1. A New Look at Hydrops Fetalis
Laura Klee RNC MSN

2. Hydrops fetalis

3. Class Objectives
At the end of this class, the learners will be able to: 1. Define the criteria used to diagnose hydrops fetalis 2. Compare immune and non-immune hydrops 3. Discuss the various causes of hydrops 4. Describe the basic pathophysiology of hydrops 5. Discuss the importance of identifying both the presence of hydrops in the fetus and the underlying cause of hydrops during gestation 6. Discuss basic care of the neonate with Hydrops and survival outcomes.

4. Hydrops Fetalis
Severe fetal condition in which there is excessive accumulation of fetal fluids in the extravascular compartments
and is the end stage of a number of conditions
Characterized by the following criteria
Severe subcutaneous edema—often with hepatosplenomegaly– and with 2 of the following:
Pleural effusions Pericardial effusions Ascites
And antenatally, polyhydramnios and thickened placenta

5. Hydrops in newborn

6. Two Main Types of Hydrops
Immune Hydrops [IHF]
Secondary to maternal RBC alloimmune response to fetal antigens
Mother develops sensitization to paternally* derived antigens on fetal RBCs [Rh (D and E), and rarely Kell, Duffy/Fya, Kidd/ Jka and ABO]
Antibodies produced cross the placenta and attack/lyse fetal RBCs resulting in severe anemia and CHF
New reports also implicate IV drug abusers who share needles becoming inadvertently sensitized
This used to be the main cause of hydrops, but is no longer the most common cause

7. Hemolytic Disease of the Newborn
10% of cases of Hydrops
The severe manifestation of HDNB aka Erythroblastosis fetalis
RhoGAM has drastically reduced the occurrence of IHF
Maternal antibodies attack on the fetal RBCs leads to
Massive hemolysis
Hyperbilirubinemia soon after birth
Liver failure
Can lead to decreased protein and albumin
Coagulopathies
Severe Anemia
Congestive heart failure leads to hydrops

8. Immune Hydrops Severe anemia leads to Decreased O2 carrying capacity
This leads to organ failure and death if severe
Heart failure ensues due to attempts at compensating for anemia, but also due to hypoxic damage to the myocardium
Heart failure leads to increased CVP, back pressure on liver with congestion as well as a reduction in the ability of the thoracic duct to return fluid from the thoracic duct
A damaged liver leads to decreased production of plasma proteins and albumin leading to decreased plasma proteins and oncotic pressure
Endothelial damage leading to leaking capillaries

9. Development of Hydrops
Normal return of intersitial fluid to veins through lymphatics
Blood Capillaries
Interstitial fluid
Lymph capillaries & veins
Large veins
Mechanisms that can cause increased interstitial fluid and cause subsequent Hydrops
Increased cap permeability or
Decreased oncotic pressure
Blood capillaries
Obstruction to lymph flow
Impaired venous return or cardiac failure
Perinatology.com

10. Nonimmune Hydrops Fetalis (NIHF)
Cases without evidence of alloimmunization
‘Everything else’
MULTIPLE causes
Now responsible for up to 90% of cases
High fetal mortality rate
High neonatal mortality rate
Estimated incidence 1:600—3 to 4000

11. What causes hydrops Disorder of fluid [distribution] management
Fluid overload
Severe anemia
Severe hypoxemia, especially ischemic/anoxic injury to the heart and liver
Which causes cardiac failure and increased CVP
Liver failure
Decreased oncotic pressure
Increased vascular permeability
Interference with lymphatic removal of fluid and return to the heart

12. Pathophysiology of NI Hydrops

13. Etiologies of NIHF Grouping Percentage Cardiovascular 21% / 20.1%
21% / %
TTTF/PLACENTA
5.6% / 4.1%
Idiopathic
17.8% / %
Syndromes
4.4% / 5.5%
Chromosomal
13.4% / %
Miscellaneous
3.7% / 3.6%
Hematologic
10.4% / %
Urinary tract
2.3%
Infections
6.7% / %
Inborn Errors
1.1%
Thoracic
6% / %
Extra thoracic tumors
0.7%
Lymphatic dysplasia
5.7% / %
GI tumors/masses
0.5%
Bellini et al and 2015

15. Cardiac causes of NIHF Responsible for about 1 in 5 cases of NIHF
Both right and left sided CHD
Systolic and/or diastolic overload conditions
High output conditions
Congestive heart failure conditions
Impaired Right heart filling conditions
Thrombosis
Tumors
Cystic hygroma

16. Causes of NIHF Cardiac Complex CHDs. Including heterotaxy syndrome
Arrhythmias, especially tachyarrythmias like SVT
Complete Heart block
Maternal SLE etc. which can cause immune mediated damage of the fetal heart causing arrhythmias and heart block
Myocarditis
Cardiomyopathy
Endocardial fibro elastosis
Notably anything that obstructs blood flow and results in cardiac failure, right atrial enlargement, right heart failure with increased CVP/preload
Arterial calcification
Intracardiac tumors (intrapericardial teratoma, rhabdomyoma…)

17. Causes of NIHF Vascular defects Arteriovenous malformations
Diffuse hemangiomatosis
Placental, umbilical cord, abdominal, liver, etc. hemangiomas
SVC or IVC occlusion
Absent ductus venosus
Umbilical torsion
Tumors causing external compression

18. Chromosomal Disorders
Beckwith Wiedemann (trisomy 11p 21)
Cri du chat (chromosomes 4 and 5)
Opitz G syndrome (5 p duplication)
Trisomies 10 mosaic, 13, 18, 21
Turners (45 XO)
Common threads in this disparate group:
Severe CHD
Disorders of lymph drainage
AV malformations
Impaired production of functional RBCs
Presence of thoracic or abdominal masses that impair venous return

19. Hematologic causes of NIHF
Hemoglobinopathies
Alpha thalassemia
No normal alpha hemoglobin chains
Destroys oxygen release at normal physiologic levels
Results in extreme hypoxia
Fetal demise common
Neonates with congestive heart failure, ascites, edema, hepatospenomegaly, prenatal and post natal asphyxia.
Reliant on repetitive transfusions with risks for contracting blood borne infections, and developing iron overload
Might benefit from stem cell transplant
Was universally fatal until in utero diagnosis and repeated in utero transfusions became available
With transfusions, chelation therapy for iron overload, and advent of stem cell transplant, the mortality rate is dropping

20. Causes of NIHF Infectious
Maternal/fetal infections TORCHES+ CLAP
Toxoplasmosis Chickenpox
Rubella Lyme disease
CMV AIDS
Herpes simplex Parvovirus B19*
Enterovirus
Syphilis
Lymphocytic choriomeningitis virus (from rat vector)

21. Thoracic Disorders
CPAM [CCAM] Congenital Pulmonary Airway Malformation
Extra-pulmonary sequestration
Congenital hydro or chylothorax
Mediastinal tumors
Constricting/restricting thoracic dystrophies associated with skeletal dysplasias
AVMs and cystic hygromas in the neck/chest
CDH
CHAOS [Congenital high airway obstruction]

22. Lymphatic Disorders Lymphatics Lymphangectasias Congenital Lymphedema
Abnormal dilatation of pulmonary lymphatic vessels
Primary or secondary
Congenital
Secondary to increased CVP in CHD
Congenital Lymphedema
Congenital absence of thoracic duct

23. Placental disorders and TTTF
Twin to twin transfusion
Placental disorder with abnormal vascular communications resulting in a donor and recipient twin
Both twins are at risk for development of hydrops
Anemic twin with CHF
Over-volumized twin with heart failure
If one twin is hydropic, the second one is at increased risk
Untreated mortality is very high, with only 10—15% survival
Treated with antenatal fetal interventions, survival exceeds 80%
Other abnormalities of the placenta also can exist and umbilical venous thrombosis is listed in this group.

24. Genetic syndromes Select achondroplasias
Arthrogryposis multiplex congenita
Eagle Barrett Syndrome (prune belly)
Fryn’s syndrome
Lethal short limbed dwarfism
Noonan syndrome*
Smith Lemli Opitz syndrome
Tuberous sclerosis*
Myotonic dystrophy*
Most of the above are autosomal recessive with 25% recurrence risk. (* Autosomal dominant)

25. Metabolic/Inborn Errors of Metabolism
Lysosomal storage disorders(10/50 types)
Glycogen storage disorders
Mucopolysaccharidosis type IV-A and Hurlers
Niemann Pick Disease
Salla Disease
Hypo and Hyperthyroidism
Carnitine deficiency
Mitochondrial disorders

26. Pathophysiology of Hydrops
Cardiac
Lymphatic disorders
Increased RV pressures lead to increased CVP
Right heart failure/ obstruction leads to back pressure and edema +
Hepatic congestion leads to hypoproteinemia and hypo albuminemia
Decreased oncotic pressure does not favor return of interstitial fluids to the vasculature, which equals—more edema
Also, elevated CVPs prevent return of lymph fluids via the thoracic duct, which…..
Fluid removal from lungs and abdominal cavity is sabotaged by lymphatic abnormalities.
Thoracic disorders
Mass effect/compression on heart limits function and/or compresses lymphatics and limits lymphatic return to venous system

27. Antenatal Diagnosis of HF
Fetal imaging
Doppler studies
Fetal cardiac ECHO
Maternal blood tests
Amniocentesis
Fetal blood sampling
Consultation with neonatology

28. Antenatal Diagnosis of HF
Fetal imaging
Ultrasound will show generalized edema
Enlarged heart
Fluid collections
General cardiac size and function
Doppler studies
Abnormal/obstructed flow in umbilical vessels, ductus venosus, hepatic veins
MCA peak velocity > 1.5 multiples of the median correlates with the degree of anemia with 100% sensitivity
Fetal cardiac ECHO
Anatomy, presence of defects, size of chambers, etc.

29. Antenatal Diagnosis of HF
Maternal blood tests
CBC, indirect Coombs
Kleihauer-Betke test [tests for fetal RCs in mother]
TORCH etc. cultures, PCRs, Acute phase titers
SSA and SSB antibodies [arrhythmias]
Fetal electrophoresis (Southeast Asia)
G6PD deficiency testing
Amniocentesis
Cell retrieval for culture and genetic testing
FISH, karyotype, microarray
DNA for Alpha thalassemia
Fetal lung maturity testing

30. Antenatal Diagnosis of HF
Fetal blood sampling
CBC and direct Coombs
Blood typing
Karyotyping, genetic testing
TORCH and viral serology
Protein and albumin levels
LFTs
Hemoglobin electrophoresis prn
Consultation with high risk perinatology and neonatology

31. Diagnostic Considerations
Etiology matters
Determines prognosis and management
Treatments available for some of the causes
Predicts future recurrence in families
Provides knowledge to parents to facilitate informed consent
Fetal interventions do come with risk
Mirror syndrome may necessitate IMMEDIATE delivery

32. Mirror syndrome Ballantyne Syndrome
Development of severe edema in the mother carrying a hydropic fetus and placenta
Seems to manifest when fetal hydrops is worsening/progressing to fatal hydrops
Associated with mild albuminuria and hypertension
Rarely associated with pre ecclampsia
Etiology is not understood
May necessitate early delivery
Is often associated with fetal demise

33. Available fetal therapy
Anti arrhythmia drugs for fetal arrhythmias
Fetal cardioversion or pacing
In utero transfusion for anemia
Drainage of cystic CPAM lesions with Cyst to amniotic shunt
Rh incompatibility, alpha thalassemia, and Parvo B19
Drainage or shunting procedures for pleural or cardiac effusion or ascites
If aspirated: sent for lymphocyte count, protein and albumin levels, PCR and cultures, ascites fluid sent for creatinine and ionogram
Placental laser therapy or ablation therapy for shared blood vessels in twin to twin transfusion syndrome
Antibiotic or antiviral therapy

34. Fetal Therapy Risks
Maternal antiarrhythmic drugs can cause complications in mother
Digoxin, Furosemide, Amiodarone, Adenosine, Procainamide, Flecainide, Sotolol and Verapamil
Fetal administration of drugs is invasive
Infection, hemorrhage and fetal demise can occur with all invasive procedures
Many fetal therapies have little clinical evidence and are based on small case series

35. Antenatal treatment of pleural effusions with secondary hydrops
29 patients treated with TAS [Thoraco- amniotic shunt placed at mean age 27.6 weeks, but with a range of 21 to 36.9 weeks
Resolution of effusions seen in 58.6%
Overall survival 72.4%
90% of the survivors required an average of 15 days in NICU, with 100% survival
42.9% required intubation % required CTs
2 required Octreotide and 1 had a pulmonary sequestration that was resected.
Persistence of hydrops was associated with mortality
AH Chon, HR Chmait et al 2019

36. EXIT Procedures for Hydrops
Ex utero intrapartum treatment
Partial delivery with placental circulation as bypass
CHAOS with Hydrops
Congenital high airway obstruction syndrome
Unilateral or bilateral pleural effusions with hydrops
Placement of pleural drains prior to intubation and ventilation
CPAM
Removal of large cyst
Subsequent to fetal intervention with displaced shunts

37. CHAOS and Hydrops: EXIT
Airway obstruction from larynx to trachea
Webs
Cysts
Tumors
Double aortic arch
Atresias or severe stenosis
Enlargement of lungs with dilatation of bronchial tree
Signs of fetal heart failure and hydrops due to compression of the heart
EXIT for CHAOS
Deep anesthesia
Partial delivery of baby
Preserved placental circulation
Endoscopic laryngoscopy and bronchoscopy
Relief of airway obstruction if possible
Tracheostomy if needed
Delivery of baby after clamping the cord
Yuan, S. 2018

38. Neonatal Hydrops Fetalis
Like the fetus, the newborn is born with severe edema and fluid collections in pleural, peritoneal, or pericardial spaces
Clinical consequences include
Respiratory compromise and failure from pleural effusions and hypoplastic lungs
Cardiac failure and cardiogenic shock
Hypovolemic shock
Intravascular volume depletion
Hypoglycemia
Acidosis
Renal dysfunction
Hepatospenomegaly
Very low reserves
Anemia if Immune Hydrops or Parvo-related
Hyperbilirubinemia if anemia, hemolysis, or reticulocytosis present

39. Management of Neonatal Hydrops
Antenatal diagnosis will assist in planning
Preparation for delivery after transfer to high risk center with NICU
Family counseling crucial
Direct resuscitation plans
Prognosis
Comfort care
Post death testing and autopsy

40. Preparation for Delivery
Appropriate equipment
Intubation supplies
Umbilical lines
Resuscitation meds, volume, blood products
Paracentesis and/or thoracentesis supplies
Chest tube set up, with chest tube care ongoing
Appropriate personnel
Location in tertiary facility
Nursing, Respiratory care, neonatology
Pediatric subspecialty physicians

41. ABCs in Delivery Room Management
Airway and Breathing: intubation and ventilation to support respiratory failure
Compromised by soft tissue edema, airway malformations or cystic hygroma
Hypoplastic lungs may necessitate increased pressures to ventilate
Immediate thoracentesis or paracentesis required to remove effusions/ascites preventing lung expansion

42. ABCs in the Delivery Room
Circulation: immediate support of myocardial dysfunction and insufficiency
Reversal of intravascular volume depletion
Normal saline and/or blood
Reversal of acidosis and assessment of oxygenation
Treatment determined by type of hydrops
Availability of blood when severe anemia is predicted

43. Immune Hydrops Transfusion to normalize hematocrit
Partial exchange transfusion prn
Aggressive treatment of hyperbilirubinemia, which develops within an hour or so
Adequate hydration
Phototherapy, likely double lights
IVIG
Exchange transfusion based on bili nomogram
Metalloporphyrins [synthetic heme analogs which are competitive inhibitors of heme oxygenase—the rate-limiting enzyme in bilirubin production]
Adequate treatment of late anemia

44. Immune Hydrops Well defined cause of hydrops
Established diagnostic criteria
With a consistent therapeutic approach
Good prognosis
Decreased incidence with use of Rho (D) immune globulin

45. NICU management… Treatment of respiratory failure
Mechanical ventilation
Surfactant
Inhaled nitric oxide [Sildenafil…Milrinone…] for PPHN
Removal of pleural effusions/chest tube management
Support of cardiovascular function
Volume support
Inotropic and pressor support
Correction/palliation of CHD
Intravascular fluid support balanced with excess fluid removal
Fluid resuscitation
Blood replacement [replacement of effusion losses]
Repletion of serum protein and albumin
Diuretics
Base fluids and medications on estimated dry weight [50th percentile for gestational age]

46. NICU management… Treatment of underlying cause
Diagnostic battery to identify cause
Immediate cardiac ECHO, X rays, necessary ultrasounds
Analysis of ascites to r/o leakage of urine versus effusion
Genetics and chromosomes
Metabolic studies
CBC, bili levels, LFTs, type and cross, electrolytes, Ca, Mg etc.
Cultures and viral studies
Supportive care and management of symptoms
Management of temperature
Correction of acid base, electrolyte and glucose abnormalities
Support of oxygenation
Pre and post operative surgical management of surgical candidates
Pain management and sedation
Ongoing search for etiology
Prevention of pressure injury related to poor perfusion and edema

47. Management of skin care
Sick & edematous patients
Severe edema poor perfusion
Mechanical ventilation
Chest tubes
Prevention of pressure injury and device injury
Skin risk assessment daily
Skin condition monitoring
Initiation of Pressure injury bundle
Frequent turning to offload
Fluidized mattress
Gel pillows for head
Mepilex foam dressing on occiput
Follow up with Wound Ostomy RN for all stage 1 injuries
Prevention of device-related injuries
Barrier under IVs and other devices

48. Prognosis and Outcome Issues
Counseling on disease and cause
Follow up with genetics and other specialty services
May be important to counsel for future recurrent risk
Palliative care and pain team consults early
Palliative care for all those with serious life threatening illnesses
Possibly for advanced directives and end of life care
Appropriate pain management for long-term ventilator needs, chest tubes, etc.

49. Management of Chylothorax
Chylothorax is a cause of and complicated by NIHF
Chyle is the lymphatic fluid collected in the splanchnic system via the thoracic duct
Leakage occurs from the thoracic duct or its tributaries
Neonatal chylothorax is often transient and resolves spontaneously but severe congenital chylothorax can persist

50. Management of Chylothorax
Initial treatment of chylothorax can include:
Holding enteral feedings and support of nutrition with TPN
Octreotide—synthetic somatostatin—which decreases chyle production
Decreases splanchnic blood flow
Inhibits of pancreatic secretions
Inhibits GI peptide hormone secretion
Minimizes lymphatic fluid excretion
Use of low fat/no fat formulas supplemented with MCTs and essential fatty acids such as Portgen, Enfaport or Vivonex TEN
Research being done on low-fat breast milk use, which helps resolve the chylothorax but results in poor growth

51. Management of Chylothorax
Chylothorax persisting longer than 5 weeks requires a pediatric surgical consultation
Thoracic duct ligation
Pleuroperitoneal shunt placement
Pleurectomy
15% of chylothorax patients die as a result of complications of therapy

52. Outcomes of Hydrops Correlated strongly with underlying cause
Mortality associated with
decreased gestational age
low 5 minute Apgar score
need for high FiO2 in first 24 hours and use of high frequency ventilation
Mortality with congenital anomalies 57.7%
Mortality with congenital chylothorax 5.9%
Mortality with complete heart block secondary to maternal collagen/autoimmune diseases without structural heart disease 25—35%
Overall survival in the 50% range, but literature still quotes ranges of 50—98%

53. References
Peebles, S. [UAMS] NICU management of Hydrops Fetalis. ANGELS Perinatal Conference uams.edu Bellini, C. et al. Etiology of non-immune hydrops fetalis: A systematic review. American Journal of Medical Genetics Bellini C et al. Etiology of non-immne hydrops fetals: An Update. American Journal of Medical Genetics. 2015: 167 (5): Bellini C. and Hennekam R. Non-immune hydrops fetalis: A short review of etiology and pathophysiology. American Journal of Medical Genetics A: Desilets, V. and Audibert, F. Investigation and management of non-immune hydrops fetalis. Journal of Obstetrics and Gynaecology, Canada (10): e1-14. Hamdan, A and Nimavat, D. Pediatric hydrops fetalis. Available at Chon, A. et al. Long-term outcomes after thoracoamniotic shunt for pleural effusions with secondary hydrops. Journal of Surgical Research : Tran, L/ Cheung, K and Kirby, M. Trisomy 21 and hydrops: Parvovirus B 19 or transient abnormal myelopoiesis? Journal of Obstetrics and Gynaecology available at Melber. et al. Novel Mutation un CCPE1 as a cause of recurrent hydrops fetalis from Hennekam lymphangectasia-lymphedema syndrome. Clinical Case reports : Perinatology.com Hydrops Fetalis.. Available at

54. References
Yuan, S. The Application of ex utero intrapartum treatment [EXIT] procedure for cardiothoracic disorders. Signa Vitae (1) EXIT to airway procedures for Congenital High Airway Obstruction Syndrome. Cincinnati Children’s Hospital. Available at Agarwal, A. et al. EXIT procedure for fetal mediastinal teratoma with large pericardial effusion: Case report and review of the literature (8): 1099—1103

55. Lymph system

56. Lymph system Left side [thoracic duct] drains about 75% of the body
Right side drains head and right arm with some of right