positive and reportedly demonstrated 486 nucleated RBC's per 100 WBC's. After delivery of the baby, the mother received 10 vials of RHIG. A Kleihauer-Betke test at the time of delivery showed approximately 5% fetal cells. The placenta showed an edematous cord with squamous metaplasia, fibromuscular hyperplasia, increased syncytial knotting (70%), edematous cotyledons and interstital calcifications. The reporting colleague would appreciate comments regarding this very interesting case report.

The following responses were received.

1. Dr. J. Lawrence Naiman (attribution with permission), a retired pediatric hematologist in Palo Alto and co-author with the late Dr. Frank A. Oski of three editions of "Hematologic Problems of the Newborn" between 1966 and 1982 (Saunders, WB, Philadelphia) offers the following comments:

"The demonstration of 4% fetal red cells in mother's blood repeatedly and by a variety of techniques certainly points to fetomaternal hemorrhage (FMH). Although hereditary persistence of fetal hemoglobin could account for the elevated Hb F in the mother, the Kleihauer-Betke results (presumably) showing a heterogeneous mixture of deeply stained RBC (containing Hb F) amid a 'sea' of unstained adult RBCs most certainly would have ruled that out (see typical photomicrograph below).

The obstetrician was correct in assuming that a single acute fetomaternal hemorrhage of the order of 200 mL (over half the estimated fetal blood voluime) was inconsistent with life. However, he and his neonatology consultants should have considered the likelihood of chronic (low-grade) fetomaternal hemorrage resulting in progressive anemia due to iron deficiency. This was first described in a newborn by Pearson and Diamond in 1959, and reported again by others, including Drs. Eshaghpour, Oski and myself back in 1966 (J. Pediatr 1966;68:806-810). It is mentioned in all three editions of our book, and also in standard texts on neonatology such as the one by Avery.

Anemia due to chronic intrauterine FMH has been well described, and if severe and progressive may lead to hydrops fetalis (demonstrable by ultrasound) and stillbirth, or hypoxic brain damage among survivors. The spontaneous onset of labor in this case was a blessing, enabling delivery of the infant before obvious hydrops appeared (the edematous cord and placenta suggested this was imminent) and in time to initiate diagnosis and treatment. A simple stained blood smear on the neonate should have shown the typical hypochromic microcytic morphology of iron deficiency, along with the report of nucleated RBCs reflecting a marrow stimulated by hypoxia.

One may ask whether an awaredness of the possibility of chronic FMH might have altered management of the pregnancy. A quick Medline search (for CHRONIC FETOMATERNAL HEMORRHAGE) reveals a number of reports of prenatal diagnosis of anemia due to chronic FMH, along with several reports of treatment by intrauterine transfusion of red cells, including some in obstetric journals e.g., Fischer RL et al. Am J Obstet Gynecol. 1990;162:203-4. Although in retrospect an informed management may not have been needed for this fetus (only time will tell), let's hope that e-Network visitors reading this discussion are now in a position to better educate their clinical colleagues the next time such a case comes their way. We cannot always rely on fortune to bail us out."

ADDENDA Aug. 18, 2003

2. Neil Blumberg MD, Director of Transfusion Medicine/Blood Bank at the University of Rochester Medical Center (attribution used with permission) reports that he has seen a few cases (perhaps 3 or 4) of astonishingly large feto-maternal bleeds over the 23 years that he has been in practice in Rochester, New York. In Dr. Blumberg's opinion, the obstetrician's assumption that the "baby would be dead with such a large bleed" is likely incorrect, because the obstetrician is assuming an acute bleed. But if the bleed is slow, large volumes of fetal cells can make their way into the maternal circulation without killing the fetus, albeit rendering the fetus anemic in most instances What one may easily forget is that red cells are long-lived. Assuming a 120 day-mean lifespan, a 1-3 mL bleed each day could lead to hundreds of milliliters of fetal blood in the maternal circulation at any given point over a several month period. This actually happens in rare instances if the data reported here are correct, and in his own experience as well.

3. In reference to the above, Dr. Naiman adds: For the record, the lifespan of newborn RBC (especially those of the premature) is significantly less than that of adult RBC. (Data summarized in our text, above.) This would not alter Dr. Blumberg's conclusion.

4. A colleague in Maryland reports having seen a case, about 7 years ago, where chronic fetal maternal hemorrhage caused a calculated fetal bleed to be greater than the estimated blood volume of the fetus. According to the reporting physician, this case presented as a fetal demise due to hydrops, and the fetus had all the manifestations of hydrops on autopsy. Nucleated red blood cells were present in the maternal circulation and the KB results were approximately 9 and 11% on repeat tests from the same sample. This case entailed the clinicians making a management decision to administer an IV formulation of RhIg (WinRho) because it seemed cruel to have to administer so many doses of an intramuscular formulation of RhIg. The doses were spaced out over 72 hours, and because of the imprecision of the initial KB results, the remaining doses needed were recalculated daily. In this case a lower total dose was administered than what the initial value on the first day would have indicated was needed. The involved obstetrician and patient were lost to follow-up, so it is not known if Rh alloimmunization was prevented.

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