Immune Fetal Hydrops

Maternal sensitisation to a fetal red blood cell (RBC) antigen (usually from a previous pregnancy) is followed in the next pregnancy by transplacental passage of the circulating maternal IgG antibody against that red blood cell antigen resulting in fetal haemolytic anaemia, and if severe, fetal hydrops. The severity of the haemolytic process is dependent on the antigen–antibody involved and the maternal antibody load. Chapter 40 details the diagnosis and management of RBC alloimmunisation. This aetiology for hydrops will not be further discussed in this chapter. However, in the approach to a fetus with fetal hydrops, immune fetal hydrops is an important condition to consider because it is one of the treatable causes with strong evidence-based approaches.

Nonimmune Hydrops Fetalis

Nonimmune hydrops fetalis has a variety of aetiologies. A systematic review of the aetiology of NIHF divided the affected cases into 14 classification groups ( Table 36.2 ). This section reviews the different NIHF aetiologies according to the same classification. Some of the aetiologies of NIHF are the focus of other chapters in this book. These aetiologies will only be mentioned briefly in this chapter.

Twin-to-Twin Transfusion Syndrome and Placental Abnormalities

Twin-to-twin transfusion syndrome (TTTS) is a complication associated with monochorionic twins caused by an imbalance of the vascular communications in the placenta between the two fetuses and represents approximately 5% of cases of NIHF. Haemodynamic and osmotic changes in the fetuses can lead to fetal hydrops in the recipient twin most commonly, but donor fetal hydrops has been identified as well. (See Chapter 44 for more details on TTTS.)

Placental chorioangiomas are rare benign placental tumours. Large chorioangiomas act as peripheral arteriovenous shunts, leading to increased cardiac output, cardiomegaly and finally heart failure and hydrops. Some cases are complicated by fetal anaemia, which further contributes to the development of the heart failure and hydrops. Umbilical cord haemangiomas have also been reported with NIHF. (See Chapter 9 for more on placental pathology.)

Cardiovascular Conditions

Cardiovascular conditions are the primary aetiology in 21% of NIHF cases and are identified as the most common group of disorder leading to NIHF. The cardiovascular aetiology can be divided into structural malformations, arrhythmias, cardiac tumours and cardiomyopathy ( Table 36.3 ). (See Chapter 29 for more details on cardiovascular conditions.)

For structural cardiac malformations, fetal hydrops can result from lesions that place a burden on the right-sided cardiac chambers, resulting in increased right atrial pressure such as left-sided obstructive lesions, hypoplastic left heart syndrome or premature closure or restriction of the ductus venosus and right-sided obstructive lesions such as pulmonary and tricuspid atresia. Nonobstructive lesions that result in right atrial volume overload such atrioventricular canal defect are reported in fetal hydrops.

Fetal tachyarrhythmias are the second most common cardiovascular abnormality associated with fetal hydrops. This aetiology has evidenced-based treatment protocols with secondary reversal of the fetal hydrops. Fetal bradyarrhythmias are less commonly associated with fetal hydrops and are not easily treatable.

Intracardiac tumours represent a rare cause of fetal hydrops. The most common fetal cardiac tumour is a rhabdomyoma with fetal hydrops caused by tumour obstruction to cardiac flow or an associated arrhythmia. Cardiac rhabdomyomas are frequently a fetal manifestation of tuberous sclerosis (autosomal dominant condition) and when suspected prenatally should result in a careful family history and assessment of the couple. (Details on fetal tumours are provided in Chapter 37 .)

Chromosomal Disorders

Chromosomal abnormalities are a frequent cause of fetal hydrops, accounting for 13% of cases according to two systematic reviews (selected publications from 1979 to 2013). However, amongst the publications included in these two reviews, the frequency of chromosomal abnormalities ranged from 0% to 77%. Other publications, which were excluded from the systematic reviews because they did not address all causes of NIHF but focused only on the incidence of chromosomal abnormalities, indicate an incidence of chromosomal abnormalities in fetal hydrops ranging from 20% to 80%. The lower frequency reported by Bellini and colleagues may in part be due, as discussed in their publication, to the difficulty in correctly classifying patients with chromosomal abnormalities and fetal hydrops. Such patients may be classified in the chromosomal category or in the cardiovascular category because the hydrops in a proportion of these patients may be secondary to the cardiac malformation present. Structural cardiac abnormalities are a common finding in trisomies 21, 18 and 13.

Another factor that may influence the frequency of chromosomal abnormality is whether or not cases of CH with fetal hydrops have been included or excluded from the study. Cohort studies of fetal hydrops that have reported on the incidence of chromosomal abnormalities and have separated the cases of fetal hydrops with CH from the cases of fetal hydrops alone, have shown a higher frequency of chromosomal abnormality in the former group (∼55% compared with 20%–25% in NIHF without CH). The most common chromosomal abnormalities were Turner syndrome and Down syndrome. Other chromosomal abnormalities seen in both groups included trisomy 18, trisomy 13 and structural chromosomal abnormalities.

Gestational age at presentation and ethnicity are other factors to consider in assessing the risk of chromosomal abnormality. A review of 100 cases of fetal hydrops in a southeast Asian population found a relatively low incidence of chromosomal abnormality (8%) compared with 22% of the cases diagnosed with haemoglobin Bart’s disease (α-thalassemia hydrops fetalis). In the same study, cases with and without chromosomal abnormalities were compared, and the mean gestational age at diagnosis in the cases with fetal hydrops and a chromosomal abnormality was 18 weeks’ gestation, 10 weeks earlier than in the group without a chromosomal abnormality.

Other cohort studies have supported the concept that aetiology varies with gestational age at presentation, and in fetuses with NIHF before 24 weeks, a chromosomal abnormality is seen in a higher percentage of cases (32% vs 45% ). However, even if fetal hydrops is detected in the third trimester, chromosome analysis is justified even if second trimester ultrasound was normal. In a series of 214 cases of fetal hydrops, 4 fetuses were diagnosed with transient abnormal myelopoiesis (1.9%) presenting between 29 and 33 weeks of gestation, and all cases had trisomy 21. This is further supported by a retrospective case series of 79 cases of trisomy 21 prenatally diagnosed. Eleven of these cases had fetal hydrops, and in three, it was associated with haepatomegaly and a myeloproliferative disorder presenting in the second and third trimesters. A diagnosis of transient myeloproliferative disorder can be suspected prenatally by the finding of blast cells and an elevated white blood cell count in fetal blood.

Haematologic Conditions

Fetal anaemia is a common finding in fetal hydrops and has multiple aetiologies, including blood group alloimmunisation (IHF), infection (discussed later), fetal haemorrhage (fetomaternal haemorrhage), donor twin in TTTS and fetal inherited hematologic disorders, most commonly α-thalassemia. Other less common inherited disorders resulting in fetal anaemia are summarised in Table 36.4 . As discussed earlier, anaemia can also result from a myeloproliferative disorder as is seen with trisomy 21 and lead to NIHF.

The percent contribution of α-thalassemia to NIHF varies greatly and is dependent on the ethnicity or geographic location of the cohort. Typically, the -thalassemia four-gene deletion (–(SEA)/–(SEA) genotype at the α globin locus, haemoglobin Bart’s hydrops fetalis) is the cause of the fetal anaemia which results in high-output cardiac failure and fetal hypoxia. Less commonly, haemoglobin H (HbH) disease caused by a double-α gene deletion (–(SEA)) inherited from one parent and Hb Constant Spring, an unstable haemoglobin variant (Hb CS; HBA2:c.427T>C), inherited from the other parent causes hydrops fetalis. α-Thalassemia carrier status is common in Southeast Asian populations, and this autosomal recessive disorder accounts for 28% to 55% of their NIHF. Most other population cohorts report approximately 10% of their cases caused by hematologic disorders.

Lymphatic Dysplasia

Over the past decade, an increased proportion of cases with NIHF have been diagnosed with conditions associated with abnormal lymphatic development (CH and NIHF, chylothorax, or chyloascites and NIHF).

As discussed in the previous section, CH and NIHF is associated with a high risk of chromosomal abnormalities. When a chromosomal cause has been excluded, a syndromic cause must be considered, with Noonan syndrome being the most common syndrome associated with CH. Noonan syndrome is an autosomal dominant disorder caused by mutations in genes that participate in RAS–mitogen-activated protein kinase signal transduction (RAS-MAPK pathway genes: PTPN11, KRAS, SOS1, RAF1, MAP2K1, BRAF, SHOC2, NRAS, CBL and RIT1 ) with PTPN11 mutations found in approximately 50% of patients. In 2006, a report of PTPN11 testing of pregnancies presenting with CH with or without hydrops or associated anomalies indicated the detection of a mutation in 16% of cases. This finding was replicated in another study that found mutations in both PTPN11 and RAF1 in pregnancies with CH, leading to the recommendation that Noonan syndrome gene testing should be considered in all cases of CH with normal karyotypes. Approximately 85% of cases of Noonan syndrome can be diagnosed by of a panel of genes responsible for Noonan syndrome and other RASopathies.

Two other groups of genetic disorders should be considered in the context of CH and fetal hydrops: fetal akinesia deformation sequence (FADS) and lethal multiple pterygium syndrome (LMPS). Both disorders have some phenotypic overlap with decreased fetal movements and arthrogryposis. A review of 79 consecutive cases of FADS showed that 15% presented with fetal hydrops. Both FADS and LMPS are genetically heterogeneous and have been shown in a proportion of cases to be caused by mutations in the neuromuscular junction genes: recessive mutations in CHRNA1, CHRND and CHRNG have been described in patients with LMPS and recessive mutations in CNTN1, DOK7, RAPSN and SYNE1 in patients with FADS, and more recently recessive mutations in RYR1 have been found in 8.3% of patients with FADS/LMPS phenotypes. It has been postulated that the decreased fetal movement in these disorders is associated with decreased lymphatic flow, leading to the CH and fetal hydrops. With exome sequencing studies being performed on cases of FADS and LMPS, it is likely that numerous additional genes causing these phenotypes will be identified.

Abnormalities in lymphatic development (chylothorax or chyloascites) can also present in the second and third trimesters. The abnormalities may be reflective of a chromosomal or genetic syndrome or primary lymphatic dysplasia. Congenital chylothorax is the most common type of pleural effusion in fetal life and is associated with fetal hydrops in 60% to 70% of cases. In one retrospective case series with 10 cases of congenital chylothorax, a diagnosis of trisomy 21 was made in one case and a diagnosis of Noonan syndrome in three cases. A larger prospective German nationwide epidemiologic study of chylothorax reported on 27 cases of chylothorax with one case with trisomy 21 and five cases with Noonan syndrome. A review of the prenatal features in a series of 47 patients with a molecular diagnosis of Noonan syndrome reported 5 patients with hydrothorax, and all five had associated polyhydramnios. Mutations in PTPN11 and SOS1 were found in four and one patients, respectively. Mutations in other genes of the RAS-MAPK pathway have been reported to cause chylothorax and fetal hydrops, including SHOC2 and CBL . Although Noonan syndrome is the most common syndrome associated with chylothorax and fetal hydrops, other syndromes that are part of the RASopathies, cardio-facio-cutaneous and Costello syndrome, can be the cause of the prenatal findings of lymphatic dysplasia.

Primary generalised lymphatic dysplasia (GLD), although rare, is a recognised cause of fetal hydrops. GLD results from an inherent developmental abnormality of the lymphatic system involving the viscera. The onset of lymphatic drainage failure can be prenatal or postnatal. Hennekam syndrome is an example of an autosomal recessive syndromic form of GLD that is characterised by lymphoedema of the limbs, genitalia and face; secondary facial dysmorphic features; intestinal lymphangiectasia; and varying degrees of intellectual disability. In severe cases, it may present prenatally with fetal hydrops. Recessive mutations in CCBE1 and FAT4 are found in fewer than 50% of Hennekam patients, indicating that the condition is genetically heterogeneous, and some genes remain unknown. Another form of recessive GLD with a high incidence of NIHF with either demise or complete resolution of the neonatal oedema followed by childhood onset of lymphoedema with or without systemic involvement has recently been reported in six families harbouring mutations in PIEZO1, a gene coding for a calcium permeable mechanically activated ion channel found in the plasma membrane of various cell types. A recent report of hydrops fetalis and pulmonary lymphangiectasia caused by autosomal dominant FOXC2 mutation which presented with lymphoedema of the lower limbs and irregularly implanted eyelashes (lymphoedema-distichiasis syndrome) in the father and numerous family members illustrates that these conditions can have variable presentations and that a thorough analysis of the familial pedigree is important. Primary congenital lymphoedema also known as Milroy disease, a dominant condition caused by mutations in FLT4 inherited as autosomal dominant or recessive , typically presents with congenital chronic swelling of the lower limbs. However, it has also been reported to present prenatally with oedema of the lower limbs and transient ascites and pleural effusions, further supporting the concept of variable presentation with the more severe cases presenting with fetal hydrops. Given the growing number of genes implicated in lymphatic anomalies, it is conceivable that de novo mutations in these genes may account for a significant proportion of the cases currently considered as idiopathic fetal hydrops. Indeed, sequencing analysis of FLT4, FOXC2 and SOX18 of 12 probands who survived in utero generalised oedema or hydrops fetalis of unknown aetiology identified mutations in FLT4 in two patients and a mutation in FOXC2 in one patient, although none of the patients had a positive family history of lymphoedema.

Infection

A variety of infectious agents have been associated with NIHF, including parvovirus B19 (most common), cytomegalovirus (CMV), herpes simplex virus, Toxoplasma gondii , rubella, syphilis and chlamydia. Infectious agents produce hydrops through effects on fetal bone marrow, myocardium or vascular endothelium. They represent 7% of cases of NIHF. Fetal infections are detailed in Chapter 42 .

Thoracic Masses

Thoracic masses account for 5% of cases of NIHF and include any thoracic pathology that has a significant mass effect and results in elevated central venous pressure. This includes congenital pulmonary airway malformations (CPAMs; see Chapter 30 ), diaphragmatic hernia (see Chapter 31 ), chylothorax (discussed under lymphatic dysplasia earlier) and intrathoracic tumours (see Chapter 37 ).

Metabolic Conditions

Inborn errors of metabolism are a recognised cause of fetal hydrops, although they are likely to be underdiagnosed given the need for specialised metabolic or genetic testing that may not be readily available. The systematic reviews of hydrops fetalis by Bellini and colleagues (including publications between 1979 and 2007 and 2008 and 2013) found that inborn errors of metabolism accounted for 1.1% and 1.3% of cases, respectively. However, another systematic review of hydrops fetalis aimed at determining the contribution of lysosomal storage disease (LSD) (the most common class of inborn error of metabolism causing NIHF) reported that of the 54 retrospective studies and case series with cases of NIHF with its workup described, only 15 (27.8%) reported testing for LSD, and the extent of this workup varied among studies. Amongst the 678 total NIHF cases identified in those 15 publications, 35 cases (5.2%) were diagnosed with LSD. In the two studies with the most extensive workup for LSD, 8 of 86 patients (9.3%) had an LSD. This finding strongly suggests that LSD and other disorders of inborn errors of metabolism may account for a significant proportion of cases of idiopathic NIHF.

At least 15 different LSDs have been reported in series or case reports as causing NIHF ( Table 36.5 ). The most common conditions reported were mucopolysaccharidosis type VII and type IVa, Gaucher disease, GM1 gangliosidosis, sialidosis, Niemann-Pick types C and A, galactosialidosis, infantile sialic acid storage disorder and mucolipidosis II. The mechanisms contributing to the development of hydrops in storage disorders may include obstruction of venous blood return resulting from organomegaly, anaemia associated with hypersplenism or reduction of erythropoietic bone marrow stem cells caused by infiltrating storage cells, and hypoproteinaemia caused by liver dysfunction.

TABLE 36.5

Only gold members can continue reading. Log In or Register to continue

Share this:

• Click to share on Twitter (Opens in new window)
• Click to share on Facebook (Opens in new window)

Related

Related posts:

1. Teratology
2. Placental Function in Maternofetal Exchange
3. Noninvasive Prenatal Diagnosis for Single-Gene Disorders
4. Diagnosis and Management of Abnormalities of the Face

Stay updated, free articles. Join our Telegram channel

Join