Managing Nonimmune hydrops fetalis

Managing
Non immune
hydrops fetalis
Dr Vidya A Thobbi
Professor and Head
Department of OBG
Al-Ameen medical college
Bijapur

Non immune hydrops fetalis
Accumulation of extracellular fluid in tissues and 2 or
more serous cavities without evidence of circulating
antibodies against red cell antigens.
Diagnosis requires generalized skin edema >5mm and
2 or more of the following:-
• Pericardial effusion
• Pleural effusion
• Ascites
• Placental enlargement>6mm
(McCoy and colleagues, Non-immune hydrops after 20 weeks gestation: review of
10 years’ experience with suggestions for management. Obstet
Gynaecol. 1995;85(4):578–82)

Incidence
•It is around 3 per 10 000 births.
•However, the incidence is much higher at the first- and second-
trimester ultrasounds because of higher fetal death rates.
All patients with fetal hydrops should be referred promptly to a
tertiary care centre for evaluation. Some conditions amenable to
prenatal treatment represent a therapeutic emergency after 18
weeks.(by SOGC 2013)
Milunsky A. Genetic disorders of the fetus: diagnosis, prevention and treatment. 5th
ed. Baltimore: John Hopkins University Press; 2004)

Presentation of fetal hydrops
• Ultrasound examination
• Fetal heart rate recording
• Ultrasound surveillance for twin to twin transfusion
syndrome in monochorionic twin pregnancy.
• Large for dates/hydramnios.
• Reduced fetal movement.
• Placental abruption.
• Maternal diabetes.
• Maternal pre-eclampsia/mirror syndrome.
• Maternal parvovirus B19 infection.

USG findings
Scalp edema Placentomegaly

Hydrocele can
be an early
manifestation
in hydrops

Placenta of Hydropic Pregnancy
Placenta of Normal Pregnancy

Soft Tissue
shadow and
pleural
effusion in
hydropic
neonate

Hydrops fetalis, Sara Peeples, MD. ANGELS Perinatal Conference.
May 5, 2010)

CATEGORIES OF DISORDERS CAUSING NIHF

Chromosomal abnormalities
• These are found in around 13% of cases, some of which will be
associated with structural fetal anomalies.
• It is important to exclude aneuploidy before offering therapy,
especially in fetuses with hydrothorax.
• Aneuploidy with hydrops has a dismissal prognosis and option of
termination of pregnancy should be offered to the patient.
Fetal chromosome analysis and genetic microarray molecular testing
should be offered where available in all cases of non-immune fetal
hydrops where available. (REC SOGC 2013)
(Keeling JW: Fetal hydrops fetal and neonatal pathology, 2nd
ed. London, Springer
Verlag, 1993, pp 253-271)

Anemia
• It is important not to transfuse the fetus before all
investigations especially the parents for alpha
thalassemia trait and fetal karyotype are available.
• Ill-advised intrauterine transfusions for the fetus with
homozygous alpha thalassemia may result in life long
transfusions, iron chelations and the associated
morbidity.
( Yang Q, McDonell SM, Khoury MK, et al: Hemochromatosis associated mortality in
the united states from 1979-1992: An analysis of multiple-cause mortality data. Ann
Intern Med 1998;20:946-953)

Twin Twin Transfusion syndrome
• Hydrops associated with TTTS has been treated with
intrauterine placental vessel ablation, amniodrainage,
umbilical cord occlusion, delivery and termination.
• In some, intrauterine fetal transfusion was deemed
necessary after selective laser therapy.
(Ville Y, Hecher K, Ganong A, et al:Endoscopic laser coagulation in the
management of severe twin-twin transfusion syndrome, BJOG 1998;105:44-
453.)

Cardiovascular defects
• The prognosis is good in general with a survival rate of as high
as 80%.
• However, there may be neurologic morbididty associated with
long duration hydrops.
(Schade RP, Stoutenbeck P, de vries LS, neurological morbidity after
supraventricular tachyarrhythmia. Ultrasound obstet Gynecol 1999:13:43-47)
• Fetal myocarditis associated with congenital infection may have
severe complications requiring perinatal heart transplantation.
(Von Kalsenberg CS, Bender G, Scheewe J, et al: A case of fetla parvovirus B19
myocarditid, terminal cardiac failure and perinatal herat transplantation. Fetal
Diagn Ther 2001;16:427-432)

• Fetal tachycardia with hydrops associated with thyrotoxicosis in
a patient with history of Graves disease can be treated with
antithyroid medications in utero.
(Ibrahim H, Asamoah A, Krouskop RW, et al:congenital chylothorax in neonatal
thyrotoxicosis, J Perinatol 1999;19:1:68-71.)

Pulmonary defects
• The survival of solid congental cystic adenomatoid malformation
masses ranges from as low as 0% with hydrops to 90% with no
hydrops, and has led some to offer open fetal surgery to those
with solid lesions and hydrops. It is associated with 50% survival
and significant maternal and fetal morbidity.
(Adzick NS, Harrison MR, Crombleholme TM et al: fetal lung lesion management and outcome,
Am J Obstet and Gynecol 1998;179:884-889)
• Percutaneous ultrasound guided injection of a vascular
sclerosant and laser vaporization. There are reports of
spontaneous resolution of hydrops associated with regression of
lesion.
(Da Silva OP, Ramanan R, Romano W, Evans M : nonimmune hydrops fetalis, pulmonary
sequestration and favorable neonatal outcome. Obstet Gynecol 1996;88:681-683)

Pulmonary defects
• The survival rates in hydrops and pleural effusion treated
conservatively is 12%, however survival rate in cases treated
with pleuroamniotic shunt is 50%. Pathogenesis is unknown, but
may be due to abnormalities of lymphatic system.
• Serial intrapleural injection of OK-432 were used to treat the
hydropic fetus, resulting in a live born infant.
• Termination of pregnancy is also an option if there is no
improvement in the hydrops after treatment.
(Rodeck CH, Fisk NM, Fraser DI, Nicolini U, Long term inutero drainage of fetal hydrothorax. N
Engl J Med 1988;319:1135-1138)
(Tanemura M, Nishikawa N, Kojima K, et al A case of successful fetal therapy fr congenital
chylothorax by intrapleural injection of OK-432. Ultrasound Obstet Gynecol 2001:18(4):371-
375)

Tumors
• Open fetal surgery has been used in small number of surgically
correctable conditions, solid pulmonary and sacrococcygeal
tumors.
• Other less invasive procedures like percutaneous alcohol,
radiofrequency ablation, thermocoagulation and ultrasound
guided instillation of alcohol.
(Coleman BG, Adzick NS, Crombleholme TM, et al: fetal therapy: state of art. J Ultrasound Med
2002:21:1257-1288)
(Lam YH, Tang MH, Shek TW: thermocoagulation of fetal sacrococcygeal teratoma. Prenat
Diagn 2002; (2):22:99-101)

Infections
• Risk of fetal hydrops is higher in mothers with asymptomatic
parvovirus B19 infection. It may be due to profound hypoplastic
anaemia. The risk of fetal loss is greater in 1st
half of pregnancy,
with most reported cases between 16 and 32 weeks.
• Absence of thrombocytopenia, acidemia and presence of
increased retic count suggests spontaneous recovery.
• In non reassuring haematological profile intrauterine transfusion is
indicated.
• The risk of fetal loss is increased, but in majority of the cases
there is successful outcome.
(Fairely CK, Miller E:observational study of effect of intrauterine transfusion on outcome of fetal
hydrops after parvovirus B19 infection. Lancet 1995;346:1335-1337)
(Schild RL, Bald R et al: intrauterine management of fetal parvovirus B19 infection. Ultrasound
Obstet Gynecol 1999;13:161-166)

Parvovirus B19
• The predominant ultrasound feature in fetuses infected by
Parvovirus B19 is ascites, sometimes associated with poorly
contractile echogenic myocardium.
• Early diagnosis of maternal infection will allow fetal assessment
and treatment by intrauterine blood transfusion.
• Recommended investigation is ELISA IgM and IgG assays
based on recombinant conformational epitopes of polyomavirus
capsid proteins 1 and 2 or polyomavirus capsid protein 2 alone,
and to use amniotic fluid or fetal serum for detection of fetal
infection by the most sensitive molecular methods available
(nested PCR or RT-PCR).
Investigation for maternal–fetal infections, and alpha-
thalassemia in women at risk because of their
ethnicity, should be performed in all cases of
unexplained fetal hydrops(REC SOGC 2013)
(Valérie Désilets, François Audibert, Investigation and Management of Non-immune
Fetal Hydrops, J Obstet Gynaecol Can 2013;35(10):e1–e14)

Clinical evaluation
• A detailed history should be taken focusing on the mother’s past
medical and reproductive history, including previous fetal, neonatal, or
infantile deaths.
• A clear determination of gestational age and history of viral
exposure/illness, travelling, bleeding, or use of medication during the
pregnancy should be obtained.
• Parental past medical history, ethnic background, and consanguinity
should be documented.
• A 3-generation pedigree, including specific questions on fetal loss,
death in infancy, developmental delay, congenital malformation, genetic
syndrome, skeletal dysplasia, chronic infantile illness, inherited
cardiomyopathies, and neurodegenerative disorders should be
completed.
• Maternal history, physical examination, and laboratory tests should be
used to rule out developing preeclampsia (mirror syndrome) and
underlying chronic illness associated with fetal hydrops (e.g., Sjogren,
lupus, uncontrolled diabetes, Graves disease).

Counselling
• Various options available have to be explained to the parents.
• Option of medical termination of pregnancy to be given in those
having structural/anatomical and chromosomal abnormalities.
• Antenatal management should be directed towards making a
diagnosis, with the aim of identifying those in whom either
prenatal or immediate post-natal intervention may be effective.
• In case of dead fetus in utero, the importance of autopsy has to
be explained to the parents i.e to identify the cause and prevent
recurrence in future pregnancies.

Step-wise investigation of non-immune fetal
hydrops
Fetal imaging
1)Detailed morphology obstetrical ultrasound in a tertiary care
centre-
-Look for site and severity of hydrops.
-Amniotic fluid volume.
-Detailed ultrasonography for congenital abnormalities and
abnormalities of placenta and cord.
-Biophysical assessment .
(2)Doppler (MCA, venous, arterial).
(3)Fetal echocardiogram.
IMAGING STUDIES SHOULD INCLUDE COMPREHENSIVE
OBSTETRIC ULTRASOUND(INCLUDING ARTERIAL AND
VENOUS FETAL DOPPLER) AND FETAL ECHOCARDIOGRAPHY.
(REC SOGC 2013)

Ultrasound findings in fetal infections causing fetal hydrops

Doppler ultrasound
• After 16 weeks of gestation, there is a significant association
between delta-MCA peak flow and delta hemoglobin
concentration, especially when the fetal Hb concentration is very
low. A peak systolic above 1.5 multiples of the median has a
100% sensitivity for detecting fetal anemia from various causes.
• The most useful predictor of perinatal death is the presence of
umbilical venous pulsations, because the most common
pathway of perinatal demise is fetal congestive heart failure. In
foetuses with congenital heart defects and hydrops, abnormal
hepatic vein and ductus venosus blood velocities, along with
umbilical venous pulsations were strongly associated with
mortality.
Hernandez-Andrade E, Scheier M, Dezerega V, Carmo A, Nicolaides KH. Fetal
middle cerebral artery peak systolic velocity in the investigation of non-immune
hydrops. Ultrasound Obstet Gynecol 2004;23:442–5.

Doppler ultrasound
• Absent or reversed end diastolic flow in the umbilical artery
reflects elevated placental resistance. Absent end diastolic flow
is common in non-survivors, and often associated with
increased cardiac afterload. Changes in UA Doppler appear
later than venous Doppler and cardiac function alterations.
(Mari G, Zimmermann R, Moise KJ, Deter RL, Correlation between middle cerebral
artery peak systolic velocity and fetal hemoglobin after 2 previous intrauterine
transfusions, Am J Obstet Gynecol, 2005 Sep;193(3 Pt 2):1117-20)

Role of uterine venous pressure
• If UVP is raised and therapy reduces it then prognosis is good.
• Hydrops characterized by elevated UVP not remedied by
surgical or medical therapy, is usually progressive and the fetus
dies in utero or requires preterm delivery for postnatal therapy.
• Hence, measurement of fetal UVP should be viewed as a guide
to therapy when fetal blood sampling is planned but it is not
itself an indication for the sampling.
(Moise KJ, Carpenter RJ et al, Do abnormal starlings forces cause fetal hydrops in
red cell alloimmunisation? Am J Obstet Gynecol 1992;167:907-912)

Fetal echocardiography
• Cardiac arrhythmias may be primary or secondary to systemic
etiology in mothers such as hyperthyroidism or autoimmune
conditions associated with high titres of circulating anti SS-A or
anti SS-B antibodies.
• Most common arrhythmias are supraventricular arrhythmias or
severe bradyarrhythmias associated with complete heart block.
• Enlargement of cardiac chambers is the most common sign of
heart failure.
• The right atrium is the final pathway for venous return and
frequently shows enlargement in situations of relative foramen
obstruction, volume overload, tricuspid valve regurgitation, and
increased afterload.
(Pajkrt E, Weisz B, Firth HV, Chitty LS. Fetal cardiac anomalies and genetic
syndromes. Prenat Diagn 2004;24:1104–15)

Maternal blood sampling
 CBC ( microcytosis-alpha
thalassemia )
 Electrophoresis
 Alpha fetoprotein
 Kleihauer-Betke
 ABO blood type and antigen
status
 Indirect Coombs (antibody
screen)
 Venereal disease research
laboratory test for syphilis
 Acute phase titers
(parvovirus, toxoplasmosis,
cytomegalovirus, rubella)
 Liver function tests, uric acid,
coagulation tests (suspected
mirror syndrome)
 SS-A, SS-B antibodies (fetal
bradyarrhythmia)
 G6PD deficiency screening.
 Thyroid function test including
antibodies.
 Blood urate, urea and
electrolytes.
(Valérie Désilets, François Audibert,
Investigation and Management of
Non-immune Fetal Hydrops, J
Obstet Gynaecol Can
2013;35(10):e1–e14)

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.
DNA extraction if alpha-thalassemia suspected.
Fetal lung maturity testing (depending on gestational age).
STEP 2: Invasive / referral / treatment-

Fetal blood sampling
It is collected from the following sites-
•Placental insertion of umbilical cord.
•Fetal insertion of umbilical cord.
•Intrahepatic veins.
•Heart
[Complication – fetal loss]

Fetal blood sampling for-
• 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)
• Hemoglobin electrophoresis (depending on ethnicity)
• Umbilical venous pressure
•PCR IgM antibodies for infection

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 gestational
age)

Step – 3 Post - delivery
Neonatal survival
 Cardiac monitoring
 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
Neonatal / fetal demise
 Freeze fetal tissues and AF
supernatant
 Bank fetal DNA
 Skeletal survey
 Placental pathology
 Autopsy
(Valérie Désilets, François Audibert,
Investigation and Management of Non-
immune Fetal Hydrops, J Obstet
Gynaecol Can 2013;35(10):e1–e14)

Management
• It is an orderly diagnostic and multidisciplinary approach.
• Fetal hydrops is a medical emergency because the hydropic
fetus is usually in a precarious state and even minimal delays
may prevent access to life-saving procedures.
• Fetal treatment options for NIHF depend on the etiology and the
gestational age at diagnosis.
• A maternal–fetal specialist should undertake this evaluation.
• Fetuses diagnosed with a treatable cause of NIHF should be
delivered in a tertiary care centre with prenatal consultation with
appropriate subspecialties including maternal–fetal medicine
specialists, geneticists, neonatologists, and pediatric surgeons.

Fetal therapies in non immune hydrops
INTRAUTERINE TRANSFUSION FOR ANAEMIA
Maternal acquired red cell aplasia and maternal fetal haemorrhage.
Fetal hemolysis and parvovirus B19 infection.
REPEATED CENTESIS OR SHUNT INSERTION
Ascitis and pleural effusion
Pulmonary sequestration and lymphangectasis.
INTRAVASCULAR OR MATERNAL TREATMENT WITH ANTI-
ARRHYTHMIC DRUGS
Fetal tachyarrhythmia and atrioventricular block.
FETAL PROCEDURES-open fetal surgery and laser vessel ablation
ANTI-THYROID DRUGS-thyrotoxicosis

Pleuroamniotic shunting
INDICATIONS
•Pleural effusion
•Thoracic cystic lesions
•Congenital cystic adenomatoid
malformation
•Pulmonary sequestration
•Pulmonary lymphangiectasia

Fetal albumin therapy
• Fetal hypoproteinemia appears to be a secondary effect.
• It may occur in a third of non immune hydrops fetus.
• It is distributed equal in frequency in groups with a high and low
UVP exception being twin to twin transfusion syndrome.
• Practice of giving fetal albumin in absence of knowing cardiac
status and albumin level cannot be recommemded, but some
suggest its use.
(Maeda H, Koyanagi T et al : intrauterine treatment of nonimmune hydrops fetalis.
Early Hum Dev 1994;29:241-249 )

• Most of the times such fetuses are delivered
with elective cesarean section.
• No evidence that mode of delivery has a
marked effect on outcome.
• Pediatric team should be aware about the
nature of fetal problem before delivery as
resuscitation is often difficult and adequate
senior assistance must be available.
• High incidence of third stage complications
should not be overlooked.

The ABCs of resuscitation of newborn with hydrops

Delivery room resuscitation of newborns with hydrops

A hydropic neonate under extensive intensive care

Complications
• Prenatal complications – preterm rupture of membranes – risk of
chorioamnionitis, preeclampsia, anaemia, hydramnios, and placental
abruption. In event of fetal surgery, the maternal risk include
anaesthetic risk, fluid overload and electrololyte imbalance and uterine
hemorrhage.
• Maternal mirror syndrome- mother developes pre eclampsia along with
severe edema similar to that of fetus. It is caused by vascular changes
in swollen hydropic placenta(Midgley and hardrug 2000) or by
antiangiogenic factors produced by hyperplacentosis(kusanour’s and
co-work 2008).
• During labor and delivery –
1.Preterm labor and dystocia.
2.Caesarean may be required in those associated with malpresentations
and cord prolapse.
3.Abruption associated with membrane rupture in polyhydramnios.
4.Postpartum hemorrhage(primary and secondary).
5.Retained placenta.
(Ville Y, Hecher K, Ganong A, et al:Endoscopic laser coagulation in the
management of severe twin-twin transfusion syndrome, BJOG 1998;105:44-
453.)

Summary of management options of fetal hydrops

Autopsy
• Autopsy should be recommended in all cases of fetal
or neonatal death or pregnancy termination.
Amniotic fluid and/or fetal cells should be stored for
future genetic testing. (by SOGC 2013)
• Detailed postnatal evaluation by a medical geneticist
should be performed on all cases of newborns with
unexplained non-immune hydrops.
Knisely AS. The pathologist and the hydropic placenta, fetus, or infant. Semin
Perinatol 1995;19:525–531.

Prognosis
• Perinatal death rate is 40-98%.
• Worst prognosis is seen in anatomic malformations found in
40% of cases.
• Only cases with CMV and arrhythmias without structural
malformations have spontaneous resolution.
• If hydrops was evident before 24 weeks then fetal mortality rate
was 95%. Euploid fetuses with hydrops who survived upto
24weeks and have a structurally normal heart had survival rate
of 20%.(Mc Coy and colleagues, 1995).
• Risk of recurrence is low unless etiology is genetic.
• Hydrops usually persists or worsens with time, it occasionally
resolves spontaneously.
• OVERALL OUTCOME FOR HYDROPS FETALIS OF ANY
CAUSE IS GENERALLY POOR.
Huang HR, Tsay PK, Chiang MC, Lien R, Chou YH. Prognostic factors and clinical
features in liveborn neonates with hydrops fetalis. Am J Perinatol 2007;24:33–
38.

RECOMMENDATIONS BY SOGC –
• All patients with fetal hydrops should be referred promptly to a tertiary
care centre for evaluation. Some conditions amenable to prenatal
treatment represent a therapeutic emergency after 18weeks.
• Fetal chromosome analysis and genetic microarray molecular testing
should be offered where available in all cases of non-immune fetal
hydrops.
• Imaging studies should include comprehensive obstetrical ultrasound
and fetal echocardiography.
• Investigation for maternal–fetal infections, and alpha-thalassemia in
women at risk because of their ethnicity, should be performed in all
cases of unexplained fetal hydrops.
• To evaluate the risk of fetal anemia, Doppler measurement of the
middle cerebral artery peak systolic velocity should be performed in all
hydropic fetuses after 16 weeks of gestation.
• Detailed postnatal evaluation by a medical geneticist should be
performed on all cases of newborns with unexplained non-immune
hydrops.
• Autopsy should be recommended in all cases of fetal or neonatal death
or pregnancy termination.

Conclusion
• Fetal hydrops is uncommon, but serious condition with a
complex pathophysiology; it is associated with a wide range of
etiologies and carries a poor prognosis.
• Comprehensive antenatal and postnatal investigatios are
necessary if the cause has to be identified, as the diagnosis
may not be made in as many as quarter of cases.
• Antenatal therapy should be directed at a specific pathological
condition, but is possible in less than a third of cases.
• In short, the largest impact of NIH is made by implementing
screening programs both preconceptually(E.g. populations at
risk for alpha thalassemia) and antenatally(E.g. nuchal
translucency; monochorionicity and TTTS surveillance; anomaly
scan, especially cardiac scans and being alert to outbreaks of
parvovirus B19 infections)

Managing Nonimmune hydrops fetalis

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