HYDROPS FETALIS HEMATOLOGIC CAUSES

hydrops fetalis hematologic causes
• Hematologic events, which lead to profound anemia and have been recognized to trigger hydrops fetalis.

• Isoimmunization (hemolytic disease of the newborn, erythroblastosis)
o Rh (most commonly D; also C, c, E, e) o Kell (K, k, Kp, Js[B])
o ABO
o MNSs (M, to date)
o Duffy (Fyb)

• Other hemolytic disorders
o Glucose phosphate isomerase deficiency (autosomal recessive)
o Pyruvate kinase deficiency (autosomal recessive)
o G-6-PD deficiency (X-linked dominant)

• Disorders of red cell production
o Congenital dyserythropoietic anemia types I and II (autosomal dominant)
o Diamond-Blackfan syndrome (autosomal dominant)
o Lethal hereditary spherocytosis (spectrin synthesis defects) (autosomal recessive)
o Congenital erythropoietic porphyria (Günther disease) (autosomal recessive)
o Leukemia (usually associated with Down or Noonan syndrome)
o Alpha-thalassemia (Bart hemoglobinopathy)
o Parvovirus B19 (B19V)

• Fetal hemorrhage o Intracranial or intraventricular o Hepatic laceration or subcapsular o Placental subchorial o Tumors (especially sacrococcygeal teratoma) o Fetomaternal hemorrhage o Twin-to-twin transfusion o Isoimmune fetal thrombocytopenia


• Several years ago, Rh disease was considered the usual cause of fetal hydrops. More recently, the use of Ig in the at-risk mother, administered prior to maternal isoimmunization, should have made this an entirely preventable disorder. Sadly, this has not been the case. While a dramatic reduction in Rh D sensitization has been realized, the disorder has stubbornly persisted in a small group of women, many of whom have become isoimmunized from repeated exposure to foreign red blood cell (RBC) antigens that contaminate needles used for illicit drug use. One recent study notes this cause for 1 in 5 women with Rh sensitization; the prevalence of hydrops in this group was a stunning 80%.

o The reduced prevalence of Rh D disease has made fetal hemolytic anemias secondary to maternal isoimmunization with other Rh-group and other blood group antigens more apparent. Many of these result in profound fetal anemia and hydrops. Because many others probably also exist, maternal antibody screening should at least search for those already demonstrated to lead to fetal hydrops. Molecular genetic technologies, specifically polymerase chain reaction (PCR) testing, have been demonstrated particularly to provide more precise and complete genotyping. Other heritable fetal hemolytic anemias have been associated with fetal hydrops. Most are uncommon, autosomal-recessive genetic diseases (pyruvate kinase deficiency, glucose phophate isomerase deficiency), and their association with fetal hydrops is limited to 1 or 2 reports. G-6-PD deficiency is a more common, X-linked recessive disorder; however, G-6-PD has been infrequently associated with fetal hydrops.

o Diagnosis is important in these rare conditions because they are compatible with a relatively normal life, and fetal transfusions should be effective. Fetal RBC hemolysis from placental transfer of maternal IgG antibody against fetal RBC antigen(s) (termed isoimmune disease) continues to account for approximately 15-20% of individuals with hydrops fetalis. Early and precise diagnosis is of enormous importance because highly effective fetal therapy is now available, and long-term outcome is unimpaired in babies with these causes for hydrops. While fetal imaging confirms the presence of hydrops, it does so only after the fact. Studies preceding and predicting fetal deterioration include amniotic fluid (AF) bilirubin (delta optical density at 450 μ using Liley extrapolations) and, more recently, measurement of fetal hematocrit and hemoglobin levels by direct sampling using cordocentesis.

• Disorders of RBC production, resulting in functional fetal aplastic anemia, cause of hydrops
o The importance of infection with B19V is increasingly recognized. Use of a sensitive and precise diagnostic test (PCR) has demonstrated that perhaps 20% of fetal hydrops is associated with this maternal/fetal infection. During seasons of particularly high prevalence, the proportion is much higher. Early diagnosis is of crucial importance because fetal treatment by direct transfusion has been demonstrated to be effective, the virus has not been demonstrated to have teratogenic effects, and growth and development of the survivors appear to be normal.

o Heritable disorders of hemoglobin alpha-chain production are important causes of hydrops in Asian populations. These hemoglobinopathies have become increasingly important in the United States because of recent immigration patterns, particularly in the West. A recent report from Hawaii over a 10-year period identifies alpha-thalassemia as the single most important cause of fetal hydrops. Homozygous alpha-thalassemia, with deletion of all 4 alpha-globin genes, results in the total absence of alpha-hemoglobin chains in the fetus. This condition, ranging from 1 in 500 to 1 in 1500 in a Thai population, has been considered to be a fatal fetal condition (Bart hydrops).

o More recently, a handful of survivors of hydrops fetalis due to alpha-thalassemia has been reported; however, all required fetal transfusions, all required repeated frequent transfusions after birth, and all surviving males had hypospadias. Thus, some health care professionals have questioned the practical and ethical basis of fetal and neonatal treatment. However, opportunities for treatment, such as stem cell transplantation, bone marrow transplantation, and gene replacement therapy, may hold promise for babies with this condition in the future. Fetal diagnosis of the condition has been confirmed (using PCR) from fetal deoxyribonucleic acid (DNA) samples of chorionic villus, fetal fibroblast (AF), and from fetal blood.

o Once disorders of hemoglobin alpha-chain production are confirmed, fetal interventions have been based on hematocrit and hemoglobin levels obtained by direct cordocentesis. Ultrasound findings are nonspecific, and they occur late. Several simple maternal screening techniques have been suggested, but DNA-based studies using a testing system that allows unequivocal identification of haplotypes commonly detected in Asian Americans (-SEA in 62%, -alpha 3.7 in 27%, -FIL in 11%) appear to be most promising in this country. Despite the current generally gloomy outlook and uncertain treatment of the baby with fetal hydrops, early diagnosis of the condition is important because maternal morbidity is very high with fetal hydrops due to alpha-thalassemia.

o Other heritable disorders of RBC production are listed, but none is very common. Some are fatal, but most are manageable after birth; some are associated with malformation syndromes. These heritable disorders all lead to hydrops in the same manner.

o Profound anemia leads to high-output cardiac failure and increased CVP. Early and precise diagnosis is important for fetuses with correctable conditions (eg, need for and timing of fetal transfusions) and for fetuses with conditions that are not correctable (to permit parents to understand options and participate in decisions about pregnancy management). Gene therapy may also hold promise for some of these babies in the future.

• Fetal hemorrhage is another important cause of fetal hydrops. Acute bleeding may be local or more generalized. Unless the origin is from a tumor mass, the bleeding may not be recognized early enough to intervene. Thus, fetal imaging is of critical importance, and a careful examination, particularly of those sites where bleeding has been associated with hydrops, is essential for prompt and proper fetal treatment.

o Isoimmune fetal thrombocytopenia is probably more common than has been reported, and, because treatment may be effective in this condition, maternal screening for platelet antibodies should be routine in all incidents in which the cause of fetal hydrops remains undetermined. Sacrococcygeal teratoma is relatively common, accounting for a measurable proportion of incidents of fetal hydrops. Controlled trials are needed to be certain that currently proposed interventions are more helpful than harmful, but these interventions hold considerable promise. Effective treatment is especially important for this condition since associated anomalies are rare, and fully normal development is possible. Once again, fetal imaging studies are the cornerstone for diagnosis and management of sacrococcygeal teratoma.

o The fetus may bleed into the mother, and this hemorrhage may be severe enough to lead to fetal death or hydrops. Disruptions of the fetomaternal circulation may be placental or related to tumors (choriocarcinoma, chorangioma), trauma, or partial placental abruption.

o Early diagnosis of fetomaternal hemorrhage is deceptively simple, requiring a maternal blood smear to assess the proportion of circulating cells with fetal hemoglobin (resistant to acid elution). Unfortunately, recent automated modifications of this test are less specific and sensitive than the original Betke-Kleihauer test, and several newer tests have been proposed. Of these tests, the most promising appear to be either immunofluorescent flow cytometry or DNA analysis using PCR. More difficult than determining which test to use is knowing when to perform the tests since, in most reported cases, the diagnosis is usually too late to allow effective fetal intervention.

o The earliest warning of the condition in most recent series has been reduced fetal body movements accompanied by sinusoidal fetal heart rate patterns and altered fetal biophysical profile. Confirmation of fetal anemia by direct cordocentesis is the final step to transfusion. Unfortunately, fetal transfusion often has been ineffective due to continued, repeated, massive fetal hemorrhages.

o Placental vascular anastomoses are present in virtually all monochorionic monozygotic pregnancies. Twin-to-twin transfusion is balanced in most circumstances, with no excessive accumulation or loss for either twin. Sizable hemorrhages occur in 5-30% of these pregnancies when the shunting is unbalanced, leaving one twin anemic and the other polycythemic. These bleeds may lead to fetal death, impaired fetal growth, high-output cardiac failure from hypovolemic shock, congestive failure from volume overload, or hydrops fetalis, depending on the size of the bleed and whether it is acute or chronic. Extreme early hemorrhages may result in fetal acardia; somewhat later, they may be detected as fetus papyraceous or as a stuck twin or vanishing twin.

o While some placental studies suggest fewer (rather than more) vascular anastomoses with resultant trapping of blood in the recipient fetus, other placental studies demonstrate excessive and abnormal placental vascular communications. Velamentous cord insertion is much more common in those fetuses with large shunts. Curiously, the recipient (polycythemic) twin usually develops hydrops, not the (anemic) donor. Even more curiously, death of the hydropic twin (whether untreated and/or spontaneous, following fetal therapy, or after selective feticide) is not uncommonly followed by the development of hydrops in the remaining twin.

o Reasons for all these events remain causes for speculation. Definitive diagnosis also is surprisingly difficult, since hydrops may occur in either (or both) twin, disparities in fetal size may not be present, and fetal hemoglobin or hematocrit levels may be well outside the reference range (high or low) in the absence of any hydrops.

o Ultrasound evidence of same-sex twins, a monochorionic placenta, with hydramnios in one sac and oligohydramnios in the other sac, often is used to make the diagnosis. These findings and disparities in fetal sizes (15-25%) are useful, but unfortunately they are not definitive. Determination of fetal hemoglobins by cordocentesis is employed; however, differences in fetal hemoglobin concentration exceeding 5 g/dL are common in the absence of hydrops, and, conversely, differences less than this may be found in individuals with hydrops.

o Significant differences in serum protein levels also may be observed in twins with hydrops fetalis, and atrial natruretic factor concentrations usually are high. Unfortunately, none of these findings are diagnostic. Clearly, earlier and more precise fetal diagnostic methods, which measure degree of functional dysfunction, are needed. Most promising in this regard are pulsed Doppler ultrasound measurements of umbilical vessel blood velocity. Such studies hold promise of providing an earlier window of opportunity for fetal diagnosis and treatment. Outcome is surprisingly poor in this condition. Most twins with hydrops die before birth (42-86%), and a shocking proportion of survivors of the condition have cardiovascular and neurologic damage. Ultrasound studies demonstrate cerebral white matter damage, suggesting antenatal necrosis in approximately one third. Follow-up studies of neurodevelopment suggest serious impairment in approximately one quarter of surviving twins.

o Many (if not most) surviving twins have significant cardiomyopathy (predominantly right-sided), usually associated with pulmonary outflow obstruction; pulmonary artery calcification and endocardial fibroelastosis also are common. Neutropenia, impaired fetal growth, reduced bone density, and mineralization have been observed in the surviving donors. Optic nerve hypoplasia has been reported, and peripheral vascular ischemic necrosis with gangrene of distal extremities has been observed in several individuals with the condition. Coagulopathy and embolic phenomena were speculated in many early studies; however, scant evidence for them exists in recent reports. Very premature delivery is common and contributes undoubtedly to the morbidity and mortality.

o Treatment successes have been reported with transfusion of the anemic fetus, plasmapheresis of the polycythemic twin, laser ablation of placental vascular anastomoses, and amnioreduction; however, failures and serious complications also have been reported with each of these.