etiology of nonimmune

7/27/2019 Etiology of Nonimmune

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RESEARCH ARTICLE

Etiology of Nonimmune Hydrops Fetalis:A Systematic Review

Carlo Bellini,1

* Raoul C.M. Hennekam,2,3

Ezio Fulcheri,4

Mariangela Rutigliani,4

Guido Morcaldi,5

Francesco Boccardo,5 and Eugenio Bonioli5

1Neonatal Intensive Care Unit, Department of Pediatrics, Gaslini Institute, University of Genoa, Genova, Italy2Institute of Child Health, Great Ormond Street Hospital for Children, University College London, London, UK3Department of Pediatrics, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands4

Department of Pathology and Surgery, S. Martino Hospital, University of Genoa, Genova, Italy5

Department of Pediatrics, Gaslini Institute, University of Genoa, Genova, Italy

Received 16 July 2008; Accepted 13 October 2008

Hydrops fetalis (HF) indicates excessive fluid accumulation

within the fetal extravascular compartments and body cavities.

HF is not a diagnosis in itself but a symptom, and the end-stage

of a wide variety of disorders. In the era before routine immuni-

zation of Rhesus (Rh) negative mothers, most cases of hydrops

were due to erythroblastosis from Rh alloimmunization, but

nowadays, nonimmune hydropsfetalis (NIHF) is more frequent,

representing 7687% of all described HF cases. We performed a

systematic reviewof thepertinent literaturebasedon theQUality

Of Reporting Of Meta-analyses (QUOROM) recommendations,

using a QUOROM flowchart and QUOROM checklist. At initial

screening 33,345 articles were retrieved. The various inclusion

and exclusion criteria aimed at obtaining data that were as

unbiased yet as complete as possible decreased the numbersdramatically, and eventually a total of 225 relevant NIHF articles

were identified, describing 6,361 individuals. We established 14

different diagnostic categories and provide the pathophysiologic

background of each, if known. All 6,361 patients were subclassi-

fied into one of the following diagnostic categories: Cardio-

vascular (21.7%), hematologic (10.4%), chromosomal (13.4%),

syndromic (4.4%), lymphatic dysplasia (5.7%), inborn errors of

metabolism (1.1%), infections (6.7%), thoracic (6.0%), urinary

tract malformations (2.3%), extra thoracic tumors (0.7%),

TTTF-placental (5.6%), gastrointestinal (0.5%), miscellaneous

3.7%), and idiopathic (17.8%). 2009 Wiley-Liss, Inc.

Key words: hydrops fetalis; nonimmune hydrops fetalis; classifi-cation; etiology; pathophysiology; systematic review; flowchart

NTRODUCTION

Hydrops fetalis (HF) is an excessive fluid accumulation within thefetal extravascular compartments and body cavities, characterizedby generalized skin thickness of>5 mm, placental enlargement,pericardial or pleural effusion, or ascites.

HF is a nonspecific finding and the end-stage of a wide varietyof disorders. In the past, before routine immunization of Rhesus

(Rh)-negative mothers, most cases of hydrops were due to eryth-roblastosis from Rh alloimmunization. At present, nonimmunehydrops fetalis (NIHF) is more frequent, comprising 7687% ofall

described HF case.NIHF has a multifactorial cause, consisting of fetal, placental,

and maternal disorders. Although diagnosis and management hasimproved in recent years, NIHF is still associated with a highmortality rate [Abrams et al., 2007]. Increased knowledge andunderstanding of the underlying mechanisms may therefore be ofgreat importance.

The most widely used review on the etiology of hydrops datesback to 1989 [Machin, 1989]. Since then, many other articles havebeen published, thoughoften reportingonly on onesingle cause, onsmall series, or on biasedseries of patients,and data were sometimescontradictory.

In this article we provide a systematic review of all availableliteratureonNIHFinordertoobtainalistofthecausesofNIHFthatis as complete and unbiased as possible and that allows us toestimate the relative frequencies of causes. We provide an NIHFpathophysiologic flowchart.

*Correspondence to:

Carlo Bellini, M.D., Ph.D., Neonatal Intensive Care Unit, Pediatrics

Department, University of Genoa, Gaslini Institute, Largo G. Gaslini 5,

16147 Genoa, Italy. E-mail: [email protected]

Published online 30 March 2009 in Wiley InterScience

(www.interscience.wiley.com)

DOI 10.1002/ajmg.a.32655

How to Cite this Article:Bellini C, Hennekam RCM, Fulcheri E,Rutigliani M, Morcaldi G, Boccardo F,Bonioli E. 2009. Etiology of nonimmunehydrops fetalis: A systematic review.

Am J Med Genet Part A 149A:844851.

2009 Wiley-Liss, Inc. 844


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METHODS

Our systematic reviewwas carried outon the basisof the QUalityOf

ReportingOfMeta-analyses(QUOROM)recommendations,using

a QUOROM flowchart and QUOROM checklist [Moher et al.,1999].

Articles on hydrops were identified in the PubMed databaseusing the term hydrops as the MeSH Heading. No date-limitwas

set. The literature searchwas updatedas of December 31,2007. Thestudy only included articles describing NIHF patients. Other

requirementswere: publication in a peer-reviewedmedicaljournal,

publication in either English, Spanish, Italian, French, German, or

Portuguese, the goals of the article had to include detection of

etiology of NIHF, study groups had to consist of 10 or more

individually reported cases, study groups had to be unselected

series of cases, cases had to be examined personally by at least one

of the authors, and the number and nature of detected abnormali-

ties had to be reported and described in detail. All references listed

in all articles thus retrieved were also hand-searched for

additional articles that may not have been found through the

PubMed search.Exclusion criteria were: studies published in other languages,

studies dealing exclusively with immune HF; immune HF cases

were also excluded in articles describing mixed series of both

immune and nonimmune patients, more than one single article

based on the same group of patients (in such cases only the most

recent article was included), and articles describing less than 10

cases; articles on studies in nonhuman subjects.

Two reviewers independently screened all titles and

abstracts (if available) from articles thus retrieved. If uncertainty

remained regarding the value of a article, the article itself was

evaluated. Studies were eliminated when both reviewers agreed

that the report did not meet the inclusion criteria. Any unresolved

issues were discussed withthe other authors, andfinal approval wasgiven by all.

All patients reported in the articles that were entered into the

study were categorized using 14 classification groups: Cardiovas-cular,hematologic, chromosomal, syndromic, lymphatic dysplasia,

inborn errors of metabolism, infections, thoracic, urinary tract

malformations, extra thoracic tumors, TTTF-placental, gastroin-

testinal, miscellaneous, and idiopathic.

The cardiovascular group included structural abnormalities,

cardiac arrhythmias, myocardiopathies (tumors, myopathy, in-

fections, inflammation, and infarction). The hematologic groupincluded causes of excessive erythrocyte loss (hemoglobinopathies,

erythrocyte enzyme disorders, and erythrocyte membrane dis-orders), causes of decreased erythrocyte production (congenital

leukemia and transient myeloproliferative disorders), and red cell

aplasia and dyserythropoiesis. Chromosomal abnormalities con-

stituted the chromosomal group, whereas syndromes, defined asclusters of structural malformations, constituted the syndromic

group, with the exclusion of inborn errors of metabolism that

constituted a group of its own. Patients were included in one of

these three latter groups only if there was an indication of a

karyotype anomaly, or an indication of a biochemical or molecular

diagnosis of inborn error of metabolism involved, or, with regards

to syndromic disorders, only if the patient description was un-

doubtedlyrelatedtoawellknownsyndrome.Ifthecausewasmerely

suspected, the patient was included in the idiopathic group. The

lymphatic dysplasia group included the cases in which congenital

lymphatic disorders were diagnosed at autopsy by specific immu-nohistochemistry techniques, or postnatally by lymphoscintigra-

phy or lymphangio-MR. Positive TORCHES-CLAP evaluation

(Toxoplasmagondii, Rubellavirus; Cytomegalovirus, Herpessimplex

virus,Enterovirus,Syphilis,chickenpox(Varicella zoster) virus, lyme

disease (Borrelia burgdoferi),AIDS, ParvovirusB19) led to inclusion

in the infection group. Thethoracic group wasmade up of disorders

that eventually cause an increase in systemic venous pressure by

impairing of venous return or lymphatic drainage. These include

cystic adenomatoid malformation of the lung, extrapulmonary

sequestration, diaphragmatic hernia, congenital hydro-chylothor-

ax, mediastinal tumors, and disorders that are usually associated

with a very small thorax, as in the case in several skeletal dysplasias.

Any genetic or syndromic disorders associated with deformation of

the thoracic skeleton causing constriction of the thoracic viscera by

skeletal dysplasia were included in this group. The urinary tract

malformations group included congenital kidney malformations,

tumors, and ureter

bladder

urethra disorders; prune-belly syn-dromes were also included in this group. All abdominal masses

resulting in venous compression or liver failure, besides those of

renal origin, were included into the extra thoracic tumors group.

The TTTS-Placental group included the so-called twin-to-twintransfusion syndrome; we also included umbilical vein thrombo-sis, umbilical cord angiomyxoma, true cord knot, chorionic vein

thrombosis, and rarer placental disorders in this group. The

Gastrointestinal group included duodenal atresia, duodenal diver-

ticulum, jejunoileal atresia, volvulus, imperforate a.u., meconium

peritonitis, and other rarer disorders; diaphragmatic hernia was

included in the thoracic group. The miscellaneous group included

only rare and occasionally observed disorders. Furthermore, withregards to all other groups, we distinguished between a proven or

very likely etiology and a suspected etiology. In the latter opinion,

the cases were included in the idiopathic group, as was done in the

one remaining undiagnosed case.

RESULTS

The QUOROM flowchart of the consecutive methodologic steps ofthe systematic review is shown in Figure 1. It summarizes the

number of articles that were accepted and rejected during the

selection procedure. In the initial screening 33,345 articles were

detected, and after the various inclusion and exclusion steps a totalof 225potentially relevant NIHF articles wereidentified,includingatotal of 6,361 individuals. These 225 references were as follows: 56

large series reports accounting for a total of 6,048 patients; 31 small

series reports accounting for 175 patients, and 138 single case

reports. Further screening of these articles allowed us to exclude

174articles describing924 individuals, leaving51 articlesdescribing

5,437 individuals to be included in the systematic review. The

etiologic NIHF classification of these 51 articles is provided inTable I. The references of all included articles are provided in the

Reference list, whereas the reference list of the other, excluded

articles is available from the authors upon request.

BELLINI ET AL. 845


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TABLEI.EtiologicNonimmuneHydropsFetalisClassification

References

Number

ofcases

Cardio-

vascular

Hematologic

Chromo-

somal

Syndromic

Lymphatic

dysplasia

Inborn

storage

diseases

Infections

Thoraci

c

Urinary

tract

malformations

Extra

thoracic

tumors

TTTF-

placental

Ga

stro-

inte

stinal

Miscel-

laneous

Idiopathic

EtchesandLemons[1979]

22

3

3

1

5

1

3

2

1

1

1

1

Schmidetal.[1988]

31

2

1

4

10

6

8

Hansmannetal.[1989]

402

71

39

47

18

89

11

23

9

8

23

64

Machin[1989]

1,3

45

370

163

172

17

19

61

132

53

86

93

179

McFaddenandTaylor[1989]

90

25

11

8

1

4

1

8

3

6

1

6

16

Jauniauxetal.[1990]

819

218

122

104

13

11

12

43

85

22

24

36

11

14

104

RuizVillaespesaetal.[1990]

59

21

3

1

4

4

6

3

1

7

1

8

Gudmundssonetal.[1991]

18

5

3

7

3

Poeschmannetal.[1991]

25

7

2

2

1

4

1

5

3

BoydandKeeling[1992]

72

42

7

11

6

6

Johnsonetal.[1992]

14

5

2

1

2

2

1

1

Larrocheetal.[1992]

38

1

2

5

2

2

3

1

4

1

1

2

14

Santolayaetal.[1992]

67

13

14

3

20

1

16

Weiner[1993]

20

1

1

6

5

2

1

3

1

Thompsonetal.[1993]

10

5

1

1

3

Aspillagaetal.[1994]

33

9

9

10

5

Lanerietal.[1994]

45

5

5

8

1

4

6

16

Jordan[1996]

57

2

18

3

34

McCoyetal.[1995]

82

19

4

13

9

3

11

5

18

Anandakumaretal.[1996]

100

23

23

10

9

2

5

1

3

24

Rejjaletal.[1996]

17

2

1

2

2

1

1

8

Bealeretal.[1997]

27

1

2

24

Iskarosetal.[1997]

45

3

35

1

2

4

Negishietal.[1997]

38

7

8

1

7

2

1

1

2

9

Essaryetal.[1998]

29

6

1

9

3

3

3

4

Yangetal.[1998]

79

15

25

5

3

2

2

4

3

20

Wyetal.[1999]

37

6

1

1

2

3

2

1

21

Lallemandetal.[1999]

94

13

31

4

1

15

3

3

8

7

9

Nakayamaetal.[1999]

51

10

4

6

6

4

5

16

Swainetal.[1999]

40

6

1

3

4

7

1

1

3

14

Wafelmanetal.[1999]

62

14

4

9

9

4

9

13

Haverkampetal.[2000]

101

25

20

11

19

6

5

15

Heinonenetal.[2000]

58

3

25

23

4

3

Has[2001]

30

9

21

Ismailetal.[2001]

55

5

14

6

8

6

3

2

11

Sohanetal.[2001]

74

11

1

23

5

11

13

1

2

7

Liuetal.[2002]

17

7

10

Rodriguezetal.[2002]

55

8

10

17

2

2

10

4

2

Mascarettietal.[2003]

21

5

1

1

1

2

2

1

8

Burinetal.[2004]

33

1

9

2

1

5

3

12

Favreetal.[2004]

79

7

2

13

3

7

13

7

15

12

(Continued)

BELLINI ET AL. 847


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diagnostic techniques that had been used in the various articles. For

example, fetal 3D echocardiography was not widely available until

just recently, allowing recent articles to be more informative than

earlier ones. Similar concepts apply to all of the 14 etiologic

categories we describe. Fortunately, after discussing such items

among the participating authors, it was always possible to unani-

mously determine which category a particular cause should be in.

The direct underlying mechanisms responsible for hydrops are

still under debate [Bukowski and Saade, 2000]. The link between a

(presumed) cause and the mechanism that eventually generates

hydrops is not always clear. The keystone of NIHF is the patho-

physiology of generalized edema. The fetus is particularly at risk of

such interstitial fluid accumulation owing to great capillary per-meability, a highly compliant interstitial compartment, and be-

cause lymphatic return is strongly influenced by central venouspressure [Bellini et al., 2006a]. Indeed, by far the majority of

disorders within the various categories can be connected to these

pathophysiologic mechanisms (Fig. 2).

Cardiovascular disorders causing hydrops include structural

abnormalities and dysfunctioning (cardiac arrhythmias; myocar-

diopathies of any origin) [Knilans, 1995]. The pathway throughwhich structural cardiac anomalies lead to hydrops is high right

atrial pressure or volume overload and right heart congestion,

resulting in increased central venous pressure and heart failure, or

obstruction of venous or arterial blood-flow which eventually leadsto edema. Inadequate diastolic ventricular filling occurring inrhythm disturbances or in cardiomyopathies leads to an increase

in central venous pressure. Hepatic venous congestion may com-

plicate the clinical picture by decreasing hepatic function, thus

leading to hypoalbuminemia.

Hematologic disorders cause hydrops by the common pathway

of anemia, resulting in cardiac failure and extramedullary hemato-

poiesis, which in turn cause liver imbalance. Loss of oxygen-carrying capacity is the end stage. Rapidly generated anemia usually

causes immediate fetal death, hydrops occurs in the presence of

slowly developing anemia [Arcasoy and Gallagher, 1995].

Inborn errors of metabolism can cause anemia or liver failure,

thus leading to hydrops. Metabolic conditions may well be an

underestimated cause due to the difficulties in reaching a definitivediagnosis in a severely ill child or after intrauterine demise. Lym-

phatic drainage will be disturbed in lymph vessel dysplasias leading

to liquid imbalance, thus producing hydrops. The central distur-

bance is a low output failure of the lymphatic system, that is, the

overall lymphatic transport is reduced. This derangement occurs

notonly in lymphatic dysplasias butalso in increased centralvenous

pressure, as this causes difficulties in draining the lymph intovenous circulation as well [Bellini et al., 2006b].

A wide variety of infectious agents have been associated with

NIHF. The main targets of infection include fetal bone marrow,

myocardium, and vascular endothelium. Intrauterine congestive

heart failure, anemia, and fetal sepsis leading to anoxia,

endothelial cell damage, and increased capillary permeability are

the mechanisms linking infections to NIHF [Barron and Pass,

1995]. Congenital cystic adenomatoid malformations and congen-

ital diaphragmatic hernia form intrathoracic masses which can

compress the heart and limit its function, and may reduce venous

return. Fetal thoracic tumors, including cystic hygromas of the neck

TABLEI.(Continued)

References

Number

ofcases

Cardio-

vascular

Hematologic

Chromo-

somal

Syndromic

Lymphatic

dysplasia

Inborn

storage

diseases

Infections

Thoraci

c

Urinary

tract

malformations

Extra

thoracic

tumors

TTTF-

placental

Ga

stro-

inte

stinal

Miscel-

laneous

Idiopathic

Rodriguezetal.[2005]

32

16

6

2

5

1

2

Roseetal.[2005]

29

10

6

7

6

Suwanrath-Kengpoletal.

[2005]

71

2

20

7

11

7

9

4

2

9

Hofstaetteretal.[2006]

95

28

11

15

14

5

4

5

2

11

Simpsonetal.[2006]

30

6

3

3

2

6

10

TrainorandTubman[2006]

28

4

4

1

2

17

Abramsetal.[2007]

573

144

30

45

44

29

5

40

4

54

21

157

Huangetal.[2007]

26

7

3

2

6

1

1

6

Kaiseretal.[2007]

24

4

3

2

7

1

1

3

3

Liaoetal.[2007]

138

10

77

6

8

21

5

11

Total

5,4

37

1,1

81

564

727

237

310

60

366

327

127

39

304

29

200

966

Percentage(%)

21.7

10.4

13.4

4.4

5.7

1.1

6.7

6.0

2.3

0.7

5.6

0.5

3.7

17.8

Overview

oftheetiologicclassificationof51articlesdescribing5,4

37individualswithnonimmunehydro

psfetalisretrievedinthepresentsystematicreviewusingQUOROM

recommendations.

848 AMERICAN JOURNAL OF MEDICAL GENETICS PART A


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and chest, and arteriovenous malformations may also have an

intrathoracic mass effect.

Twin-to-twin transfusion syndrome causes an imbalance in

blood flow between donor and recipient twin. While it has beenextensively studied [Mahieu-Caputo et al., 2003; Galea et al., 2005;

Van Den Wijngaard et al., 2007], the pathophysiology is still notfully understood, although it seems likely to be linked to volemia

disturbances and a subsequent increase in central venous pressure.

The number and variability in nature of other causes of hydrops

is enormous. In some cases the pathophysiology is clear, such as

maternal systemic lupus erythematosus in which anticardiolipin

crossing the placenta causes fetal heart dysfunction. But for others,

it remains uncertain, as is true for many syndromic disorders.

Further classification based on pathophysiology of edema forma-tion would be helpful.

Several of the above categories operate through a common,

general pathophysiologic mechanism. Disorders leadingto conges-

tive heart failure, disorders characterized by decreased plasma

osmotic pressure and increased capillary permeability, and disor-ders with obstructed lymphatic flow all lead to abnormal watertransport between the capillary plasma and extravascular tissues

(Fig. 2). Output cardiac failure leads to venous hypertension and to

hypoxia that predispose to epithelial damage in the capillaries,

resulting in the loss of fluid to the extravascular compartment.Low plasma colloid osmotic pressure leads to severe loss of

fluid to the interstitial compartment which the lymphatic systemcan only partly reabsorb in the intravascular compartment, while

obstructed lymphatic flow cannot reabsorb water from the inter-stitium to theintravascularcompartment[Brace, 2004; Belliniet al.,

2006a].

Most categories (Table I) can be assigned to one or more of

the pathophysiologic mechanisms shown in Figure 2, while the

idiopathic group, makingup 15.8% of allpublishedcases,cannotbe

assigned to any of the groups. In addition, it is often not possible to

reliably classify patients assigned to the chromosomal and syn-

dromic disorders groups (17.8%) in one of the pathophysiologicpathways. For instance, one may assume that cardiac malforma-

tions would be the cause in the majority of trisomy 21 patients;

however, isolated lymphangiectasia might also be the cause

[Rutigliani et al., 2007]. This indicates that a total of 33.6% of all

cases cannot be reliably assigned to one of the pathophysiologic

mechanisms.

Further insight in this field and the grouping of patients on thebasis of these mechanisms, as well as careful study of the results of

diagnostic and therapeutic strategies and prognosis, will ultimately

improve our knowledge of NIHF.

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FIG. 2. Flowchart indication of the various possibilities in the pathophysiology of nonimmune hydrops fetalis (NIHF).

BELLINI ET AL. 849


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