Download NON IMMUNE FETAL HYDROPS: An Overview

Wyno Journal of Medical Sciences Vol. 2, (3), PP. 26-31 March. 2013
Available online at http://www.wynoacademicjournals.org/med_sciences.html
ISSN 2320-1282 Copy Right©2013 wyno academic Journals
NON IMMUNE FETAL HYDROPS: An Overview
Dr. Sreelakshmi Kodandapani1*, Dr. Roopa P S2 , Dr. Muralidhar V Pai3
Dept of ObGyn, Kasturba Medical College , Manipal 576104,
Email: [email protected]
Ph: 9448244311
Accepted Date: 18Th March, 2013
Abstract
Hydrops fetalis is accumulation of extracellular fluid in fetal body cavities: pleural, pericardial, scalp and body wall edema
and ascites. Non immune hydrops is universal edema unassociated with erythroblastosis. Ultrasound is the diagnostic tool.
Various structural abnormalities in the fetus may subsequently lead to hydrops and hence require follow up scan in all
cases. Hydrops is due to several factors leading to accumulation of edema. Structural and rhythm cardiac abnormalities are
the most common cause followed by chromosomal abnormalities. Fetal anemia is rare but one of the few which can be
treated. Anemia is detected by Doppler of middle cerebral artery. Hereditary inborn errors of metabolism cause recurrent
hydrops and has poor prognosis. Few management options are available and discussed.
Key words: Hydrops Fetalis, Ultrasound, Fetal Anemia, Doppler.
Introduction
Hydrops fetalis (HF) is defined as accumulation of extracellular fluid in fetal body cavities like pleural, pericardial, scalp
and body wall edema and ascites (Ulrich et al 2000). Non immune hydrops fetalis (NIHF) was first distinguished from
immune hydrops by Edith Potter in 1943; described as a “universal edema unassociated with erythroblastosis” (Potter
1943). When first described, NIHF constituted 20% of all cases, but with effective anti D prophylaxis for immune hydrops,
NIHF constitutes 90% cases of fetal hydrops. Isolated ascites, pericardial and pleural effusion have specific etiologies and
hence not recognized as fetal Hydrops (Ulrich et al 2000)
Pathophysiology
Apkon et al. (1995) has reported that the development of edema can be attributed to one the following principal factors
given below (Apkon M 1995).
1. Primary myocardial failure:
Example: cardiac arrhythmia, severe anemia G6PD deficiency, homozygous alpha thalassemia.
2. High output failure:
Example: arteriovenous shunt, vein of Galen malformation, chorioangioma of placenta, twin to twin transfusion
syndrome
3. Decreased plasma oncotic pressure either due to decreased albumin formation or excretion.
Example: congenital hepatic cirrhosis, congenital nephritic syndrome.
4. Increased capillary permeability:
Example: congenital infections like TORCH
5. Obstruction of lymph flow
Example: Turner syndrome
6. Obstruction of venous return due to space occupying lesion
Example: cystic adenomatoid malformation, diaphragmatic hernia
Etiology
The causes for NIHF have been reported to vary by several aspects (Ismail et al 2001). Structural and rhythm cardiac
abnormalities are the most common cause followed by chromosomal abnormalities. Complex cardiac defects cause hydrops
by primary myocardiac failure. They cause early hydrops, sometimes as early as first trimester. Inherited metabolic
disorders such as infantile Gaucher's disease, GM1 gangliosidosis, sialidosis (neuraminidase deficiency),
mucopolysaccharidosis type IV A (Morquio's disease type A) and I-cell disease have been implicated as a cause of NIHF or
neonatal ascites. Parvo virus B 19 infection has been considered as a causative agent in the cases of fetal anemia shown by
peak systolic velocity of middle cerebral artery Doppler flow, with IgM positivity after 7-14 days in maternal serum (Xu J
1|P ag e
27. Med. Sci.
2003). This is more common between 17 and 24 weeks of gestation. Parvo virus B 19 is a single stranded DNA virus,
destroys rapidly proliferating cells with special affinity for erythroid series (affects final stage of maturation) leading to red
cell aplasia lasting approximately for 10 days with complete recovery in 2 to 3 weeks. Hence, there is a definite role for a
timely diagnosis and management (intrauterine transfusion). Adenovirus infection of fetus also causes anemia but is self
limiting, hence at next follow up there is a possibility of resolution of hydrops. If mother has uncontrolled hyperthyroidism,
there is always a possibility for fetal thyroid dysfunction, hence intrauterine growth restriction, tachycardia, cardiac failure,
hydrops, advanced bone age, and goiter (Marx H et al 2008). Twin to twin transfusion syndrome is one of the causes
leading to hydrops of stage IV disease according to Quintero staging system. Massive polyhydramnios is seen in recipient
twin with high mortality in untreated cases.
Hematologic disorders
Hematologic disorders constitute 10% of all causes related to NIHF. Hematologic disorders are responsible for 10% of
cases of NIHF. This includes disorders of hemoglobin synthesis, primarily homozygous α-thalassemia, selected erythrocyte
enzymopathies, and parvovirus B 19 infection. Amongst all types of thalassemias, only α-thalassemia major has HbBarts
hydrops fetalis (David1998). Each person normally has a total of four α-globin genes, two of which are encoded in tandem
(in cis) on each chromosome 16 (Table 1). There are α-thalassemia deletions that remove either one or two α-globin genes
on each chromosome 16. If, both parents are carriers of a deletion removing two α-globin genes in cis on one chromosome
16, there is a one in four risk that in each pregnancy, the fetus might inherit both parental deletion mutations, and lack all αglobin genes. Because, α-globin chains normally are produced throughout gestation, fetuses without α-globin gene would
suffer from severe anemia, and thus hypoxia, heart failure, and HF. They would usually survive in utero until the third
trimester of gestation when they would succumb to their genetic defects. In contrast to a normal fetus whose major
hemoglobin is Hb F (α2γ2), these fetuses have primarily Hb Bart’s (γ4). This disorder, first described in 1960, is known as
homozygous α-thalassemia or Hb Bart’s hydrops fetalis syndrome. Abnormal erythrocyte membrane mechanical stability
as well as structural and functional abnormalities in spectrin, the principal structural protein of the erythrocyte membrane
results in deformed erythrocyte. Hence, these erythrocytes can’t maintain normal shape and undergo premature hemolysis,
leading to anemia and hydrops (Gallagher et al 1998).
Diagnosis:
Routine ultrasound has been recommended as the initial diagnosis of NIHF (Moise et al 2008; Jauniaux et al, 1997; Graves
et al 1984). Clinical suspicion is possible in severe polyhydramnios only to lead to late diagnosis. Generalized skin edema
has been reported as one of the most common features. Skin edema of 20 mm at the back of the neck is common symptom
evident frequently during NIFH. This is the rationale of nuchal translucency. Fetal ascites of any amount is abnormal and
needs further evaluation (Fig1). Pleural effusion is also significantly featured in the NIFH (Fig 2). Hepatosplenomegaly,
calcification of bowel should be looked for, which are seen in TORCH infections. Cardiac rhythm rate should be seen, as
supraventricular tachycardia is one of the common and treatable causes for NIHF.
Middle cerebral artery Doppler peak systolic velocity (PSV) is a mandatory parameter cited in NIHF. Fetal anemia is
considered, if PSV is more than 1.5 MoMs for that period of gestation. Hence, fetus requires further evaluation for the
causes of anemia. Point noteworthy here is rapidly generated anemia usually causes immediate fetal death, whereas
hydrops occurs in the presence of slowly developing anemia, most common being Parvo virus B19 infection. Fetal
echocardiography should be done to look for cardiac tumors, myopathy, and contractile dysfunction.
Pericardial fluid of more than 2 mm is considered significant. Vein of Galen malformation in the cranium, any vascular
malformations of high output like sacrococcygeal teratoma, chorioangioma cases require follow up, as these are prone for
high output failure, hence hydrops. Same analogy applies for obstructive anomalies like cystic adenomatoid malformation
which blocks venous return, hence follow up to look for hydrops.
Placental thickness should be measured in all cases because of placental edema. 3D scan helps in determination of facial
dysmorphology like hypertelorism, micrognathia, low-set ears, iris coloboma, multiple contractures, areflexia, and genital
abnormalities which give clue for inborn errors of metabolism.
Other investigations:
Chorionic villous sampling is considered in less than 14 weeks for karyotyping and single gene disorders. Technically, the
sampling can be more difficult when the placenta is oedematous and the single needle aspiration technique should be
avoided, but early amniocentesis may be more complicated and associated with complications. Evaluation of single gene at
cis chromosome 16 should be looked for homozygous thalassemia alpha major in positive family history and in south Asia.
2|P ag e
28. Kodandapani et al
Parvo virus B19: Every case of NIHF without any obvious structural malformation requires parvovirus IgM and IgG
testing in maternal serum. It is positive after 10 to 14 days of infection. DNA polymerase chain reaction (PCR) is done in
doubtful cases only.
Placental examination for Hofbauer cells (foamy cells): Hofbauer cells may be present in a normal pregnancy and may
be a common finding early in pregnancy, their presence in association with fetal hydrops and in particular, with recurrent
fetal hydrops strongly suggests an inherited metabolic storage disorder as the cause of the hydrops and requires evaluation
of enzyme and single gene studies.
Diagnosis and management of early NIHF (less than 20 weeks gestation): Increased nuchal translucency is the first
sign; followed by generalized skin edema, particularly at the back wherein thickness may reach up to 15 to 20 mm
(Jauniaux et al 1997). Most commonly this is associated with abnormal karyotype like trisomy 21, 18 with complex
structural cardiac defect. Trisomy 21 can have hydrops without cardiac anomaly due to anemia and myeloproliferative
disorder. Prognosis is poor even in fetuses of normal karyotype. Before 20 weeks, placental edema is a consistent feature
with skin edema, thickness over 25 mm. Ultrasound measurement of placental thickness is considered for early prediction
of homozygous α-thalassemia. Detailed anomaly scan is recommended to rule out structural anomalies like
atrioventricular defects, omphalocoele, molar changes in placenta for triploidy. Parvovirus B19 infection are less
likely to cause early hydrops unless they directly affect myocardium. Rare causes of fetal anemia include homozygous αthalassemia and abnormal erythrocyte membrane mechanical stability due to spectrin protein structural and functional
abnormality. Maternal serum sample for metabolic screening should be considered in cases of normal karyotype,
consanguineous marriage, history of stillbirth and recurrent hydrops.
Inborn errors of metabolism (IBM) and other hereditary disorders: IBM causes hydrops either by anemia or by liver
failure. This may account for up to 10 % of the total cases. IBM should be considered in cases of normal karyotype and no
congenital malformations. Nuchal translucency is normal in first trimester. Here, placental thickness and amniotic fluid will
be normal. But, it is unusual to diagnose the index case but many cases are reported as recurrent hydrops. They are also
reported in varied gestation, from as early as first trimester. Diagnosis is by both enzyme studies and specific gene studies
Mucopolysaccharidoses are a family of lysosomal storage disorders caused by deficiency of enzymes catalyzing the
stepwise degradation of glycosaminoglycans (or mucopolysaccharides). Accumulation of glycosaminoglycans eventually
resulted into dead cell, tissue, and organ dysfunction, with the most severe forms often manifesting as HF in utero.
Prognosis & counseling
Cardiac arrhythmias: Isolated congenital heart block results from congenital malformation of the conducting system,
leading to bradycardia. This requires follow up, timely delivery and permanent pacemaker. In cases of tachyarrhythmias
like atrial flutter and supraventricular tachycardia, parenteral administration of digoxin with flecanide or sotolol brings back
to sinus rhythm.
Parvo virus B19: Fetal death is more in expectant management than in cases managed by intrauterine transfusion. Hydrops
is expected to resolve by 4 weeks. No vaccine is available to prevent infection. Intravenous immunoglobulin is
recommended for chronic infection only in immunodeficient individuals. Hence, timely diagnosis results in good outcome.
If fetal hyperthyroidism is diagnosed, treatment involves modulation of maternal antithyroid drugs. If fetal hypothyroidism
has resulted from administration of antithyroid drugs to the mother, this treatment intra-amniotic thyroxine is considered.
Early delivery may need to be considered in the case of fetal thyroid dysfunction, depending on the gestation at diagnosis
and the severity of fetal symptoms.
Prognosis for α-thalassemia is poor as most cases succumb to death due to severe fetal hypoxia either in third trimester or
in early hours after birth. Intrauterine transfusions are done in few cases but many had neonatal complications. Hence, it is
advisable for prenatal diagnosis and pre-pregnancy counseling for the couple with hemoglobin electrophoresis.
Prognosis for inborn errors of metabolism is poor leading to recurrent hydrops with recurrence in subsequent pregnancy
being 25% (Jones 1995; Huang HR 2007; Ismail 2001; Santo 2011).
A retrospective study by Santo et al published in prenatal diagnosis, a unique paper comparing prenatal diagnosis with
postnatal diagnosis and follow up has concluded that diagnosis is possible in 56%, survival in 48%, with risk of
neurodevelopmental delay in 11%. (Santo et al 2011)
3|P ag e
29. Med. Sci.
Table 1: Hereditary disorders, enzyme deficiency and Gene
Disorder
Enzyme deficiency
Homozygous α thalassemia
Absent α globin chain
Spectrin deficiency
Mucopolysaccharidoses type VII
β glucouronidase
Single gene mutation
Chro16 cis arm
point mutation of the p-spectrin
gene, S2019P
Chromosome 7 band q 11
Checklist at ultrasound for diagnosis of fetal hydrops
 Involvement of pleural, pericardial, fetal ascites and nuchal edema
 Heart rate, rhythm and structural abnormalities by fetal echocardiography
 Peak systolic velocity of middle cerebral artery by Doppler
 Placental thickness, which usually corresponds to the period of gestation and never more than 4 cm
 Facial dysmorphology which may give clue to inborn errors of metabolism
Evaluation algorithm
Fluid in any two body cavities at ultrasound: Hydrops
look for the following:
Obvious obstructive anomaly
Ex: Thoracic mass
High vascular anomaly
Ex: sacrococcygeal teratoma
Vein of Galen malformation
fetal anemia
Parvovirus B19 IgM
Positive for IgM
Consider cordocentesis
Ready IUT and DNA PCR Hydrops resolves by 4 weeks
cardiac arrhythmias
Tachyarrhythmias
treat by Digoxin
Negative, then consider
family history of consanguinity
offspring of hydropic fetus/ stillbirth
consider amniocentesis to rule out
Inborn errors of metabolism
Key messages:
 Hydrops fetalis is defined as accumulation of extracellular fluid in at least two fetal body cavities (pleural,
pericardial, scalp and body wall edema and ascites)
 There are two main causes: immune hydrops (Rh incompatilibity) & non-immune fetal hydrops (NIHF)
 Isolated ascites, pericardial effusion and pleural effusion have specific etiologies and hence are not fetal Hydrops
 When first described, NIHF constituted only 20% of all cases, but after effective anti D prophylaxis for immune
hydrops, NIHF constitutes 90% cases of fetal hydrops
 Structural and rhythm cardiac abnormalities are the most common cause followed by chromosomal abnormalities;
supraventricular tachycardia is one of the common and treatable causes.
 Inherited metabolic disorders and parvo virus B 19 infection are other important causes.
 Parvo virus B 19 infection causes hydrops by causing destruction of fetal RBCs. Fetal anemia is considered if PSV
is more than 1.5 MoMs for that period of gestation.
 Twin to twin transfusion syndrome is one of the causes leading to hydrops of stage IV disease according to
Quintero staging system
 Ultrasound is the basic investigation considered for diagnosis, but further invasive procedures are considered after
provisional diagnosis
 Maternal serum sample for metabolic screening should be considered in cases of normal karyotype,
consanguineous marriage, history of stillbirth and recurrent hydrops
4|P ag e
30 Kodandapani et al.
Fig1: 2D ultrasound picture with fetus at abdominal level showing ascites and small bowel floating in the abdomen
Fig2: 2D ultrasound picture at thoracic level of the fetus showing bilateral pleural effusion and lungs
References:
1. Apkon M (1995). Pathophysiology of hydrops fetalis. Semin Perinatol. 19: 437-446
2. David HK, John SW (1998). Hydrops Fetalis Caused by α-Thalassemia: An Emerging Health Care Problem. J of
Am of Hem. 91:2213-2219
3. Gallagher GP, Weed SA, Tse WT, Benolt L(1995). Recurrent Hydrops Fetalis associated with a Nucleotide
Substitution in the Erythrocyte, 8-Spectrin Gene. J. Clin. Invest. 95:1174-1182
4. Graves GR, Baskett TF (1984). Nonimmune hydrops fetalis: antenatal diagnosis and
management. Am J Obstet
Gynecol. 148: 563–565
5. Huang HR, Tsay PK, Chiang MC (2007). Prognostic factors and clinical features in liveborn neonates with hydrops
fetalis. Am J Perinatol 24: 33–38
5|P ag e
31. Med. Sci.
6. Ismail KMK, Martin WL, Ghosh S (2001). Etiology and outcome of hydrops fetalis. J Matern Fetal Med 10: 175–
181.
7. Jauniaux E(1997). Diagnosis and Management of early non immune hydrops fetalis. Prenatal Diagn.13: 1261–1268
8. Jones DC (1995). Nonimmune fetal hydrops: diagnosis and obstetrical management. Semin Perinatol. 447–461.
9. Marx H, AminP, Lazarus JH(2008). Hyperthyroidism and pregnancy. BMJ. 336:663-7
10. Moise KJ (2008). Ultrasound Evaluation of Hydrops Fetalis. In Ultrasonography in Obstetrics and Gynecology.
5th ed (Callen). Phildelphia. 676-697.
11. Potter EL (1943). Universal edema of fetus unassociated with erythroblastosis. Am J Obstet Gynecol . 154:85-90.
12. Santo S, Mansour S, Thilaganathan B, Homray T, Papageorghiou (2011). Prenatal diagnosis of non-immune
hydrops fetalis: what do we tell the parents? Prenat Diagn 31: 186–195.
13. Ulrich S, Gruslin A. Fetal Hydrops and Ascites (2003). In Diagnostic Imaging of Fetal Anomalies. Ed by Nyberg.
Phildelphia. 713-743.
14. Xu J, Raff TC, Muallem NS, Neubert GA (2003). Hydrops Fetalis secondary to Parvovirus B19 Infections. J Am
Board Fam Pract. 16:63– 68
6|P ag e