INTRODUCTION — Hydrops fetalis refers to the presence of at least two abnormal fluid collections in the fetus, including fluid in serous cavities (eg, ascites, pleural effusions, pericardial effusions) and generalized skin edema. Nonimmune hydrops fetalis (NIHF) comprises the subgroup of cases not caused by red blood cell alloimmunization (eg, RhD, Kell). Multiple fetal anatomic and functional disorders can cause NIHF, which can be lethal.
This topic will review issues related to NIHF. Red blood cell alloimmunization is discussed separately. (See "RhD alloimmunization in pregnancy: Overview" and "Management of non-RhD red blood cell alloantibodies during pregnancy".)
PREVALENCE — The prevalence of NIHF ranges from 1 in 1500 to 1 in 4000 births [1-6]. Wide variations in reported prevalence are due to differences in definitions, populations (eg, Southeast Asian populations have a high prevalence of alpha- and beta thalassemia ), thoroughness of evaluation, and whether late pregnancy terminations were included.
The widespread use of anti-D immune globulin dramatically decreased the prevalence of RhD alloimmunization and associated hydrops after 1968 when the drug became available. As a result, NIHF now accounts for >90 percent of hydrops cases .
PATHOGENESIS — Dysregulation of the net fluid movement between the vascular and interstitial spaces leading to NIHF can be caused by fetal disorders with one or more of the following features :
●Obstructed lymphatic drainage in the thoracic and abdominal cavities
●Increased capillary permeability
●Increased central venous pressure
●Decreased osmotic pressure
However, the pathogenesis of NIHF is incompletely understood. Further investigation is needed to understand the complex interplay between fetal myocardial function, maintenance of intravascular volume, and neural and circulating plasma proteins and hormones, and to explain how each factor contributes to hydrops. Although the exchange of fluid between the plasma and the interstitium is determined by the hydrostatic and oncotic pressures in each compartment, actual capillary hemodynamics differ from that predicted by the Starling equation because the structure of the interstitial space and the capillary filtration barrier are much more complex than was once believed. (See "Pathophysiology and etiology of edema in adults".)
CLINICAL PRESENTATION AND FINDINGS
Presentation — In asymptomatic pregnant patients, NIHF may be discovered incidentally during prenatal sonography performed for standard obstetric indications (eg, anatomic survey, fetal growth). In other cases, hydrops is discovered on prenatal sonography performed intermittently specifically to monitor fetuses known to be at risk for disorders associated with NIHF.
When hydrops is associated with polyhydramnios, NIHF may be discovered during a work-up for uterine size greater than dates. Rarely, hydrops is associated with the early onset of maternal preeclampsia (ie, Mirror syndrome) and NIHF may be discovered as part of the fetal evaluation of this disorder.
Fetal findings — NIHF is defined by fetal findings. Two or more of the following findings should be present on ultrasound examination:
●Ascites – In its early stage, fetal ascites appears as a rim of echolucent fluid just inside the abdominal wall (image 1) or surrounding the bladder or liver. If there is a large amount of ascites, the bowel may appear compressed in the central abdomen (image 2), and its walls may be accentuated due to increased ultrasound transmission afforded by the excess intraabdominal fluid [4,9]. Pseudoascites (image 3), which is a hypoechoic band consisting of abdominal wall muscles, should not be mistaken for ascites.
Isolated fetal ascites can result from several disorders and is not considered hydrops since only one compartment is affected. In a systematic review, etiologies included genitourinary (24 percent), gastrointestinal (20 percent), viral or bacterial infection (9 percent), cardiac (9 percent), genetic disorders (8 percent), chylous ascites (6 percent), metabolic storage disorders (3 percent), other structural disorders (4 percent), other causes (4 percent), and idiopathic (13 percent) . Approximately 6 percent of initial diagnosis of isolated ascites progressed to hydrops and 30 percent spontaneously resolved.
●Pleural effusions – Pleural effusions appear as a rim of hypoechoic fluid just inside the chest wall, outlining the lungs. The effusion may be unilateral or bilateral, and may compress the lung tissue (image 4A-C). Persistent effusions that develop before 20 weeks of gestation may inhibit lung growth and development, resulting in pulmonary hypoplasia, which may be fatal in the neonatal period. A variety of techniques for prenatal diagnosis of severe pulmonary hypoplasia have been reported, but none are consistently reliable .
●Pericardial effusion – A pericardial effusion appears as a rim of echolucent fluid surrounding the heart (image 5) but may be difficult to visualize with standard two-dimensional images. It is important to not mistake physiologic pericardial fluid or the hypoechoic myocardium for an abnormal effusion. Using M-mode helps in measuring pericardial effusions accurately and differentiating between physiologic and pathologic pericardial fluid when the diagnosis is uncertain .
During second-trimester fetal ultrasonographic examination, pericardial fluid greater than 2 mm in thickness that increases on serial examinations suggests a pathologic etiology. Visualization of pericardial fluid up to 2 mm thick is common and should not be regarded as pathologic , and even fluid up to 7 mm thick may be benign .
●Skin edema – Generalized skin edema is a late sign of fetal hydrops (image 6). Pathologic skin edema has been defined as subcutaneous tissue thickness >5 mm; however, fat under the scalp or in the posterior nuchal region should not be mistaken for skin edema.
In addition, NIHF may be associated with polyhydramnios and placental thickening. However, these findings are not included in the fluid collections needed for diagnosis of hydrops.
●Polyhydramnios is defined as a single deepest pocket ≥8 cm or an amniotic fluid index ≥24 cm . It is present in up to 75 percent of pregnancies complicated by NIHF. (See "Polyhydramnios: Etiology, diagnosis, and management", section on 'Diagnosis'.)
●In general, a placental thickness ≥4 cm in the second trimester and ≥6 cm in the third trimester is considered abnormal and should prompt further investigation [15,16]. In NIHF, placental thickening is likely due to intravillous edema. However, in patients with massive polyhydramnios, the excessive amniotic fluid can make the placenta appear thinned or compressed.
Maternal findings — Patients carrying a hydropic fetus may have uterine size large for dates and may notice decreased fetal movement. Severe polyhydramnios may lead to shortness of breath, which may necessitate treatment or delivery. (See "Polyhydramnios: Etiology, diagnosis, and management", section on 'Management of polyhydramnios in singleton pregnancies'.)
Although hydrops is a fetal condition, in some cases, there are associated maternal disorders, such as preeclampsia (Mirror syndrome) or theca lutein cysts [17-21].
Mirror syndrome — Mirror syndrome (also called Ballantynes syndrome) refers to a condition of generalized maternal edema, often with pulmonary involvement, that "mirrors" the edema of the hydropic fetus and placenta. Although usually associated with NIHF, it can also occur with immune-mediated hydrops. The pathogenesis has not been firmly established, but at least in some cases, the hydropic placenta increases production of soluble fms-like tyrosine kinase (sFlt1), which is an important mediator of maternal endothelial and vascular abnormalities in preeclampsia . (See "Preeclampsia: Pathogenesis".)
Mirror syndrome can occur any time during the antepartum period and may persist postpartum . It may present with rapid weight gain, increasing peripheral edema, and progressive shortness of breath, or with a clinical presentation and course similar to preeclampsia with severe features. In contrast to preeclampsia, the maternal hematocrit is often low (hemodilution) rather than high (hemoconcentration), amniotic fluid volume is often high (polyhydramnios) rather than low (oligohydramnios), and the fetus always shows signs of hydrops [24,25]. A systematic review of reports on Mirror syndrome noted that key maternal signs were edema (80 to 100 percent), hypertension (57 to 78 percent), and proteinuria (20 to 56 percent), and the overall rate of fetal death was 56 percent . Severe maternal complications, such as pulmonary edema, occurred in 21 percent of cases. (See "Polyhydramnios: Etiology, diagnosis, and management" and "Preeclampsia: Clinical features and diagnosis".)
Delivery is usually required to induce remission of maternal symptoms. In the review described above, maternal symptoms disappeared 4.8 to 13.5 days after delivery . Interventions that result in reversal of fetal hydrops, including selective feticide of a hydropic twin, can also reverse the maternal disorder, thereby allowing prolongation of the pregnancy [25,27-30]. Spontaneous resolution of Mirror syndrome has also been described after spontaneous resolution of fetal hydrops related to parvovirus infection and after fetal death. Resolution is associated with a fall in sFlt1 .
However, prompt delivery is indicated, even in NIHF with a treatable etiology, because pregnant patients with severe features of preeclampsia can deteriorate rapidly. These decisions should be made on a case-by-case basis, taking into account the severity of the maternal condition, the severity of the fetal condition, and the potential for rapid resolution of hydrops.
Theca lutein cysts — Theca lutein cysts are luteinized follicle cysts that form as a result of overstimulation from high human chorionic gonadotropin (hCG) levels or extreme sensitivity to hCG. Theca lutein cysts associated with NIHF have been attributed to elevated hCG production from the hydropic placenta.
●Generalized skin edema (skin thickness >5 mm)
POSTDIAGNOSTIC EVALUATION — An attempt to determine the etiology of the hydrops should be made at the time of diagnosis, since several etiologies can be confirmed or excluded based upon ultrasound findings.
The etiology can be determined prenatally or postnatally in 60 to 85 percent of cases . The remaining cases are considered idiopathic (ie, no anatomic malformation detected prenatally or postnatally, no maternal red cell antibodies, middle cerebral artery (MCA) peak systolic velocity (PSV) <1.5 multiples of the median (MoM); as well as no neonatal anemia, known monogenetic disorders, fetal tumors, or lysosomal storage disorders; as well as negative maternal infection screening [eg, cytomegalovirus, toxoplasmosis, syphilis, parvovirus B19], euploid fetal karyotype, and normal microarray). (See 'Etiology and prenatal management of disorders associated with hydrops' below.)
General approach — Hydrops is associated with a broad spectrum of disorders. Prenatally, the key issues are to (1) identify those cases caused by disorders that are treatable in utero and (2) deliver the fetus when the benefits of prolonging pregnancy are exceeded by the risk of imminent fetal demise. Prenatally or postnatally, it is also important to identify disorders with a risk of recurrence in future pregnancies.
●Fetal survey and echocardiography – We perform a thorough sonographic evaluation of the fetus, placenta, umbilical cord, and amniotic fluid to look for causes of NIHF that can be diagnosed by imaging, such as major fetal or placental structural abnormalities, arrhythmias, and twin-to-twin transfusion syndrome.
A fetal echocardiogram should also be performed as it may detect previously unrecognized cardiac abnormalities, which may be the etiology or a consequence of hydrops . (See "Congenital heart disease: Prenatal screening, diagnosis, and management" and "Fetal arrhythmias".)
●MCA-PSV – We perform Doppler assessment of the fetal MCA-PSV to screen for fetal anemia. An MCA-PSV ≥1.5 MoM for the gestational age is an accurate noninvasive tool for predicting moderate to severe fetal anemia of any etiology (ie, immune or nonimmune) [34,35]. (See "RhD alloimmunization in pregnancy: Management", section on 'Assess for severe anemia using MCA-PSV in fetuses at risk'.)
If MCA-PSV is ≥1.5 MoM, we try to determine the cause of the anemia (eg, parvovirus B19 infection, alloimmunization, fetomaternal bleeding, hemoglobinopathy). (See 'Anemia' below.)
●Pedigree – If the cause for NIHF is not identified by these examinations, we obtain a detailed family history (three generation pedigree). A genetic counselor can be helpful in obtaining a thorough history. (See "Genetic counseling: Family history interpretation and risk assessment".)
The patient's ethnic background and personal and family history are reviewed to look for heritable disorders associated with hydrops, such as alpha thalassemia, metabolic disorders, and genetic syndromes. We ask about consanguinity since this increases the probability of a recessive disorder, some of which present with fetal hydrops.
●Infection exposure – We also ask about recent exposure to individuals, particularly children, with an infection. Parvovirus B19 is the most common infectious etiology of hydrops, accounting for approximately 15 percent of cases . (See "Parvovirus B19 infection during pregnancy".)
●Laboratory examination – We perform the following laboratory evaluation. The sequence is determined by the most likely diagnoses in a specific patient, cost, and invasiveness. Some tests are performed simultaneously, as the results of individual tests may not be available for several days to weeks, thus precluding sequential studies.
•Complete blood count with red blood cell indices – A mean corpuscular volume (MCV) <80 femtoliters (fL) in the absence of iron deficiency suggests thalassemia. The biological father's MCV should be determined. If both parents have MCV <80 fL, additional studies are required to make a definitive diagnosis.
Initially, hemoglobin analysis is performed either by high-performance liquid chromatography or isoelectric focusing to identify abnormal hemoglobins associated with thalassemia (eg, hemoglobin F, hemoglobin A2, hemoglobin H) (table 1).
If hemoglobin analysis suggests alpha thalassemia (eg, high percentage of hemoglobin Bart's), then DNA-based testing for alpha globin gene deletions is required to establish a diagnosis. (See "Prenatal screening and testing for hemoglobinopathy" and "Methods for hemoglobin analysis and hemoglobinopathy testing", section on 'Patient with suspected thalassemia'.)
•Blood type and antibody screen – A positive screen for antibodies directed against red blood cell antigens suggests immune-mediated fetal anemia. (See "RhD alloimmunization in pregnancy: Overview" and "Management of non-RhD red blood cell alloantibodies during pregnancy".)
•Kleihauer-Betke acid elution smear or flow cytometry to exclude the possibility of significant fetomaternal hemorrhage [15,37]. (See "Spontaneous massive fetomaternal hemorrhage", section on 'Measuring the volume of FMH'.)
•Serology – Maternal immunoglobulin M (IgM) and IgG serologies are obtained for the most common infectious causes of NIHF: parvovirus B19, cytomegalovirus, and toxoplasmosis.
-Parvovirus B19 is the most common of these. Ultrasound findings include fetal anemia and myocardial dysfunction. (See "Parvovirus B19 infection during pregnancy".)
-Cytomegalovirus infection is characterized by bilateral periventricular hyperechogenicities (calcifications), but these may not be seen until the late second trimester (image 7). (See "Cytomegalovirus infection in pregnancy", section on 'Prenatal (fetal) diagnosis'.)
-Toxoplasmosis is characterized by intracranial hyperechogenic foci or calcifications and cerebral ventricular dilation. (See "Toxoplasmosis and pregnancy", section on 'Fetal infection'.)
Hydrops is also a characteristic finding of congenital syphilis; therefore, a treponemal or nontreponemal antibody test should be obtained if not recently performed as part of routine prenatal care. (See "Syphilis in pregnancy", section on 'Serologic testing'.)
In asymptomatic pregnant patients, there is a low yield from serology for rubella, varicella, adenovirus, coxsackie virus, and other less common infectious agents. We obtain these tests if the patient's history, physical examination, or ultrasound findings suggest one of these infections. We also may obtain them as a last resort if no etiology for NIHF has been determined by other testing. We do not obtain serology for herpes simplex virus (HSV) unless the patient has a history of primary genital HSV prior to onset of NIHF. In these cases, we prefer to send polymerase chain reaction (PCR) of amniotic fluid and correlate with maternal serology.
-Karyotype/microarray – Fetuses with NIHF and structural abnormalities should undergo microarray on amniocytes as they are at high risk of having a chromosomal abnormality. In the absence of a structural abnormality, the frequency of an abnormality is lower, and the diagnostic performance of microarray does not appear to be significantly better than with conventional G-band karyotype .
-Advanced genomic testing – If the microarray is normal, assessing genes for recognized pathogenic variants (genotyping), single gene sequencing, multiple gene sequencing or genotyping through panels, or testing for specific deletions or duplications can be performed as appropriate for the disorder(s) under consideration . Some commercial laboratories offer targeted gene panels to analyze a group of genes implicated in NIHF, but the panels vary among laboratories and the yield of such testing is unclear. In a study of 127 fetuses with NIHF who underwent exome sequencing, the diagnostic yield was 29 percent and significantly higher than the 18 percent yield expected from a large NIHF-targeted gene panel . Overall, targeted gene panels detected only 11 to 62 percent of the pathogenic variants detected by exome sequencing. Furthermore, exome sequencing as an initial genetic test can simplify workflow and result in cost savings compared with targeted panels followed by exome sequencing for nondiagnostic cases. As genomic testing becomes more complex (including the option of clinical exome sequencing), consultation with a genetic counselor or geneticist can help direct the appropriate test when a genetic etiology is suspected but standard testing is nondiagnostic. Appropriate pretest and posttest genetic counseling by a provider experienced in the complexities of genomic sequencing are recommended. (See "Prenatal genetic evaluation of the fetus with anomalies or soft markers".)
In a meta-analysis of 21 studies evaluating the incremental yield of next-generation sequencing over standard prenatal diagnostic testing (microarray, G-banded karyotype) in NIHF, the pooled incremental yields of exome sequencing in the overall group of NIHF (306 cases), isolated NIHF (109 cases), and NIHF associated with additional fetal structural anomalies (109 cases) were 29, 21, and 39 percent, respectively . When a causative pathogenic variant was documented, the most common genetic disorders were: RASopathies (30.3 percent, 27 out of 89), primarily due to PTPN11 variants (12 out of 27); musculoskeletal disorders (14.6 percent, 13 out of 89), primarily due to RYR1 variants (5 out of 13); and inborn errors of metabolism (12.4 percent, 11 out of 89), primarily due to GUSB variants (5 out of 11). The incremental yield for causative pathogenic variants was similar regardless of severity of hydrops. Other types of disorders detected by exome sequencing include musculoskeletal disorders, lymphedema disorders, neurodevelopmental disorders, cardiovascular disorders, hematologic disorders, kidney disorders, ciliopathies, and overgrowth disorders.
-Testing for infection – An infectious etiology for NIHF should be excluded by maternal serologic testing. If amniocentesis for genetic studies is performed before serologic findings are available, we obtain an additional 10 mL of amniotic fluid to send for PCR for cytomegalovirus, parvovirus B19, and toxoplasmosis [1,42].
-Amniotic fluid alpha-fetoprotein (AFP) – If congenital nephrotic syndrome of the Finnish type (Finnish nephrosis) is suspected because of enlarged, hyperechogenic kidneys and/or an elevated maternal serum AFP level, an amniotic fluid AFP level should be obtained and may be increased more than 10-fold.
-Other tests – A 10 mL sample of amniotic fluid should also be frozen and stored in order to test for rare lysosomal storage diseases  in the at-risk patient (consanguinity, previous family history, Ashkenazi Jewish or French Canadian descent) or after other investigations have been nondiagnostic [9,44,45]. Alternatively, cells can be cultured, frozen, and stored in case additional studies are required.
•Paracentesis – If the diagnostic evaluation described above does not reveal the cause, a sample of fetal ascitic fluid can be aspirated and analyzed for cell count and cytology, cytoplasmic vacuoles in lymphocytes, total protein, beta-2-microglobulin, total IgM, gamma-glutamyl transpeptidase, aspartate aminotransferase, aminopeptidase M, and total alkaline phosphatase.
One study reported lymphocytes accounted for over 80 percent of the cell population in cases of chylous ascites, vacuolated cells were observed in 100 percent of cases of storage diseases, low protein levels (<10 g/L) were observed in 75 percent of cases of urinary and genitourinary origin, high digestive enzymes levels (eg, gamma-glutamyl transpeptidase, aminopeptidase M, intestinal alkaline phosphatase) were observed in 100 percent of cases of digestive origin, and high beta-2-microglobulin values (>5 mg/L) were observed in 100 percent of infectious cases; however, there were ≤14 cases (hydrops or ascites alone) in each of these categories . Prognosis and management depend on the etiology.
ETIOLOGY AND PRENATAL MANAGEMENT OF DISORDERS ASSOCIATED WITH HYDROPS — Fetal disorders associated with NIHF are typically grouped into etiologic categories (eg, chromosomal, hematologic, cardiothoracic, neoplastic, etc). Many of these disorders are listed in the following table (table 2). Many others have been described in case reports; a complete list is beyond the scope of this topic.
The proportion of hydrops cases attributable to each etiologic category depends, in part, on the gestational age at presentation. NIHF prior to 24 weeks of gestation is usually related to an aneuploidy, while cardiac, pulmonary, and infectious etiologies account for the majority of cases after 24 weeks [47,48].
Cardiovascular abnormalities — Abnormalities of the cardiovascular system are responsible for as many as 40 percent of cases of NIHF . Numerous cardiac lesions have been implicated (table 2), the three major subgroups are structural anomalies, arrhythmias, and vascular abnormalities. NIHF associated with cardiovascular abnormalities tends to present in the third trimester .
Structural — The most commonly encountered cardiac lesions associated with hydrops are atrioventricular septal defect, hypoplastic left and right heart, and isolated ventricular or atrial septal defects. Other less common anomalies include Tetralogy of Fallot and premature closure of the ductus arteriosus. Many of these lesions are also associated with aneuploidy. Fetal cardiac tumors (eg, rhabdomyomas, teratomas) are rare, but are often associated with hydrops, ventricular obstruction, and/or arrhythmia .
Surgical resection of mediastinal/pericardial teratomas in utero is possible, with good results . Fetal cardiac intervention is an investigational procedure that has been performed for severe aortic stenosis with evolving hypoplastic left heart syndrome (HLHS), pulmonary atresia with intact ventricular septum and evolving hypoplastic right heart syndrome, and HLHS with intact or highly restrictive atrial septum . (See "Cardiac tumors", section on 'Fetal and neonatal intrapericardial teratoma'.)
However, most structural lesions are not amenable to in utero therapy and, in the setting of early-onset hydrops, the prognosis for these pregnancies is poor, with a mortality rate close to 100 percent . Patients should be offered genetic counseling, as the recurrence risk of congenital cardiac defects is as high as 2 to 5 percent .
Arrhythmias — Both tachyarrhythmias and bradyarrhythmias can lead to hydrops. The mechanism is believed to be high output cardiac failure with progressive venous congestion in the former and low cardiac output in the latter.
●Tachyarrhythmias – Tachyarrhythmias associated with NIHF include supraventricular tachycardia (most commonly), followed by atrial flutter, reentrant tachycardias (eg, Wolf-Parkinson-White syndrome), long QT, and ventricular tachycardia. Fetal tachyarrhythmias can often be treated by maternal administration of rate controlling agents; however, in cases of hydrops, disturbances in the placental transfer may render maternal therapy inadequate [54,56]. In such cases, the drugs can be administered directly to the fetus. (See "Fetal arrhythmias", section on 'Tachyarrhythmias'.)
In pregnant patients with Graves' disease, fetal tachycardia, particularly in combination with goiter, advanced bone age, poor growth, or craniosynostosis, suggests fetal hyperthyroidism from transplacental passage of maternal thyroid-stimulating hormone receptor antibody. Cardiac failure and hydrops may occur with severe disease. Maternal treatment with propylthiouracil or methimazole is an effective transplacental treatment of affected fetuses. (See "Hyperthyroidism during pregnancy: Treatment", section on 'Fetal or neonatal hyperthyroidism'.)
●Bradyarrhythmias – One-half of persistent bradyarrhythmias are caused by structural abnormalities . Complex congenital lesions that affect the AV nodal region result in anatomic interruptions in the conduction system leading to atrioventricular dissociation and bradycardia. The other one-half of persistent bradyarrhythmias are related to maternal autoimmune disorders in which maternal IgG antibodies cross the placenta and cause direct damage to fetal bundle of His and Purkinje fibers. (See "Fetal arrhythmias", section on 'Bradyarrhythmias'.)
Aneuploidy — Aneuploidy is responsible for 7 to 16 percent of NIHF cases . The most common aneuploidy associated with NIHF is monosomy X (Turner syndrome), which accounts for 42 to 67 percent of aneuploid cases . Other aneuploidies associated with hydrops include trisomy 21 (23 to 30 percent of cases); trisomy 13, 18, and 12 (10 percent of cases); tetraploidy; triploidy; and, rarely, deletions and duplications [49,57]. NIHF related to aneuploidy typically presents in the first and second trimesters .
The mechanism for fluid accumulation in these fetuses may involve obstruction or incomplete formation of the lymphatic system in the neck or abdomen, leading to lymphatic dysplasia, which can be seen sonographically as lucency under the skin, rather than diffuse skin thickening. Other mechanisms include cardiac failure related to congenital heart disease (present in 15 to 25 percent of aneuploid fetuses)  and transient abnormal myelopoiesis, a congenital leukemia associated with trisomy 21 . (See "Sonographic findings associated with fetal aneuploidy".)
The prognosis is generally poor, with a mortality rate approaching 100 percent . Management of the pregnancy with an aneuploid fetus depends on the prognosis for the specific chromosomal anomaly and the severity of coexistent anomalies. In nonlethal aneuploidies, fetal and maternal surveillance for signs of decompensation and possible early delivery are warranted. (See 'Pregnancy and delivery management' below.)
Syndromes — Syndromes account for 5 to 10 percent of NIHF . NIHF can be considered syndromic based on molecular findings, gene sequencing, or phenotypic/clinical findings seen on ultrasound/physical examination/autopsy.
Many genetic syndromes have been associated with NIHF (table 2), including Opitz-Frias hypertelorism hypospadias syndrome, Familial Nuchal Bleb, Noonan syndrome, acrocephalopolydactylous dysplasia (also known as Elejalde syndrome), thoracoabdominal syndrome, lymphedema distichiasis syndrome, lethal multiple pterygium syndrome, arthrogryposis multiplex congenita, congenital myotonic dystrophy, Pena Shokeir syndrome, Neu-Laxova syndrome, Miller-Dieker syndrome, and yellow nail syndrome [60-63].
Some monogenic mutations associated with NIHF include PSAT1, PTPN11, PIEZO1, CCBE1, EPHB4, FOXC2, FOXP3, SOX18, and ITGA9, but many others have been reported in one or more case reports . In a pregnancy loss/stillbirth database, lethal multiple pterygium syndrome accounted for 6 percent of all hydropic cases in the database .
Anemia — Severe fetal anemia accounts for 10 to 27 percent of hydrops . It may be due to a variety of causes, including hemorrhage, hemolysis, defective red cell production, and production of abnormal hemoglobins. Specific conditions associated with fetal anemia are listed in the table (table 2). The mechanism for hydrops is thought to be high output cardiac failure.
Hydrops is observed when the fetal hemoglobin is less than half the median value for gestational age . In general terms, fetal anemia is most likely to result in hydrops when the hemoglobin concentration is ≤5 g/dL, which approximates a hematocrit <30 percent. A presumptive diagnosis of moderate to severe fetal anemia is made by Doppler assessment of the fetal middle cerebral artery (MCA) peak systolic velocity (PSV) ≥1.5 multiples of the median (sensitivity and specificity for severe anemia 75.5 and 90.8 percent, respectively) and can be confirmed by obtaining a fetal blood sample by cordocentesis. Whether to perform cordocentesis, follow MCA-PSV serially, transfuse in utero, or deliver the fetus depends on the gestational age and cause of anemia.
The major causes of anemia can be determined as follows:
●Alloimmunization as a cause of fetal anemia is suggested by positive results on maternal screening for antibodies directed against red blood cell antigens and excluded by negative results. (See "RhD alloimmunization in pregnancy: Overview" and "Management of non-RhD red blood cell alloantibodies during pregnancy".)
●Parental mean corpuscular volume <80 femtoliters in the absence of iron deficiency suggests alpha or beta thalassemia (table 1). Further testing with hemoglobin analysis is indicated to establish a diagnosis (algorithm 1). (See "Prenatal screening and testing for hemoglobinopathy".)
Alpha thalassemia major is the most common cause of NIHF among Southeast Asian populations. Profound acidosis, hypoxia, and hydrops develop early in the midtrimester, followed by intrauterine fetal demise unless the fetus is serially transfused. (See "Diagnosis of thalassemia (adults and children)" and "Pathophysiology of thalassemia" and "Molecular genetics of the thalassemia syndromes".)
●Anemia secondary to massive fetomaternal transfusion is diagnosed by Kleihauer-Betke smear or flow cytometry. Transfusion or delivery can be life-saving. (See "Spontaneous massive fetomaternal hemorrhage".)
●Parvovirus B19 infection is an infectious etiology of anemia. The laboratory diagnosis of maternal infection relies primarily upon IgG and IgM antibody testing to determine preexisting immunity, acute infection, or susceptibility. Polymerase chain reaction testing on amniotic fluid is the method of choice to make the fetal diagnosis. Fetal infection and treatment are discussed in more detail below. (See 'Infection' below.)
Infection — Infections are responsible for 5 to 10 percent of NIHF (table 2) [32,66]. Parvovirus B19 is the most common infection associated with hydrops, followed by cytomegalovirus, toxoplasmosis, and syphilis. Not all fetuses with the infections in the table develop hydrops and causation has not been proven for all of the infections. In some cases, a causative organism may not be identified.
Sonographic signs (in addition to hydrops) that suggest in utero infection include calcifications of the brain, liver, or pericardium; microcephaly; cerebral ventriculomegaly; hepatosplenomegaly; and growth restriction.
The pathogenesis for hydrops related to infection is not well understood in most cases; parvovirus B19 is an exception. This virus attacks red blood cell progenitors, hepatocytes, and myocardial cells causing transient aplastic crisis, hepatitis, and myocarditis [4,66-68]. Since these processes are self-limited, the prognosis is generally good if the fetus is supported by intrauterine fetal transfusions until the disease remits. Platelet concentrates should also be available for transfusion since some fetuses may also be profoundly thrombocytopenic. (See "Parvovirus B19 infection during pregnancy".)
In contrast, the development of hydrops in fetuses with most other infections reflects multisystem failure (eg, myocarditis leading to heart failure, liver involvement leading to hypoalbuminemia) and is a poor prognostic sign. Therapy, if available, is directed toward the infectious agents.
Thoracic and lymphatic abnormalities — Thoracic abnormalities (table 2) account for up to 10 percent of hydrops. These lesions can cause mediastinal shift and can increase intrathoracic pressure and can obstruct venous return to the heart, leading to peripheral venous congestion, or they may obstruct the lymphatic duct, resulting in lymphedema. Interference with fluid exchange between the lung and amniotic cavity may contribute to polyhydramnios.
Fetal pleural effusions may be isolated or associated with hydrops, which confers a worse prognosis [69-72]. They can be related to aneuploidy (such as trisomy 21 or Turner syndrome), structural malformations or tumors (eg, involving the heart, lungs, lymphatic system), congenital infection (eg, cytomegalovirus, parvovirus B19, toxoplasmosis), and genetic syndromes . The most common thoracic masses associated with NIHF are congenital pulmonary airway malformation (CPAM, formerly known as congenital cystic adenomatoid malformation) and bronchopulmonary sequestration (see "Congenital pulmonary airway malformation: Prenatal diagnosis and management" and "Bronchopulmonary sequestration: Prenatal diagnosis and management"). Primary congenital pulmonary lymphangiectasis results from thoracic duct obstruction, while secondary congenital pulmonary lymphangiectasis is a consequence of thoracic masses or congenital heart defects or a component of a discrete syndrome [73-75]. Primary congenital pulmonary lymphangiectasis leads to hydrops by reducing venous return or cardiac tamponade and may be treated by pleuroamniotic shunting at midgestation to prevent pulmonary hypoplasia. Generalized lymphangiectasis syndrome results from systemic lymphatic vessel ectasia . In this condition, subcutaneous and visceral lymphedema occurs concomitantly with chylothorax. Hydrops results from gastrointestinal protein loss, chylothorax, and diffuse lymphatic leak.
The overall prognosis of hydropic fetuses with congenital pulmonary lesions depends, in part, on the gestational age at the time pulmonary abnormalities developed. Persistent pleural effusions before 20 weeks of gestation can compromise lung growth and function and thus are a poor prognostic sign. The degree of pulmonary hypoplasia cannot be reliably determined sonographically . Therapeutic issues include the following:
●Needle aspiration of pleural effusions is not recommended, except as a prelude to shunting, because the fluid usually reaccumulates within 48 hours [5,77]. If pleural fluid is obtained, the diagnosis of chylothorax is confirmed by a fetal pleural effusion cell count with >80 percent lymphocytes in the absence of infection .
●For fetuses with CPAM, a course of maternal betamethasone administration is a medical option and has become the first-line therapy at less than 32 weeks in hydropic fetuses or fetuses determined to be at risk for developing hydrops because of a CPAM volume ratio (CVR) >1.6. The therapeutic mechanism for resolution of hydrops is unknown, but it may be related to steroid-induced accelerated lung maturation or mass involution. The course of betamethasone may also improve outcomes in the event of a preterm delivery. (See "Congenital pulmonary airway malformation: Prenatal diagnosis and management", section on 'Maternal betamethasone administration'.)
●In fetuses with large pleural effusions (eg, hydrothorax, chylothorax), placement of a pleuroamniotic shunt may alleviate the increased intrathoracic pressure, thereby reducing the risk of pulmonary hypoplasia [9,69,78,79]. It may also reduce venous and lymphatic obstruction and allow hydrops to resolve.
This approach is supported by systematic reviews that found the survival rate for fetuses with pleural effusion and hydrops who were shunted was significantly higher than for those who underwent expectant management (over 60 percent versus less than 25 percent survival, respectively) [77,80]. However, only uncontrolled observational data from case reports and small case series were available for review; no controlled trials have been performed.
●Open fetal surgery has been performed for management of thoracic lesions potentially causing pulmonary hypoplasia or hydrops, but this type of intervention is investigational and only available at specialized centers . One small study of pleurodesis in 45 hydropic fetuses reported it was less effective than shunting .
Twin gestation — In both monochorionic and dichorionic twins, hydrops may develop in one or both twins from any of the etiologies that affect singleton pregnancies described above.
In addition, monochorionic twin gestations are at risk for hydrops from three disorders unique to these twin pregnancies: twin-to-twin transfusion syndrome (TTTS), twin anemia-polycythemia sequence (TAPS), and twin reversed arterial perfusion (TRAP). Polyhydramnios/oligohydramnios sequence is the defining characteristic of TTTS. One or both twins may develop NIHF, but usually the recipient twin is affected because of hypervolemia and increased central venous pressure. Hydrops of the donor twin is a sign of advanced stage TAPS. In TRAP, the hydropic twin has no normal cardiac structures. Treatment of TTTS, TAPS, and TRAP involves in utero procedures (eg, ablation, cord ligation, reduction amniocentesis). Prenatal diagnosis and management are reviewed separately.
Genitourinary malformations — Abnormalities of the genitourinary tract account for a very small proportion of NIHF. A rare disorder of renal function, congenital Finnish type nephrosis, leads to hypoproteinemia and NIHF from decreased colloid oncotic pressure. The combination of an elevated maternal serum alpha-fetoprotein level and enlarged hyperechogenic fetal kidneys suggests the diagnosis. (See "Congenital and infantile nephrotic syndrome", section on 'Congenital Nephrotic Syndrome of Finnish type'.)
Urinary ascites has been associated with hydrops by an unknown mechanism.
Gastrointestinal malformations — Anomalies of the gastrointestinal tract associated with NIHF are listed in the table (table 2) . Ascites and polyhydramnios are characteristically observed with these disorders. More widespread edema may be present when the fetus is aneuploid. The prognosis depends upon the fetal karyotype and the severity of any associated disorders (eg, cystic fibrosis).
Placental and umbilical cord lesions — Fetal/placental vascular tumors can lead to NIHF due to high output heart failure from arteriovenous shunting. Large chorioangiomas of the placenta may lead to NIHF by this mechanism and can be difficult to treat. The risk increases with increasing size of the chorioangioma. For chorioangiomas ≥2, ≥4, ≥6, ≥8, ≥10 cm, the frequency of fetal hydrops was approximately 15, 16, 20, 28, and 52 percent, respectively, in a systematic review that was derived from case reports and limited by ascertainment bias . Intrauterine embolization and endoscopic laser coagulation of the feeding vessels have been successful in pilot studies, but complications such as fetal bleeding, exsanguination, and death have also occurred [83-87]. In the systematic review, 57 percent had resolution of hydrops or hyperdynamic circulation after treatment, but perinatal mortality occurred in 31 percent .
Cord lesions associated with NIHF include angiomyxoma, aneurysm, venous thrombosis, umbilical vein torsion, true knots, and amniotic bands . (See "Umbilical cord abnormalities: Prenatal diagnosis and management".)
Fetal tumors — Fetal tumors and lesions that have been associated with NIHF include sacrococcygeal, mediastinal, or pharyngeal teratoma; neuroblastoma; and large hemangiomas. NIHF has also been associated with fetal tuberous sclerosis and fetal tumors obstructing the vena cava, portal vein, or femoral vessels.
Fetuses with these tumors and lesions may develop cardiac failure or hepatic failure, resulting in NIHF. Intervention, if possible, depends on the type of tumor. (See "Sacrococcygeal teratoma", section on 'Prenatal detection' and "Umbilical cord abnormalities: Prenatal diagnosis and management" and "Tuberous sclerosis complex: Genetics, clinical features, and diagnosis".)
Inborn errors of metabolism — Inborn errors of metabolism comprise a heterogeneous group of autosomal recessive disorders that may present in the fetal period as NIHF; they account for 1 to 2 percent of cases . In one study, the overall incidence of lysosomal storage disease (LSD) was 5.2 percent of all NIHF cases tested for any LSD, 17.4 percent in idiopathic NIHF cases, and 24.6 percent of idiopathic NIHF cases where a comprehensive LSD workup was done . There were 35 cases of LSD, and the three most common LSDs were mucopolysaccharidosis type VII, Gaucher disease, and GM1-gangliosidosis. In another series of 28 cases of LSD, the most common disorders were galactosialidosis, sialic acid storage disease, mucopolysaccharidosis type VII, and Gaucher disease .
These rare genetic disorders are due to lack of specific enzymes necessary to process various metabolites within the lysosome in organs such as the brain, heart, liver, and kidneys. The pathogenesis of hydrops is likely related to congestion of abdominal viscera from accumulation of these metabolites, leading to hepatitis and other organ damage ; ultrasound often shows hepatomegaly, splenomegaly, or hepatosplenomegaly . This process then leads to increased hydrostatic pressure, decreased oncotic pressure, and possibly cardiomyopathy and cardiac dysfunction . Decreased erythropoiesis resulting in anemia may also play a role.
Panels for testing for some causative storage disorders are available in some laboratories. An attempt at prenatal diagnosis is an option with cases of recurrence within a pedigree or when NIHF occurs in a structurally normal fetus and no cause has been identified after a standard work-up [32,88,91].
There is no specific therapy in the antenatal period; in utero death usually occurs. It is important to make an accurate diagnosis postnatally and offer genetic counseling, as the risk of recurrence in a future pregnancy is as high as 1 in 4. (See "Inborn errors of metabolism: Epidemiology, pathogenesis, and clinical features" and "Inborn errors of metabolism: Identifying the specific disorder" and "Inborn errors of metabolism: Classification".)
Skeletal dysplasias — Skeletal dysplasias associated with NIHF include achondroplasia, achondrogenesis, osteogenesis imperfecta, osteopetrosis, thanatophoric dysplasia, short-rib polydactyly syndrome, and asphyxiating thoracic dysplasia . The mechanism may involve altered venous return, cardiac tamponade, or hepatic dysfunction with hypoproteinemia. Prenatal diagnosis is based on recognition of skeletal abnormalities. (See "Approach to prenatal diagnosis of the lethal (life-limiting) skeletal dysplasias" and "Skeletal dysplasias: Approach to evaluation".)
PROGNOSIS — NIHF is associated with an overall perinatal mortality rate of 50 to 98 percent [2,3,36,37,92-94]. Among live born infants, mortality was 43 percent by one year of age in one large series . Despite advances in fetal diagnosis and therapy, the mortality rate has not changed substantially in recent years.
Prognosis depends upon the etiology, the gestational age at onset, the gestational age at birth, and whether pleural effusions are present. In general, the earlier hydrops occurs, the poorer the prognosis. In particular, pleural effusions and polyhydramnios prior to 20 weeks of gestation are poor prognostic signs because of increased risks of pulmonary hypoplasia and preterm prelabor rupture of membranes/preterm birth. On the other hand, absence of aneuploidy and absence of major structural abnormalities confer a better prognosis [42,95].
PREGNANCY AND DELIVERY MANAGEMENT
Counseling and planning — Pregnancy counseling and management are guided by the etiology and severity of NIHF and whether it can be treated successfully.
●When a specific etiology is known or suspected, antenatal consultation with relevant subspecialty services is advisable and may help to guide decisions about the appropriate extent of fetal monitoring and intervention. Delivery of potentially viable neonates should occur at a tertiary care center with coordination of the obstetric, maternal-fetal medicine, neonatal, and pediatric subspecialty teams.
Conditions amenable to fetal therapy often require urgent treatment, which may necessitate referral to a specialized center. Counseling should include a discussion of the potential risks and benefits of the available interventions versus expectant management, taking into account the severity of the underlying condition and the anticipated response to the intervention .
For cases with a lethal prognosis, pregnancy termination or postnatal comfort (palliative) care are options.
●When the etiology is not known and the prognosis is uncertain, options include fetal monitoring with active intervention if there is fetal deterioration and parental support with no fetal intervention. Pregnancy termination is also an option.
Maternal and fetal monitoring — Maternal blood pressure and lymphedema should be monitored at least weekly for development of Mirror syndrome, as prompt delivery is usually indicated if it develops. (See 'Mirror syndrome' above.)
In the absence of a lethal etiology of NIHF, antenatal fetal surveillance is generally performed because of the high risk of fetal death and the possibility that early delivery will be beneficial. We perform nonstress testing or biophysical profile testing at least weekly, with delivery if there is evidence of fetal decompensation at a viable gestational age.
In addition, we perform Doppler assessment of the umbilical vein as development of umbilical venous pulsations in hydropic fetuses is an ominous finding associated with demise in over 70 percent of patients . Serial Doppler velocimetry of the middle cerebral artery is not useful in the absence of suspected fetal anemia and Doppler velocimetry of the umbilical artery is not useful in the absence of fetal growth restriction (either abdominal circumference or estimated fetal weight <10th percentile).
Antepartum corticosteroid therapy is indicated if the underlying etiology of the hydrops is not believed to be lethal and if preterm intervention is planned should deterioration of the fetal condition occur . (See "Antenatal corticosteroid therapy for reduction of neonatal respiratory morbidity and mortality from preterm delivery".)
Delivery — Spontaneous or indicated preterm birth is common, occurring in 66 percent of pregnancies . Based on expert opinion, new-onset or worsening NIHF in a pregnancy that has reached 34+0 weeks is a reasonable indication for delivery, although care should be individualized . In the absence of a known lethal anomaly, maternal or fetal deterioration, or other indication for earlier intervention, we suggest delivery at 37+0 to 38+0 weeks. Preterm delivery <34+0 weeks is a poor prognostic factor .
If neonatal intervention will be withheld because of the poor prognosis, vaginal birth is preferred. Cesarean birth is performed for routine obstetric indications and is commonly required because delivery is often prompted by a deterioration in the fetal condition antepartum or the high frequency of nonreassuring intrapartum fetal heart rate patterns. Dystocia during delivery is also a concern and increases the risk of birth trauma regardless of mode of delivery. Ultrasound-guided percutaneous in utero needle aspiration of a large collection of ascites prior to delivery may reduce the risk of dystocia and facilitate neonatal resuscitation.
Ex utero intrapartum therapy (EXIT) — Congenital cardiac and thoracic abnormalities that result in NIHF very commonly result in rapid declines in pulmonary and/or cardiac function in the neonatal period that require immediate intervention. Depending on the etiology of NIHF, specific interventions to support the neonate may be indicated at delivery.
For example, a fetus with a large pulmonary lesion, mediastinal shift, and hydrops may benefit from ex utero intrapartum therapy (EXIT) performed at cesarean delivery . In EXIT, the fetus is partially delivered and intubated prior to clamping the umbilical cord. Alternatively, uteroplacental blood flow and gas exchange are maintained by using inhalational agents to provide uterine relaxation and amnioinfusion to maintain uterine volume. This provides a multidisciplinary team sufficient time to initiate extracorporeal membrane oxygenation (EXIT to ECMO) to stabilize the neonate, thus allowing for a more controlled surgery by the pediatric surgical teams at a later time and place. However, the benefit of this approach is controversial and it is associated with increased maternal bleeding and need for transfusion [100,101].
Stillborns — We recommend autopsy in all cases of fetal death or pregnancy termination associated with NIHF. Consultation with a medical geneticist is also advisable. Storage of amniotic fluid and/or fetal cells has been suggested for future genetic testing . (See "Stillbirth: Maternal and fetal evaluation".)
NEWBORN CARE — Management of the newborn is reviewed separately. (See "Postnatal care of hydrops fetalis".)
RECURRENCE RISK — The risk of recurrent NIHF depends upon the underlying etiology; therefore, every effort should be made to determine the cause. If hydrops was related to an anatomical variant (eg, congenital heart disease), the recurrence risk is minimal when the anatomic variant is not identified in the subsequent pregnancy. Hydrops related to a specific viral exposure (eg, parvovirus B19) should not recur because the mother will have developed immunity. By contrast, the risk of recurrent NIHF can be high when hydrops has a genetic basis, such as in alpha thalassemia.
As noted above, the clinician cannot always determine the etiology of fetal hydrops. Genetic consultation can be useful in these cases as the quality of information from genetic testing continues to evolve. In cases where no cause is found, the likelihood of recurrent hydrops is low [103-105]. However, since the risk of recurrence is not zero, a midtrimester sonogram to evaluate for signs of hydrops in subsequent gestations is reasonable.
SUMMARY AND RECOMMENDATIONS
●Definition – Hydrops fetalis refers to two or more abnormal fluid collections in fetal soft tissues and serous cavities. Nonimmune hydrops fetalis (NIHF) comprises the subgroup of cases not caused by red blood cell alloimmunization (eg, RhD, Kell). (See 'Introduction' above.)
●Clinical findings and diagnosis – The diagnosis of hydrops is based on the presence of two or more of the following findings on ultrasound examination: pleural effusion, pericardial effusion, ascites, generalized skin edema >5 mm. (See 'Diagnosis' above.)
•Patients carrying a hydropic fetus may have uterine size large for dates and may notice decreased fetal movement, both issues often related to associated polyhydramnios. Although hydrops is a fetal condition, in many cases there are associated maternal findings, such as generalized edema with or without preeclampsia (ie, Mirror syndrome). (See 'Maternal findings' above.)
•Hydrops is associated with a broad spectrum of diseases, including aneuploidy, structural abnormalities, metabolic disorders, anemia, and infection (table 2). An attempt to determine the etiology should be made at the time of diagnosis, since several etiologies can be confirmed or excluded based upon ultrasound findings. The cause of hydrops can be determined prenatally or postnatally in 60 to 85 percent of cases. (See 'Etiology and prenatal management of disorders associated with hydrops' above and 'Postdiagnostic evaluation' above.)
•The goals are to (1) identify those cases caused by disorders that are treatable in utero and (2) deliver the fetus when the benefits of prolonging pregnancy are outweighed by the risk of fetal demise or risk of maternal decompensation. Prenatally or postnatally, it is important to identify disorders with a risk of recurrence in future pregnancies. Our approach to prenatal diagnosis is illustrated in the algorithm (algorithm 2). (See 'General approach' above.)
●Prognosis – The presence of hydrops is a poor prognostic indicator for perinatal survival (see 'Prognosis' above). Management and intervention are dictated by the underlying disease process and the gestational age at detection. Fetal anemia, fetal arrhythmias, and complications of monochorionic twin pregnancy are potentially amenable to in utero intervention. (See 'Arrhythmias' above and 'Anemia' above and 'Twin gestation' above.)
●Pregnancy management – Maternal-fetal medicine specialists and neonatologists should be involved in the management of these pregnancies. Close surveillance of maternal status is important because of increased risks of Mirror syndrome. In addition (see 'Pregnancy and delivery management' above):
•NSTs and BPPs – In the absence of a lethal etiology of NIHF, we perform nonstress testing or biophysical profile testing at least weekly, with delivery if there is evidence of fetal decompensation at a viable gestational age.
•Umbilical vein Doppler – We perform Doppler assessment of the umbilical vein as development of umbilical venous pulsations in hydropic fetuses is an ominous finding associated with demise in over 70 percent of patients.
•Antenatal corticosteroids – Antenatal corticosteroid (ACS) therapy is indicated if the gestational age is between 24 and 34 weeks, the underlying etiology of the hydrops is not believed to be lethal, and if intervention is planned should deterioration of the fetal condition occur. Some providers administer a course of ACS after 34 weeks of gestation in patients at high risk for late preterm birth. (See "Antenatal corticosteroid therapy for reduction of neonatal respiratory morbidity and mortality from preterm delivery".)
•Timing of delivery – Preterm birth <34 weeks is a poor prognostic factor and should be avoided in the absence of deterioration in maternal or fetal status. New onset or worsening of NIHF in a pregnancy that has reached 34 weeks is a reasonable indication for delivery, although care should be individualized. However, in the absence of clinical deterioration or other indication for earlier intervention, we suggest delivery at 37 to 38 weeks.
•Route of delivery – Vaginal birth is preferred if neonatal intervention will be withheld because of the poor prognosis. Cesarean birth is performed for routine obstetric indications; however, it is commonly required because delivery is often prompted by a deterioration in the fetal condition antepartum and because of the high frequency of category II and III fetal heart rate patterns intrapartum.
Ultrasound guided percutaneous in utero needle aspiration of a large collection of pleural fluid and/or ascites prior to delivery may reduce the risk of dystocia and facilitate neonatal resuscitation.
●Risk of recurrence – The risk of recurrent NIHF depends upon the underlying etiology. (See 'Recurrence risk' above.)