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Publicly Available Published by De Gruyter October 2, 2017

Non-immune fetal hydrops of metabolic origin: a case report and a review of the literature

Ana Carvoeiro ORCID logo, Filipa Carvalho, Nuno Montenegro and Alexandra Matias

Abstract

Aim

To propose a diagnostic algorithm for non-immune fetal hydrops (NIFH) of metabolic origin based on a review of the literature and on the workup of a clinical case.

Background

The etiology of NIFH is complex and remains unexplained in 15%–25% of patients. The appropriate work up beyond an initial approach is still not well defined but it should include screening for metabolic conditions. Inborn errors of metabolism comprise a heterogeneous group of autosomal recessive rare inherited disorders, among which lysosomal storage disorder is the most common subtype.

Case description

We report a case of a 30-year-old pregnant, primiparous woman, referred to a tertiary hospital at 22 weeks of gestation because of a fetal hydrops. The second trimester obstetric ultrasound showed a hydrothorax and a large subcutaneous edema. At 30 weeks of gestation, the fetal health status deteriorated and a massive hepatomegaly was detected. The metabolic study of the amniotic fluid supernatant suggested a lysosomal disease. The ominous prognosis of the condition motivated the parents to opt for a termination of pregnancy. The autopsy study confirmed the existence of a metabolic disease.

Conclusion

The incidence of inborn errors of metabolism may be significantly higher in NIHF than reported previously. Consequently, an extensive investigation for the etiology of NIHF including the screening for metabolic disorders seems to be crucial for a definitive diagnosis.

Clinical relevance

Despite the lack of treatment options for the majority of these disorders, it is of great importance to follow an established workup, in order to identify the index case as soon as possible, as pregnancy management decisions and prenatal counselling in future pregnancies will depend on a more precise diagnosis.

Background

Fetal hydrops (FH) describes a condition in which a pathological fluid accumulation occurs in at least two serous cavities (abdomen; pleura; pericardium) or in fetal soft tissues (subcutaneous edema) [1], [2]. Hydrops is usually first recognized by ultrasound examination during the first or second trimester of gestation [3]. Frequently, significant fluid collections, such as ascites, pleural effusions, pericardial effusion and generalized skin edema (defined as a skin thickness >5 mm [4]) are easily detected by ultrasound, but fluid accumulation may also be limited and thus escape routine ultrasound detection [1], [3]. Other sonographic findings such as placental thickening (typically defined as a placental thickness ≥4 cm in the second trimester or ≥6 cm in the third trimester [5], [6]) and polyhydramnios can raise the suspicion of hydrops [1]. Decreased fetal movements and maternal pre-eclampsia may also be relevant [3].

Hydrops fetalis can be divided into immune hydrops fetalis (IHF) associated with antigen-antibody mediated red cell hemolysis, and non-immune hydrops fetalis (NIHF), associated with a wide range of etiological factors [7], [8]. It was Edith Potter who first distinguished NIHF from IHF in 1943 and at that time NIHF was described as a “universal edema unassociated with erytroblastosis” [9]. At that time, NIHF constituted 20% of all cases [10], but, since 1970, effective rhesus iso-immunization prophylaxis has led to a significant decline in the prevalence of IHF [3]. Nowadays, NIHF constitutes up to 90% of all described hydrops fetalis cases [11], [12], with the prevalence in published series reported as 1 in 1700–3000 pregnancies [13], [14].

Bellini et al. [15] recently reviewed and classified causes of NIHF in order of prevalence: cardiovascular disorders (20.1%), lymph vessels dysplasia (15%), hematologic abnormalities (9.3%), chromosome imbalances (9.0%), infections (7.0%), syndromic (5.5%), twin-to-twin transfusion syndrome and placental causes (4.1%), miscellaneous cases (3.6%), intrathoracic masses (2.3%), gastrointestinal disorders (1.3%), inborn errors of metabolism (1.3%), urinary tract malformations (0.9%), extra-thoracic tumours (0.7%) and idiopathic (19.8%).

Inborn errors of metabolism (IEM) comprise a heterogeneous group of autosomal recessive rare inherited disorders, with lysosomal storage disorders (LSD) as the most common subtype [16].

The etiology of NIHF is complex and remains unknown in 15%–25% [11] of patients and the search for the underlying causes may be extensive [17]. The appropriate work up beyond an initial approach is still not well defined but it should include screening for metabolic conditions. In fact, higher incidences of LSD as the underlying cause of NIHF in a recent study [18], demand more awareness regarding metabolic disorders. The poor prognosis for IEM [7] is also one of the main reasons why an accurate prenatal diagnosis of metabolic disorders is essential, as it would facilitate consideration of specific therapies before the occurrence of irreversible complications [7] and it would provide better prenatal/genetic counselling.

In the present paper we describe both a case of NIHF caused by a metabolic disorder and a review of the literature pertaining to this condition. This review aims to identify the IEM related to NIHF, to define appropriate indications for metabolic diseases testing and to propose a diagnostic algorithm for NIHF of metabolic origin.

Case description

A 30-year-old pregnant primiparous Portuguese woman with a spontaneous pregnancy, was referred to a tertiary hospital at 22 weeks of gestation because of a hydrops fetalis. The past and family histories were not significant. The parents were non-consanguineous. Maternal prenatal first trimester screening tests showed an A and Rh+ blood type, negative results for HIV, HBV, HCV and VDRL tests and immunity to CMV and rubella. The first trimester ultrasound at 12 weeks and 4 days of gestation, revealed a nuchal translucency of 2.9 mm and the presence of nasal bones. The combined screening was negative.

The second trimester obstetric ultrasound, at 20 weeks and 6 days of gestation, showed hydrops fetalis with generalized edema of the superior abdominal wall, chest cavity and skull. A large pleural effusion (hydrothorax) compressing the heart and both lungs was noticed. The remaining anatomical and structural parameters, as well as the amount of amniotic fluid (AL), were considered as normal attending to the specific gestational age reference range. Placenta was high posterior. As soon as this accumulation of fluid in more than two fetal compartments was revealed, the patient was submitted to an amniocentesis for karyotype evaluation.

The subsequent scan at 22 weeks of gestation showed a worsening of the hydrothorax that developed bilaterally (Figure 1). The persistence of subcutaneous edema (Figure 2A), a small volume ascites (Figure 2B) and a larger amount of amniotic fluid were the other anomalous ultrasonographic findings. Morphological parameters were normal, and the gender diagnosis revealed a male fetus. A hemodynamic evaluation was carried out with Doppler evaluation of flow in the umbilical artery, middle cerebral artery and ductus venosus, which was within normal range. In order to clarify the etiology of this hydrops fetalis, a standardized approach was chosen (Figure 6), which will be later described and discussed. The following diagnostic hypotheses were excluded: intrauterine anemia, intrauterine heart failure, hypoproteinemia, chromosomal anomalies, infectious diseases and structural abnormalities.

Figure 1: 
Major bilateral hydrothorax at 22 weeks of gestation.

Figure 1:

Major bilateral hydrothorax at 22 weeks of gestation.

Figure 2: 
Two-dimensional (2D) scan at 22 weeks of gestation. Incresead nuchal fold thickness (subcutaneous edema) (A) small ascites (B).

Figure 2:

Two-dimensional (2D) scan at 22 weeks of gestation. Incresead nuchal fold thickness (subcutaneous edema) (A) small ascites (B).

At 24 weeks of gestation, the progressive worsening of fetal hydrops, namely the pleural effusion, determined the insertion of a bilateral pigtail thoracic catheter, which improved the fetal condition. More precisely, at 26 weeks not only was a generalized reabsorption of the pleural effusions recorded, but also a decrease in subcutaneous edema was recorded (Figure 3C). No sign of ascites were noticed and a normal amount of amniotic fluid was measured (Figure 3B).

Figure 3: 
2D scan at 26 weeks of gestation. Signs of subcutaneous edema (A) Resolution of the pleural effusion after introduction of the pigtail catheter (B) and skin edema around the head (C).

Figure 3:

2D scan at 26 weeks of gestation. Signs of subcutaneous edema (A) Resolution of the pleural effusion after introduction of the pigtail catheter (B) and skin edema around the head (C).

Nevertheless, at 27 weeks a deterioration of the fetal health status was observed (Figure 4): the amniotic fluid index (AFI) increased to 26, 5 cm (Figure 4A) which consubstantiated a polyhydramnios. Other fetal anomalies also appeared: a left cardiac axis deviation of 58° (Figure 4C), an increase in the echogenicity and volume of the lungs, a hepatomegaly (Figure 4B) with lateral deviation of the umbilical vein (Figure 4D) and the presence of dysplastic external ear (Figure 5).

Figure 4: 
At 27 weeks an aggravation of the fetal hydrops was recorded. There was an increase in amniotic fluid – polyhydramnios (A). A newly arising hepatomegaly was detected (B) with left cardiac axis deviation (58°) (C) and lateral deviation of the umbilical vein (D).

Figure 4:

At 27 weeks an aggravation of the fetal hydrops was recorded. There was an increase in amniotic fluid – polyhydramnios (A). A newly arising hepatomegaly was detected (B) with left cardiac axis deviation (58°) (C) and lateral deviation of the umbilical vein (D).

Figure 5: 
Malformation of the external ear (probably caused by a subcutaneous edema).

Figure 5:

Malformation of the external ear (probably caused by a subcutaneous edema).

At 30 weeks of gestation, and following invasive diagnostic procedures, the “Filipin test” was performed and it showed by fluorescence microscopy an intracellular accumulation of unesterified cholesterol, pointing to the diagnosis of Niemann-Pick disease type C.

The understanding of the ominous prognosis of this condition motivated the parents to opt for a termination of pregnancy.

Post-mortem examination, namely the placental histopathology showed marked Hofbauer and stroma villous cells vacuolization, supporting the prenatal diagnosis of an underlying LSD. The absence of trophoblastic cells vacuolization ruled out mucolipidosis and gangliosidosis as differential diagnosis. The diagnosis of mucopolysaccharidosis type IV and VII was put forward. However, considering the absence of osteodyplasia, the most probable final diagnosis was mucopolysaccharidosis type VII (Sly syndrome).

Discussion

NIHF is a serious and life-threatening condition [18]. Although the incidence is very low, NIHF accounts for a disproportionate share (3%) of overall mortality in the perinatal period [19]. In fact, this incidence may be higher because intrauterine fetal death and in utero spontaneous resolution probably mask the true incidence [18].

Bellini et al., in a recent systematic review, updates a list of the causes of NIHF and reports that these can be found in up to 85% of cases [11].

In the last few years increased interest for IEM as an underlying cause of NIHF was demonstrated in a large number of case reports and some large series [20]. Bellini et al. reported that the percentage of cases among the group of NIHF with a final diagnosis of IEM remains almost the same (1.3%) [15] when compared with an older review which reported a percentage of 1.1% [11]. However, in another recent systematic review, LSD occurrence was seen in 5.2% of NIHF cases and 17.4% if all idiopathic cases were taken into consideration. Furthermore, in a prospective study in 33 cases of NIH during 2006–2016, a higher percentage of LSD (21%) was reported. So, although the incidence of metabolic IEM as a cause of NIHF or isolated fetal ascites is still uncertain, its significance is undeniable.

Most of IEM are lysosomal storage diseases (LSDs) and Whybra et al. reported that 12 different LSDs may be associated with NIHF [20]. These LSDs, caused by two deleterious mutations with a complete deficiency of the enzyme or transport protein, include cases with mucopolysaccharidosis type IV and VII (Sly syndrome) (27%), infantile sialic acid storage disease (ISSD, 18%), galactosialidosis (12%), sialidosis (12%) GM1 gangliosidosis, I-cell disease (12%), type 2 Gaucher disease (10%), Niemann-Pick type A and C (NPC and NPA, Wolman disease and Farber disease [20], [21] (Table 1).

Table 1:

Lysosomal storage diseases and non-lysosomal inborn errors of metabolism associated with NIHF (adapted from Whybra et al. [20]).

Inborn errors of metabolism (IEM)
Lysosomal storage disorders Non-lysosomal inborn errors of metabolism
Mucopolysaccharidosis type VII Glycogenosis: Type IV (Anderson disease)
Infantile sialic acid storage disease Congenital disorder of glycosylation: Congenital disorder of glycosylation type 1a
Galactosialidosis Peroxismal disorder

Zellweger syndrome
Sialidosis

GM1 – gangliosidosis
Fatty acid oxidation defects: Long-chain-hydroxyacyl CoA dehydrogenase

deficiency (LCHAD)

Primary carnitine deficiency
Gaucher disease

I-cell disease

Niemann-Pick type C
Cholesterol biosynthesis defects: Smith-Lemli-Opitz syndrome

Greenberg syndrome: hydrops-ectopic calcification moth-eaten skeletal dysplasia

Conradi Hunermann syndrome: chondrodysplasia punctate
Mucopolysaccharidosis type IV

Niemann-Pick type A

Wolman disease

Farber disease



Others: Citric acid cycle defect (fumarase deficiency)

Neonatal hemochromatosis

Transaldolase deficiency

S-adenosylhomocysteine hydrolase deficiency

Congenital erythropoietic porphyria

Associations of NIHF with Hurler disease [22] (mucopolysaccharidosis type I) and multiple sulfatase deficiency [16] are doubtful [20]. There are also non-lysossomal inborn errors of metabolism that can present with hydrops fetalis which include glycogenosis disorders, congenital disorders of glycosylation, peroxismal disorders, fatty acid oxidation defects, cholesterol biosynthesis defects and other metabolic disorders [20] (Table 1).

The mechanism contributing to the development of hydrops fetalis in storage diseases is not well understood, but may involve the obstruction of venous blood return resulting from visceromegaly which is a consequence of accumulation of storage material [14]. Other conditions may trigger ascites and hydrops fetalis such as: anemia, caused by hypersplenism or the reduction of erythropoietic stem cells associated with infiltration of storage cells; congestive heart failure, hypoproteinemia and liver dysfunction [21].

Usually, IEM will not be considered until there is a case index [17] justifying the importance of a systematic diagnostic approach, including screening for metabolic conditions (Figure 6).

Figure 6: 
Diagnostic algorithm for the clinical evaluation of a fetus with NIHF of metabolic origin. NIHF, Non immune hydrops fetalis; AF, amniotic fluid; MCA PSV, the fetal middle cerebral arterial (MCA) peak systolic velocity (PSV); IEM, inborn errors of metabolism.

Figure 6:

Diagnostic algorithm for the clinical evaluation of a fetus with NIHF of metabolic origin. NIHF, Non immune hydrops fetalis; AF, amniotic fluid; MCA PSV, the fetal middle cerebral arterial (MCA) peak systolic velocity (PSV); IEM, inborn errors of metabolism.

We present a case of NIHF with a prenatal diagnosis of LSD in a first pregnancy.

NIHF initial work up must consider the presence of possible consanguinity, as LSDs are inherited in an autosomal recessive manner which was not the case in this setting. Combined screening was negative. According to the literature, most IEM usually present with normal nuchal translucency, placental thickness and amniotic fluid [23]. In the present case, sonographic identification of a hydropic fetus occurred at 20 weeks of gestation with the presence of ≥2 abnormal fluid collections (ascites, hydrothorax and subcutaneous edema) [4].

It was important to rule out potentially treatable conditions detected by ultrasound and by fetal echocardiogram (as fetal cardiac anomalies are among the most common causes of NIHF) [1]. The complimentary Doppler flowmetry, including middle cerebral artery (MCA), umbilical artery and ductus venosus evaluation, was within normal range. An amniocentesis was performed and fetal karyotype was normal (46, XY). A polymerase chain reaction (PCR) study in the amniotic fluid for microorganisms was negative.

The next step was to evaluate the maternal status. She was A Positive and the search for irregular agglutinins was negative. Kleihauer-Betke stain for fetal hemoglobin, maternal hemoglobin electrophoresis, a direct analysis of fetal hematocrit and hemoglobin by fetal blood sampling showed no alterations. Serologic test results for TORCH infections (toxoplasmosis, rubella, cytomegalovirus syphilis, parvovirus B19 and herpes infections) was negative.

Because of the existence of a massive pleural effusion at 24 weeks of gestation, a bilateral pigtail thoracic catheter was introduced. Though a transient HF resolution was achieved, a later (27 weeks of gestation) ultrasound showed a general deterioration of the fetal health status, exacerbation of the pleural effusion and the development of hepatomegaly.

As the initial comprehensive work up was negative, a metabolic study of the amniotic fluid was undertaken. A “Filipin staining” was positive with visualization of an abnormal accumulation of unesterified cholesterol in the endosomal/lysosomal compartment leading to suspicion of NPC [24] (similar cases are described [25]). The recent emergence of two classes of plasmatic biomarkers, oxysterols (cholestane-3β, 5α, 6β-triol and 7-ketocholesterol [26], [27]) and lysosphingolipids (lysophingomyelin and isoform 509 [28], [29], [30]) for the diagnosis of NPC and NPA modify the future diagnostic approach of these specific diseases.

Both parents were studied for the existence of the mutation causing NPC but the result was negative pointing out to a de novo mutation.

Autopsy and analysis of the placenta were undertaken. Placental histology strongly suggested MPS VII or Sly syndrome as the most probable diagnostic hypothesis [31], [32]. This post-mortem examination was crucial to refine the diagnosis, which was not, as initially thought, a NPC syndrome.

Post-mortem examination should include postnatal autopsy (babygram, photo documentation), skin biopsy (DNA isolation for genetics and cultivated cells for biochemical tests), tissue sample (unfixed – liver, spleen, heart) for histopathological and histochemical examinations and placenta analysis [20]. Placental histology can serve as a valuable diagnostic tool as it may be done even if the family does not allow the autopsy [20]. A diagnosis of MPS VII following post-mortem examination has significant implications for future pregnancies. In fact, MPS VII prenatal diagnosis is now possible following chorionic villus sampling or amniocentesis by glucuronidase assay or direct gene analysis [31], [33].

Wonkyung et al. [34] recently stated that the most predictive antenatal ultrasound finding of neonatal death in NIHF was the number of fluid collection sites. In another study, Kim et al. developed an “ultrasonographic severity scoring of NIHF” (USNIH), defined as the total number of abnormal fluid collections. Once more, perinatal mortality rate was significantly higher in cases with USNIHF of ≥3 than in those with USNIHF of 2 [35].

Pregnancy management decisions in the case of NIHF will rely on the gestational age at which NIHF is identified, the etiology and if the condition is treatable or not. If NIHF is identified prior to viability, pregnancy termination can be offered, because of the bad prognosis [1]. If gestational age is ≥24 weeks, it has to be taken in consideration if the case is amenable to fetal therapy and be immediately treated or referred to a specialized center [1]. In both situations the pregnancy termination should always be considered an option.

In our case, the lack of therapeutic options associated with the worsening of the fetal status motivated the parents to terminate the pregnancy at 30 weeks of gestation.

Conclusion

From the analysis of this case and regarding the literature reviewed here it can be concluded that the incidence of IEM may be significantly higher in NIHF than reported in previous studies. Moreover, an extensive investigation for the etiology of NIHF including the screening for metabolic disorders seems to be essential to refine the final diagnosis.

Clinical relevance

Despite the lack of treatment options for the majority of these disorders, it is of great importance to reach a diagnosis and to identify the index case as soon as possible as pregnancy management decisions will depend on that. Finally, we highlight the importance of genetic counselling, which should be proposed to the families for future pregnancies.

Author’s statement

  1. Conflict of interest: Authors state no conflict of interest.

Material and methods

  1. Informed consent: Informed consent has been obtained from all individuals included in this study.

  2. Ethical approval: The research related to human subject use has complied with all the relevant national regulations, and institutional policies, and is in accordance with the tenets of the Helsinki Declaration, and has been approved by the authors’ institutional review board or equivalent committee.

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Received: 2017-03-19
Accepted: 2017-07-11
Published Online: 2017-10-02

©2017 Walter de Gruyter GmbH, Berlin/Boston

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