RESEARCH ARTICLE
Etiology of Non-Immune Hydrops Fetalis:
An Update
Carlo Bellini,1* Gloria Donarini,2 Dario Paladini,2 Maria Grazia Calevo,3 Tommaso Bellini,1
Luca A Ramenghi,1 and Raoul C Hennekam4
1
Neonatal Intensive Care Unit, Department of Intensive Care, Gaslini Institute, Genoa, Italy
2
Fetal Medicine and Surgery Unit, Gaslini Institute, Genoa, Italy
3
Department of Epidemiology, Biostatistics and Committees, Gaslini Institute, Genoa, Italy
4
Department of Pediatrics, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands
Manuscript Received: 5 May 2014; Manuscript Accepted: 28 December 2014
Hydrops fetalis is an excessive fluid accumulation within the fetal
extra vascular compartments and body cavities. Non-immune
hydrops fetalis (NIHF), due to causes other than Rh alloimmu-
nization, is the cause in >85% of all affected individuals. Herein
we present an update of our earlier systematic literature review
[Bellini et al., 2009] using all publications between 2007 and
2013. We excluded most of the initial 31,783 papers by using
strict selection criteria, thus resulting in 24 relevant NIHF
publications describing 1,338 individuals with NIHF. We sub-
divided the affected individuals into 14 classification groups
based on the cause of NIHF (percentage of the total group):
Cardiovascular (20.1%), Hematologic (9.3%), Chromosomal
(9.0%), Syndromic (5.5%), Lymphatic Dysplasia (15.0%), In-
born Errors of Metabolism (1.3%), Infections (7.0%), Thoracic
(2.3%), Urinary Tract Malformations (0.9%), Extra Thoracic
Tumors (0.7%), TTTF-Placental (4.1%), Gastrointestinal
(1.3%), Miscellaneous (3.6%), Idiopathic (19.8%). We discuss
the results of the review. There may be some shifts in the
percentages of etiological categories as compared to the previous
review, but the small numbers within each category make
drawing firm conclusions hazardous. We highlight the need
for multi-center series of NIHF cases collected and classified
using the same schemes in diagnostic work-ups to allow for
comparisons of larger numbers of cases. Ó 2015 Wiley Periodicals, Inc.
Key words: hydrops fetalis; nonimmune hydrops fetalis;
classification; etiology; pathophysiology; systematic review
INTRODUCTION
The term Hydrops Fetalis (HF) refers to an excessive fluid accu-
mulation within the fetal extra vascular compartments and body
cavities; it is characterized by generalized skin thickness of >5 mm,
placental enlargement, pericardial, or pleural effusion, or ascites. In
2009, we published a systematic review to establish the etiology of
Non-Immune Hydrops Fetalis (NIHF), based on the literature up
to December 2007 [Bellini et al., 2009a]. Since then, a considerable
Ó 2015 Wiley Periodicals, Inc.
How to Cite this Article:
Bellini C, Donarini G, Paladini D, Calevo
MG, Bellini T, Ramenghi LA, Hennekam
RC. 2015. Etiology of non-immune
hydrops fetalis: An update.
Am J Med Genet Part A 167A:1082–1088.
number of additional papers on etiological findings in NIHF have
been published, suggesting the need for updating our review, that is
provided herein. Here we provide an update of our review by
systematic analysis of the additional literature since January 2007.
METHODS
The systematic review was carried out on the basis of the PRISMA
recommendations [Preferred Reporting Items for Systematic
Reviews and Meta-Analyses] [http://www.prisma-statement.org]
using a PRISMA flow chart and PRISMA checklist [Moher et al.,
2009].
Papers on all forms of hydrops were identified in the Pub Med
database using “Hydrops” as the MeSH term heading. All literature
published between January 1st, 2007 and December 31st, 2013 was
included. Our previous systematic review already included the
papers published in the year 2007, but since papers may become
available only several months after the official publication date, we
re-started the survey as of January 1st, 2007 but carefully avoided
Conflict of interest: None.


Correspondence to:
Dr. Carlo Bellini, MD, PhD, Neonatal Intensive Care Unit, Department
of Intensive Care, University of Genoa, Gaslini Institute, Largo G. Gaslini
5, Genoa 16147, Italy.
E-mail: carlobellini@ospedale-gaslini.ge.it
Article first published online in Wiley Online Library
(wileyonlinelibrary.com): 25 February 2015
DOI 10.1002/ajmg.a.36988
1082
BELLINI ET AL.
scoring publications twice. The same methodology was followed as
in the earlier review [Bellini et al., 2009a]. In short, the study
included papers only: (i) If they described Non-Immune Hydrops
Fetalis patients; (ii) If the paper dealt with a significant number of
affected individuals (10 or more); (iii) If the study group was an
unselected (unbiased) series of affected individuals; (iv) If they had
been published in a peer-reviewed medical journal; (v) If at least the
abstract had been published in either English, Spanish, Italian,
French, German, or Portuguese; (vi) If one of the goals of the paper
was to detect the causes of NIHF; (vii) If affected individuals had
been examined by at least one of the authors personally; (viii) If the
number and nature of the detected abnormalities were reported and
described in detail. All the references of all the papers thus retrieved
were also hand-searched for additional papers that had not been
found through the PubMed search.
Two reviewers (CB; GD) independently screened all titles and
abstracts from the manuscripts thus retrieved. If uncertainty
remained regarding the usefulness of a paper for the goal of the
study, the paper itself was evaluated. Studies were eliminated when
both reviewers agreed that the report did not meet the inclusion
criteria. Any unresolved issues were discussed with the other
authors, and final approval was given by all.
Data were categorized on the basis of the same 14 etiologic
classification categories used in the/our- choose previous article/
review- choose, using the same definitions: Cardiovascular, Hema-
tologic, Chromosomal, Syndromic, Lymphatic Dysplasia, Inborn
Errors of Metabolism, Infections, Thoracic, Urinary Tract Malfor-
mations, Extra Thoracic Tumors, TTTF-Placental, Gastrointesti-
nal, Miscellaneous, Idiopathic [Bellini et al., 2009a].
Results are provided both as absolute numbers and relative
frequencies. Parameters between groups were compared using
x2 or Fisher’s exact test for the various variables in a diagnostic
category. A P-value less than 0.05 was considered statistically
significant, and all P-values were based on two tailed tests. Statistical
analysis was performed using SPSS for Windows (SPSS, Inc.,
Chicago, IL).
RESULTS
The PRISMA flow chart of the consecutive methodological steps of
the present systematic review (Fig. 1) summarizes the number of
papers that were accepted and rejected during the various steps of
the selection procedure. We initially retrieved 31,783 papers on
hydrops fetalis. We evaluated 663 of these papers in detail, and
excluded 639 of them, accounting for 1,536 patients from 636
biased and small series and single case reports, and 3 papers (188
patients) which overlapped with the 2009 review [Bellini et al.,
2009a](Fig. 1). At the end of the review process, we ended up with 24
papers describing 1,338 individuals . The references of the papers
that were excluded from analysis are available from the authors
upon request. The etiological NIHF classification of these 24 papers
is provided in Table I. In Table II the overall results of the 2009
review (1979–2007) and present review (2008–2013) are compared,
providing the percentage of each etiological classification of the
total causes. The most frequent causes within each category of NIHF
causes are provided in Table III.
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DISCUSSION
Here we provide the results of a systematic review of the literature
on NIHF published in the 2008–2013 period (Table I) and compare
these to the previous review — performed with the same method-
ology — of the literature published in the 1979–2007 period [Bellini
et al., 2009a] (Table II), using the same diagnostic categories. We
performed statistical analyses to detect differences in the results of
the two reviews and indeed found the P-value to show significant
differences for some etiological categories, but confidence intervals
are very wide for each category and all differences still fall within this
interval (Table II). For several categories no differences were found,
such as for Syndromes, Inborn errors of metabolism, Infections,
Extra thoracic tumors, TTTF-placental, Gastrointestinal and Uri-
nary Tract Malformations, and Miscellaneous. The Chromosomal
category shows the limitation we already mentioned in the earlier
review: it is frequently difficult or impossible to correctly classify
patients with a chromosome imbalance, since they can be classified
either in the Chromosomal category or in the (presumed) patho-
genetic mechanism leading to the Hydrops, such as the Cardiovas-
cular category: a fetus with trisomy 21 or trisomy 18 who also has a
major cardiac malformation can be assigned to the Chromosomal
category but also to the Cardiovascular category since the heart
malformation is likely the cause of the hydrops. In general, an
increase in categorization-based pathogenesis may lead to a de-
crease in the percentage of patients assigned to the Chromosomal
category. Indeed, this was found in the present review (Table II).
This may indicate that in the last few years authors have paid more
attention to pathophysiological mechanisms when assigning etiol-
ogies to cases of NIHF. This is also evident in the percentage of cases
assigned to the Lymphatic dysplasia category which showed a
remarkable increase in the present review compared to the previous
review. The recent literature describing the relationship between
NIHF and congenital lymphatic dysplasia may well have led to
increased awareness of the role of lymphatic system disorders in
NIHF [Rodrı́guez et al., 2002 Bellini et al., 2006a, 2006b; Randen-
berg 2010a, 2010b; Bellini and Hennekam, 2012; Désilets and
Audibert, 2013]. Indeed, assigning patients with, for instance,
Turner syndrome to the Lymphatic dysplasia category may have
led to a further decrease in the Chromosomal category. A further
example of the influence on assignment to a particular category may
be prune belly anomaly. Typically this is a sequence in which the
abdominal wall abnormalities are caused by an obstruction of the
urinary tract, which may lead to ascites and subsequently HF. No
doubt others will put this into the Syndromic category. In fact this is
not a real problem as long as the definition of the various categories
and the categorization is done with sufficient detail.
It was disappointing to find that the percentage of cases in the
Idiopathic category had not decreased, and in fact, to some extent,
even increased (Table II). Our previous review [Bellini et al., 2009a]
pointed out the need for careful and detailed diagnostic work-up of
NIHF cases using the various pathophysiological pathways which
could lead to a decrease in cases assigned to the Idiopathic category.
We and others have subsequently described the various pathophys-
iological mechanisms leading to NIHF [Bellini et al., 2006a; Ran-
denberg 2010a, 2010b; Bellini and Hennekam, 2012]. It may be
however, that using pathophysiological mechanisms in describing
1084
Figure 1. PRISMA flow diagram indicating the ratio of inclusion and exclusion of papers, and the numbers. All steps were performed
independently by two reviewers.
causes of HF has only recently been introduced in practice, and the
results described in publications in the 2008–2013 period still reflect
the earlier ways of categorizing the causes of HF.
The present re-evaluation of publications on NIHF also shows
shifts in issues that have been given particular attention. For
example, in the last few years increased interest for inborn errors
of metabolism and NIHF was demonstrated in a large number of
case reports and some larger series [Gort et al., 2012; Whybra et al.,
2012]. Still, the percentage of cases in the total group of NIHF with a
final diagnosis of Inborn error of metabolism remains practically
unchanged (Table II). We noticed that in publications dedicated to
specific causes of NIHF the information on the general methodol-
ogy that was followed to detect the etiology of the NIHF was very
limited, thus significantly hampering the meaning of the findings
pointing towards a specific cause. Only retrospective studies on
large (>10) series of patients (Table I) were used in our review.
AMERICAN JOURNAL OF MEDICAL GENETICS PART A
These data are usually obtained from study populations from a
single center. This causes the number of really large series actually to
be very small. The total number of patients reported in both our
reviews is 6,775 (Table II), and the median number of patients per
publication is 90 (1.26%). This number is in fact too low to allow for
meaningful conclusions.
Next to the tabulation of the various categories we have listed the
most frequent disorders per category as well (Table III), and the
major literature sources for each category. This can be useful in case
either the amount of blood for an affected fetus or newborn is
limited, or the means to study an affected subject is limited and only
the main disorders should be checked for. Clinical practice guide-
lines dealing to educate readers about the causes of NIHF in the aim
to tentatively standardize the approach to NIHF are available in
literature [Bellini et al., 2009b; Désilets and Audibert, 2013]. An
short overview of procedures that are indicated in either fetuses or
TABLE I. Overview of the Etiological Classification of 24 Papers Describing 1,338 Individuals With Non- Immune Hydrops Fetalis Retrieved in the Present Systematic Review

Inborn Extra
Number Lymphatic storage Urinary tract thoracic TTTF-
References of cases Cardiovascular Hematologic Chromosomal Syndromic dysplasia diseases Infections Thoracic malformations tumors placental Gastrointestinal Miscellaneous Idiopathic
BELLINI ET AL.

[Teixeria et al., 19 5 5 1 1 2 2 1 2
2008]
[Bellini et al., 2009] 79 9 6 10 2 18 11 7 8 1 7
[Borna et al., 2009] 19 3 1 2 2 11
[Ghalamkarpour 12 3 9
et al., 2009]
[Simms et al., 8 8
2009]
[Czernik et al., 215 44 18 19 38 9 23 20 44
2010]
[Taweevisit et al., 78 16 20 2 5 1 5 4 10 3 12
2010]
[Tongsong et al., 69 50 19
2010]
[Bautall et al., 25 7 5 2 4 3 1 1 2
2011]
[Al-Buhtori et al., 13 3 3 7
2011]
[Fukushima et al., 214 40 4 27 59 9 3 14 11 47
2011]
[Pejić et al., 2011] 11 1 2 1 4 3
[Ruano et al., 2011] 48 3 18 17 2 8
[Santo et al., 2011] 71 7 5 2 4 13 4 13 3 3 1 3 13
[Wyatt et al., 2011] 40 15 13 9 1 2
[Yang et al., 2011] 27 16 8 3
[Fritsch et al., 116 14 1 26 5 15 2 14 8 1 4 1 25
2012]
[Gort et al., 2012] 30 2 28
[Takci et al., 2013] 34 4 3 1 8 3 1 1 3 10
[Moreno et al., 53 4 15 10 3 3 4 3 1 2 1 7
2013]
[Ng et al., 2013] 29 5 2 1 1 4 1 4 2 9
[Hasnani-Samnani 55 15 2 9 2 27
et al., 2013]
[Croonen et al., 19 15 4
2013]
[Taweevisit et al., 54 10 29 3 3 3 6
2013]
Total 1338 269 124 120 74 201 18 93 31 12 10 55 18 48 265
Percentage 20.1 9.3 9.0 5.5 15.0 1.3 7.0 2.3 0.9 0.7 4.1 1.3 3.6 19.8
1085
1086 AMERICAN JOURNAL OF MEDICAL GENETICS PART A

TABLE II. Comparison of Results of the Earlier Systematic Review (1979–2007) and Present Review (2008–2013)

1979–2007 (A) 2008–2013 (B) 1979–2013

Number Number (CI ; CIþ); Number

Categories of cases Percentage of cases Percentage P-value (A vs. B) of cases Percentage
Cardiovascular 1181 21.7 269 20.1 (15.3–24.9); P ¼ 0.20 1450 21.4
Hematologic 564 10.4 124 9.3 (4.2–14.4); P ¼ 0.25 688 10.1
Chromosomal 727 13.4 120 9.0 (3.9–14.1); P ¼ 0.0001 847 12.5
Syndromic 237 4.4 74 5.5 (0.3–10.7); P ¼ 0.07 311 4.6
Lymphatic dysplasia 310 5.7 201 15.0 (10.1–19.9); P ¼ 0.0001 511 7.5
Inborn Errors of Metabolism 60 1.1 18 1.3 (0–6.5); P ¼ 0,55 78 1.1
Infections 366 6.7 93 7.0 (1.8–12.2); P ¼ 0.82 459 6.8
Thoracic 327 6.0 31 2.3 (0–7.6); P ¼ 0.0001 358 5.3
Urinary tract malformations 127 2.3 12 0.9 (0–6.2); P ¼ 0.001 139 2.0
Extra thoracic tumors 39 0.7 10 0.7 (0–5.9); P ¼ 0.95 49 0.7
TTTF-placental 304 5.6 55 4.1 (0–9.3); P ¼ 0.04 359 5.3
Gastrointestinal 29 0.5 18 1.3 (0–6.5); P ¼ 0.002 47 0.7
Miscellaneous 200 3.7 48 3.6 (0–8.9); P ¼ 0.94 248 3.7
Idiopathic 966 17.8 265 19.8 (15–24,6); P ¼ 0.09 1231 18.2
Total 5437 1338 6775

infants with NIHF is provided in Figure 2. Details regarding the
various studies can be found in our earlier published diagnostic
flow-chart [Bellini et al., 2009b].
We realize that in the near future whole exome or genome
sequencing will be within reach for an increasing number of
colleagues studying fetuses or newborns with HF, which will allow
studying more causes using samples of less size. Especially a targeted
approach using whole exome sequencing for all genes known to
have caused HF in humans in the past, should allow a significant
increase in diagnostic yield. Indeed one of us (RCH) has initiated a
targeted whole exome sequencing of a set of genes (80) that, if
mutated, can lead to hydrops. However, this has just started, and
there are no results available of a large series at present. Also in
literature such series is not available at present.
We conclude therefore, like in 2009 [Bellini et al., 2009a], that
single center studies are unlikely to yield a sufficiently large number

TABLE III. Most Frequently Reported Disorders Leading to NIHF Within Etiological Categories

Etiological classification Most frequently reported entities Main References (and refs cited therein)
Cardiovascular Structural malformations (especially hypoplastic left Machin, 1989; Anandakumar et al., 1996
heart, endocardial cushion defect) Arrhythmias
Chromosomal 45,X0; trisomy 21, trisomy 18 Machin, 1989; Jauniaux et al., 1990; Iskaros
et al., 1997
Hematologic Alpha-thalassemia (pm geography!), fetomaternal- Mari et al., 2003; Borna et al., 2009; Désilets
transfusion et al., 2013
Lymphatic dysplasia Congenital lymphatic dysplasia Bellini et al., 2009
Infections Parvo-B19, CMV, Adeno-/ Enterovirus Barron and Pass, 1995; Essary et al., 1998;
von Kaisenberg and Jonat, 2001; Xu et al.,
2003; de Jong et al., 2006
TTTF-placental Both donor and recipient fetus Quintero, 2003; van Gemert et al., 2001
Thoracic CCAM, diaphragmatic hernia, extrapulmonary Crombleholme et al., 2002
sequestration, hydro-/ chylo-thorax
Syndromic Noonan syndrome Désilets et al., 2013
Urinary Tract Malformations Urethral obstruction, prune belly syndrome, Mandakini et al., 2006
Inborn Storage Diseases Lysosomal storage disease Whybra et al., 2012; Désilets et al., 2013
Extra Thoracic Tumors Vascular tumors, teratoma, leukemia, hepatic tumors, Isaacs, 2007; Funk et al., 2014
neuroblastoma
Gastrointestinal Meconium peritonitis, gastrointestinal obstructions Machin, 1989; Bischoff et al., 2010
BELLINI ET AL.
Figure 2. Suggested flow-chart for prenatal and postnatal diagnosis of NIHF [slightly modified from Bellin et al., 2009b and Désilets and
Audibert, 2013].
of NIHF cases that warrant being published separately, and call
upon colleagues to decide on carefully drawn NIHF pathophysio-
logical flow-charts and diagnostic work-up schemes, share results,
and collate these into descriptions of larger series of NIHF cases.
Calls from larger institutions such as NIH in the US and EU in
Europe which allow submissions dedicated to HF research are
missing and would be a significant stimulus in this. Registries exist
now in both US and Europe for specific Mendelian disorders but are
hardly available if dedicated to a specific sign, while a registry for HF
would be a major step forwards. The above steps will be the only way
we will be able to obtain sufficient data to offer adequate support to
that families with a child with NIHF.
1087
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