MILITARY MEDICINE, 171, 10:995, 2006
Recurrent Idiopathic Nonimmune Hydrops Fetalis: A Case Report
Guarantor: Col Ali Rustu Ergur, Turkish Armed Forces
Contributors: Col Ali Rustu Ergur, Turkish Armed Forces; Maj Levent Tutuncu, Turkish Armed Forces;
Maj Murat Muhcu, Turkish Armed Forces; Col Yusuf Z. Yergok, Turkish Armed Forces
A recurrent idiopathic nonimmune hydrops fetalis case in two
subsequent pregnancies was observed in a woman with no
child. In both pregnancies, all the detailed analysis, including
a high level of ultrasonography, amniocentesis, serologic eval-
uation, routine blood work, hemoglobin electrophoresis, and
glucose 6-phosphate/dehydrogenase level and postdelivery au-
topsy, was done, and after no clue of etiologic agent, preg-
nancy termination was applied for both. This case report illus-
trates the importance of recurrence of nonimmune hydrops
fetalis in the absence of any etiology. Mostly, it is hard to
establish an etiologic diagnosis for adequate management of
subsequent pregnancies.
Introduction
N onimmune hydrops fetalis (NIHF) is a condition of hydropic
fetus due to causes other than Rh isoimmunization includ-
ing mainly cardiovascular, hematologic, neoplastic, chromo-
somal, hereditary, or infectious disorders.1,2 Mostly, it is hard to
ascertain the underlying reason in fetuses with NIHF, and in
those with specific etiologies, treatment options are very lim-
ited. The frequency of hydrops is approximately 1:2000 to
1:3000 with 85 to 90% contribution of nonimmune causes;
prognosis is poor even in fetuses with a detected underlying
reason.3 The contribution of nonimmune hydrops to the total
perinatal mortality rate has increased from 0.1% to 3% in the
last decade.4
The etiology of some NIHF cases remains unclear even after
thorough investigation.5 The incidence of “idiopathic cases” of
NIHF has not changed in the last decade and is approximately
20%.6,7 On the other hand, the recurrence of idiopathic NIHF
cases is very seldom and is sometimes attributed to genetic
factors.6 To date, eight case reports5,8 –14 for recurrent NIHF
have been reported and only two of them had no etiologic
factor.8,9
In this case report, we present a patient with two losses due to
idiopathic NIHF in a very short time interval. Also, we wanted to
evaluate the realities behind idiopathic NIHF, whether they are
real idiopathic cases or whether they have etiologies that we
cannot find.
Case Report
A 23-year-old woman (T.Y.), gravida one, para zero, was
referred to our department due to the detection of fetal hy-
dropic condition by another obstetrician. We performed a
detailed ultrasound examination and detected a fetus with
Department of Obstetrics and Gynecology, Gulhane Military Medical Academy,
Haydarpasa Training Hospital, Istanbul 34668, Turkey.
This manuscript was received for review in May 2005. The revised manuscript was
accepted for publication in January 2006.
Reprint & Copyright © by Association of Military Surgeons of U.S., 2006.
995
severe generalized edema, ascites, hydrothorax, and hydropic
skull (Fig. 1). The biometric evaluation of the affected fetus
was in concordance with its age of gestation as 18 weeks of
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pregnancy. The detailed evaluation did not give us any clue of
congenital malformations except an echogenic intracardiac
focus with 9.3 mm of nuchal translucency. The placental
thickness and the amount of amniotic fluid were normal. The
maternal blood group was O Rh positive and the indirect
Coombs was negative. The serologic evaluation of the preg-
nant woman for toxoplasmosis, rubella, cytomegalovirus,
herpes simplex, syphilis, and parvovirus B-19 showed us no
infectious serum titers. All other routine analysis, including
hemoglobin electrophoresis and glucose 6-phosphatase level,
was in normal limits with a hemoglobin concentration of 11.2
g/dL and 34% of hematocrit. Thereafter, the fetal karyotype
was evaluated to detect the chromosomal causes of the hy-
drops according to the data that chromosomal abnormalities
account for two-thirds of hydrops etiologies, and the result
was normal karyotype, 46 XY. The parents were asked about
genetic disorders, especially the clues of metabolic ones in
their family, and no special condition to explain the fetal
hydrops was found. Therefore, no analysis was performed
related to specific autosomal recessive genes. The pregnancy
was terminated with oral and vaginal misoprostol application
1 week later; after delivery, macroscopic evaluation of the
fetus revealed no external pathology except generalized hy-
dropic condition. The fetal hematologic evaluation, including
whole blood analysis and hemoglobin electrophoresis, was in
the normal limits. Also, the autopsy of the fetus confirmed our
findings with no sign of congenital pathology that might be
the cause of hydrops but skin and placental edema, ascites,
and pleural and pericardial effusions. The bulky placenta was
pale and friable. The umbilical cord was also edematous. The
microscopic examination revealed edematous changes mostly
affecting the central parts of the villi and Hafbauer cells were
striking in some areas. Neither neoplastic cellular infiltration
nor abnormal vascular organization was present. Accumula-
tion of metabolites within trophoblastic cells, resulting in
cytoplasmic changes and/or thickening of the trophoblastic
layer suggesting any of the known genetic metabolic disor-
ders, was not seen.
Ten months from the termination of the first pregnancy, the
patient became pregnant again and had the same hydropic
fetal signs of a new complicated 20 weeks of pregnancy. One
more time, all of the detailed analysis, including high level of
ultrasonography, karyotyping, serologic evaluation, and post-
delivery autopsy, was done. This time, the fetus was a chro-
mosomally normal female, 46 XX, and all completed analysis
for the etiology again did not give us any clue about the
hydrops occurrence. The fetus was delivered by oral and vag-
inal misoprostol and presented no pathologic finding. We
Military Medicine, Vol. 171, October 2006
996
Fig. 1. Transverse ultrasonographic view of the hydropic fetal skull.
could not find any possible explanation for nonimmune hy-
drops fetalis conditions in both pregnancies, although com-
plete detailed analyses for etiology detection were performed.
Discussion
Most NIHF cases represent themselves without any known
etiology.5–7 A previous history of a fetus with NIHF warrants
specific attention, although the majority of subsequent preg-
nancies are not affected by NIHF.15,16 In the literature to date,
only two recurrent idiopathic NIHF have been reported (by
Cumming8 and Zimmer9). As the third one, our patient having
two subsequent pregnancies with fetuses affected by NIHF led
us to search for a reason, but we could not find the etiologic
agent.
The mechanisms for causing NIHF are the conditions re-
sulting in blocked or decreased lymphatic drainage, ob-
structed venous return, system defects causing anemia, car-
diac failure, abnormal vascularization causing high output
cardiac failure, infections including parvovirus B-19, de-
creased fetal oncotic pressure, and genetic abnormalities.17
Genetic abnormalities, cardiac malformations, and infections
are the three etiologic factors most often seen in NIHF pa-
tients with known etiology. The conditions known to cause
NIHF represent approximately 80% of the cases; the rest of
them are called idiopathic.6,7 The disease might recur in pa-
tients with known etiology, and diagnostic tools help to dif-
ferentiate the affected fetuses. However, it is still hard to find
the reason for recurrent NIHF in some patients.
Upon diagnosis of hydrops fetalis, a diligent search for an
underlying cause should include a fetal karyotype, hemoglo-
bin concentration, studies for fetal infections (including par-
vovirus B-19, cytomegalovirus, and syphilis), and a thorough
sonographic scan for cardiac or other anomalies.18 In the
study of Iskaros et al.,19 chromosomal abnormalities were the
most prominent etiologic factor with an incidence of 77.8%,
and 4 of 45 cases were classified as idiopathic in the absence
of any reason. On the other hand, we performed all of the
necessary analyses to evaluate the etiology in both pregnan-
cies, but were unable to detect any. Some genetic disorders
Military Medicine, Vol. 171, October 2006
Case Report
like metabolic and lysosomal storage diseases except chromo-
somal abnormalities may also cause NIHF. Genetic diseases
such as glycosylation disorder,13 carbohydrate-deficient
glycoprotein syndrome,10 !-glucuronidase deficiency,14 and
sialic acid storage disease11 may be reasons for recurrent
NIHF. The diagnosis of these genetic disorders is mainly done
using data obtained from the affected family members. It is
impossible to screen for all of these kinds of genetic diseases
in the affected fetuses; in the absence of signs of diseases in
the parents, we did not have any chance to screen for these
kinds of nonchromosomal genetic disorders. Of course, it is
possible to suspect that the reason may be genetic instead of
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idiopathic in our case report.
The presence of NIHF early in gestation is a very poor
prognostic indicator.17 The diagnosis of NIHF carries a 50% to
98% fetal mortality rate.15–16 If the case is the recurrence of
NIHF, then the mortality rate sharply increases. It is logical to
end the pregnancy in those cases with recurrent idiopathic
NIHF. With new developments in fetal therapy, different
causes of NIHF may be amenable to intrauterine treatment if
the diagnosis is done in the latter period of pregnancy.19
However, there is little information available on the manage-
ment of NIHF diagnosed in early pregnancy.19 In our patient,
hydropic fetuses were diagnosed before 20 weeks of preg-
nancy, and in accordance with literature statistics, we de-
cided to terminate both pregnancies.
This case report illustrates the importance of recurrence of
NIHF in the absence of etiologic agents. Re-evaluating family
members, especially for nonchromosomal genetic diseases,
and giving the family information about the chance of recur-
rence are even more important. Most importantly, it is hard to
establish an etiologic diagnosis for adequate management of
subsequent pregnancies.
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Military Medicine, Vol. 171, October 2006