2. Contents
1. Definitions
2. The concept of Rh alloimunization
3. Historical perspective
4. Introduction to fetal hydropis
1. Pathophysiology
2. Clinical manifestation
3. Management
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3. Objectives
• At the end of this lecture, you will be able to
✓ Understand the concept of Rh sensitization
✓ Narrate the historical milestones associated with Rh sensitization
✓ Explain the pathophysiology of Rh sensitization
✓ Outline the management of women with Rh – blood group
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4. Definitions
• Sensibilization
✓ Alloimmunized but anti – body titer is negative
• Sensitization
✓ Anti – body titer screen is detectable
• Rh antigen
✓ Rhesus antigen
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5. Concept of Rh Sensitization
• Exposure to foreign red cell antigens ➔ Production of anti – red cell
antibodies
✓ This process is called red cell alloimunization
✓ It can also be called: Rhesus alloimmunization or Rhesus Sensitization
• These formed antibodies will be actively transported across the
placenta and destroy fetal RBC
✓ This will lead to fetal anemia, hyperbilirubinemia and finally hydrops
fetalis
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7. Historical Perspective
• 1609
✓ First case of HDFN described by a midwife in French
✓ French literature: Twin gestation, the first was stillborn and the second
developed jaundice and died soon latter
• 1932
✓ Diamond2 proposed that the clinical entities of erythroblastosis fetalis,
icterus gravis neonatorum, and hydrops fetalis represented different
manifestations of the same disease
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8. • 1939
✓ Levine and Stetsondescribed an antibody in a woman who
gave birth to a stillborn fetus
✓The patient experienced a severe hemolytic transfusion reaction
after later receiving her husband’s blood
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9. • 1940
✓Landsteiner and Weiner injected red blood cells from rhesus monkeys into
rabbits
✓The antibody isolated from these rabbits was used to test human blood
samples from whites, and agglutination was noted in 85% of individuals
•1941
✓Levine and colleagues were able to demonstrate a causal relationship
between Rhesus D (RhD) antibodies in RhD-negative women and HDFN in their
offspring
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10. • 1945
✓ Wallerstein started therapy for HDFN by exchange transfusion
✓ Sir William Liley
o Proposed the use of amniotic fluid bilirubin assessment as an indirect measure of the
degree of fetal hemolysis
o Started fetal intraperitoneal transfusion
✓ Charles Rodek
o First successful IVT
o One year after this trial researchers from Denmark performed similar successful IVTs
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11. •1990
✓ Introduction of genetic techniques using amniocentesis to determine
fetal red cell typing
• 21st century
✓ Noninvasive detection of fetal anemia through Doppler ultrasound of
the fetal middle cerebral artery (MCA) and the usue of fetal typing
through cell – free – fetal DNA in maternal plasma
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12. • History of Rhesus prophylaxis
✓The history of rhesus prophylaxis can be traced to three unique
individuals
oVincent Freda ➔ Obstetric resident
o John Gorman ➔ Pathology resident
o William Polak➔ Senior proteinist
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13. Introduction
•Hydrops fetalis (Latin) = Edema of the Fetus
✓Defined as a collection of fluid in at least two serous compartments
•Is of 2 types
✓Immune hydrops and
✓Nonimmune hydrops
oMore common
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14. Immune Hydrops
•Red Cell Alloimmunization
✓Formation of antibodies for red cell antigens
✓Perinatal consequence
oHemolysis and
oAnemia
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15. Diagnostic Methods
1. Maternal antibody determination
2. Fetal blood typing
3. Amniocentesis to follow the severity of HDFN
4. Fetal blood sampling
5. Ultrasound
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17. •Epidemilogy
✓15% of world population Rh negative
✓Sensitization declining currnetly
o Antental and Postpartum administration of RhIG
✓Why do cases still continue to occur?
o Maternal sensitization in the first two trimesters of pregnancy,
o Inadvertent omission of RhIG, and
o Inadequate dosing after delivery
o Low ANC attendane and Low socioeconomic status
o No immune globulins to prevent alloimmunization to other red cell
antigens
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18. • Incidence of HDFN
✓ 1st pregnancy ➔ Near zero
✓ 2nd Pregnancy ➔ 3%
✓ 3rd pregnancy ➔ 10%
✓ Incidence rises with subsequent pregnancy
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19. •Pathogenesis
✓Fetal-maternal interface is not an absolute barrier
oConsiderable cell trafficking
✓Fetomaternal Hemorhage
oAdequate dose of putative antignes (foreign fetal red cell antigens) →
Stimulate the maternal immune system → B- Lymphocyte clones that
recognize the foreign fetal red cell antigens established → Immunoglobulins
produced → titer detected 5 to 16 weeks after the sensitizing event
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20. • Causes of fetomaternal hemorrhage
✓ Labor and delivery
✓Abruption placenta
✓ Ectopic pregnancy
✓Abortion
✓GTD
✓ Rh +ve blood transfusion
✓ Absent cytotrophoblast placenta (defective barrier)
✓Grandmother theory
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21. • The immune response of an Rh-negative individual to RhD-positive
red cells has been characterized into one of three groups:
✓ (1) responders ➔ 60 – 70%
✓(2) hyporesponders ➔ 10 – 20%
✓(3) nonresponders 10 – 20%
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23. •In subsequent pregnancies
✓B-lymphocytes will have the memory of foreign invasion (by
foreign fetal antigens) → Upon second exposure B-lymphocytes
will be transformed into Plasma Cells → Proliferate rapidly and a
large mass of IgG is produced →Readily crossess the placenta
→Attaches to fetal erythrocytes → Sequestered by the MȻ in the
fetal spleen → Extravascular hemolysis → Anemia
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25. •Anemia - hallmark of red cell alloimmunization
✓ Enhanced hematopoiesis
o Bone marrow
➢ When hemoglobin deficit exceeds 2 g/dL
o Liver
➢ When hemoglobin deficit exceeds 7 g/dL
✓ Increased umbilical artery lactate level is noted when the fetal Hgb falls below 8 g/dL
✓ Increased venous lactate can be detected when the hemoglobin level falls below 4 g/dL
✓ Cardiac output increases
✓ 2,3-DPG levels are increased
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26. •Why hydrops fetalis in red cell alloimmunization?
✓Proposed mechanisims
1. Liver shifted to erythrocyte production
➢Decreased plasma colloid osmotic pressure
2. Tissue hypoxia
➢Increased capilary permeability
3. Iron overload from hemolysis
➢Free radical formation
4. Increased central venous pressure
➢Impaired lymphatic drainage because of raised central venous pressure
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27. ✓Male fetus
oBad prognositic factor
➢13 fold increased risk of hydrops
➢ 3.38 fold increased risk of perintal mortality
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28. •Diagnosis
✓ Maternal antibody determination
o Antibody screening
o Titer
o Critical titer
✓ Paternal zygosity
o Heterozygous Vs Homozygous
✓ Fetal genotype testing
o Amniocentesis
o Cell free fetal DNA
✓ MCA-PSV
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35. •First Sensitized Pregnancy
✓Sesitized ➔ follow titer till it reaches critical titer ➔ Once critical titer is
reached start follow up with MCA PSV ➔ If PSV > 1.5 MoM take cord
blood (cordocentesis) for hct determination ➔ If cord blood hct < 30
start intrauterine transfusion ➔ Then deliver at 37-38 weeks of gestation
•Previsouly sensitized pregnancy
✓Start MCA PSV at 18 weeks of gestation
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36. Intrauterine Transfusion
Intravascular
◦ Higher survival
◦ Less ET
◦ Shorter NICU stay
◦ Which vessel?
◦ Dactus venosus
◦ Where?
◦ Intrahepatic
Intraperitoneal
◦ In nonhydropic fetuses
◦ Gestational age earlier than 22 wks
◦ Slow and stable
◦ Absroved 7-10 Days
◦ Serves as a reservior between
transfusions
◦ Amount of blood
◦ (GA-20) X 10
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37. Complications of IUT
Perinatal loss ➔ 1.2 – 3.8%
Fetal distress needing emergent
delivery ➔ 5%
Rare
◦ PPROM
◦ Chorioamnionitis
The need for neonatal transfusion
because of bonemarrow suppression
by donor antibodies
Neurodevelopmental impairement ➔
4.8%
Hearing loss
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38. Other options of management
Plasmapheresis
IVIG
Artificial insemination with red cell
antigen–negative donor semen,
Surrogate pregnancy, or
preimplantation diagnosis (if the father
is heterozygous)
Monoclonal anti-D blocking antibodies
Protease inhibitors
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39. Prevention of Sesitization
O neg universal donor during emergency
RhIG
◦ Blunt abdominal trauma in pregnncy
◦ Early pregnancy complications
◦ ANC
◦ Obstetric procedures
◦ at 28 weeks
◦ at 40 weeks
◦ after delivery
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41. 41
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Only three antibodies—anti-RhD, antiRhc, and anti-
Kell (K1)—cause significant enough fetal hemolysis
that treatment with IUT is considered necessary.
85% of cases involved anti-D; 10%, anti-K1; and 3.5%,
anti-c. In addition, one case each of anti-E, anti-e,
and anti-Fya was also reported
42. Is suppression of alloimmunization possible?
◦ Many trials failed
◦ Rh hapten
◦ Intensive plasma exchange
◦ High-dose IVIG administration
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45. Nonimmune Hydrops
• Nonimmune Hydrops
✓ Heterogeneous disorder with a large number of possible
causes and associations
✓ Elucidation of the cause is of primary importance,
✓ Perinatal mortality rate of 52% to 98% is typical
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46. •Initial Symptoms and Signs
✓Routine Vs Ultrasound ordered for specific indication
✓Ascites is the earliest symptom
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47. •Maternal complications of pregnancy are increased in Nonimmune Hydrops
✓Hydramnios,
✓Pregnancy-induced hypertension,
✓Severe anemia,
✓Postpartum hemorrhage,
✓Preterm labor,
✓Birth trauma,
✓Gestational diabetes,
✓A retained placenta, or difficult delivery of the placenta are all frequently
mentioned in large series
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48. •Mirror syndrome (Pseudotoxemia)
✓Rare
✓ Patients generally experience edema or pulmonary
edema, and they may have hypertension and proteinuria
✓The patients may be gravely ill but recover after delivery
✓The syndrome may also develop after the birth
✓ As the fetal hydrops reversed,so did maternal symptoms,
and a term delivery subsequently occurred
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49. •Ultrasonography
✓NIH is more commonly defined as:
o Edema with one or more effusions, or
o Effusions in at least two spaces—that is, two of the following must be present:
➢Ascites,
➢Pleural effusion,
➢Pericardial effusion, or
➢Skin edema
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54. ✓Metabolic Diseases
o Lysosomal storage diseases
o DM
✓Infection
o TORCHS
o Parvovirus B19
✓Other malformations
o Chondrodysplasias
o Fatal dwarfing syndromes
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55. •Management
✓ Depends on etiology, gestational age, and signs and
symptoms
✓Maternal compromise, such as preeclampsia or antenatal
hemorrhage - terminate the pregnancy regardles of the
outocme
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56. •Recurrence Risk
✓Do not reasure parents with “this condition does not recure”!
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58. •Comments and Recommendations
✓Chart keeping
o Adress
o Order
o Time
✓Cervical rippening
✓ TORCHS Screen
✓Anti D?
✓Cord blood sample?
✓Partograph in IUFD?
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59. References
1. Robert K. Creas, et al., CREASY & RESNIK'S MATERNAL-FETAL MEDICINE
Principles and Practice 7ed2014: Saunders, an imprint of Elsevier Inc.
2. Gabbe, et al., Obstetrics: Normal and Problem Pregnancies 7ed2017:
Elsevier, Inc.
3. DUTTA, D., DC Dutta's Textbook of Obstetrics including Perinatology and
Contraception. 7th ed2013, India: Jaypee Brothers Medical Publishers (P) Ltd.
4. UpToDate 21.2
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