The normal placenta is divided in two layers: the cytotrophoblast and the syncytiotrophoblast. The direct contact between the maternal circulation and the fetal circulation is avoided by this membrane of the placenta. Normally, the placental blood pressure is higher than in the intervillous space(3). When an alteration of this barrier occurs, the fetal blood cells enter the maternal vessels and this may be a stimulating event for antibody production against fetal red blood cells, than the maternal clotting system may be activated, limiting the effect of the hemorrhage. Clotting is less likely to be activated if there is ABO compatibility, and the bleeding may continue with dramatic effects(4,5). The rapidity of fetal blood loss is an additional major factor affecting morbidity and mortality(6).
N.E. Lewis found in a retrospective study that villous dysmaturity/immaturity, villous edema, and nucleated red blood cells (RBCs) in fetal vessels are compatible with fetal anemia. These are the most important placental abnormalities associated with FMH, detected by flow cytometry(7).
S. Ravishankar also found that placental parenchymal pallor, intervillous thrombi and the presence of nucleated RBCs are highly associated with documented FMH in both normal pregnancies and pregnancies associated with fetal or neonatal death(8).
Molecular techniques helped establishing that the bi-directional fetomaternal trafficking of cells and nucleic acids during pregnancy is a well-known fact. It is known that HLA (human leukocyte antigen) is deposited in the skin of pregnant women.
Maternal cells and nucleic acids have been found in umbilical cord blood and in autopsy tissue of non-transfused neonates(9).
Some authors found that the incidence of massive FMH would be estimated to be approximately 3 per 1000 births(10). Other authors postulate that FMH >20 to 30 mL at delivery is estimated to happen in approximately 1 in 200 to 300 deliveries(10,11).
Some other authors appreciate that FMH >80 mL is estimated to occur in 1 in 1000 deliveries. The same authors estimate that FMH >150 mL is estimated to occur in 1 in 5000 deliveries(12). Some risk factors have been identified: multiple gestation, low birth weight or traumatic injuries. These risk factors are not always present and the literature cites some FMH cases that occurred spontaneously(13).
Abdominal trauma, amniocentesis, external cephalic version, placental abruption, pre-eclampsia, placenta praevia, placental mesenchymal dysplasia and manual removal of the placenta are some obstetrical events that can be associated with FMH(14,15).
Bowman suggested that 75% of all pregnancies have a degree of FMH(16).
D.W. Laube found that FMH was responsible for nearly 14% of the unexplained fetal deaths and 3% of all fetal deaths(17).
FMH represents the transfer of fetal blood into the maternal circulation and vice-versa. Antenatal massive FMH is a pathological condition with a wide spectrum of clinical variation(18). The entry of fetal blood cells into the maternal blood stream may occur before or during delivery(12).
Defining massive FMH is difficult because more factors need to be clarified: the volume of lost blood, the rate of blood lost, the chronicity of the phenomena and gestational age.
Volumes of 10 to 150 mL of fetal erythrocytes lost in the maternal circulation have been proposed to define a massive FMH(19).
Some authors have used a volume of 30 mL as the definition of massive FMH because this is the volume of fetal blood that will require one full unit of Rh immune globulin to prevent Rh sensitization in a mother with concerns for alloimmunization(20).
There are some authors that tried to correlate the volume of blood loss with clinical outcomes. Anemia may be compensated at birth, or be only minimal if FMH has been <50 ml. Large volumes of FMH may result in severe consequences secondary to fetal anemia.
The most severe consequences are stillbirth, neurologic sequelae or neonatal death. Massive FMH is described by other authors as the loss of 20 mL/kg, which represents 20 percent of the fetoplacental blood volume and it’s associated with high fetal/neonatal morbidity or mortality(21,22). R.A. Brace postulates that experiments in sheep show that the rapidity of fetal blood loss is an additional major factor affecting morbidity and mortality(6,21).
Clinical presentation and diagnosis
The presentation is frequently without a clear precipitating factor. The diagnosis of this condition may be performed in the majority cases only after the injury happened.
There are many cases when the diagnosis is possible just postpartum and retrospectively. The most common antenatal presentation is very unspecific: the mother can percept persistent decreased fetal activity and decreased fetal activity can be observed(18).
Testing for FMH should be considered in some of the following situations: decreased fetal movements, hydrops, unexplained elevated middle cerebral artery Doppler and stillbirth(23). Sinusoidal fetal heart rate it’s often associated with fetal anemia.
Some authors found that sinusoidal fetal heart rate pattern occurred in only approximately 10% of FMH cases(24). Some rare, unusual presentations as maternal hemoglobin elevation before delivery secondary to FMH are cited in the literature(25). If the fetal bleeding is massive, the mother can experience a transfusion reaction that becomes manifest trough the following signs and symptoms: fever and chills, nausea and edema(26).
As presented, the initial symptoms of FMH are very nonspecific. If the blood loss is compensated by the fetus, the pregnancy can continue. Fetal tachycardia can be a presenting symptom, secondary to increasing cardiac output(27,28,29). It is not known the length of time that the fetuses can tolerate FMH. If the fetus cannot compensate the blood loss, high-output heart failure and hydrops fetalis are the following consequences(3,27,30).
Many diagnostic modalities for FMH are available but the difficulty in diagnosing the disease comes from the fact that all the diagnostic tests are not so accurate. The most frequently used and also the oldest test is acid elution test (Kleihauer-Betke test).
Erythrocytes containing fetal hemoglobin, which is resistant to acid elution, remain red, while adult RBCs become colorless. The number of fetal cells is then counted and reported as a percentage of the amount of adult cells. The volume of FMH is estimated by multiplying the percentage of fetal blood cells by 5000 (the average maternal blood volume, in mL).
A Kleihauer-Betke test over 2.5% is associated with adverse fetal outcome(1,3,31-33). Although is a quantitative test, it has many disadvantages: it’s time consuming, it’s dependent to technician skills, can overestimate or underestimate the number of fetal cells in maternal conditions leading to Hb F production (such as thalassemia) or with advancing gestational age as Hb F content of fetal RBCs decreases, respectively(1,35).
Another alternative to diagnose FMH is flow cytometry. This test is a quantitive, an automatic test that measures the monoclonal antibodies bined to fetal hemoglobin. Although it is more accurate than the Kleihauer-Betke test, few hospitals use it due to high costs of the method(13,36).
The rosette test is a qualitative screen of fetomaternal bleeding that indirectly identifies the presence of Rh D-positive fetal cells in Rh-negative mothers(37). Even if this test is positive, a quantitative test is still needed(38).
H. Tsuda postulates that early diagnosis of FMG it is usually not possible using the non-stress test and ultrasound except in unusual cases(39).
F. Bellussi postulates that the most accurate predictor of FMH is fetal middle cerebral artery peak systolic velocity. In his research cardiotocography result was always abnormal in case of FMH but the pattern was frequently nonspecific(40).
G. Mari found in her study that the sensitivity was 100% for the prediction of moderate and severe anemia in the fetuses without hydrops by measuring the middle cerebral artery peak systolic velocity. The false positive rate of the method was 12%(41).
C.Y. Liao describes a fatal case of FMH in which the use of pulsatility and resistance index of umbilical artery and MCA did not reveal any abnormalities(42).
Another important exam in obstetric practice is the analysis of the placenta.
The management of the FMH is challenging. Clinical FMH is rare(10,11,12). The evaluation of FMH needs confirmation with Kleihauer-Betke test or flow cytometry. The wellbeing of the fetus must be evaluated through non-stress test and middle cerebral artery peak systolic velocity. Middle cerebral artery peak systolic velocity values of greater than 1.5 MOM suggest possible fetal anemia. Ultrasonographic evaluation for the presence of hydrops fetalis should also be performed(43,44). To prevent sensitization, Rh immune globulin must be administered to all Rh-negative women with suspected antenatal FMH. The administration of steroids may be considered when delivery is anticipated prior to 34 gestational weeks(30,45,46).
When suspected, FMH has two management options: intrauterine transfusion or delivery depending on the wellbeing of the fetus and gestational age.
The presence of an experienced personnel to perform cordocentesis might also be an issue. Repeated intrauterine transfusion might be needed to correct continuous bleeding(18,45).
In some cases it is difficult to determine the best moment for the following transfusions because the rate of FMH is unpredictable. Because transfused erythrocytes are partially adult in origin, blood testing and middle cerebral artery peak systolic velocity measurements may be false negative(13). Intrauterine transfusion corrects fetal anemia and can prolong gestation until a more mature gestational age is reached. Perinatal death varies between 31% and 50%. T.M. Lindenburg concluded that intrauterine transfusion is a safe method to threat anemia caused by different pathologies, but a risk-benefit balance must be considered(47). L. Weisberg postulates that fetal blood transfusion has the advantage of allowing in utero cardiovascular stabilization and suggests in utero stabilization (rather than immediate delivery without transfusion). This practice reduces the risk of early neonatal morbidity from pulmonary hypertension, ventilation instability, hypoglycemia, and metabolic abnormalities(48).
FMH is followed by fetal anemia which has severe consequences such as neurologic injury, stillbirth, or neonatal death(3). The outcome for fetuses that experience a FMH is variable and includes anemia, fetal tachycardia and neurogical sequelae(1,49).
K. Venkatnarayan says that neonatal deaths due to FMH are associated with shock at birth or soon after(22). Chronic FMH has a better outcome because it allows fetal hemodynamic compensation.
An acute FMH has a bad outcome(22). C. Rubod reports 48 patients with massive FMH: 6 fetal deaths, 9 newborns needed neonatal intensive unit care, and 5 had transfusions. He concluded that long-term follow-up was not associated with neurological sequelae(10).
Z. Kecskes in his retrospective study identified 16 infants treated for FMH. Adverse outcomes were identified in 5 infants (31%): death in 3 patients and periventricular leukomalacia in 2 patients(49). B.D. O’Leary concludes that no reduction in rates of fatal FMH has been made in the past 25 years(50).
FMH is a rare clinical entity. Most frequently there is no precipitating factor. Many studies demonstrate that the most frequent sign for FMH is decreased fetal activity. Antenatal diagnosis is difficult because the presenting signs are often nonspecific and because diagnostic tests available are not accurate.
Other diagnostic methods and management protocols are needed. The follow-up of neonates from this pregnancies is required.