1. MANAGEMENT OF RHESUS NEGATIVE PREGNANCY
DR MALLESWAR RAO K
(MBBS, MD, DGO)
FORMER CONSULTANT CSS & HOD
DEPARTMENT OF OBSTETRICS & GYNAECOLOGY
ESI HOSPITAL, SANATHNAGAR
HYDERABAD

2. Outline Introduction Epidemiology Pathophysiology Management
Problems in our setting
Recommendations
Conclusion
References

3. Introduction
The Rhesus (Rh) blood group system is one of the 35 current human blood group systems
It's the second most important system after the ABO system
At present, the Rh system consists of 50 defined blood group antigens (Ag), among which the five Ag D, C, c, E, e are the most important

4. ... Introduction ...
The D Ag, also called the Rh factor is the most immunogenic[1] of them though the others are still clinically relevant
The Rh factor is a red cell surface antigen named after the rhesus monkey in which it was first discovered.[1]
An individual either has or does not have the D antigen on the surface of their red blood cells (RBCs)

5. ... Introduction ...
The status is usually indicated by the suffices Rh+ for those that have, or Rh- for those who lack the D antigen
These suffices are attached to the ABO blood type
An Rh-negative pregnant woman is one who lacks this antigen on the surface of their red cells.

6. ... Introduction ... Historical time line
1937: Rh blood type discovery by Karl Landsteiner & Alexander Wiener, and noted to be distinct from ABO blood type
1939: The D antigen was incidentally discovered but yet unnamed. This followed a case of haemolytic disease of the newborn observed in a the infant of a 25 year old G2 P1 woman, blood group O who received O type blood
This case was subsequently published[2] by Philip Levine and Rufus Stetson

7. ... Introduction ... ... Historical time line ...
1940: This unnamed factor was realised to be similar to the earlier discovered blood type and a connection was made to it[3]
1946: Exchange transfusion created by Wiener for treatment of Rh disease
1960: The concept of anti-RhD for the prevention of Rh disease was proposed by Ronald Finn
1963: First successful intrauterine transfusion for treatment of Rh disease was carried out by Sir William Liley

8. ... Introduction ... Historical time line
1964: First prophylactic injection for Rh disease was given
1968: Immunoglobulin G antibody was first approved for use in USA (as RhoGAM) and mcg within 3 days postpartum
1973: Reports in the USA said 50,000 babies' lives had been saved since approval
1981: Rh IgG approved for routine postpartum and antepartum administration by the US Food and Drug Administration

9. Epidemiology
Globally, the Basque population (of Spain) has the highest incidence of Rh negativity (30-35%)[4]
Otherwise,
Whites: 15-16%
African Americans: 8%
Black Africans: 4%
Asians and others, 2% or less

10. ... Epidemiology Nigerian studies
4.5% prevalence rate at Enugu,[5] Southeast
0.7% incidence rate at Kaduna,[6] North
5.5% prevalence rate at Ogbomosho,[7] Southwest

11. Erythroblastosis Fetalis (Red Cell Alloimmunization)
the first description of erythroblastosis fetalis (hemolytic disease of the newborn) dates back to 1609 until the early 1900s that the role of alloimmunization in the pathogenesis of erythroblastosis was established In the past, Rh alloimmunization also has been referred to as Rh sensitization or Rh isoimmunization.

12. Pathophysiology
Two commonest systems for blood group classification:[8]
ABO system
Rhesus system
ABO system: Groups A, B AB, O antigen (Ag)
Rhesus system: C, c, D, E, e and G.[4]
There's no 'd' Ag. The letter represents absence of 'D' Ag
The D antigen is considered to be the most immunogenic (aka Rh factor)

13. ... Pathophysiology ...

14. ... Pathophysiology ...

15. ... Pathophysiology ...
There are two possible alleles for each of the c or C, D and e or E
An individual inherits one haplotype from each parent
Rh positive: presence of at least one of either C, D or E antigens regardless of the combination (ie, homozygous or heterozygous)
Rh negative: cde/cde genotype (always homozygous)

16. ... Pathophysiology ...

17. ... Pathophysiology ... The D antigen
The Rh-positive father may be homozygous (45%) or heterozygous (55%) for D
If homozygous for D, all children will test positive
If heterozygous, his children will have a 50% chance of being RhD-positive
Thus if 'D' antigen is specifically tested, its absence will give a negative result regardless of the presence of the other antigens (C, E)

18. ... Pathophysiology ...

19. ... Pathophysiology ...
The amount of foetal blood necessary to produce Rh incompatibility varies, but as little as 0.1 mL of Rh+ cells have been documented.[4]
Studies have suggested that up to 30% of persons (non- responders) with Rh- blood never develop Rh incompatibility even when challenged with large volumes of Rh+ blood[1]
Rh alloimmunisation occurs by 1 of 2 mechanisms
After incompatible blood transfusion

20. ... Pathophysiology ...
After foeto-maternal haemorrhage between mother and an incompatible foetus
Foeto-maternal haemorrhage may occur during pregnancy (10%) or delivery (90%)[1]
Notwithstanding, foetal RBCs have been detected in the maternal blood in all three (7, 16, 29%) trimesters without an apparent predisposing factor[4]
The initial maternal response to Rh sensitisation is low levels of immunoglobulin (Ig) M antibodies (Ab)

21. ... Pathophysiology ... Within 6 weeks to 6 months, IgG Ab are formed
These are confined to maternal circulation being unable to cross the placental barrier
Within 6 weeks to 6 months, IgG Ab are formed
These are able to cross the placenta and destroy foetal Rh- positive cells
Therefore, first-born infants with Rh-positive blood type are not affected
The short period of 1st exposure of mother to foetal RBCs is insufficient for production of significant IgG Ab response

22. ... Pathophysiology ...
Subsequent pregnancies may trigger a rapid & robust Ab response - Anamnestic response
Anamnestic theories:
Grandmother theory
“Sensibilization” theory
Maternal O blood type appears particularly protective

23. ... Pathophysiology ... Sequence of inutero events
Maternal IgG enters foetal circulation via placenta
Destruction of foetal red cells occur - foetal anaemia [HCT<30%]
Haem is formed and converted to bilirubin – foetal hyperbilirubinaemia
Both are neurotoxic, but effectively cleared by placenta and metabolised by the mother
Extramedullary erythropoeisis is stimulated
Immature erythroblasts are produced

24. ... Pathophysiology ... When cell destruction exceeds production
Severe anaemia occurs
More demand on extramedullary sites to produce more red cells – hepatosplenomegaly
Heart failure eventually results, with ascites, oedema and pericardial effusion – erythroblastosis foetalis
Hydrops foetalis, occurs when the haematocrit falls below 15%. Often results in foetal death shortly before or after birth
Male to Female foetus = 13.1 to 1

26. ... Pathophysiology ...
The risk and severity of sensitisation response increases with each subsequent pregnancy involving an ABO- compatible foetus with Rh-positive blood
Without prophylaxis, this risk is 16% after two deliveries;
1.5-2% occur antepartum
7% within 6 months of delivery
7% manifest early in 2nd pregnancy
With prophylaxis, the risk drops to 0.1%

27. ... Pathophysiology
The aforementioned risk depends on the 3 main factors
Volume of transplacental haemorrhage
Extent of the maternal immune response
Concurrent presence of ABO incompatibility (protective – risk drops to 1.5-2%)[4]
Rh incompatibility is only of medical concern for females who are pregnant, or plan to get pregnant in future

28. Maternal Immunologic Response:
30% of Rh-negative individuals appear to be immunologic “nonresponders”who will not become sensitized
ABO incompatibility diminishes the risk of alloimmunization to about 1.5% to 2.0% after the delivery of an Rh-positive fetus
The effect is most pronounced if the mother is type O and the father is type A, B, or AB.

29. Management
This includes history taking, clinical examination, appropriate investigations, and treatment
Two groups of women are catered for
Unsensitised Rh-negative women
Sensitised Rh-negative women
There is usually no specific finding on the history and clinical examination for the woman that is not sensitised

30. Interesting, right?
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