SOGC CLINICAL PRACTICE GUIDELINE

It is SOGC policy to review the content 5 years after publication, at which time the document may be re-affirmed or revised to
reflect emergent new evidence and changes in practice.

No. 363, August 2018 (Replaces No. 297, October 2013)

No. 363-Investigation and Management of

Non-immune Fetal Hydrops

Outcomes: To provide better counselling and management in cases

This Clinical Practice Guideline prepared by the authors, of prenatally diagnosed non-immune hydrops.
and approved by the Society of Obstetricians and
Gynaecologists of Canada (SOGC)’s Genetics Committee Evidence: Published literature was retrieved through searches of
and Board of Directors. PubMed or MEDLINE, CINAHL, and The Cochrane Library in
2017 using key words (non-immune hydrops fetalis, fetal hydrops,
Valérie Désilets, MD, Sherbrooke, QC fetal therapy, fetal metabolism). Results were restricted to
Isabelle De Bie, MD PhD, Montréal, QC systematic reviews, randomized controlled trials/controlled clinical
trials, observational studies, and significant case reports.
François Audibert, MD, Montréal, QC
Additional publications were identified from the bibliographies of
these articles. There were no date or language restrictions.
Searches were updated on a regular basis and incorporated in the
guideline to September 2017. Grey (unpublished) literature was
Disclosure statements have been received from all authors.
identified through searching the websites of health technology
Genetics Committee: Francois Audibert, MD, Montréal, QC; Jo- assessment and health technology-related agencies, clinical
Ann Brock, MD, Halifax, NS; Richard N. Brown, MD, Beaconsfield,
QC; Carla Campagnolo, MSc, London, ON; June C. Carroll, MD,
Toronto, ON; Isabelle De Bie, MD, PhD, Montréal, QC; Jo-Ann CHANGES IN PRACTICE
Johnson, MD, Calgary, AB; Nanette Okun (chair), MD, Toronto,
ON; Melanie Pastuck, RN, Cochrane, AB; Karine Vallee-Pouliot, 1. Fetal chromosome analysis through aCGH (microarray) mo-
RM, Montréal, QC; R. Douglas Wilson, MD, Calgary, AB; Rhonda lecular testing should be offered where available in all cases
Zwingerman, MD, Toronto, ON. of non-immune fetal hydrops.
Key Words: Non-immune hydrops fetalis, fetal hydrops, fetal 2. Fetal autopsy is strongly recommended in all cases of fetal
therapy, fetal metabolism or neonatal death or pregnancy termination for which no di-
agnosis is reached prenatally.

Abstract
Objective: To describe the current investigation and management of KEY MESSAGES
non-immune fetal hydrops with a focus on treatable or recurring
etiologies.
1. All patients with fetal hydrops should be referred promptly to
a tertiary care centre for evaluation.
2. Some conditions amenable to prenatal treatment represent
J Obstet Gynaecol Can 2018;40(8):1077–1090
a therapeutic emergency after 18 weeks.
https://doi.org/10.1016/j.jogc.2017.12.011 3. To evaluate the risk of fetal anemia, Doppler measurement
Copyright © 2018 The Society of Obstetricians and Gynaecologists of of the middle cerebral artery peak systolic velocity should be
Canada/La Société des obstétriciens et gynécologues du Canada. Pub- performed in all hydropic fetuses.
lished by Elsevier Inc. All rights reserved.

This document reflects emerging clinical and scientific advances on the date issued, and is subject to change. The information should not be
construed as dictating an exclusive course of treatment or procedure to be followed. Local institutions can dictate amendments to these opin-
ions. They should be well documented if modified at the local level. None of these contents may be reproduced in any form without prior written
permission of the publisher.
Patients have the right and responsibility to make informed decisions about their care in partnership with their health care providers. To fa-
cilitate informed choice, women should be provided with information and support that is evidence based, culturally appropriate, and tailored to
their needs. The values, beliefs, and individual needs of each patient and their family should be sought, and the final decision about the care
and treatment options chosen by the patient should be respected.

AUGUST JOGC AOÛT 2018 • 1077

SOGC CLINICAL PRACTICE GUIDELINE

practice guideline collections, clinical trial registries, and national 3. Imaging studies should include comprehensive obstetrical ultra-
and international medical specialty societies. sound (including arterial and venous fetal Doppler) and fetal
Benefits, Harms, and Costs: These guidelines educate readers echocardiography (II-2A).
about the causes of non-immune fetal hydrops and its prenatal 4. Investigation for maternal–fetal infections and alpha-thalassemia in
counselling and management. It also provides a standardized women at risk because of their ethnicity should be performed in all
approach to non-immune fetal hydrops, emphasizing the search cases of unexplained fetal hydrops (II-2A).
for prenatally treatable conditions and recurrent genetic etiologies. 5. To evaluate the risk of fetal anemia, Doppler measurement of the
middle cerebral artery peak systolic velocity should be performed
Values: The quality of evidence in this document was rated using the in all hydropic fetuses after 16 weeks of gestation. In case of sus-
criteria described in the Report of the Canadian Task Force on pected fetal anemia, fetal blood sampling and intrauterine transfusion
Preventive Health Care. should be offered rapidly (II-2A).
Recommendations: 6. All cases of unexplained fetal hydrops should be referred to a medical
genetics service where available. Detailed postnatal evaluation by
1. All patients with fetal hydrops should be referred promptly to a ter-
a medical geneticist should be performed on all cases of newborns
tiary care centre for evaluation. Some conditions amenable to prenatal
with unexplained non-immune hydrops (II-2A).
treatment represent a therapeutic emergency after 18 weeks, al-
7. Autopsy is strongly recommended for all cases of fetal or neonatal
lowing prolongation of pregnancy with improved fetal/neonatal
death for which no diagnosis is reached prenatally (II-2A).
outcomes (II-2A).
2. Fetal chromosome analysis through array comparative genomic hy-
bridization (microarray) molecular testing should be offered where
available in all cases of non-immune fetal hydrops (II-2A).

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 No. 363-Investigation and Management of Non-immune Fetal Hydrops

Table 1. Key to evidence statements and grading of recommendations using the ranking of the Canadian Task Force
on Preventive Health Care
Quality of evidence assessmenta Classification of recommendationsb
I: Evidence obtained from at least 1 properly randomized controlled A. There is good evidence to recommend the clinical preventive
trial. action.
II-1: Evidence from well-designed controlled trials without B. There is fair evidence to recommend the clinical preventive action.
randomization. C. The existing evidence is conflicting and does not allow to make a
II-2: Evidence from well-designed cohort (prospective or recommendation for or against use of the clinical preventive action;
retrospective) or case-control studies, preferably from more than 1 however, other factors may influence decision making.
centre or research group. D. There is fair evidence to recommend against the clinical preventive
II-3: Evidence obtained from comparisons between times or places action.
with or without the intervention. Dramatic results in uncontrolled E. There is good evidence to recommend against the clinical
experiments (such as the results of treatment with penicillin in the preventive action.
1940s) could also be included in the category. I. There is insufficient evidence (in quantity or quality) to make a
III: Opinions of respected authorities, based on clinical experience, recommendation; however, other factors may influence decision
descriptive studies, or reports of expert committees. making.
a
The quality of evidence reported in these guidelines has been adapted from The Evaluation of Evidence criteria described in the Canadian Task Force on Pre-
ventive Health Care.
b
Recommendations included in these guidelines have been adapted from the Classification of recommendations criteria described in The Canadian Task Force on
Preventive Health Care.

INTRODUCTION including pericardial or pleural effusions, and ascites. Poly-

hydramnios or placental thickening (>6 cm) are often
H ydrops fetalis is defined as the accumulation of ab-
normal fluid in at least 2 different fetal compartments.
It implies an excess of total body water, which is usually
associated. When the fluid accumulation is limited to 1 cavity,
for example, isolated ascitis or pleural effusion, the situa-
tion should be described in terms of the involved site, since
evident as extracellular accumulation of fluid in tissues and this may be helpful in narrowing the differential diagnosis.
serous cavities.1,2 It generally presents as subcutaneous edema, The 3 primary mechanisms associated with hydrops are in-
accompanied by effusions in 2 or more serous cavities trauterine anemia, intrauterine heart failure, and
hypoproteinemia. In addition to these 3 basic mecha-
nisms, fetal hydrops has a causal relationship with a variety
of structural abnormalities that interfere with the
ABBREVIATIONS fetoplacental circulation. Chromosomal anomalies (aneu-
AF amniotic fluid ploidy, deletion, duplication) and skeletal dysplasia may also
CBC complete blood count be associated with hydrops through a variety of
CMV cytomegalovirus mechanisms.1,2
DNA deoxyribonucleic acid
Fetal hydrops carries a poor prognosis; however, several eti-
ELISA enzyme-linked immunosorbent assay
ologies can be treated in utero with potential good results.
FISH fluorescent in situ hybridization
The growing number of recognized etiologies requires a
GA gestational age
comprehensive and systematic search for causes, in particu-
Hb hemoglobin lar for treatable or recurrent conditions. The goal of this
HbH hemoglobin H guideline is to propose a standardized approach to the in-
HIV human immunodeficiency virus vestigation and management of non-immune fetal hydrops
IgG immunoglobulin G with a focus on the rare treatable or potentially recurring
IgM immunoglobulin M causes (Table 1).
MCA middle cerebral artery
MPS mucopolysaccharidosis Recommendation
NIHF non-immune hydrops fetalis 1. All patients with fetal hydrops should be referred
QF-PCR quantitative fluorescent polymerase chain reaction promptly to a tertiary care centre for evaluation. Some
RT-PCR real-time polymerase chain reaction conditions amenable to prenatal treatment represent
SOGC Society of Obstetricians and Gynaecologists of Canada a therapeutic emergency after 18 weeks, allowing pro-
TORCH toxoplasmosis, rubella, cytomegalovirus, herpes simplex
longation of pregnancy with improved fetal/neonatal
UA umbilical artery
outcomes (II-2A).

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SOGC CLINICAL PRACTICE GUIDELINE

DEFINITIONS of patients.1,6,19–23 A growing number of conditions can result

in NIHF. A systematic review has recently analyzed a total
Immune Versus Non-Immune Fetal Hydrops of 225 relevant articles describing 5437 individual cases of
Immune Hydrops
NIHF.24 All cases were sub-classified into 1 of the follow-
Maternal red cell alloimmunization occurs when a preg- ing diagnostic categories: cardiovascular (21.7%), hematologic
nant woman has an immunological response to a paternally- (10.4%), chromosomal (13.4%), syndromic (4.4%), lym-
derived antigen that is foreign to the mother and inherited phatic dysplasia (5.7%), inborn errors of metabolism (1.1%),
by the fetus.3 The maternal antibodies may cross the pla- infections (6.7%), thoracic (6.0%), urinary tract malforma-
centa, bind to antigens present on the fetal erythrocytes, and tions (2.3%), extra-thoracic tumours (0.7%), twin-to-twin
cause hemolysis, hydrops fetalis, and fetal death. The prog- transfusion or placental (5.6%), gastrointestinal (0.5%), mis-
nosis of this condition has been considerably improved over cellaneous (3.7%), and idiopathic (17.8%). See Table 2 for
the last decades, due to interventions including antenatal and
details.
postpartum Rhesus immune globulin, non-invasive prena-
tal surveillance with cerebral Doppler, and intrauterine
transfusion. The complete description and management of Chromosomal Abnormalities
this condition is beyond the scope of this guideline.3,4 Chromosomal abnormalities are the cause of NIHF in 25%
to 70% of cases.25 The risk of fetal aneuploidy is higher when
Non-immune Hydrops identified earlier in gestation or when fetal structural anoma-
Non-immune hydrops fetalis refers to hydrops in the absence lies are seen.5,26 Fetal chromosome analysis is indicated in
of maternal circulating red cell antibodies.5 With the intro- all cases of hydrops. Array comparative genomic hybrid-
duction of widespread immunoprophylaxis for red cell ization microarray testing is the preferred method of
alloimmunization and the use of in utero transfusions for investigation in all NIHF cases as the National Institute of
immune hydrops therapy, non-immune causes have become Child Health and Human Development Microarray Study
responsible for at least 85% of all cases of fetal hydrops.6 has shown additional sub-microscopic (pathogenic) copy
The reported incidence is around 3 per 10 000 births; number variants (smaller than can be seen by standard cy-
however, the incidence is much higher at the first and second togenetic studies) in 7% of fetuses with congenital anomalies
trimester ultrasounds because of higher fetal death rates.7 and normal karyotype.27,28 This analysis can be performed
on amniotic fluid, chorionic villous sampling, or postnatally.
Hydrops in the First Trimester and Cystic Hygroma
Recommendation
Signs of hydrops can be found as early as in the first tri-
mester. This is usually seen in association with increased 2. Fetal chromosome analysis through array compara-
nuchal translucency and/or cystic hygroma,8,9 a septated cystic tive genomic hybridization (microarray) molecular
structure in the occipitocervical region and sometimes the testing should be offered where available in all cases
axillary region. The evaluation of increased nuchal trans- of non-immune fetal hydrops (II-A).
lucency and cystic hygroma with or without fetal hydrops
differs from that of non-immune fetal hydrops and is beyond
the scope of this guideline. Pertinent SOGC guidelines can Cardiac Etiologies
be found elsewhere.10–13 Cardiac aetiologies account for 10% to 20% of cases of
NIHF.2,29 These include not only structural abnormalities,
but also cardiac arrhythmias, tumours, physiological dys-
Twin Gestation as a Different Situation function due to infection, inflammation, infarction, and
Non-immune fetal hydrops in 1 or both twins may imply arterial calcification. Cardiac and intrathoracic lesions that
a different etiology, especially in monochorionic twins, given result in right atrial pressure or volume overload seem to
the possibility of twin-to-twin transfusion syndrome. Review be most commonly associated with hydrops fetalis. Fetal
articles discussing the assessment and management of twin- cardiac tumours, cardiomyopathy, and other myocardial con-
to-twin transfusion syndrome and other complications ditions probably result in hydrops fetalis by a similar
specific to twin pregnancies are available elsewhere.13–18 mechanism. Fetal tachyarrhythmia has been shown to result
in elevation of atrial pressure and is the most treatable of
cardiac causes of hydrops fetalis.22 Fetal bradyarrhythmias
ETIOLOGIES
are less easily treatable and a rare causative mechanism of
Despite extensive investigations, the etiology of non- hydrops fetalis, except when the fetal heart rate is persis-
immune fetal hydrops may remain unknown in 15% to 25% tently below 50 per minute.

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 No. 363-Investigation and Management of Non-immune Fetal Hydrops

Infectious Diseases

Variousa
561
8.3
Intrauterine infections are a common cause of fetal hydrops
(4% to 15%), with parvovirus B19 infection and second-
ary anemia the most frequent.30 Fetal toxoplasmosis, syphilis,
Idiopathic
cytomegalovirus, and varicella can also present as fetal
1231
18.2
hydrops, with commonly associated findings such as hepa-

No
tomegaly, splenomegaly, or ascites (Tables 2 and 3).2,31
Strategies for the prenatal screening and diagnosis of
Lymphatic
dysplasia
511
7.5
No
maternal–fetal infections are detailed below.

Hematological Disorders
Yes (placental laser
Placental (TTTS)

Hematological disorders can be identified in 7% of cases

of NIHF. Some ethnicities may be at increased risk of fetal
359
5.3

presentations of alpha-thalassemia. For example, homozy-

therapy)

gous alpha-thalassemia accounted for 55.1% of NIHF

diagnosed after 20 weeks in Southern China.32
Syndromic

Structural Congenital Anomalies

311
4.6

Structural congenital anomalies should be evaluated as they

No

represent a large group of disorders that can be identified

through detailed fetal imaging and may be treatable. Primary
Yes (thoraco-amniotic

chylothorax,2,33 congenital cystic adenomatoid malformation,34

various fetal tumours,35 and metabolic diseases have been
Thoracic

also described as causal factors of hydrops.36,37

358
5.3

Including: inborn storage disease, urinary tract malformation, extra-thoracic tumors, gastrointestinal, miscellaneous.
shunting)

Single-Gene Disorders
Known single-gene disorders affecting metabolic path-
ways, hematological conditions, skeletal dysplasia, neurologic
parvovirus)
Yes (IUT for

disorders, cardiomyopathies, congenital nephrosis, congeni-

Infection
459
6.8

tal lymphedema, and mitochondrial mutations have been

reported as causes of potentially recurring fetal hydrops.22
Table 2. Conditions associated with non-immune fetal hydrops

However, many families have had more than 1 child with

Chromosomal

fetal or neonatal hydrops in whom the underlying genetic

defect has not been discovered. Some genes may be ex-
847
12.5

pressed specifically during fetal development, whereas others

IUT: intrauterine transfusion; TTTS: twin-to-twin transfusion syndrome.
No

may represent an early-onset form of a known pediatric dis-

order (e.g., Gaucher, fetal akinesia, glycogen storage disorder
Hematologic

type IV).38,39 The identification of a single gene disorder not

Yes (IUT)
688
10.1

only helps in predicting the outcome of the current preg-

nancy, but also has an impact on the management or
Based on total number of 6775 cases of NIHF.

screening of future pregnancies in the family.22

Yes (anti-arrythmic
Cardiovascular

Recent data suggest that metabolic disorders may be re-

sponsible for some idiopathic NIHF. Lysosomal storage
1450
21.4

For fetal tachyarrhythmias only.

disorders are the group of disorders most commonly in-

drugs
Adapted from Bellini et al.22

volved in NIHF. Hydrops fetalis is a relatively common

b

presentation in mucopolysaccharidosis type VII,40 infan-

tile galactosialidosis,41 type 2 Gaucher disease, and infantile
Potential fetal

free sialic acid storage disease. At least 15 other inborn errors

therapy
Cases, n

of metabolism may cause NIHF37,42: GM1 gangliosidosis,

Niemann-Pick type A, Niemann-Pick type C, MPS I, MPS
%

IVA, mucolipidosis II, sialidosis, multiple sulfatase deficiency,

a

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SOGC CLINICAL PRACTICE GUIDELINE

Table 3. Ultrasound findings in fetal infections causing fetal hydrops

Infection CNS Cardiac Abdominal Placental/AF IUGR
Toxoplasmosis + + + Rare
Syphilis + + Rare
Rubella + + + +
Parvovirus + + +
CMV + + + + +
Varicella + + + +
28
Adapted from Klein et al.
CNS: central nervous system; IUGR: intrauterine growth restriction.

Farber disease, Wolman disease, I cell disease, glycogen Clinical Evaluation

storage disease IV,39 transaldolase deficiency,43 Pearson syn- A detailed history should be taken focusing on the moth-
drome (mitochondrial disorder), and congenital disorders er’s past medical and reproductive history, including previous
of glycosylation. Specific enzyme assays are available to test fetal, neonatal, or infantile deaths. A clear determination of
for some of these disorders on cultured amniocytes or for GA and history of viral exposure/illness, travelling, bleed-
specific metabolite measurement in amniotic fluid ing, or use of medication during the pregnancy should be
supernatant.38,44–47 obtained. Parental past medical history, ethnic background,
and consanguinity should be documented. A 3-generation
Diagnosing or ruling out a metabolic disorder as the causal pedigree, including specific questions on fetal loss, death in
factor for NIHF is important because these single gene dis- infancy, developmental delay, congenital malformation,
orders carry a 25% risk of recurrence, and their identification genetic syndrome, skeletal dysplasia, chronic infantile illness,
may allow for prenatal diagnosis at an earlier stage in future inherited cardiomyopathies, and neurodegenerative disor-
pregnancies. Prenatal diagnosis of such conditions also fa- ders should be completed. Maternal history, physical
cilitates postnatal management. Despite thorough examination, and laboratory tests should be used to rule out
investigations, earlier reports conclude that at least 28% of developing preeclampsia (mirror syndrome) and underly-
cases of NIHF remain unexplained2; a recent systematic ing chronic illness associated with fetal hydrops (e.g., Sjogren,
review of the literature found that 17.8% were considered lupus, uncontrolled diabetes, Graves disease).
idiopathic.24 Additional tools such as next-generation se-
quencing panels or biochemical panels may become suitable Non-invasive Testing
adjuncts to the investigation of fetal hydrops once the phe- Timely referral to a maternal–fetal medicine specialist allows
notype has been as clearly defined as possible through for detailed and comprehensive ultrasound examination and
autopsy or clinical evaluation. the early identification of any treatable causes. A careful
search for structural fetal anomalies or genetic syndromes,
signs of fetal infection, and evidence of umbilical cord or
PRENATAL MANAGEMENT placental anomalies may rapidly indicate the cause of hydrops.

Fetal hydrops mandates urgent referral to a maternal–fetal Multiple mechanisms of hydrops may coexist, and the
medicine specialist for rapid evaluation because some primary cause is often not obvious. Determination of prog-
situations must be considered true prenatal medical emer- nosis is important and may be achieved by a semi-quantitative
gencies, particularly after 16 to 18 weeks. Triage depends measure of heart failure. Specific questions may be ad-
on GA, etiology, and severity. Ultrasound examination dressed through arterial and venous Doppler ultrasound in
including umbilical artery and middle cerebral artery Doppler conjunction with fetal echocardiogram.48
studies may guide lifesaving treatments such as in utero
transfusions, fetal cardioversion, or placement of diver- Doppler Ultrasound
sion shunts. Table 4 outlines the baseline investigations The measurement of MCA peak systolic velocity to assess
for all fetal hydrops. One should not wait for complete fetal anemia is essential to the management of fetuses with
results before initiating referral, invasive diagnostic proce- NIHF. After 16 weeks of gestation, there is a significant as-
dures, or treatments. sociation between delta-MCA peak flow and delta Hb

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Table 4. Step-wise investigation of non-immune fetal hydrops

STEP 1: Urgent
Fetal imaging
• Detailed morphology obstetrical ultrasound in a tertiary care centre and the assessment of the fetal venous and arterial circulation
• Doppler (MCA, venous, arterial)
• Fetal echocardiogram
Maternal blood
• CBC
• Kleihauer-Betke
• ABO blood type and antigen status
• Indirect Coombs (antibody screen)
• Venereal disease research laboratory test for syphilis
• Acute phase titres (parvovirus, toxoplasmosis, cytomegalovirus, rubella)
• Liver enzymes, uric acid, coagulation tests (suspected mirror syndrome)
• SS-A, SS-B antibodies (fetal bradyarrhythmia)
• Depending on ethnic origin: Hb electrophoresis, G6PD deficiency screen
STEP 2: Invasive / referral / treatment
Amniotic fluid
• FISH or QF-PCR on uncultured amniocytes, followed by karyotype or microarray analysis
• PCR for CMV
• PCR for parvovirus-B19/toxoplasmosis (selected cases)
• CMV and bacterial cultures in selected cases
• Inform the laboratory to keep the amniotic cells and supernatant for future studies
• DNA extraction if alpha-thalassemia suspected
• Fetal lung maturity testing (depending on GA)
Fetal blood sampling (maternal fetal medicine specialist)
• CBC, white blood cell count differential, platelets
• Direct Coombs’ test
• Blood group and type
• Karyotype (standard) with genetic microarray consideration
• TORCH/viral serologies
• Protein/albumin/liver function tests (not on all cases)
• Hb electrophoresis (depending on ethnicity)
Cavity aspiration (may be done at the time of amniocentesis)
• Lymphocyte count
• Protein/albumin
• Creatinin/ionogram (ascites)
• PCR for CMV and viral and bacterial cultures
Consider consultation with neonatalogy (depending on GA)
STEP 3: Post delivery
Placental Examination in all cases
If neonatal survival:
• Detailed physical examination
• Cranial ultrasound
• Abdominal ultrasound
• Cardiac monitoring
• Echocardiography
• CBC, liver function tests, creatinine kinase, albumin, protein
• TORCH, viral culture
• Specialized testing guided by results of prenatal work-up
If neonatal / fetal demise
• Clinical pictures
• Fetal cells culture (skin, others)
• Freeze fetal tissues and AF supernatant
• Bank fetal DNA
• Skeletal survey
• Placental pathology
• Autopsy10

concentration, especially when the fetal Hb concentration An abnormal ductus venosus waveform helps both to iden-
is very low.49 A peak systolic above 1.5 multiples of the tify a fetus at risk for cardiac anomalies and to predict
median has a 100% (95% CI 86%–100%) sensitivity for de- prognosis.51 In a group of fetuses with congenital heart
tecting fetal anemia from various causes.4,50 defects and hydrops, abnormal hepatic vein and ductus

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SOGC CLINICAL PRACTICE GUIDELINE

venosus blood velocities, along with umbilical venous pul- Search for Fetal Infections
sations were strongly associated with mortality.52 The most This section describes the different laboratory tests for in-
useful predictor of perinatal death in fetal hydrops is the fectious disorders that may present as fetal hydrops, mainly
presence of umbilical venous pulsations, because the most to review the limitations of these tests. Tests need to be pri-
common pathway of perinatal demise is fetal congestive heart oritized as shown in the algorithm presented in Table 4. Fetal
failure.48 ultrasound may reveal a pattern of findings typical of a par-
ticular infectious agent. Laboratory methods for the
Arterial Doppler is an indicator of the redistribution of fetal assessment of viral infections are in 2 categories: serology
cardiac output affecting the blood flow in the descending and virus or parasite detection.28 Serology is very sensitive
aorta and in the UA. Absent or reversed end diastolic flow but often cannot conclusively determine the time of infection,
in the umbilical artery reflects elevated placental resis- which may be critical for risk assessment. Traditional sero-
tance. Absent end diastolic flow is common in non-survivors, logical tests, which measure antibody levels including IgM
and often associated with increased cardiac afterload.52 and IgG usually require 2 samples separated by a significant
Changes in UA Doppler appear later than venous Doppler time period for determination of seroconversion or a sub-
and cardiac function alterations. stantial rise in titre.28 IgM identification is more indicative
than IgG of a recent infection; however, IgM may persist
several months or even years in some cases. IgM can also
Fetal Echocardiogram
be negative at the time of fetal hydrops if the seroconversion
Fetal echocardiogram is used to assess cardiac anatomy and occurred several weeks earlier. Various tests may distinguish
function. Congenital cardiac malformations are common with between IgG and IgM and may allow diagnosis in 1 serum
an underlying genetic syndrome or a chromosome anomaly. sample, but biological and technical difficulties are common
Depending on the type of the cardiac malformation, a and may cause false-positive and false-negative results.57 Ma-
syndromic differential diagnosis should be considered and ternal toxoplasmosis, rubella, cytomegalovirus, herpes simplex,
investigated.53 and parvovirus B19 serologies are commonly searched for
suspicion of fetal infection. A study of 476 patients in the
Cardiac arrhythmia may be primary or may occur second-
United Kingdom found that, among TORCH agents, only
ary to a systemic etiology such as hyperthyroidism or in
CMV was commonly found as a cause of fetal ultrasound
mothers with autoimmune conditions associated with high
findings.58 The archived serum from routine first trimester
titres of circulating anti–SS-A or anti–SS-B antibodies.54,55
baseline tests is very useful, when available, to establish prior
The 2 most common important fetal arrhythmias are su-
immune status and to document seroconversion. Testing for
praventricular tachyarrhythmias and severe bradyarrhythmias
rare infectious diseases (syphilis, enterovirus) may be con-
associated with complete heart block.55 Finally, congestive
sidered in particular clinical situations (ultrasound findings,
heart failure may be secondary to other systemic causes that
HIV-positive mother, clinical symptoms).
need to be evaluated. In fact, when identifying a cardiac com-
ponent in the context of NIHF, this important finding should
not be considered a final diagnosis in and of itself. A careful Parvovirus B19
search for underlying maternal illness or single-gene disor- Infection during pregnancy may affect the fetus, resulting
der is indicated. in hydrops or fetal demise.59 The predominant ultrasound
feature in fetuses infected by parvovirus B19 is ascites,49
Enlargement of the cardiac chambers is a common sign of sometimes associated with poorly contractile echogenic myo-
heart failure.55 The right atrium is the final pathway for venous cardium. Early diagnosis of maternal infection will allow fetal
return and frequently shows enlargement in situations of assessment and treatment by intrauterine blood transfu-
relative foramen obstruction, volume overload, tricuspid valve sion. Unfortunately, mothers are often unaware of their
regurgitation, and increased afterload. Normally, the ratio infection until fetal signs are observed. Confirmation of B19
of the cardiac circumference over the thoracic circumfer- infection requires laboratory assessment, which is compli-
ence at the level of the 4-chamber view should be less than cated by the nature of the viral infection and immune
0.5.56 response. Serology, using ELISAs, relies on recombinant an-
tigens, and concordance is low among all commercial assays
Recommendation available. In the absence of a “gold standard” assay, false
3. Imaging studies should include comprehensive ob- positive and false negative results prevail.
stetrical ultrasound (including arterial and venous fetal Furthermore, maternal IgM may have dropped below the
Doppler) and fetal echocardiography (II-2A). detection limit by the time fetal hydrops is identified.60 Viral

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culture is difficult and virus detection is based on various or PCR. Quantitative PCR in the amniotic fluid can
molecular assays. In spite of several studies there is no con- determine the viral load and could be useful for the
sensus regarding the most appropriate clinical specimen and assessment of fetal impact and prognosis, although the clini-
method for detection of viral DNA. Currently, on practical cal value of this test is still under investigation.64 Further
grounds, it is recommended to use ELISA IgM and IgG information on CMV infection in pregnancy is available in
assays based on recombinant conformational epitopes of a previously published SOGC guideline.62
polyomavirus capsid proteins 1 and 2 or polyomavirus capsid
protein 2 alone, and to use amniotic fluid or fetal serum for Varicella-zoster Virus
detection of fetal infection by the most sensitive molecu- Varicella-zoster virus is rarely found as a cause of fetal
lar methods available (nested PCR or RT-PCR). 60 hydrops.65 The primary tool for assessing maternal infec-
Recommendations for evaluation and treatment of tion is isolation of the virus from maternal lesions. Type-
parvovirus infection during pregnancy have been pub- specific IgG assays must be applied to determine recurrent
lished by the SOGC Maternal–Fetal Medicine and Infectious maternal infections. Antigen detection or DNA detection
Diseases Committees.61 by PCR in skin lesion samples are additional tools for the
rapid and sensitive diagnosis of symptomatic current in-
Rubella fection. Prenatal diagnosis can be performed by PCR
If the patient is not immune to rubella, serial IgG and IgM detection of the virus in AF, but false negative results are
titres should be done. If congenital rubella is strongly sus- common and positive results do not necessarily correlate
pected, amniotic fluid culture or fetal blood sampling for with fetal damage.66 Neonatal infection is diagnosed by virus
IgM determination is indicated as infection leads to severe culture or PCR in skin lesions or other clinical specimens
fetal morbidity. Postnatal determination is achieved through in case of a disseminated form.
evaluation of IgG and IgM levels, along with viral isolation.
Other viral Infections
Cytomegalovirus A few studies report fetuses with NIHF caused by various
CMV is excreted in the urine of the infected fetus, so de- subtypes of Coxsackie virus and adenovirus identified
tection of the virus in AF has proven to be a highly sensitive through targeted PCR amplification in affected fetal
and reliable method.62 Numerous studies have focused on tissues.20,67
the most appropriate timing for performing amniocentesis
to yield the best sensitivity for detection of fetal infection. Testing for Alpha-thalassemia
These studies clearly indicated that AF should be collected The most severe form of alpha-thalassemia is called Bart’s
after 21 gestational weeks and after at least 6 weeks’ maternal disease.68 The absence of normal copies of alpha-Hb genes
infection. Most studies state that the timing of amniocen- in a fetus causes severe anemia leading to hydrops during
tesis is more critical for sensitivity in detecting the virus in fetal life.68 This autosomal recessive condition occurs at a
AF than the laboratory methods used. If invasive testing is higher frequency in some ethnic groups such as Mediter-
performed, PCR is the preferred method for detection of ranean, African, and South-East Asian populations.68 From
CMV in amniotic fluid. Problems with molecular contami- a practical point of view in Canada, one can take the ap-
nation (false-positive results) and the need to address proach that any patient who is not Japanese, Korean,
prognostic issues led to the development of quantitative PCR Caucasian of Northern European ancestry, First Nations,
assays; the highly advanced real-time PCR is the most up- or Inuit should be screened.68 Carriers are suspected on the
to-date method.62,63 basis of the presence of low red blood cell volume (mi-
crocytosis) with normal ferritin. HbH bodies identified on
Laboratory testing to determinate intrauterine CMV infec- blood smear examination are characteristic of alpha-
tion involves several steps that should be done simultaneously thalassemia carrier status. Even in the absence of HbH
in fetal hydrops. Maternal primary or recurrent infection is bodies, when microcytosis is present, molecular testing should
assessed by serology using IgM, IgG, and IgG-avidity assays. be performed in both parents to look for the frequent de-
A second blood sample should be sought to demonstrate letion and rarer point mutations.
antibody kinetics typical of the current infection and not
of a remote infection or a non-specific reaction. If mater- In cases suspected of alpha-thalassemia, MCA Doppler
nal primary infection has been established and the pregnancy should be done to confirm anemia. When anemia is sus-
continues, prenatal diagnosis follows at 21 to 23 weeks’ ges- pected, it should be confirmed by fetal blood sampling for
tation or at 6 to 9 weeks after seroconversion (if known). rapid initiation of treatment (intrauterine transfusion). The
Detection of CMV in AF is achieved by virus culturing and/ diagnosis should be further confirmed by fetal DNA testing

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SOGC CLINICAL PRACTICE GUIDELINE

through amniocentesis or placental biopsy.68 If fetal blood Table 5. Lysosomal enzymatic assays used for NIHF
is taken by cordocentesis, Hb Bart’s can be identified. When
a. Beta-galactosidase (GM1)
confirmed, parents should be informed of the poor
b. Beta-glucuronidase (MPS VII)
prognosis and counselled about the 25% recurrence risk and
c. Beta-glucosidase (Gaucher)
the availability of invasive prenatal diagnosis for future preg-
d. Neuraminidase (sialidose)
nancies. Intrauterine transfusion in affected fetuses has been
reported with various results.69 e. Beta-galactosidase and neuraminidase (galactosialidose)
f. Sphyngomyelinase (Niemann-Pick A and B)
g. Mucolipidosis type II
Invasive Investigation
Fetal chromosome analysis through array comparative
genomic hybridization microarray testing should be con- future studies. Diagnosing a metabolic disorder as the causal
ducted in all cases of unexplained NIHF. Rapid aneuploidy factor for NIHF is important because these single-gene dis-
testing using QF-PCR or FISH techniques on amniotic fluid, orders carry a 25% recurrence risk. Their identification may
placental biopsy, or cord blood can provide information on allow for prenatal diagnosis at an earlier stage in future
common aneuploidies within 24 to 48 hours. Amniotic fluid pregnancies.22,44 Prenatal diagnosis of such conditions also
should also be obtained for viral and bacterial cultures, viral/ facilitates postnatal management. Fetal cavity aspiration may
parasitic-specific PCR studies, and single-gene analysis when be used as a diagnostic and therapeutic measure. A lym-
clinically indicated. In selected cases, the supernatant can phocyte count (pleural effusion, cystic hygroma), biochemical
be used for biochemical studies.37,70 Amniotic cells should studies, protein/albumin determination, histology, and viral
be kept in culture for future studies and DNA extraction and bacterial cultures are indicated.22,44
or frozen for later analysis.
Recommendations
Fetal blood sampling to determine fetal Hb levels may be 4. Investigation for maternal–fetal infections and alpha-
performed under the following circumstances: MCA Doppler thalassemia in women at risk because of their ethnicity
results suggestive of fetal anemia, documented parvovirus should be performed in all cases of unexplained fetal
B19 seroconversion, parental microcytic anemia from at- hydrops (II-2A).
risk ethnicity, and documented fetal bleeding. Baseline studies 5. To evaluate the risk of fetal anemia, Doppler mea-
to consider on fetal blood sampling include CBC, plate- surement of the middle cerebral artery peak systolic
lets, direct Coombs’ test, blood group, karyotype, TORCH/ velocity should be performed in all hydropic fetuses
parvovirus B19 (IgM), and albumin. If fetal anemia is strongly after 16 weeks of gestation. In case of suspected fetal
suspected, O-negative CMV-negative maternally cross- anemia, fetal blood sampling and intrauterine trans-
matched blood should be ready for transfusion. In specific fusion should be offered rapidly (II-2A).
situations (positive family history, recurring hydrops), tar-
geted metabolic investigations may also be performed. For
example, fetal blood sample was used to diagnose a con- PROGNOSIS
genital disorder of glycosylation type Ia in a 27-week fetus NIHF from all causes has a high mortality rate. Fetal chro-
with NIHF.71 The fetal loss rate after cordocentesis was mosomal anomaly, GA <24 weeks and fetal structural
11.32% in a group of hydropic fetuses, probably due in part anomalies other than chylothorax are indicators of a poor
to the high loss rate associated with hydrops itself.72 prognosis. However, fetal treatment has significantly im-
proved survival in selected cases.
Specific enzyme assays are available to test for lysosomal
storage disorders on cultured amniocytes (N- When a pregnancy is continued with known fetal hydrops, the
acetylglalactosamine-6S-sulfatase, beta-glucuronidase, beta- occurrence of maternal “mirror” syndrome should be care-
galactosidase, beta-glucosidase, alpha-iduronidase, a-D- fully monitored. Mirror syndrome, also referred to as Ballantyne’s
neuraminidase, sphingomyelinase) or specific metabolite syndrome, is defined as the development of maternal edema sec-
measurement in amniotic fluid supernatant (total hexos- ondary to fetal hydrops.24,73 Severe preeclampsia is usually
aminidase, betaglucoronidase, alpha-mannosidase, associated with the syndrome. Because the maternal prognosis
chitotriosidase).44,45 These assays must be performed by a can be poor, the option of continuing a pregnancy with fetal
specialized biochemical genetics laboratory. The recom- hydrops should be carefully discussed.
mended metabolic investigation for unexplained fetal hydrops
is shown in Table 5. The laboratory should be informed of Excluding chromosomal abnormalities, the survival rate of
the need to keep frozen supernatant and amniotic cells for NIHF is about 31% to 48%.7 Most of the causes, a large

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 No. 363-Investigation and Management of Non-immune Fetal Hydrops

proportion of which are lethal disorders, respond poorly neurodevelopmental outcomes in 5 children who pre-
to therapy. Without treatment the prognosis is generally poor, sented with fetal heart block and hydrops fetalis. In his series
except in the rare case of spontaneous resolution of of 10 fetuses, 3 died in utero, 2 died from dilated cardio-
parvovirus B19 infection.74 myopathy at age 9 months and 4 years, and 5 survived.79

In a series of 38 cases of NIHF, Negishi et al. reported a These results demonstrate that the prognosis of NIHF
23% survival rate in the treatment group.33 The presence differs markedly between different etiological groups. It is
of a chromosomal anomaly, along with an earlier age at de- essential to attempt to identify the etiology to better predict
tection of NIHF, was associated with a poorer outcome. prognosis, offer prenatal treatment when available, and deliver
In a series of 30 cases of NIHF diagnosed between 10 and in a tertiary perinatal care centre to improve postnatal
14 weeks of gestation, all cases resulted in spontaneous abor- outcome.
tion, intrauterine fetal death, or pregnancy termination.26 In
another series of 45 cases diagnosed between 11 and 17 Recommendation
weeks, only 2 resulted in a normal outcome.75 McCoy et al. 6. All cases of unexplained fetal hydrops should be re-
reported a survival rate of <5% for infants with hydrops ferred to a medical genetics service where available.
diagnosed before 24 weeks of gestation and 20% survival Detailed postnatal evaluation by a medical geneticist
for infants diagnosed after 24 weeks of gestation.20 should be performed on all cases of newborns with
unexplained non-immune hydrops (II-2A).
In a report on 23 women with NIHF, termination of preg-
nancy was performed for 10 chromosomal and 5 structural
abnormalities, and there was 1 intrauterine fetal death.76 One PERINATAL MANAGEMENT
baby with diaphragmatic hernia died in the neonatal period
from pulmonary hypoplasia despite reversal of hydrops by Fetal Treatment
in utero shunting, and 1 baby with treated polyhydram- Fetal hydrops is a medical emergency that mandates urgent
nios was born at 30 weeks and died on day 5. The remaining referral to a maternal–fetal medicine specialist and a medical
5 cases, in which structural and chromosomal abnormali- geneticist for rapid evaluation. The hydropic fetus is usually
ties were excluded, had fetal therapy between 22 and 32 in a precarious state and even minimal delays may prevent
weeks’ gestation (4 shunt insertions, 1 blood transfusion) access to life-saving procedures.
and in all the hydrops reversed and the pregnancy contin-
ued to at least 35 weeks’ gestation. All 5 neonates were Fetal treatment options for NIHF depend on the etiology
discharged from hospital alive and well. Fetal therapy in cases and the GA at diagnosis. A maternal–fetal specialist should
of NIHF with normal structure and karyotype was asso- undertake this evaluation. Options available consist of (1)
ciated with a very good outcome.76 intrauterine transfusion for anemia; (2) repeated centesis or
shunt insertion for pleural effusion, ascites, or thoracic cystic
Two recent studies address the issues of postnatal survival lesions; (3) intravascular or maternal treatment with anti-
in live-born neonates with hydrops. Data from a large na- arrhythmic drugs to treat fetal tachyarrhythmia, in close
tional database77 reveals that mortality rates were highest collaboration with cardiologists; and (4) laser surgery for
among neonates with congenital anomalies (57.7%) and severe and early twin-to-twin transfusion syndrome with
lowest among neonates with congenital chylothorax (5.9%). hydrops (stage IV), and open fetal surgery where available,
Factors associated with death were younger GA, low or laser or radiofrequency ablation for major structural
5-minute Apgar score, and need for high levels of support anomalies associated with NIHF (Table 6).
during the first 24 hours of life (high oxygen needs and high-
frequency ventilation). Of the 597 neonates included in the Fetuses diagnosed with a treatable cause of NIHF should
study, 115 were transferred from another hospital, 215 died be delivered in a tertiary care centre with prenatal consul-
before discharge, and 267 were discharged from the hospital.77 tation with appropriate subspecialties including maternal–
Huang et al. reported a 50% survival rate in a group of 28 fetal medicine specialists, geneticists, neonatologists, and
live-born neonates with NIHF.78 The survival rate was 83% pediatric surgeons. Antenatal consultation allows for pa-
in infants with lymphatic malformations. Preterm birth at rental counselling, adequate preparation of the resuscitation
less than 34 weeks and low serum albumin concentration team, and planning of specialized equipment required in the
were two poor prognostic factors for survival.78 delivery room. Pre-delivery cavity aspiration (pleural effu-
sions, severe ascitis, severe polyhydramnios) by the
Few studies have examined the long-term outcome of NIHF perinatologist may facilitate neonatal management and reduce
identified prenatally. Breur et al. reported normal maternal complications. Postnatal therapy begins with vig-

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SOGC CLINICAL PRACTICE GUIDELINE

Table 6. Fetal therapies for non-immune hydrops Recommendation

1. Intrauterine transfusion for anemia 7. Autopsy is strongly recommended for all cases of fetal
– Maternal acquired pure red cell aplasia
– Maternal fetal hemorrhage
or neonatal death for which no diagnosis is reached
– Fetal hemolysis (G6PD) prenatally (II-2A).
– Fetal parvovirus infection
2. Repeated centesis or shunt insertion
– Pleural effusion
CONCLUSION
– Ascitis
– Thoracic cystic lesions The prognosis of NIHF differs markedly between differ-
– Congenital cystic adenomatoid malformation ent etiological groups. Recent progress in prenatal genetics
– Pulmonary sequestration and maternal–fetal medicine provides us with newer tools
– Pulmonary lymphangiectasia
to identify the underlying etiology. Prompt access to
3. Intravascular or maternal treatment with anti-arrhythmic drugs
– Fetal tachyarrhythmia
maternal–fetal medicine units for fetal evaluation and treat-
– Atrioventricular block (anti–SS-A/SS-B) ment has improved outcomes. It is essential to attempt to
4. Fetal procedures: open fetal surgery or laser vessel ablation/ identify the etiology to better predict prognosis, offer treat-
radio frequency ablation ment when appropriate, and assess recurrence risk to plan
– Congenital cystic adenomatoid malformation for the management of future pregnancies.
– Sequestration
– Sacrococcygeal teratoma
– Twin-to-twin transfusion syndrome (stage IV)
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