What is the definition of fetal anemia?

Fetal anemia can be defined using either hemoglobin or hematocrit values. A hemoglobin value that is more than 2 SD below the mean is diagnostic of fetal anemia. Normally, fetal hemoglobin concentration increases with advancing gestation ( Figure 1 ). Reference ranges for fetal hemoglobin concentrations as a function of gestational age (from 18 to 40 weeks of gestation) have been established using fetal blood sampling ( Table 1 ).

Relationship between fetal hemoglobin across gestational age

SMFM. The fetus at risk for anemia. Am J Obstet Gynecol 2015 .

Reproduced, with permission, from Mari et al.

The severity of fetal anemia can be categorized based on hemoglobin concentrations expressed as multiples of the median (MoM) for gestational age as mild (MoM 0.83–0.65), moderate (MoM 0.64–0.55), and severe (MoM <0.55). Severe anemia can lead to hydrops fetalis and fetal death. Hydrops related to anemia is rare in fetuses with hemoglobin concentrations greater than 5 g/dL, a value corresponding to 0.47 MoM at 18 weeks of gestation and 0.36 MoM at 37 weeks of gestation. Using a fetal hematocrit of less than 30% as a cutoff for fetal anemia appears equally reliable as using hemoglobin levels and is often used in routine clinical care.

What are the causes of fetal anemia?

Fetal anemia can result from a large number of pathologic processes ( Table 2 ). The most common causes in the United States are maternal alloimmunization and parvovirus infection. Other causes include inherited conditions such as alpha-thalassemia and genetic metabolic disorders as well as acquired conditions, such as fetal blood loss and infection. Fetal anemia can occur in association with Down syndrome, because of transient abnormal myelopoeisis, a leukemic condition that occurs in approximately 10% of infants with Down syndrome. Vascular tumors and arteriovenous malformations of the fetus or placenta are also rare causes of fetal anemia.

Maternal red blood cell alloimmunization occurs when the immune system is sensitized to foreign erythrocyte surface antigens, stimulating the production of immunoglobulin G (IgG) antibodies. These IgG antibodies can cross the placenta and lead to hemolysis if the fetus is positive for the specific erythrocyte surface antigens. This process, known as hemolytic disease of the fetus and newborn, can result in extramedullary hematopoiesis, reticuloendothelial clearance of fetal erythrocytes, fetal anemia, hydrops fetalis, and fetal death.

The most common routes of maternal alloimmunization are blood transfusion or fetomaternal hemorrhage associated with delivery, trauma, spontaneous or induced abortion, ectopic pregnancy, or invasive obstetric procedures. The introduction of Rh (D) immune globulin in 1968 has greatly decreased the incidence of fetal anemia caused by Rh (D) alloimmunization in North America. As a result, other alloantibodies have increased in relative importance. These include antibodies to other antigens of the Rh blood group system (c, C, e, E) and other atypical antibodies also known to cause severe fetal anemia, such as anti-Kell (K, k), anti-Duffy (Fy ^a ), and anti-Kidd (Jk ^a , Jk ^b ) ( Table 3 ).

Parvovirus is the most commonly reported infectious cause of fetal anemia. In the fetus, the virus has a predilection for erythroid progenitor cells, leading to inhibition of erythropoiesis and resultant anemia. The risk of a poor outcome for the fetus is greatest when the congenital infection occurs before 20 weeks of gestation. The risk of fetal death has been reported to be 15% at 13–20 weeks of gestation, and 6% after 20 weeks of gestation. In most cases, the anemia is transient, but in severe cases, fetal intravascular transfusion may be needed to support the fetus through this aplastic crisis.

A number of viral, bacterial, and parasitic infectious diseases, including toxoplasmosis, cytomegalovirus (CMV), coxsackie virus, and syphilis, have in rare cases been associated with fetal anemia and hydrops.

Fetal anemia can occur as a complication of monochorionic twin pregnancies, a condition referred to as twin anemia-polycythemia sequence. This condition has been reported to occur spontaneously in 3–5% of monochorionic twins or after laser therapy for twin-twin transfusion syndrome (TTTS) in 13% of cases. Twin anemia-polycythemia sequence is distinct from TTTS because it occurs in the absence of amniotic fluid abnormalities characteristic of classical TTTS. Fetal anemia can also result from fetomaternal hemorrhage, which may occur as an isolated acute event or as a chronic, ongoing hemorrhage.

Several inherited disorders are associated with fetal anemia. Alpha-thalassemia is the most common of these and occurs primarily in individuals of Southeast Asian descent. The severe hemolytic anemia associated with alpha-thalassemia typically leads to hydrops fetalis and fetal demise. Less common causes of fetal anemia and hydrops include erythrocyte enzymopathies such as glucose-6-phosphate dehydrogenase deficiency, pyruvate kinase deficiency, and maternal acquired red cell aplasia. Genetic conditions associated with aplastic anemia that may present in fetal life include Fanconi anemia and Diamond Blackfan anemia. Inherited metabolic disorders, particularly lysosomal storage diseases such as various mucopolysaccaridoses, Gaucher disease, and Niemann-Pick disease have also been reported to cause fetal anemia and hydrops.

What are the causes of fetal anemia?

Fetal anemia can result from a large number of pathologic processes ( Table 2 ). The most common causes in the United States are maternal alloimmunization and parvovirus infection. Other causes include inherited conditions such as alpha-thalassemia and genetic metabolic disorders as well as acquired conditions, such as fetal blood loss and infection. Fetal anemia can occur in association with Down syndrome, because of transient abnormal myelopoeisis, a leukemic condition that occurs in approximately 10% of infants with Down syndrome. Vascular tumors and arteriovenous malformations of the fetus or placenta are also rare causes of fetal anemia.

Maternal red blood cell alloimmunization occurs when the immune system is sensitized to foreign erythrocyte surface antigens, stimulating the production of immunoglobulin G (IgG) antibodies. These IgG antibodies can cross the placenta and lead to hemolysis if the fetus is positive for the specific erythrocyte surface antigens. This process, known as hemolytic disease of the fetus and newborn, can result in extramedullary hematopoiesis, reticuloendothelial clearance of fetal erythrocytes, fetal anemia, hydrops fetalis, and fetal death.

The most common routes of maternal alloimmunization are blood transfusion or fetomaternal hemorrhage associated with delivery, trauma, spontaneous or induced abortion, ectopic pregnancy, or invasive obstetric procedures. The introduction of Rh (D) immune globulin in 1968 has greatly decreased the incidence of fetal anemia caused by Rh (D) alloimmunization in North America. As a result, other alloantibodies have increased in relative importance. These include antibodies to other antigens of the Rh blood group system (c, C, e, E) and other atypical antibodies also known to cause severe fetal anemia, such as anti-Kell (K, k), anti-Duffy (Fy ^a ), and anti-Kidd (Jk ^a , Jk ^b ) ( Table 3 ).

Parvovirus is the most commonly reported infectious cause of fetal anemia. In the fetus, the virus has a predilection for erythroid progenitor cells, leading to inhibition of erythropoiesis and resultant anemia. The risk of a poor outcome for the fetus is greatest when the congenital infection occurs before 20 weeks of gestation. The risk of fetal death has been reported to be 15% at 13–20 weeks of gestation, and 6% after 20 weeks of gestation. In most cases, the anemia is transient, but in severe cases, fetal intravascular transfusion may be needed to support the fetus through this aplastic crisis.

A number of viral, bacterial, and parasitic infectious diseases, including toxoplasmosis, cytomegalovirus (CMV), coxsackie virus, and syphilis, have in rare cases been associated with fetal anemia and hydrops.

Fetal anemia can occur as a complication of monochorionic twin pregnancies, a condition referred to as twin anemia-polycythemia sequence. This condition has been reported to occur spontaneously in 3–5% of monochorionic twins or after laser therapy for twin-twin transfusion syndrome (TTTS) in 13% of cases. Twin anemia-polycythemia sequence is distinct from TTTS because it occurs in the absence of amniotic fluid abnormalities characteristic of classical TTTS. Fetal anemia can also result from fetomaternal hemorrhage, which may occur as an isolated acute event or as a chronic, ongoing hemorrhage.

Several inherited disorders are associated with fetal anemia. Alpha-thalassemia is the most common of these and occurs primarily in individuals of Southeast Asian descent. The severe hemolytic anemia associated with alpha-thalassemia typically leads to hydrops fetalis and fetal demise. Less common causes of fetal anemia and hydrops include erythrocyte enzymopathies such as glucose-6-phosphate dehydrogenase deficiency, pyruvate kinase deficiency, and maternal acquired red cell aplasia. Genetic conditions associated with aplastic anemia that may present in fetal life include Fanconi anemia and Diamond Blackfan anemia. Inherited metabolic disorders, particularly lysosomal storage diseases such as various mucopolysaccaridoses, Gaucher disease, and Niemann-Pick disease have also been reported to cause fetal anemia and hydrops.

What is the appropriate management for the patient at risk for fetal anemia?

Women with pregnancies with the conditions listed in Table 2 , most commonly red blood cell alloimmunization and parvovirus infection, are considered at risk for fetal anemia. The management of such patients is based on the suspected etiology. In women with red cell alloimmunization, parental assessment and testing are key initial steps to determine the potential fetal antigen status ( Figure 2 ). This can be done through parental zygosity testing, direct genotyping of the fetus with amniocentesis, or noninvasive fetal genotyping from maternal blood using cell-free DNA.

Algorithm for clinical management of the red cell alloimmunized pregnancy

GA, gestational age; MCA , middle cerebral artery; MoM , multiples of the median; PSV , peak systolic velocity.

SMFM. The fetus at risk for anemia. Am J Obstet Gynecol 2015 .

Modified from Moise and Argoti.

At this point in time, only cell-free DNA testing for Rh (D) is clinically available in the United States, whereas in Europe assays have been developed for c, E, and Kell antigens. Currently cell-free DNA testing is reported to detect the Rh (D) genotype with a sensitivity of 97.2% and a specificity of 96.8%. Another recent study reported the accuracy for Rh (D) by trimester: 99.1% in the first trimester, 99.1% in the second trimester, and 98.1% in the third trimester.

In alloimmunized women who do not undergo fetal or paternal testing and do not have a prior history of an affected pregnancy, serial antigen titers can be measured and followed up until they surpass a critical titer that places the fetus at risk for the development of severe anemia and hydrops. The critical titer is set by each laboratory and may be different for various red cell antigens. Titers should be repeated serially every 4 weeks and then more frequently if they are found to be rising or with advancing gestational age. Once the critical titer is reached, 2 options exist for subsequent evaluation: fetal antigen testing (cell-free fetal DNA testing for Rh [D] or amniocentesis for fetal Rh genotyping) or initiation of ultrasound surveillance with middle cerebral artery (MCA) Doppler assessment.

The potential benefit of fetal antigen testing first is to avoid multiple serial MCA Doppler assessments (often weekly) in an antigen-negative fetus. However, cell-free DNA testing for fetal Rh (D) type is not 100% sensitive, particularly at earlier gestational ages, so a small number of at risk fetuses may be missed if this approach is chosen. Although uncommon, maternal titers can increase, even in antigen-negative fetuses. Given the approximately 10% false-positive rate of MCA Doppler for the detection of severe anemia, without confirmation of fetal antigen status, women are at risk for unnecessary procedures including invasive testing. Clinicians managing alloimmunized women should be aware of these potential issues.

In women who are at risk for fetal anemia caused by parvovirus exposure, maternal antibody status (eg, immunoglobulin M positive status or IgG seroconversion) is useful to determine prior exposure and the presence of immunity. Although the peak risk for hydrops is 4–6 weeks after maternal infection, weekly evaluation of MCA Doppler studies and ultrasound surveillance for fetal hydrops are often continued for up to 10–12 weeks after exposure.

How is the diagnosis of fetal anemia made?

An algorithm for the screening and diagnosis of fetal anemia is presented in Figure 2 . The definitive diagnosis of fetal anemia is generally made by fetal blood sampling, whereas screening is performed with MCA Doppler.