Related to this topic:  | UK GuidelinesEquipment | Books | Your Experience | Other resources | Glossaries
Print options: Printer friendly version of this leaflet (html)     Other options:  AddThis Social Bookmark Button (what's this?)

PatientPlus articles are written for doctors and so the language can be technical. However, some people find that they add depth to the articles found in the other sections of this website which are written for non-medical people.

Rhesus Haemolytic Disease

Synonyms: Haemolytic disease of the newborn, erythroblastosis fetalis.

The condition was first described by a French midwife in a set of twins in 1609. It was later termed erythroblastosis fetalis when Diamond and his co-workers recognised the relationship between erythroblasts in the circulation, anaemia, fetal hydrops and jaundice. The rhesus blood group system was identified in 1940 and the link between rhesus haemolytic disease and alloimmunisation was recognised in 1953.

Rhesus alloimmunisation (Greek: allo = 'other' or 'different from') begins with red blood cells from a rhesus positive fetus crossing the placental barrier during pregnancy and delivery and entering the maternal blood circulation. A rhesus positive father and a rhesus negative mother are required for this situation to develop. The incompatible antigens introduced result in a primary immune response and stimulate the production of maternal antibodies. A very small amount of fetal-maternal haemorrhage needs to occur (less than 0.1ml), and most goes unrecognised. Primary exposure can also be the result of amniocentesis, chorionic villus sampling, and cordocentesis.
Several fetal rhesus antigens may cause alloimmunisation (c,C,d,D, e and E) and this can also occur with the Kell, Duffy, ABO and other blood group systems. The vast majority of haemolytic disease is caused by the rhesus D antigen.

There are rarely any problems during primary exposure, but subsequent pregnancies result in large amounts of maternal anti-D antibodies being produced, and the risk increases with each gestation. These are capable of crossing the placenta, where they affix to fetal red blood cells, which then become recognised as 'foreign' by the fetal immune system and haemolysed by fetal macrophages and lymphocytes. Significant haemolysis results in anaemia, hyperbilirubinaemia, and the production of excessive erythropoid tissue in the liver, spleen, bone marrow, skin and placenta. In severe cases, multi-organ dysfunction and hypoproteinaemia can develop.

Epidemiology1,2

The incidence of fetomaternal haemorrhage is about 75% of all pregnancies. About 10% of RhD positive babies are born each year in England and Wales (62,000) to RhD negative mothers. The frequency of haemolytic disease of the newborn (HDN) before immunoprophylaxis became available in 1969, was one baby in every 2200 births. Anti-D prophylaxis (mostly administered postnatally) and advances in neonatal care have reduced the frequency of HDN by almost a factor of 10, to 1 in 21,000 births. Deaths attributed to RhD alloimmunisation have fallen from 46/100,000 births before 1969, to 1.6/100,000 in 1990.This may not be entirely attributable to immunoglobulin; changes in abortion rates and racial composition may also play a part.

Risk Factors1

  • Immunisation during first pregnancy
  • Immunisation during second or subsequent pregnancy
  • Failed prophylaxis
  • Over 99% of women have a FMH (fetomaternal haemorrhage) less than 4ml at delivery. 50% of women who have larger feto-maternal haemorrhages occur after normal deliveries. However, the following clinical circumstances are more likely to be associated with large FMH:
  • Traumatic deliveries including caesarean section
  • Manual removal of the placenta
  • Stillbirths and intrauterine deaths
  • Abdominal trauma during the third trimester
  • Multiple pregnancies (at delivery)
  • Unexplained hydrops fetalis
Presentation

Ante-natally, the first indication of the condition is the presence of anti-D antibodies in the mother as detected by the indirect Coombs test. All Rhesus negative women have this test performed in the UK at the first antenatal visit.
Routine ultrasound screening may detect hydrops fetalis (see below) or polyhydramnios.
Infants born to alloimmunised mothers may appear clinically normal in mild cases. Diagnostic findings include jaundice (yellow amniotic fluid, yellow vermix, yellow skin), pallor and hepatosplenomegaly. Kernicterus (bilirubin encephalopathy) is a serious risk, and hypoglycaemia is common. Hydrops fetalis may present antenatally as polyhydramnios (excessive amniotic fluid) or postnally with subcutaneous oedema, pericardial effusion, pleural effusion, ascites and hepatosplenomegaly. The placenta may be thickened.

Differential Diagnosis3

Other causes of haemolytic disease of the newborn

  • Rh system antibodies
  • ABO system antibodies
  • Kell system antibodies
  • Duffy system antibodies (rare)
  • MNS and s system antibodies (rare)

Other causes of neonatal jaundice:

Causes of non-immune hydrops fetalis:

Investigations3
  • Indirect Coombs test should be performed at the first antenatal visit for all rhesus negative mothers. If the test is positive, antibody titres should be monitored with serial samples.
  • Antenatal ultrasound may detect signs of hydrops fetalis (see above). Doppler ultrasound of the middle cerebral artery has largely replaced fetal blood sampling as an initial test for the detection of fetal anaemia.4
  • Fetal Blood Sampling: If the Doppler scan confirms anaemia, fetal blood sampling should be considered. The sample can be taken at the site of cord insertion or from the hepatic vein.
    The procedure is done under the guidance of ultrasound imaging. The intrahepatic site causes less fetal distress but is technically more difficult. Fetal loss varies from 1-20% depending on the site of sampling and the condition of the fetus.
    A full blood count (FBC) shows and biochemical indices should be analysed:
Management

In utero

As soon as the blood samples confirm anaemia, transfusion should commenced by with Group O negative packed cells cross matched with maternal blood. This is best done at 18 weeks, but samples can be taken 16 weeks if necessary. Further transfusions should be dictated by serial Doppler scans. Following successful transfusion, delivery should be anticipated between 37-38 weeks. If complications arise, delivery at 32 weeks should be considered. The mode of delivery can be dictated by obstetric considerations.5

After delivery3,5

50% of babies born to mothers with high maternal antibody titres have normal haemoglobin and bilirubin levels, but should be monitored for the onset of late anaemia at 6-8 weeks.
25% have moderate disease, and may require transfusion. Significant hyperbilirubinaemia may develop within the first 24 hours after birth which may require phototherapy to avoid kernicterus.
The remaining 25% will have severe disease and either be stillborn or have hydrops fetalis. Live babies will require resuscitation, intensive support, transfusion, and correction of acidosis.

Complications

The late sequelae of kernicterus (extrapyramidal, auditory, and visual abnormalities and cognitive deficit) occasionally occur, but are rarely seen with the success of modern treatment.5 Other potential complications include late-onset anaemia, graft-versus-host-disease, infections, and various metabolic abnormalities. One meta-analysis showed a significant link between feto-maternal rhesus incompatibility and schizophrenia.6

Prevention

Anti-D immunoglobulin prophylaxis should be given to all Rhesus negative women who have not already been sensitised. It can be given soon after delivery and antenatally at 28 and 34 weeks. Treatment is also indicated after other sensitising events such as abortion, miscarriage, amniocentesis, ectopic pregnancy, abdominal trauma. For further details see Anti-D (Rho) Immunoglobulin (Giving Anti-D).


Document References
  1. RCOG; Use of Anti-D for Rh Prophylaxis Guideline (2002)
  2. Joseph KS, Kramer MS; The decline in Rh hemolytic disease: should Rh prophylaxis get all the credit?; Am J Public Health. 1998 Feb;88(2):209-15. [abstract]
  3. Wagle S, Deshpande P; Hemolytic Disease of Newborn eMedicine.com 2006
  4. Oepkes D, Seaward PG, Vandenbussche FP, et al; Doppler ultrasonography versus amniocentesis to predict fetal anemia. N Engl J Med. 2006 Jul 13;355(2):156-64. [abstract]
  5. Kumar S, Regan F; Management of pregnancies with RhD alloimmunisation. BMJ. 2005 May 28;330(7502):1255-8.
  6. Cannon M, Jones PB, Murray RM; Obstetric complications and schizophrenia: historical and meta-analytic review. Am J Psychiatry. 2002 Jul;159(7):1080-92. [abstract]
Acknowledgements EMIS is grateful to Dr Laurence Knott for writing this article. The final copy has passed scrutiny by the independent Mentor GP reviewing team. ©EMIS 2007.
DocID: 2730
Document Version: 21
DocRef: bgp464
Last Updated: 7 Feb 2007
Review Date: 6 Feb 2009




















Disclaimer: Patient UK has no control of the content of the above links. Inclusion does not imply endorsement by Patient UK.

Advertise on this site










Disclaimer: Patient UK has no control of the content of the above links. Inclusion does not imply endorsement by Patient UK.

Advertise on this site


PS - Health and Poverty

Perhaps the biggest cause of ill health in the world is poverty. Help to Make Poverty History. For example, why not lend some of your money to disadvantaged communities to enable them to trade their way out of poverty through schemes such as Shared Interest.

See also MAKEPOVERTYHISTORY North East for details and links to campaigns against poverty.

^ Top of Page