Timely referral to a maternal–fetal medicine specialist allows for detailed and comprehensive ultrasound examination and the early identification of any treatable causes.
Antenatal identification of the etiology would allow for appropriate counselling of parents and help clinicians provide parents with early options such as medical termination of pregnancy, planned delivery, or active antenatal treatment.
Diagnostic studies may be considered best by temporal grouping (fetal, maternal, placental, neonatal, postmortem). Assessments generally proceed from low-risk noninvasive tests to higher-risk invasive techniques as required for precise and complete diagnosis to properly manage the individual pregnancy.
Obtain several maternal laboratory studies concurrent with the initial fetal imaging assessment.
Assessment of maternal blood type (red cells) and antibody screen (identification, and quantitation when indicated, of maternal plasma antibodies) are standard screening tests recommended in most guidelines for prenatal care. Recently, the introduction of new molecular genetic techniques (eg, PCR) has demonstrated considerable promise; however, definitive comparisons with standard methods are not yet available. More than 85% of Rh-sensitized women whose anti-D titers were 1:512 or higher were found to be HLA type DQBI allele*0201. Although this single study suggests that HLA typing may be of value in the prospective management of isoimmunization, this observation requires confirmation and further study.
Qualitative and quantitative estimates of the proportion of red cells containing fetal hemoglobin in the maternal circulation are of particular value, including the following:
The Betke-Kleihauer technique depends on the different vulnerability of cells containing fetal hemoglobin from those with adult hemoglobin when subjected to acid-elution.
A newer method using flow cytometry has also been found to be useful.
Results using either method must be interpreted with considerable caution, since poor sensitivity and specificity of these diagnostic tests has been demonstrated in several studies.
The search for maternal-fetal infection must be intensive.
Syphilis serology was a standard prenatal screening test for decades. More recently, the test has been used more selectively, despite the absence of any good evidence for this change. If fetal hydrops is suspected, syphilis serology is mandatory with repeat serial testing and, very importantly, with dilution of maternal serum. The prozone effect has been demonstrated repeatedly with fetal hydrops due to syphilis, thus dilution of maternal serum to avoid false-negative results is required.
Antibody screens for common fetal infections (toxoplasmosis, other infections, rubella, CMV infection, and herpes simplex [TORCH]) and more sensitive and specific enzyme-linked immunosorbent assay (ELISA) studies for individual infectious agents have been used for many years. More recently, the PCR technique is generally accepted as the criterion standard and should be used whenever possible.
Hemoglobin electrophoresis for alpha-thalassemia heterozygosity has been useful in ethnically at-risk populations.
In regions where ethnic diversity is high, routine screening may be preferable to selection based on ethnicity. More recently, PCR screens and colorimetric monoclonal antizeta antibody tests for heterozygote alpha-thalassemia have been demonstrated as economically feasible screening procedures.
Maternal serum screening tests (multiple-marker, triple-screen, triple-marker), commonly used if fetal anomaly is suspected, are of uncertain value with fetal hydrops.
In one study, positive screening tests (any of the 3 used) with a sensitivity of only 60% in 19 cases of Turner syndrome distinguished some fetuses with cystic hygroma and/or hydrops from those without. Individual components of these tests were examined separately in several other studies.
Elevated AFP levels have been reported in hydrops associated with fetomaternal hemorrhage, umbilical cord hemangioma, polycystic kidneys, CMV, and parvovirus; however, AFP levels are similar in babies with Turner syndrome with or without hydrops. Use of AFP screening as an index of fetal aplastic crisis in maternal Parvovirus infection has been recommended but is of dubious value because several fetal deaths have been observed with AFP levels within reference range. The precise diagnostic value of AFP screening is uncertain because definitive studies are not available.
Low levels of unconjugated estriol (uE3) have been found in one hydropic baby with Smith-Lemli-Opitz syndrome, but the test has not demonstrated value in distinguishing between babies with or without hydrops, and normal levels have been observed in several hydropic deaths.
Human chorionic gonadotropin levels have been reported as significantly elevated in hydrops with sacrococcygeal teratoma, choriocarcinoma, Parvovirus, Turner syndrome, and Down syndrome; however, these levels have also been normal in several hydropic fetal deaths related to Parvovirus.
In a single study, inhibin-A levels were markedly elevated in 12 fetuses with Turner syndrome with hydrops and were reduced significantly in those fetuses without hydrops.
Maternal serum IgG placental alkaline phosphatase levels are increased with fetal hydrops; currently, clinical utility of this finding is untested.
Direct invasive sampling studies of fetal amniotic fluid (AF) or placental tissues have demonstrated value for definitive diagnosis, monitoring of treatment efficacy, and accurate prognosis in a number of conditions associated with hydrops.
Elevated levels of AF bilirubin, as measured by the spectrophotometric extrapolation technique first described by Liley, have been demonstrated to be highly sensitive predictors of the severity of fetal anemia due to isoimmunization. 
Specificity is somewhat less because alpha-feto bilirubin may also be elevated due to maternal hemoglobinopathy or hepatitis and in association with impaired fetal swallowing due to fetal gastrointestinal obstruction and a number of fetal CNS disorders.
More recent reports have suggested the use of ultrasonographic methods to detect fetal anemia; however, routine use of such noninvasive methods is not justified in the absence of definitive evidence of their superior sensitivity and specificity, at less risk, when compared with the standard proven method of AF bilirubin analysis.
Direct enzyme assays or biochemical analyses of measurements of levels of specific metabolic products may be indicated in the pregnancy at risk of hydrops because of inborn errors of metabolism.
Such studies may use samples from the mother and father (red cells, serum, urine, tissue), fetus (skin fibroblast cultures or leukocytes from AF, fetal red cells, white cells, serum samples from direct cordocentesis, serous effusions), placenta (chorionic villous sampling, placental biopsy), or AF.
Examples include biochemical analyses of urine or AF for abnormal oligosaccharide, mucopolysaccharide, and sphingolipid metabolites when lysosomal disorders are suspected or determination of AF 7-dehydrocholesterol reductase if history and findings suggest Smith-Lemli-Opitz syndrome.
Fetal serum endothelin levels are elevated more than 2-fold in recipients; however, these levels are normal in donors with twin-to-twin transfusion syndrome.
Endothelin levels were related to presence of and severity of hydrops in these cases. Changes in fetal serum liver enzymes, particularly alanine transaminase and glutamyl transpeptidase, have been demonstrated to occur following correction of the anemia by fetal transfusion. Whether or not these observations may be of diagnostic or prognostic use is currently untested.
Direct fetal diagnostic studies for Parvovirus include histologic staining methods (RBC), digoxigenin-labeled B19.
DNA probe (PCR), and avidin-biotin complex immunohistochemical and immunofluorescent studies, among others. Currently, PCR methods appear to be best, although definitive studies providing sensitivity and specificity are not available.
Karyotyping is always indicated if history or ultrasound results reveal a constellation of findings consistent with a chromosomal aberration or if maternal or family history is suggestive.
Fetal karyotyping and genetic microarray molecular testing should be conducted in all cases of unexplained nonimmune hydrops fetalis.
Chromosomal analyses may be performed on desquamated fetal epithelial cells in AF, fetal tissue biopsy samples, or placental (fetal tissue) biopsy samples.
An increase in AFP has been observed in almost 1 in 10 (8.4%) genetic amniocenteses; fetal mortality exceeded 1 in 10 (14%) when such AFP elevations occurred. Evidence of fetomaternal bleeding is present in 3 of 4 chorionic villous samplings. Thus, careful weighing of benefit versus risk must be made whenever direct invasive diagnostic methods are considered.
To obtain more precise information concerning fetal status, direct fetal sampling by cordocentesis (or periumbilical sampling) has been used with increasing frequency.
Acidemia, hypoxemia, and hypercarbia are found in most studies of fetal acid-base balance and blood-gas status obtained at time of direct fetal treatment. These results are nonspecific and anticipated, and, although they may be of use in immediate management, they are unlikely to be of value in longer-term care of the fetus with hydrops.
Analyses of serous effusion fluids (pleural, pericardial, or ascitic, most commonly) have been of surprisingly little value. For example, lymphocyte counts considered characteristic of congenital chylothorax when found in the newborn infant have been observed in pleural effusions from fetuses with CMV disease.
Serologic tests for specific infections, hemoglobin or hematocrit measurements, platelet counts, white cell counts and morphologic analyses, specific enzyme analyses, and karyotyping are just a few of the more common measurements obtained. While this information may be invaluable in specific cases, use of such invasive methods on a routine basis carries significant risks.
Fetal sampling by cordocentesis is followed by significant bradycardia in almost 1 in 20 samplings (3.8%); of those with such complication, almost two thirds die (61.5%).
Elevated AF alkaline phosphatase has been observed in association with fetal hydrops due to Turner syndrome.
Although this is likely to be a nonspecific finding, further study is necessary.
The fetal biophysical profile has been demonstrated to be abnormal in severe hydrops.
Cardiotocographic records obtained 12 hours prior to fetal death demonstrate absence of short-term and long-term variability, absence of tachycardia, presence of late decelerations, and terminal bradycardia.
Sinusoidal heart-rate patterns have been observed consistently in hydrops associated with severe fetal anemia related to isoimmunization and fetomaternal hemorrhage.
Once the possibility of fetal hydrops is considered or suspected, sophisticated and complete fetal imaging studies are an initial absolute necessity. Hydrops is defined by the presence of serous effusions in a fetus with subcutaneous tissue edema. Some authors have distinguished the presence of a single effusion (pleural, peritoneal) as an entity distinct from hydrops; however, more recent evidence suggests that an isolated effusion often (if not usually) progresses to overt fetal hydrops.
Exceptions appear to be isolated chyloperitoneum/ascites (usually associated with obstructive uropathy and, thus, not true hydrops) and pleural or peritoneal effusions that regress spontaneously (see Treatment). Thus, careful, complete and serial imaging is required to establish the diagnosis and the extent of the hydrops.
Examples of radiographic findings are shown in the images below.
The equipment used must be capable of providing high-resolution images at large depth. Linear array transducers are commonly used; however, sector scanners provide better views of the heart and many other structures.
Range-gated Doppler capability is optimal for functional physiologic assessments. Use of high-frequency transvaginal 2-dimensional and pulsed-wave/color Doppler flow mapping particularly has been promising.
The initial imaging study may provide important clues concerning the origin of the fetal condition. For example, most arrhythmias and anomalies may be detected even in the process of establishing the initial diagnosis. However, in most cases, more complex, serially repeated studies may be required to accurately define the constellation of findings in the fetus.
Specific echocardiographic assessment of fetal cardiac structure and function is required in most cases of fetal hydrops. Essential elements of this examination should include definitive results concerning (1) assessment of biventricular outer dimensions in diastole and of the cardiothoracic ratio, (2) presence or absence of AV valve regurgitation, and (3) umbilical vessel blood flow velocities and pulsations.
Biventricular diameter in diastole had 100% sensitivity and 86% specificity for detection of cardiac failure in one study. These observations, confirmed by results from several other reports, address the basic underlying pathophysiologic disturbance in faltering cardiac output of the fetus with hydrops and increased CVP.
The presence of AV valve regurgitation is a common finding, suggesting right-heart failure or increased preload. Persistence of serious functional AV valve incompetence following treatment interventions is ominous, particularly in terms of fetal outcome. The proportion of atrial area taken up by the regurgitant jet is related to hydrops. The proportion of systolic time during which AV valve insufficiency is demonstrated is also related to hydrops. In one study, AV valve insufficiency was pansystolic in all babies with hydrops.
Umbilical and fetal abdominal vessel pulsations, flow velocities, and waveforms have been studied by several investigators in hydrops caused by tachyarrhythmias, alpha-thalassemia, and twin-twin transfusion. Because sensitivity, specificity, and predictive values are not available, the practical clinical value of these studies is uncertain. However, the results available to date suggest that they may provide valuable quantitative and qualitative pathophysiologic information and may even be predictive of fetal deterioration prior to the development of overt hydrops in some situations.
Umbilical venous (UV) blood flow, normally nonpulsatile, demonstrates pulsatile (or double-pulsatile) flow, a finding consistent with an increased fetal CVP. Pulsed Doppler duplex ultrasound studies demonstrate higher UV and inferior vena cava (IVC) blood velocity and blood flow, suggesting an increase in the preload (cardiac) index. Studies of IVC, hepatic vein, and ductus venosus blood flow demonstrate similar results. In hydrops caused by sustained tachycardia, reversal of blood flow (or increased retrograde flow) with systolic forward flow and diastolic reverse flow is present at heart rates exceeding 220 bpm; these abnormalities are reversed by successful fetal treatment with return of the heart rate to 210 bpm or less. Great interindividual differences in the time required for this reversal are observed.
Myocardial function is impaired with hydrops, and the severity of this functional cardiomyopathy is reflected by the degree and persistence of AV valve incompetence and UVC/IVC flow patterns in the fetus.
Abnormalities in umbilical artery (UA) blood flow are also found. UA early-diastolic blood flow velocity is absent, and end-diastolic UA velocity is reversed. The UA pulsatility index (PI) is increased in feto-fetal transfusion hydrops, and, most importantly, this abnormal finding usually precedes and predicts the development of hydrops in the recipient/hydropic twin. PI also improves parallel to clinical improvement in fetal condition. Abnormal UA blood flow patterns in alpha-thalassemia hydrops include an increased acceleration slope, more linear decline from maximum systole to end diastole, and reduced spectral broadening; fetal aortic waveforms also demonstrate distorted systolic peaks, flow turbulence, and greatly elevated diastolic frequencies.
Elevated umbilical venous pressures, found in approximately two thirds of individuals with fetal hydrops, return to normal with successful treatment. Such measurements, obtained by cordocentesis at time of fetal treatment, may be useful in assessing the success of fetal therapies that require a direct invasive approach.
The Society of Obstetricians and Gynaecologists of Canada in 2013 published guidelines for the investigation and management of nonimmune fetal hydrops.  The recommendations in this publication include the following:
All patients with fetal hydrops should be referred promptly to a tertiary care center for evaluation.
Fetal chromosome analysis and genetic microarray molecular testing should be offered where available in all cases of nonimmune fetal hydrops.
Imaging studies should include comprehensive obstetrical ultrasound (including arterial and venous fetal Doppler) and fetal echocardiography.
Investigation for maternal–fetal infections, and alpha-thalassemia in women at risk because of their ethnicity, should be performed in all cases of unexplained fetal hydrops.
To evaluate the risk of fetal anemia, Doppler measurement of the middle cerebral artery peak systolic velocity should be performed in all hydropic fetuses after 16 weeks of gestation. In case of suspected fetal anemia, fetal blood sampling and intrauterine transfusion should be offered rapidly.
All cases of unexplained fetal hydrops should be referred to a medical genetics service. Detailed postnatal evaluation by a medical geneticist should be performed on all cases of newborns with unexplained nonimmune hydrops.
Autopsy should be recommended in all cases of fetal or neonatal death or pregnancy termination. Amniotic fluid and/or fetal cells should be stored for future genetic testing.
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