RHESUS BLOOD GROUP

Clinical impact of Rhesus disease

Mechanism of action of anti-D

Recommended route / dose 

Available products

Recommendations for anti-D prophylaxis

Routine antenatal prophylaxis - Summary of NICE Guidelines

Half-life of anti-D & recurrent sensitizing events

Evidence

RHESUS BLOOD GROUP

• Six major antigens - C, D, E; c,d,e. However, there are at least 50 antigens in this blood group system
• An individual with the C antigen cannot have the c antigen; same for D & E antigens
• D antigen is most antigenic - individuals with D antigen are Rhesus positive. 16% of Caucasians are Rhesus negative while 0.3% of Asians are Rhesus negative
• Immune response to Rhesus antigens is slow and peak antibody titres are attained 2-4 months after exposure. Transfusion reaction in an unsensitized individual is therefore delayed
• D antigen causes severe Rhesus disease. C & E antigens can cause mild fetal haemolysis. Usually the first pregnancy is not affected, but may be if the mother had received incompatible blood products
• The offspring of two Rh negative individuals must be Rh negative. The offspring of a Rh negative and a Rh positive individual may be Rh negative as the Rh positive parent may be heterozygous

Clinical impact of Rhesus disease

2005 (NICE estimates)

• ~ 65,000 RhD-positive babies born to RhD negative women
• Without routine antenatal prophylaxis, but with the use after sensitising events, 1% of women would have become sensitised.
• Of these, approximately 550 would go on to have a further pregnancy.
• ~ 520 affected pregnancies in England and Wales per year would require close monitoring
• ~10% of these babies would require intrauterine transfusions.
• Fetal anaemia and HDN would lead to:

~37 fetal or neonatal deaths,

~21 children with minor developmental problems

~8 children with major developmental problems.

1971 (Walker et al.)

• 14% of affected pregnancies resulted in stillbirths.
•  Of the survivors, 30% had severe disease almost certainly fatal without treatment
•  An additional 30% had moderate disease which would manifest as severe hyperbilirubinaemia that untreated may result in brain damage and/or death.
•  Therefore, it can be estimated that approximately 50% of children with untreated haemolytic disease of the newborn (HDN) will die of the disease or develop brain damage

The use of anti-D immunoglobulin has contributed to substantial reduction in perinatal morbidity and mortality from Rhesus disease.

Mechanism of action

• Administered anti-D immunoglobulin binds to and removed Rh +ve fetal red cells before the maternal immune system encounters these cells and becomes sensitized.

Recommended route / dose                             

• im, some available iv; s/c if bleeding disorder

Sensitizing events

• At least 250 IU before 20 weeks
• At least 500 IU after 20 weeks + Kleihauer test
• Administer within 72h of event
• 500IU covers 4ml fetal red cells
• 100-125 IU per additional ml of fetal red cells

Post-partum

• 500 IU within 72h of birth if baby Rh +ve
• Need a robust system to identify Rh +ve babies and ensure treatment is not missed or delayed

Where bleeding continues intermittently after 12 weeks gestation anti D should be given at 6 weekly intervals

Available products

RAADP = Routine Antenatal Anti-D Prophylaxis

 Recommendations for anti-D prophylaxis

• Intramuscular anti-D Ig is best given into the deltoid muscle as injections into the gluteal region often only reach the subcutaneous tissues and absorption may be delayed.
• Anti-D Ig should be given as soon as possible after the sensitising event but always within 72 hours. If it is not given before 72 hours, every effort should still be made to administer the anti-D Ig, as a dose given within 9-10 days may provide some protection
• Therapeutic termination of pregnancy: Anti-D Ig should be given to all non-sensitised RhD negative women having a therapeutic termination of pregnancy, whether by surgical or medical methods, regardless of gestational age
• Ectopic pregnancy: Anti-D Ig should be given to all non-sensitised RhD negative women who have an ectopic pregnancy
• Spontaneous miscarriage: Anti-D Ig should be given to all non-sensitised RhD negative women who have a spontaneous complete or incomplete abortion after 12 weeks of pregnancy. Anti-D Ig should be given when there has been an intervention to evacuate the uterus. On the other hand, the risk of immunisation by spontaneous miscarriage before 12 weeks' gestation is negligible when there has been no instrumentation to evacuate the products of conception and anti-D Ig is not required in these circumstances
• Threatened miscarriage: Anti-D Ig should be given to all non-sensitised RhD negative women with a threatened miscarriage after 12 weeks of pregnancy. Where bleeding continues intermittently after 12 weeks' gestation, anti-D Ig should be given at 6-weekly intervals. Routine administration of anti-D Ig is not recommended before 12 weeks gestation. However it may be prudent to administer anti-D Ig where bleeding is heavy or repeated or where there is associated abdominal pain particularly if these events occur as gestation approaches 12 weeks
• Prophylaxis following sensitising events before delivery - Anti-D Ig should be given to all non-sensitised RhD negative women after the following potentially sensitising events during pregnancy:
  
  1) invasive prenatal diagnosis (amniocentesis, chorion villus sampling, fetal blood sampling)
  
  2) other intrauterine procedures (e.g. insertion of shunts, embryo reduction)
  
  3) antepartum haemorrhage
  
  4) external cephalic version
  
  5) closed abdominal injury
  
  6) intrauterine death
• Postnatal prophylaxis - At least 500 IU of anti-D Ig must be given to every non-sensitised RhD negative woman within 72 hours following the delivery of a RhD positive infant. A test to detect FMH greater than 4ml must also be undertaken, so that additional anti-D Ig can be given as appropriate
• Some women who have received anti-D Ig during pregnancy may have detectable anti-D in their blood at delivery. Because it may be difficult or impossible to distinguish between such passive anti-D Ig and weak anti-D resulting from early immunisation, anti-D Ig should be given to any eligible woman with weak anti-D antibody at delivery unless it has been clearly confirmed that she is already sensitised
• Transfusion of RhD positive blood components
  RhD positive platelet transfusions: Prophylaxis against possible Rh alloimmunisation by red cells contaminating the platelet product should be given. Each unit of platelets prepared according to the UK Guidelines from one whole blood donation contains less than 1 X 10 E9 (< 0.1ml rbc). 250iu (50mcg) anti-D Ig should be given following every three adult doses of platelets. Patients who have marked thrombocytopenia should be given the anti-D Ig subcutaneously to avoid the possibility of a haematoma following intramuscular injection.
  Inadvertent transfusion of RhD positive blood: When less than 15ml of RhD positive blood have been transfused to a RhD negative woman capable of childbearing, the appropriate dose of anti-D Ig should be given (Grade B recommendation). When more than 15ml have been transfused, it is preferable to use the larger anti-D Ig IM preparation (2500iu or 5000iu). The dose should be calculated on the basis that 500iu of anti-D Ig will suppress immunisation by 4ml of RhD positive red blood cells.
  
  When more than 2 units of RhD positive blood have been transfused, consideration should be given to undertaking an exchange transfusion to reduce the load of RhD positive red blood cells in the circulation and the dose of anti-D Ig required to suppress immunisation.

Routine antenatal prophylaxis - Summary of NICE Guidelines

• Anti-D immunoglobulin can be administered routinely in the third trimester as prophylaxis against small amounts of FMH that can occur in the absence of observable sensitising events. This is known as routine antenatal anti-D prophylaxis (RAADP)
• The use of anti-D immunoglobulin for RAADP is in addition to the administration of anti-D immunoglobulin following potentially sensitising events, and its use in either indication is not affected by prior use in the other.
• Women given anti-D for sensitising events should still be given routine prophylaxis even if this is due on the following day. Women who have been given routine anti-D should still be treated for sensitising events even if these occur on the following day
• RAADP can be given as two doses of anti-D immunoglobulin of 500 IU (one at 28 weeks and one at 34 weeks gestation), as two doses of anti-D immunoglobulin of 1000–1650 IU (one at 28 weeks and one at 34 weeks gestation), or as a single dose of 1500 IU either at 28 weeks or between 28 and 30 weeks gestation.
• May not be cost-effective and unnecessary when the woman:
  
  1) Has opted to be sterilised after the birth of the baby
  
  2) Is in a stable relationship with the father of the child, and the father is known or found to be RhD-negative
  
  3) Is certain that she will not have another child after her current pregnancy.
  
  However, it may be difficult for the woman to be certain about these factors . A woman's decision not to be given routine anti-D prophylaxis should always be respected.
  
  The difference between routine prophylaxis at 28 and 34 weeks and prophylactic anti-D given because of likely sensitisation should be clearly explained to the woman.
  
  A woman's use of routine prophylaxis at 28 and 34 weeks should not be affected by whether she has already had antenatal anti-D prophylaxis for a potentially sensitising event early in pregnancy.
  
  A woman's use of postpartum anti-D prophylaxis should similarly not be affected by whether she has had routine antenatal prophylaxis or prophylaxis as the result of a sensitising event.
   

Half-life of anti-D & recurrent sensitizing events

• The average biological half life of normal IgG is 23 days
• The half life of anti-D IgG measured by specific antibody activity is ~ 24 days in nonpregnant women and 21 days in pregnant Rh-negative women.
• The lower mean value of antibody concentrations in pregnant women reflects the well-documented transfer of 10-15% of the antibody across the placenta into the fetal circulation.
• Women with recurrent vaginal bleeding in early pregnancy should be given anti-D every 6 weeks
• In late pregnancy (after 20 weeks), a Kleihauer test should be performed to assess feto-maternal haemorrhage and andi-D administered as appropriate. With repeated bleeds, further anti-D should be administered at least every 6 weeks.

Evidence

Meta-analysis was conducted on three groups of studies:
 

• Group 1, involving 6400 women, included the results of four studies (one randomised, three non-randomised) which used a regimen of 500 IU at 28 weeks and 34 weeks and reported results for primigravidae. The rate of postnatal anti-D sensitisation was 0.89% (95% confidence interval (CI) 0.21% to 1.56%) in the control group and 0.30% (95% CI 0.22% to 0.38%) in the group treated antenatally.
• Group 2, involving 11,400 women, included the results of the three studies (none of them randomised) using a regimen of 1500 IU at 28 weeks. These studies included both primigravidae and multigravidae. The rate of postnatal anti-D sensitisation was 1.60% (95% CI 0.37% to 2.83%) in the control group and 0.34% (95% CI 0.28% to 0.40%) in the antenatal treatment group.
• Group 3, involving 4700 women, included the results of the two community-based UK studies which used a regimen of 500 IU at 28 weeks and 34 weeks and which reported results for primigravidae. The rate of postnatal anti-D sensitisation was 0.95% (95% CI 0.18% to 1.71%) in the control group and 0.35% (95% CI 0.29% to 0.40%) in the antenatal treatment group.
• Two doses of anti-D immunoglobulin 500 IU at 28 and 34 weeks into pregnancy appear to be as effective as one 1500 IU dose at 28 weeks.

 Reference
Pregnancy - routine anti-D prophylaxis for rhesus negative women. NICE Guidance
http://www.nice.org.uk/guidance/index.jsp?action=byID&o=12047