Hydrops fetalis

Fetomaternal hemorrhage (FMH) is a common obstetrical occurrence most often associated with small volumes of blood transferred across the placenta. Fetomaternal hemorrhage leads to alloimmunization of Rh D-negative mothers, resulting in an increased risk of hemolytic disease of the newborn. Massive FMH involving volumes of blood greater than 30 mL can cause substantial fetal morbidity and mortality. Massive FMH may present with signs and symptoms such as decreased movement, sinusoidal heart rhythms, or fetal anomalies. We present 3 cases of clinically unexpected massive FMH of 206, 88, and 155 mL. The treating clinicians were unaware of any fetal or maternal signs or symptoms of FMH until contacted by the laboratory. These cases illustrate the necessity for FMH quantitation, even in the absence of clinical suspicion. Additional studies are needed to find better ways to identify these patients in advance. Development of criteria allowing identification of patients at risk would be of benefit to both mother and baby.

(Arch Pathol Lab Med. 2004;128:463-465)

Fetomaternal hemorrhage (FMH) is a common obstetrical event occurring in the majority of pregnancies, usually without any antepartum maternal or fetal signs.1,2 Most are small-volume blood transfers from fetus to mother of less than 1 mL; transfer from mother to fetus is unusual.1 Conversely, massive FMH of greater than 30 mL occurs in only about 3 of 1000 pregnancies3 and often has known antecedent fetal manifestations, such as decreased movement, sinusoidal heart rhythms, peripartum anemia, and fetal anomalies.2,4 Fetal outcomes may be compromised by still births, hydrops fetalis, cardiac complications, and increased rates of postpartum infant death.2,4,5

The causes of FMH may be iatrogenic or associated with obstetrical complications. Fetomaternal hemorrhage may result from antepartum procedures (eg, amniocentesis, percutaneous umbilical blood sampling, intrauterine manipulation, caesarian section) or clinical complications (eg, threatened abortion, abruptio placentae, and placenta previa).2,6 A significant proportion of massive FMH cases is idiopathic.7

Fetomaternal hemorrhage is most important in Rh D antigen-negative women with Rh D-positive pregnancies. It may be an acute or chronic process. Maternal sensitization arises in up to 17% of these women if they do not receive anti-D prophylaxis.8 An anamnestic maternal response may cause hemolytic disease of the newborn with succeeding pregnancies.2 Since the risk and extent of FMH is a function of gestational age,1 Rh immune globulin is recommended to be given both at 28 weeks' gestation and immediately postpartum to Rh D-negative women with Rh D-positive (or Rh D-unknown) pregnancies.3,6,9

Quantifying the volume of FMH is paramount, since the amount of Rh immune globulin needed to be administered is directly proportional to the amount of transferred blood. In many laboratories, FMH screening is performed by the erythrocyte rosette test, and then quantitation is done (if indicated) by a more sensitive technology, such as Kleihauer-Betke acid elution (KB) or flow cytometry for fetal hemoglobin.6 More precise and accurate results are obtained using flow cytometry for quantification of FMH than with KB. When using flow cytometry for quantitation of massive FMH, the use of antibody to fetal hemoglobin may give lower estimates of FMH when compared with identification of fetal cells using anti-D.10,11

Most US institutions adhere to guidelines established by the American Association of Blood Banks for the prevention and diagnosis of potential hemolytic disease of a newborn. Despite general awareness of the importance of antiD administration, not all women are treated in accordance with the guidelines, resulting in inadequate treatment in some patients.12 Since FMH and ultimately alloimmunization can occur in the absence of any antecedent events, screening and quantitation of FMH in Rh D-negative mothers bearing Rh D-positive babies should be routinely performed by blood banks.2 To illustrate, we present 3 cases of clinically unsuspected massive FMH.

REPORT OF CASES

Each of the following cases had no clinical signs of FMH before or after delivery, except as noted. In each case, a normal-appearing placenta with a 3-vessel cord was delivered without incident, and no signs of abruption or other abnormal obstetric process were observed. In each case, the treating clinicians and their colleagues were astonished by the presence of such a marked FMH and were unaware that massive FMH is not exceedingly rare.

Case 1

A 33-year-old, gravida 1, para 0, white woman at 41 4/7 weeks' estimated gestational age delivered a 3800-g infant by spontaneous vaginal delivery. Apgar scores were 9 and 9 at 1 and 5 minutes, respectively. The mother's blood was group A, D- E-; Fy(a+). The infant's blood was group A, D+ E + ; Fy(a-). Kleihauer-Betke testing suggested an FMH volume of 206 mL (Figure 1). Rh immune globulin (2400 µg) was administered to the mother intramuscularly before involvement of a transfusion medicine physician. Confirmatory flow cytometry was performed on blood samples drawn approximately 8 hours antepartum and immediately postpartum. Fetomaternal hemorrhage was quantified at 307 and 316 mL on antepartum and postpartum maternal specimens, respectively (Figure 2). Flow cytometry did not detect maternal blood in the fetal circulation. Immunoserology confirmed these findings, showing E-positive cells from the fetus in the mother's circulation, however no Fy(a+) cells from the mother were detected in the fetal circulation. Both antepartum and postpartum maternal specimens were weak D-positive with mixed field. A specimen drawn from the mother on postpartum day 10 was negative for weak D testing. The antibody screen was positive for iatrogenic anti-D (due to Rh immune globulin administration). Despite the presence of anti-D, KB testing showed that 9 mL of fetal blood still remained in circulation.

Case 2

A 32-year-old, gravida 4, para 2, Hispanic woman at 36 6/7 weeks' estimated gestational age delivered an infant via elective cesarean section. Apgar scores were 8 and 9 at 1 and 5 minutes, respectively. The mother's blood was group A, D-, and the baby's was group A, D+. The erythrocyte rosette screen was positive, and subsequent KB testing estimated an FMH of 88 mL. An intravenous Rh immune globulin preparation (1200 µg) was recommended instead of intramuscular, due to the relatively large volume required. A KB screen of the mother's blood 10 hours after the intravenous immune globulin infusion was entirely negative for fetal cells.

Case 3

A 26-year-old, gravida 2, para 1, white woman delivered a full-term infant by cesarean section for nonreassuring heart tracings. The procedure was performed without excess maternal bleeding, the infant appeared in no acute distress, and the amniotic fluid was clear. Apgar scores were 4 and 8 at 1 and 5 minutes. Only when routine testing indicated an infant hematocrit of 11% did the obstetrician suspect anything out of the ordinary. A positive erythrocyte rosette screen prompted quantitation. KleihauerBetke testing estimated an FMH of 155 and 140 mL on antepartum and postpartum maternal specimens, respectively. Rh immune globulin (300 µg) had been administered intramuscularly per hospital protocol. An additional 1500 µg was administered intravenously when results of the FMH quantitation became available. Kleihauer-Betke testing with blood drawn 6 hours after immune globulin infusion showed 60 mL of fetal cells remaining in the maternal circulation.

The mother's blood type was group B, D- e+ . The infant's type was group AB, D+ e-. Immunoserology found no common antigen for which the baby was positive and the mother negative. A sensitive serological method was used to test for the presence of maternal cells positive for the e antigen in the fetal circulation (a rosette technique with appropriate controls), and none were detected. The infant required blood transfusion, did well, and was discharged from intensive care on day 6 of life.

COMMENT

Each of the 3 cases of massive FMH was unsuspected by the clinicians. There were no clinical signs noted antepartum or postpartum that would suggest that screening for massive FMH was required, except for the fetal anemia detected in case 3. In each case, massive FMH occurred before delivery; this timing was confirmed by a combination of methodologies. Passage of cells from the mother to the fetus was not demonstrated. Of interest, intravenous Rh immune globulin showed a significant decrease (or total clearance) of fetal cells, as determined by KB testing within 10 hours of administration. The additional KB tests performed after the administration of antiD were ordered because few data are available on the kinetics of red cell clearance by anti-D after massive FMH. Subsequent testing for the presence of a naturally occurring anti-D was not done in any of the cases, and the patients were unavailable for follow-up. In case 1, 8 doses of intramuscular immune globulin were administered per protocol before involvement of a physician. Large amounts of circulating Rh D-positive cells may be found in Rh Dnegative persons as a result of massive FMH or via administration of Rh-positive blood, which happens inadvertently or during blood shortages. Further studies need to be conducted to evaluate the role of immune globulin in clearing large amounts of Rh-positive cells and the relationship between residual fetal cells and the effectiveness of anti-D prophylaxis.

These cases support research findings that suggest that all Rh D-negative women bearing Rh D-positive babies should have FMH screening and subsequent quantitation when the screen is positive.2,3,6 It should be noted that these cases were only discovered because these Rh D-negative mothers were screened for Rh immunoglobulin dosing. There are likely many cases of massive FMH in Rh D-positive women, most of which go undetected. Massive FMH can occur without any clinical suspicion or antecedent predisposing events.1,2,4 In a case review study of fetal deaths, it was concluded that clinical risk factors do not predict the likelihood of massive FMH.4 More than half of the FMH cases in another study occurred before labor or caesarian section. The majority of cases appeared silently, without any evidence of a predisposing condition.2 Therefore, FMH screening (and quantitation if positive) is recommended even in the presence of an apparently normal pregnancy and delivery.10 These cases suggest that massive FMH is more common than many clinicians suppose. Additional studies are needed to help identify these patients in advance. Potential fetal morbidity secondary to FMH might be avoided. With increased physician awareness, vigilant screening can reduce perinatal and postpartum morbidity and mortality caused by maternal sensitization to the Rh D antigen. If FMH quantitation is not performed, a routine 300-µg dose of Rh immune globulin may not be sufficient to prevent alloimmunization.1,2,4

The authors appreciate the expert hematologic and immunoserologic assistance from the clinical laboratories at the University of Washington and the Puget Sound Blood Center in Seattle, Wash, and TriCore Reference Laboratories, Albuquerque, NM. Special thanks go to L. A. Reid, MT,SBB(ASCP), R. Armour, BB(ASCP), and B. Nonemaker, MT(ASCP).

References

1. Bowman JM, Pollock JM, Penston LE. Fetomaternal transplacental hemorrhage during pregnancy and alter delivery. Vox Sang. 1986;51:117-121.

2. Sebring ES, Polesky HF. Fetomaternal hemorrhage: incidence, risk factors, time of occurrence, and clinical effects. Transfusion. 1990;30:344-357.

3. ACOG practice bulletin. Prevention of Rh D alloimmunization. No. 4, May 1999 (replaces educational bulletin No. 147, October 1990). Clinical management guidelines for obstetrician-gynecologists. American College of Obstetrics and Cynecology. Int J Gynaecol Obstet. 1999;66:63-70.

4. Samadi R, Greenspoon JS, Gviazda I, Settlage RH, Goodwin TM. Massive fetomaternal hemorrhage and fetal death: are they predictable? J Perinatol. 1999; 19:227-229. 5

. Rosenn B, Ben Chetrit A, Palti Z, Hurwitz A. Sinusoidal fetal heart rate pattern due to massive feto-maternal transfusion, Int J Gynaecol Obstet. 1990;31: 271-273.

6. Hartwell EA. Use of Rh immune globulin: ASCP practice parameter. American Society of Clinical Pathologists. Am J Clin Pathol. 1998;110:281-292.

7. Giacoia GP. Severe fetomaternal hemorrhage: a review. Obstet Gynecol Surv. 1997;52:372-380.

8. Vaughan JI, Manning M, Warwick RM, Letsky EA, Murray NA, Roberts IA. Inhibition of erythroid progenitor cells by anti-Kell antibodies in fetal alloimmune anemia. N Engl J Med. 1998;338:798-803.

9. Mills L, Napier JA. Massive feto-maternal haemorrhage: effect of passively administered anti-D in the prevention of Rh sensitization and haemolytic disease of the newborn. Br J Obstet Gynaecol. 1988;95:1007-1012.

10. Chen JC, Davis BH, Wood B, Warzynski MJ. Multicenter clinical experience with flow cytometric method for fetomaternal hemorrhage detection. Cytometry. 2002;50:285-290.

11. Kennedy GA, Shaw R, Just S, et al. Quantification of feto-maternal haemorrhage (FMH) by flow cytometry: anti-fetal haemoglobin labelling potentially underestimates massive FMH in comparison to labelling with anti-D. Transfus Med. 2003;13:25-34.

12. Howard HL, Martlew VJ, McFadyen IR, Clarke CA. Preventing Rhesus D haemolytic disease of the newborn by giving anti-D immunoglobulin: are the guidelines being adequately followed? Br J Obstet Gynaecol. 1997;104:37-41.

Sam Pourbabak, MD; Chad R. Rund, DO; Kendall P. Crookston, MD, PhD

Accepted for publication November 17, 2003.

From the Departments of Internal Medicine (Drs Pourbabak and Crookston) and Pathology (Drs Rund and Crookston), University of New Mexico School of Medicine, Albuquerque.

The authors have no relevant financial interest in the products or companies described in this article.

Reprints: Kendall P. Crookston, MD, PhD, University of New Mexico Health Sciences Center, Department of Pathology, MSCO8-4640, One University of New Mexico, Albuquerque, NM 87131 (e-mail: kcrookston@ bigfoot.com).

Copyright College of American Pathologists Apr 2004
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