This site is intended for health professionals only

ANTI-D: Antenatal anti-D immunoglobulin


When a fetus is Rhesus D (RhD) positive and the mother is RhD negative, maternal antibodies can cause haemolytic disease of the fetus and newborn (HDFN). Anti-D immunoglobulin reduces the morbidity and mortality associated with HDFN1 and NICE now advocates using non-invasive prenatal testing (NIPT) to guide treatment.2 This module updates midwives and other healthcare professionals about HDFN and anti-D immunoglobulin prophylaxis: “one of the true ‘success’ stories in modern obstetrics.”3



After studying this module you should:

  • Understand the biological basis of RhD incompatibility
  • Appreciate which women are at high-risk of sensitisation
  • Recognise the clinical manifestations of HDFN
  • Understand the role of antenatal anti-D prophylaxis and NIPT


  • Read the clinical review: if you don't have a printed version, click here to download a pdf
  • Complete the online assessment
  • Receive CPD certificate


Reviewed by: Professor Jayne Marshall University of Leicester PhD, MA, PGCEA, ADM, RM, RGN, PFHEA

References: 1. Vox Sanguinis 2015;109:99-113; 2. NICE (2016) High-throughput non-invasive prenatal testing for fetal RHD genotype; 3. BJOG 2016;123:1347.



    In association with:


    Please log in or register to take this module

    The content of this website is subject to editorial review however you should seek independent validation where required. Content on the website is correct at the time of publishing, and will be reviewed every 2 years aligned to medical best practice.


    Pre-learning reflection

    Please take a moment to answer these pre-learning questions.  Once completed, click next step below to continue into this module.  These answers will be logged on your certificate of learning which will be emailed to you on completion as evidence of your learning.


    Previous step

    Red blood cells


    The average adult has about 30 trillion erythrocytes (red blood cells) circulating around their body

    • Erythrocytes account for about a quarter of all cells in the human body

    • Each erythrocyte bristles with proteins and sugars embedded in the cell membrane; these allow, for example, the cell to
      interact with the rest of the body, and to import and export chemicals

    The structures of these proteins and sugars differ from person to person, largely determined by genes inherited from their biological parents

    • Many of the variations have no biological significance; a few have severe clinical consequences, exemplified by incompatible blood transfusions

    • If a person receives a transfusion of incompatible blood, erythrocytes can clump (agglutinate) and burst. This releases
      haemoglobin, which can cause kidney damage





    Already studied the clinical review? Go straight to the test here
    Previous step

    Blood transfusions


    More than 30 groups of proteins, carbohydrates, lipids and other substances make-up a person’s blood group
    • The ABO group is comprised of sugars; the Rh group are proteins
    • The immune system of a person whose erythrocytes express an A sugar recognises a type A blood transfusion as normal; however, the immune system will attack a type B infusion
    • If the person is AB, their immune system will not attack either a type A or B transfusion
    • A person with neither sugar (type O) will mount an immune response to both a type A and B infusion. Their blood can be given as a transfusion to people with any other group1
    Incompatibilities between maternal and fetal A and B groups can occasionally cause mild HDFN2

    Several antibodies triggered by other antigens on erythrocytes potentially induce HDFN
    • These reactions, which occur in about 1 in 500 pregnancies, are less likely to induce severe HDFN than the Rh antigens2






    Compatibility of blood groups


    Previous step

    Rhesus (Rh) system


    Rh proteins control the movement of molecules (probably ammonia and carbon dioxide) across the cell membrane1

    • Humans express at least 52 Rh antigens, most of which are clinically insignificant; however, the RhD antigen is associated with HDFN1,2

    The genes that encode Rh antigens are inherited. So, a RhD-negative mother can carry a RhD-positive fetus if the father is RhD-postive3

    In England between April 2013 and March 2014, about 15% of births were to RhD-negative women. About 40% of these women gave birth to RhD-negative fetuses4

    The prevalence of RhD-negativity depends on ethnic origin2,5

    • About 15% of people of white European origin are RhD-negative
    • Rates are lower (3-7%) in people of black African origin
    • RhD-negative status is rare among people of Eastern Asian origin (less than 1%)






    Computer model showing the structure of human
    RhC glycoprotein

    Previous step

    Fetomaternal haemorrhages

    • During pregnancy, small amounts of fetal blood enter the maternal circulation (fetomaternal haemorrhages)1
    • Transfer of RhD-positive cells from the fetus to the maternal circulation can cause a RhD-negative mother to produce antibodies against the RhD-antigen (sensitisation)1

    • The risk of sensitisation and, in turn, HDFN increases when larger amounts of fetal blood enter the maternal circulation2

    • The risk is particularly high following ‘potentially sensitising events’ (table right)1, 3

    • The maternal circulation includes fetal cells and debris, such as from syncytiotrophoblasts. The concentration of cells and debris increases during pregnancy, triggering clinically ‘silent’ sensitisation, mainly during the third trimester4








    Adapted from British Committee for Standards in Haematology guidelines6
    Previous step

    Haemolytic disease of the fetus and newborn


    Immunoglobulin G (IgG) antibodies are actively transported across the placenta1

    IgG targeting the RhD-antigen attacks fetal erythrocytes, which causes the signs and symptoms of HDFN1

    The destruction of fetal erythrocytes can increase bilirubin levels1

    • In utero, the placenta clears bilirubin.2 The relatively immature liver of the neonate cannot adequately remove excessbilirubin, resulting in neonatal jaundice1
    • Mild jaundice is not harmful and usually responds to phototherapy and exchange transfusion2
    • If left untreated, neonates may develop severe hyperbilirubinaemia and, in some cases, irreversible damage to the central nervous system (‘kernicterus’)1
    • In children affected by kernicterus, bilirubin deposits in the basal ganglia and brain stem nuclei can cause severe athetoid cerebral palsy, and hearing and psychomotor problems1



    Previous step

    Antenatal prophylaxis


    Potentially sensitising events introduce fetal RhD antigen into the maternal circulation. The anti-D immunoglobulin neutralises the fetal antigen and so, therefore, protects against sensitisation

    • Anti-D immunoglobulin can be administered routinely in the third trimester as prophylaxis against ‘silent sensitisation’1
    • Women who receive anti-D immunoglobulin following a potentially sensitising event can receive routine prophylaxis and vice versa1

    Anti-D immunoglobulin is highly effective

    • Routine postpartum anti-D prophylaxis reduced the incidence of RhD-sensitisation to about 2%2
    • Rates of sensitisation declined further to 0.17-0.28% after the introduction of routine antenatal anti-D prophylaxis during the third trimester3
    • Mortality associated with HDFN declined from 46 to 1.6 per 100,000 of the population3

    NICE guidance recommends routine antenatal anti-D prophylaxis for all RhD-negative pregnant women who are not known to be sensitised to the RhD-antigen1



    Previous step

    Antenatal prophylaxis


    Anti-D immunoglobulin is produced from pooled plasma donated by RhD-negative people who have received a transfusion of RhD-positive erythrocytes to stimulate production of RhD-antibodies; supplies of anti-D immunoglobulin, however, are limited

    NICE recommends high-throughput NIPT to determine fetal RHD genotype and to guide antenatal prophylaxis with anti-D
    immunoglobulin to reduce unnecessary use and conserve supplies

    High-throughput NIPT for fetal RHD genotype involves analysing cellfree fetal DNA (cfDNA) in maternal blood

    • The assay detects and amplifies sequences from fetal RHD and theRHD pseudogene.
    • Levels of cfDNA in maternal blood increase throughout pregnancy

    Between 2 and 4 in 1,000 women with a RhD-positive fetus will have a negative result on NIPT. As they would not be offered  antenatal anti-D immunoglobulin they remain at risk of sensitisation

    Between 13 and 57 in 1,000 women with a RhD-negative fetus will have a positive result on NIPT and, as a result, be offered antenatal anti-D immunoglobulin unnecessarily



    Previous step


    Now that you have reviewed the learning, please complete the following multiple choice questions to test what you've learnt and receive your CPD certificate.
    Which of these statements are incorrect? Please indicate all that may apply
    Previous step


    Which of these is not a potentially sensitising event? Please indicate all that may apply
    Previous step


    Which of these are possible signs and symptoms of HDFN? Please indicate all that may apply
    Previous step


    Complete the sentence: Routine postpartum anti-D prophylaxis reduces the incidence of RhD-sensitisation to about ____.
    Previous step


    Complete the sentence: Based on the high-throughput NIPT for fetal RhD genotype, between ____in 1,000 women with a RhD-positive fetus will have a negative result.
    Previous step

    Post-learning reflection

    Please take a moment to answer these post-learning questions.  These answers will be logged alongside your pre-learning responses on your certificate of learning which will be emailed to you on completion as evidence of your learning.




    Previous step

    References and further reading

    Ashoor G, Syngelaki A, Poon LCY et al. Fetal fraction in maternal plasma cell-free DNA at 11–13 weeks’ gestation: Relation to maternal and fetal characteristics. Ultrasound in Obstetrics & Gynecology 2013;41:26-32.

    Bolton-Maggs PHB, Davies T, Poles D et al. Errors in anti-D immunoglobulin administration: Retrospective analysis of 15 years of reports to the UK confidential haemovigilance scheme. BJOG 2013;120:873-878.

    Cooper C, Blood: A Very Short Introduction. 2016, Oxford University Press.

    de Haas M, Finning K, Massey E et al. Anti-D prophylaxis: Past, present and future. Transfusion Medicine 2014;24:1-7.

    de Haas M, Thurik FF, Koelewijn JM et al. Haemolytic disease of the fetus and newborn. Vox Sanguinis 2015;109:99-113.

    Martin FO, de Menezes SS, Chiba AK et al. RHD gene polymorphisms in alloimmunized RhD-negative individuals with high rate of racial admixture. Transfusion and Apheresis Science 2013;48:113-116.

    NICE High-throughput non-invasive prenatal testing for fetal RHD genotype Published: 9 November 2016 Available at:

    NICE Routine antenatal anti-D prophylaxis for women who are rhesus D negative Published: May 2011 Available from:

    Qureshi H, Massey E, Kirwan D et al. BCSH guideline for the use of anti-D immunoglobulin for the prevention of haemolytic disease of the fetus and newborn. Transfusion Medicine 2014;24:8-20.

    Silver RM RhD immune globulin: Over 50 years of remarkable progress! BJOG 2016;123:1347.

    Singleton BK, Green CA, Avent ND et al. The presence of an RHD pseudogene containing a 37 base pair duplication and a nonsense mutation in Africans with the Rh D-negative blood group phenotype. Blood 2000;95:12-18.

    Struble CA, Syngelaki A, Oliphant A et al. Fetal fraction estimate in twin pregnancies using directed cell-free DNA analysis. Fetal Diagnosis and Therapy 2014;35:199-203.

    Previous step
    Previous step
    Previous step

    Your feedback...

    To finish this module and get your result and certificate, please complete this feedback and press submit