What is the underlying pathogenesis of NIHF?

The common pathophysiology underlying the many etiologies of hydrops fetalis is an imbalance in the regulation of fluid movement between the vascular and interstitial spaces, with an increase in interstitial fluid production or a decrease in lymphatic return. Various mechanisms thought to lead to NIHF include increased right heart pressure, resulting in increased central venous pressure (eg, structural heart defects); obstruction of venous or arterial blood flow (eg, pulmonary masses); inadequate diastolic ventricular filling (eg, arrhythmias); hepatic venous congestion leading to decreased hepatic function and hypoalbuminemia; increased capillary permeability (eg, congenital infection); anemia leading to high output cardiac failure and extramedullary hematopoiesis, often with resultant hepatic dysfunction; lymphatic vessel dysplasia and obstruction (eg, cystic hygroma); and reduced osmotic pressure (eg, congenital nephrosis). The precise pathogenesis of NIHF depends on the underlying disorder, and in many cases remains unclear. Pathophysiologic mechanisms that contribute to the development of hydrops are described in Table 1 according to underlying etiology or category.

What are the causes of NIHF?

NIHF can result from a large number of underlying pathologies ( Table 1 ). The differential diagnosis is extensive, and the success in identifying a cause partially depends on the thoroughness of efforts to establish a diagnosis. Although older studies considered many cases to be idiopathic, more recent, larger series and a systematic review report that a cause can be found in nearly 60% of cases prenatally and in 85% when postnatal detection is included.

A number of series have been published describing the many disorders associated with NIHF. Review of these indicates that the most common etiologies of NIHF include cardiovascular causes, chromosomal anomalies, and hematologic abnormalities. Other conditions associated with NIHF include fetal malformations, particularly thoracic abnormalities, twin-twin transfusion syndrome, congenital infection, placental abnormalities, fetal tumors, and genetic or metabolic disorders ( Table 1 ).

Overall, cardiovascular abnormalities are the most common cause of NIHF in most series, accounting for about 20% of cases. NIHF can result from cardiac structural abnormalities, arrhythmias, cardiomyopathy, cardiac tumors, or vascular abnormalities. In most cardiac cases, hydrops is likely caused by increased central venous pressure due to a structural malformation or from inadequate diastolic ventricular filling. The most common congenital heart defects reported in association with NIHF are right heart defects. The prognosis of NIHF due to cardiac structural abnormalities is poor, with combined fetal and infant mortality reported as 92%, largely due to the severity of the heart defects that cause in utero congestive heart failure.

Both tachyarrhythmias and bradyarrhythmias can lead to NIHF. The most common tachyarrhythmias are supraventricular tachycardia and atrial flutter, and both can often be successfully treated with transplacental medical therapy. We recommend maternal treatment with antiarrhythmic medications for NIHF secondary to fetal tachyarrhythmia unless the gestational age is close to term or there is a maternal or obstetrical contraindication. Medication selection and dosing are reviewed elsewhere.

Fetal bradycardia is most commonly caused by congenital heart block, which may occur secondary to an immune etiology such as transplacental passage of anti-Sjogren’s-syndrome-related antigen A, also called anti-Ro, or the combination anti-Ro/SSA and anti-La/SSB antibodies associated with maternal autoimmune disease. It may also result from structural abnormalities affecting cardiac conduction, as with endocardial cushion defects in the setting of a heterotaxy syndrome. Once third-degree atrioventricular block has developed, treatment with corticosteroid therapy has not been shown to be beneficial, and in the setting of hydrops the prognosis is poor. For this reason, in-utero therapy for fetal bradyarrhythmia resulting in hydrops is considered investigational and is not generally recommended outside of a research setting.

Chromosomal abnormalities , particularly Turner syndrome (45,X) and Down syndrome (trisomy 21) are also common causes of NIHF, accounting for 13% in a large systematic review. In prenatal series, aneuploidy is the most common cause of NIHF, particularly when identified early in gestation. Turner syndrome is associated with 50-80% of cases of cystic hygromas, which result from a lack of communication between the lymphatic system and venous drainage in the neck. Lymphatic dysplasia likely leads to the development of NIHF in these cases.

NIHF has been described in association with other aneuploidies, including trisomies 13 and 18, and triploidy. In some cases, hydrops occurs due to cardiovascular malformations in aneuploid fetuses. NIHF has also been reported in trisomy 21 in the absence of structural heart defects. Some such cases occur due to a transient abnormal myelopoiesis, a leukemic condition that occurs in about 10% of infants with Down syndrome. Postnatally, transient abnormal myelopoiesis is often mild and self-limiting; prenatally, it is less common but typically more severe. For these reasons, we recommend that NIHF is an indication to offer prenatal diagnosis with karyotype, fluorescence in situ hybridization, and/or chromosomal microarray analysis, even when severe anemia is present ( Figure 2 ). Screening with noninvasive prenatal testing may detect some chromosomal causes but provides more limited information about possible genetic etiologies, and therefore we recommend diagnostic testing.

Workup of nonimmune hydrops fetalis∗

AFAFP , amniotic fluid alpha fetoprotein; CBC , complete blood count; CMA , chromosomal microarray; CMV , cytomegalovirus; G6PD , glucose-6-phosphate dehydrogenase deficiency; MCA PSV , middle cerebral artery peak systolic velocity; MCV , mean corpuscular volumne; MoM , multiple of the median; PCR , polymerase chain reaction; RPR , rapid plasma reagin.

∗Assuming negative indirect Coombs test, thereby excluding alloimmunization; ∗∗CMV/toxoplasmosis testing if fetal anomalies suggestive of infection; ∗∗∗Either amniocentesis or FBS; ∗∗∗∗Available in some laboratories.

SMFM. Nonimmune hydrops fetalis. Am J Obstet Gynecol 2015 .

Fetal anemia , which can result in immune hydrops if caused by blood group alloimmunization, can also lead to NIHF. Etiologies include inherited conditions such as hemoglobinopathies, as well as acquired conditions, such as hemolysis, fetomaternal hemorrhage, parvovirus infection, or red cell aplasia.

Among the hemoglobinopathies, the most common cause of NIHF is alpha thalassemia. This autosomal recessive disorder is common in Southeast Asian populations, where it accounts for 28-55% of NIHF. The incidence in most other series of NIHF is about 10%. Parents can be screened by evaluation of the mean cell volume, which will be <80 fL in thalassemia carriers. Definitive diagnosis of an affected fetus can be made by detection of one of the common DNA deletions or point mutations that account for most cases. Conversely, a fetal blood sample can be evaluated for the presence of the abnormal Bart’s hemoglobin seen in this condition. Bart’s hemoglobin is an ineffective oxygen carrier, thus the fetus with alpha thalassemia will suffer severe intrauterine hypoxia from an early gestational age. The resultant NIHF will typically present in the late second or early third trimester.

Fetal anemia may also occur due to fetal hemorrhage . NIHF occurs only with significant fetomaternal bleeding that is not enough to lead to fetal hypovolemia and death. Fetomaternal hemorrhage leading to hydrops may occur as either an isolated acute event, or as a chronic, ongoing hemorrhage. With either, a Kleihauer-Betke smear will show the presence of fetal cells in the maternal peripheral blood in most cases. Flow cytometry can also be used to estimate the volume of fetal bleeding into the mother. This is an important diagnosis to make, because even with a massive fetomaternal hemorrhage, intravascular fetal transfusion can be lifesaving. For this reason, we recommend that NIHF due to anemia from fetomaternal hemorrhage be treated with transfusion, unless the pregnancy is at an advanced gestational age and risks associated with delivery are considered to be less than those associated with the procedure.

Other, less common causes of fetal anemia and hydrops include G-6-PD deficiency, erythrocyte enzymopathies such as pyruvate kinase deficiency, and maternal acquired red cell aplasia.

NIHF has been reported in association with a number of viral, bacterial, and parasitic infectious diseases , including parvovirus, cytomegalovirus, syphilis, and toxoplasmosis. In most series, such infections account for 5-10% of NIHF. Although the associations are less clear, NIHF has also been reported to occur with Coxsackie virus, trypanosomiasis, varicella, human herpesvirus 6 and 7, herpes simplex type 1, respiratory syncytial virus, congenital lymphocytic choriomeningitis virus, and leptospirosis. Fetal infection can cause NIHF due to anemia, anoxia, endothelial cell damage, increased capillary permeability, and myocarditis.

Parvovirus is the most commonly reported infectious cause of NIHF. In the fetus, the virus has a predilection for erythroid progenitor cells, leading to inhibition of erythropoiesis and subsequent anemia. The risk of a poor outcome for the fetus is greatest when the congenital infection occurs in the early second trimester (<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. In most cases, the anemia is transient and fetal intravascular transfusion can support a fetus through this aplastic crisis. However, development of NIHF is associated with high mortality, and outcomes are reported to be significantly improved following fetal intrauterine transfusion. For this reason, we recommend fetal intrauterine transfusion for NIHF due to parvovirus infection, unless the pregnancy is at an advanced gestational age and risks associated with delivery are considered to be less than those associated with the procedure.

Fetal thoracic abnormalities , including masses as well as congenital hydrothorax, can also be associated with NIHF. The most frequent pulmonary lesion associated with NIHF is a congenital pulmonary airway malformation (CPAM). With a large lesion or effusion, mediastinal shift may impair venous return and cardiac output, and the associated esophageal compression may result in polyhydramnios. Hydrops occurs in only about 5% of fetuses with CPAM but confers a poor prognosis without treatment. If the lesion is macrocystic, the cyst may be treated with needle drainage or thoracoamniotic shunt placement. If predominantly solid (microcystic), both corticosteroid therapy and in utero resection have been advocated, and corticosteroid treatment is currently recommended as a first-line treatment. Large bronchopulmonary sequestrations have also been treated with a needle procedure involving neodymium:yttrium-aluminium-garnet laser of the feeding vessel.

The most common etiology of an isolated effusion leading to NIHF is chylothorax, caused by lymphatic obstruction. The fluid may be sampled at the time of needle drainage or shunt placement, and the diagnosis is confirmed by the finding of a fetal pleural cell count with >80% lymphocytes in the absence of infection. Reported survival exceeds 50% in hydropic fetuses treated with thoracoamniotic shunt placement.

Twin-twin transfusion syndrome results from an imbalance in blood flow caused by anastomoses in the placentas of monochorionic twin pregnancies. In severe cases, one or both twins may develop NIHF, although more commonly the recipient twin is affected, likely due to hypervolemia and increased central venous pressure. Cases of twin-twin transfusion sequence with hydrops have a very poor prognosis without treatment, and laser therapy is considered by most experts to be the best available therapeutic approach to improve the prognosis. Selective termination via umbilical cord coagulation is also an option for pregnancies with twin-twin transfusion sequence resulting in NIHF. Another complication of monochorionic twinning that may result in NIHF is twin-reversed arterial perfusion sequence. Radiofrequency ablation of the acardiac twin has been advocated for severe cases, including those with hydrops, with reported overall survival of 80%.

Structural urinary and gastrointestinal abnormalities are less common causes of NIHF. A ruptured bladder or renal collecting system may cause urinary ascites and mimic NIHF. Congenital nephrotic syndromes have been reported to cause NIHF due to hypoproteinemia. Surviving infants may have massive proteinuria at birth and develop renal failure in childhood.

Few primary abnormalities of the gastrointestinal tract have been associated with NIHF. Those that have been reported include diaphragmatic hernia, midgut volvulus, gastrointestinal obstruction, jejunal atresia, malrotation of the intestines, and meconium peritonitis. Intraabdominal masses may cause NIHF due to obstruction of venous return, while gastrointestinal obstruction and infarction may lead to decreased colloid osmotic pressure due to protein loss. Hepatic disorders such as cirrhosis, hepatic necrosis, cholestasis, polycystic disease of the liver, and biliary atresia have been reported in association with NIHF, most likely due to hypoproteinemia. Hemangioma of the liver has also been reported as a cause of NIHF, probably due to arteriovenous shunting resulting in cardiac failure.

Neoplastic diseases or fetal tumors can occur in utero and have been associated with NIHF. Relatively common in this category are lymphangiomas, hemangiomas, sacrococcygeal, mediastinal, and pharyngeal teratomas, and neuroblastomas. Many of these are very vascular and lead to NIHF due to high output cardiac failure. Fetal therapy has been offered for cases of solid sacrococcygeal teratoma resulting in NIHF, and in a recent systematic review, open fetal surgery resulted in survival in 6 of 11 cases (55%), and minimally invasive therapy was associated with survival in 6 of 20 (30%). Tuberous sclerosis is an autosomal dominant disorder characterized by fibroangiomatous tumors in multiple organs, most typically the cortex of the brain, the skin, and the kidneys. Cardiac rhabdomyomas and liver fibrosis are also sometimes present. NIHF has been reported in association with tuberous sclerosis, probably either as a result of cardiac failure due to rhabdomyomas (resulting in obstruction to filling or outflow), or hepatic failure due to fibrosis.

Placental and cord lesions that have been associated with NIHF include chorioangiomas, angiomyxoma of the cord, aneurysm of the umbilical artery, cord vein thrombosis, umbilical vein torsion, true knots, and amniotic bands. Placental chorioangiomas are relatively common, occurring in about 1% of pregnancies. While small lesions are usually not clinically significant, those measuring >5 cm can act as high volume arteriovenous shunts and lead to hydrops due to high output cardiac failure. Other vascular tumors and arteriovenous malformations can similarly cause NIHF. Hemangiomas have been reported to cause NIHF, likely due to severe anemia, hypoproteinemia, and/or extramedullary erythropoiesis.

A large number of skeletal dysplasias have been associated with NIHF, including achondroplasia, achondrogenesis, osteogenesis imperfecta, osteopetrosis, thanatophoric dysplasia, short-rib polydactyly syndrome, and asphyxiating thoracic dysplasia. In all of these, the mechanism is unclear, although it has been proposed that hepatic enlargement occurs secondary to intrahepatic proliferation of blood cell precursors to compensate for a small bone-marrow volume. This may cause large vessel compression and lead to anasarca in these fetuses.

Inborn errors of metabolism and other genetic conditions are historically associated with 1-2% of cases of NIHF, which may be transient or manifest as isolated ascites. Inherited metabolic disorders that have been implicated as a cause of NIHF are most typically lysosomal storage diseases such as various mucopolysaccharidoses, Gaucher disease, and Niemann-Pick disease. In a recent review of the literature including 678 cases of NIHF, lysosomal storage diseases occurred in 5.2% of all NIHF cases, and in 29.6% of idiopathic NIHF cases if a comprehensive workup for these conditions is done. Proposed mechanisms involve visceromegaly and obstruction of venous return, decreased erythropoiesis and anemia, and/or hypoproteinemia. Although such disorders are a relatively uncommon cause of NIHF, they are important because of the high recurrence risk of these mainly autosomal recessive disorders. Careful histology of the placenta, liver, spleen, and bone marrow will often provide a clue that a metabolic storage disorder was present. For many such disorders, testing is available to determine a diagnosis and for prenatal diagnosis in a subsequent pregnancy. Panels of causative storage disorders can be tested for in some laboratories, and this should be considered for cases of NIHF in a structurally normal fetus in which another cause has not been identified, or with cases of recurrence within a family.

A number of other syndromes have been associated with NIHF. Many of these are disorders associated with lymphatic dysfunction, such as Noonan and multiple pterygium syndrome, both of which frequently present with cystic hygroma; idiopathic chylothorax, in which a local pleuromediastinal lymph vessel disturbance occurs as the possible pathogenic mechanism; yellow nail syndrome, a dominantly inherited congenital lymphedema syndrome; and congenital pulmonary lymphangiectasia. Familial recurrence in some of these cases suggests a hereditary maldevelopment of lymphatic vessels.

What are the causes of NIHF?

NIHF can result from a large number of underlying pathologies ( Table 1 ). The differential diagnosis is extensive, and the success in identifying a cause partially depends on the thoroughness of efforts to establish a diagnosis. Although older studies considered many cases to be idiopathic, more recent, larger series and a systematic review report that a cause can be found in nearly 60% of cases prenatally and in 85% when postnatal detection is included.

A number of series have been published describing the many disorders associated with NIHF. Review of these indicates that the most common etiologies of NIHF include cardiovascular causes, chromosomal anomalies, and hematologic abnormalities. Other conditions associated with NIHF include fetal malformations, particularly thoracic abnormalities, twin-twin transfusion syndrome, congenital infection, placental abnormalities, fetal tumors, and genetic or metabolic disorders ( Table 1 ).

Overall, cardiovascular abnormalities are the most common cause of NIHF in most series, accounting for about 20% of cases. NIHF can result from cardiac structural abnormalities, arrhythmias, cardiomyopathy, cardiac tumors, or vascular abnormalities. In most cardiac cases, hydrops is likely caused by increased central venous pressure due to a structural malformation or from inadequate diastolic ventricular filling. The most common congenital heart defects reported in association with NIHF are right heart defects. The prognosis of NIHF due to cardiac structural abnormalities is poor, with combined fetal and infant mortality reported as 92%, largely due to the severity of the heart defects that cause in utero congestive heart failure.

Both tachyarrhythmias and bradyarrhythmias can lead to NIHF. The most common tachyarrhythmias are supraventricular tachycardia and atrial flutter, and both can often be successfully treated with transplacental medical therapy. We recommend maternal treatment with antiarrhythmic medications for NIHF secondary to fetal tachyarrhythmia unless the gestational age is close to term or there is a maternal or obstetrical contraindication. Medication selection and dosing are reviewed elsewhere.

Fetal bradycardia is most commonly caused by congenital heart block, which may occur secondary to an immune etiology such as transplacental passage of anti-Sjogren’s-syndrome-related antigen A, also called anti-Ro, or the combination anti-Ro/SSA and anti-La/SSB antibodies associated with maternal autoimmune disease. It may also result from structural abnormalities affecting cardiac conduction, as with endocardial cushion defects in the setting of a heterotaxy syndrome. Once third-degree atrioventricular block has developed, treatment with corticosteroid therapy has not been shown to be beneficial, and in the setting of hydrops the prognosis is poor. For this reason, in-utero therapy for fetal bradyarrhythmia resulting in hydrops is considered investigational and is not generally recommended outside of a research setting.

Chromosomal abnormalities , particularly Turner syndrome (45,X) and Down syndrome (trisomy 21) are also common causes of NIHF, accounting for 13% in a large systematic review. In prenatal series, aneuploidy is the most common cause of NIHF, particularly when identified early in gestation. Turner syndrome is associated with 50-80% of cases of cystic hygromas, which result from a lack of communication between the lymphatic system and venous drainage in the neck. Lymphatic dysplasia likely leads to the development of NIHF in these cases.

NIHF has been described in association with other aneuploidies, including trisomies 13 and 18, and triploidy. In some cases, hydrops occurs due to cardiovascular malformations in aneuploid fetuses. NIHF has also been reported in trisomy 21 in the absence of structural heart defects. Some such cases occur due to a transient abnormal myelopoiesis, a leukemic condition that occurs in about 10% of infants with Down syndrome. Postnatally, transient abnormal myelopoiesis is often mild and self-limiting; prenatally, it is less common but typically more severe. For these reasons, we recommend that NIHF is an indication to offer prenatal diagnosis with karyotype, fluorescence in situ hybridization, and/or chromosomal microarray analysis, even when severe anemia is present ( Figure 2 ). Screening with noninvasive prenatal testing may detect some chromosomal causes but provides more limited information about possible genetic etiologies, and therefore we recommend diagnostic testing.

Workup of nonimmune hydrops fetalis∗

AFAFP , amniotic fluid alpha fetoprotein; CBC , complete blood count; CMA , chromosomal microarray; CMV , cytomegalovirus; G6PD , glucose-6-phosphate dehydrogenase deficiency; MCA PSV , middle cerebral artery peak systolic velocity; MCV , mean corpuscular volumne; MoM , multiple of the median; PCR , polymerase chain reaction; RPR , rapid plasma reagin.

∗Assuming negative indirect Coombs test, thereby excluding alloimmunization; ∗∗CMV/toxoplasmosis testing if fetal anomalies suggestive of infection; ∗∗∗Either amniocentesis or FBS; ∗∗∗∗Available in some laboratories.

SMFM. Nonimmune hydrops fetalis. Am J Obstet Gynecol 2015 .

Fetal anemia , which can result in immune hydrops if caused by blood group alloimmunization, can also lead to NIHF. Etiologies include inherited conditions such as hemoglobinopathies, as well as acquired conditions, such as hemolysis, fetomaternal hemorrhage, parvovirus infection, or red cell aplasia.

Among the hemoglobinopathies, the most common cause of NIHF is alpha thalassemia. This autosomal recessive disorder is common in Southeast Asian populations, where it accounts for 28-55% of NIHF. The incidence in most other series of NIHF is about 10%. Parents can be screened by evaluation of the mean cell volume, which will be <80 fL in thalassemia carriers. Definitive diagnosis of an affected fetus can be made by detection of one of the common DNA deletions or point mutations that account for most cases. Conversely, a fetal blood sample can be evaluated for the presence of the abnormal Bart’s hemoglobin seen in this condition. Bart’s hemoglobin is an ineffective oxygen carrier, thus the fetus with alpha thalassemia will suffer severe intrauterine hypoxia from an early gestational age. The resultant NIHF will typically present in the late second or early third trimester.

Fetal anemia may also occur due to fetal hemorrhage . NIHF occurs only with significant fetomaternal bleeding that is not enough to lead to fetal hypovolemia and death. Fetomaternal hemorrhage leading to hydrops may occur as either an isolated acute event, or as a chronic, ongoing hemorrhage. With either, a Kleihauer-Betke smear will show the presence of fetal cells in the maternal peripheral blood in most cases. Flow cytometry can also be used to estimate the volume of fetal bleeding into the mother. This is an important diagnosis to make, because even with a massive fetomaternal hemorrhage, intravascular fetal transfusion can be lifesaving. For this reason, we recommend that NIHF due to anemia from fetomaternal hemorrhage be treated with transfusion, unless the pregnancy is at an advanced gestational age and risks associated with delivery are considered to be less than those associated with the procedure.

Other, less common causes of fetal anemia and hydrops include G-6-PD deficiency, erythrocyte enzymopathies such as pyruvate kinase deficiency, and maternal acquired red cell aplasia.

NIHF has been reported in association with a number of viral, bacterial, and parasitic infectious diseases , including parvovirus, cytomegalovirus, syphilis, and toxoplasmosis. In most series, such infections account for 5-10% of NIHF. Although the associations are less clear, NIHF has also been reported to occur with Coxsackie virus, trypanosomiasis, varicella, human herpesvirus 6 and 7, herpes simplex type 1, respiratory syncytial virus, congenital lymphocytic choriomeningitis virus, and leptospirosis. Fetal infection can cause NIHF due to anemia, anoxia, endothelial cell damage, increased capillary permeability, and myocarditis.

Parvovirus is the most commonly reported infectious cause of NIHF. In the fetus, the virus has a predilection for erythroid progenitor cells, leading to inhibition of erythropoiesis and subsequent anemia. The risk of a poor outcome for the fetus is greatest when the congenital infection occurs in the early second trimester (<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. In most cases, the anemia is transient and fetal intravascular transfusion can support a fetus through this aplastic crisis. However, development of NIHF is associated with high mortality, and outcomes are reported to be significantly improved following fetal intrauterine transfusion. For this reason, we recommend fetal intrauterine transfusion for NIHF due to parvovirus infection, unless the pregnancy is at an advanced gestational age and risks associated with delivery are considered to be less than those associated with the procedure.

Fetal thoracic abnormalities , including masses as well as congenital hydrothorax, can also be associated with NIHF. The most frequent pulmonary lesion associated with NIHF is a congenital pulmonary airway malformation (CPAM). With a large lesion or effusion, mediastinal shift may impair venous return and cardiac output, and the associated esophageal compression may result in polyhydramnios. Hydrops occurs in only about 5% of fetuses with CPAM but confers a poor prognosis without treatment. If the lesion is macrocystic, the cyst may be treated with needle drainage or thoracoamniotic shunt placement. If predominantly solid (microcystic), both corticosteroid therapy and in utero resection have been advocated, and corticosteroid treatment is currently recommended as a first-line treatment. Large bronchopulmonary sequestrations have also been treated with a needle procedure involving neodymium:yttrium-aluminium-garnet laser of the feeding vessel.

The most common etiology of an isolated effusion leading to NIHF is chylothorax, caused by lymphatic obstruction. The fluid may be sampled at the time of needle drainage or shunt placement, and the diagnosis is confirmed by the finding of a fetal pleural cell count with >80% lymphocytes in the absence of infection. Reported survival exceeds 50% in hydropic fetuses treated with thoracoamniotic shunt placement.

Twin-twin transfusion syndrome results from an imbalance in blood flow caused by anastomoses in the placentas of monochorionic twin pregnancies. In severe cases, one or both twins may develop NIHF, although more commonly the recipient twin is affected, likely due to hypervolemia and increased central venous pressure. Cases of twin-twin transfusion sequence with hydrops have a very poor prognosis without treatment, and laser therapy is considered by most experts to be the best available therapeutic approach to improve the prognosis. Selective termination via umbilical cord coagulation is also an option for pregnancies with twin-twin transfusion sequence resulting in NIHF. Another complication of monochorionic twinning that may result in NIHF is twin-reversed arterial perfusion sequence. Radiofrequency ablation of the acardiac twin has been advocated for severe cases, including those with hydrops, with reported overall survival of 80%.

Structural urinary and gastrointestinal abnormalities are less common causes of NIHF. A ruptured bladder or renal collecting system may cause urinary ascites and mimic NIHF. Congenital nephrotic syndromes have been reported to cause NIHF due to hypoproteinemia. Surviving infants may have massive proteinuria at birth and develop renal failure in childhood.

Few primary abnormalities of the gastrointestinal tract have been associated with NIHF. Those that have been reported include diaphragmatic hernia, midgut volvulus, gastrointestinal obstruction, jejunal atresia, malrotation of the intestines, and meconium peritonitis. Intraabdominal masses may cause NIHF due to obstruction of venous return, while gastrointestinal obstruction and infarction may lead to decreased colloid osmotic pressure due to protein loss. Hepatic disorders such as cirrhosis, hepatic necrosis, cholestasis, polycystic disease of the liver, and biliary atresia have been reported in association with NIHF, most likely due to hypoproteinemia. Hemangioma of the liver has also been reported as a cause of NIHF, probably due to arteriovenous shunting resulting in cardiac failure.

Neoplastic diseases or fetal tumors can occur in utero and have been associated with NIHF. Relatively common in this category are lymphangiomas, hemangiomas, sacrococcygeal, mediastinal, and pharyngeal teratomas, and neuroblastomas. Many of these are very vascular and lead to NIHF due to high output cardiac failure. Fetal therapy has been offered for cases of solid sacrococcygeal teratoma resulting in NIHF, and in a recent systematic review, open fetal surgery resulted in survival in 6 of 11 cases (55%), and minimally invasive therapy was associated with survival in 6 of 20 (30%). Tuberous sclerosis is an autosomal dominant disorder characterized by fibroangiomatous tumors in multiple organs, most typically the cortex of the brain, the skin, and the kidneys. Cardiac rhabdomyomas and liver fibrosis are also sometimes present. NIHF has been reported in association with tuberous sclerosis, probably either as a result of cardiac failure due to rhabdomyomas (resulting in obstruction to filling or outflow), or hepatic failure due to fibrosis.

Placental and cord lesions that have been associated with NIHF include chorioangiomas, angiomyxoma of the cord, aneurysm of the umbilical artery, cord vein thrombosis, umbilical vein torsion, true knots, and amniotic bands. Placental chorioangiomas are relatively common, occurring in about 1% of pregnancies. While small lesions are usually not clinically significant, those measuring >5 cm can act as high volume arteriovenous shunts and lead to hydrops due to high output cardiac failure. Other vascular tumors and arteriovenous malformations can similarly cause NIHF. Hemangiomas have been reported to cause NIHF, likely due to severe anemia, hypoproteinemia, and/or extramedullary erythropoiesis.

A large number of skeletal dysplasias have been associated with NIHF, including achondroplasia, achondrogenesis, osteogenesis imperfecta, osteopetrosis, thanatophoric dysplasia, short-rib polydactyly syndrome, and asphyxiating thoracic dysplasia. In all of these, the mechanism is unclear, although it has been proposed that hepatic enlargement occurs secondary to intrahepatic proliferation of blood cell precursors to compensate for a small bone-marrow volume. This may cause large vessel compression and lead to anasarca in these fetuses.

Inborn errors of metabolism and other genetic conditions are historically associated with 1-2% of cases of NIHF, which may be transient or manifest as isolated ascites. Inherited metabolic disorders that have been implicated as a cause of NIHF are most typically lysosomal storage diseases such as various mucopolysaccharidoses, Gaucher disease, and Niemann-Pick disease. In a recent review of the literature including 678 cases of NIHF, lysosomal storage diseases occurred in 5.2% of all NIHF cases, and in 29.6% of idiopathic NIHF cases if a comprehensive workup for these conditions is done. Proposed mechanisms involve visceromegaly and obstruction of venous return, decreased erythropoiesis and anemia, and/or hypoproteinemia. Although such disorders are a relatively uncommon cause of NIHF, they are important because of the high recurrence risk of these mainly autosomal recessive disorders. Careful histology of the placenta, liver, spleen, and bone marrow will often provide a clue that a metabolic storage disorder was present. For many such disorders, testing is available to determine a diagnosis and for prenatal diagnosis in a subsequent pregnancy. Panels of causative storage disorders can be tested for in some laboratories, and this should be considered for cases of NIHF in a structurally normal fetus in which another cause has not been identified, or with cases of recurrence within a family.

A number of other syndromes have been associated with NIHF. Many of these are disorders associated with lymphatic dysfunction, such as Noonan and multiple pterygium syndrome, both of which frequently present with cystic hygroma; idiopathic chylothorax, in which a local pleuromediastinal lymph vessel disturbance occurs as the possible pathogenic mechanism; yellow nail syndrome, a dominantly inherited congenital lymphedema syndrome; and congenital pulmonary lymphangiectasia. Familial recurrence in some of these cases suggests a hereditary maldevelopment of lymphatic vessels.