We'd like to understand how you use our websites in order to improve them. Register your interest. Rhesus Rh isoimmunization is an important clinical entity in India and other developing countries, which is responsible for fetal anemia and hydrops fetalis, and if not treated, it can result in intrauterine fetal demise. Rh isoimmunization is responsible for severe jaundice in neonates, which can be severe enough to cause kernicterus with debilitating consequences, if not treated adequately. It can be prevented with simple measures and treated if recognized in time.

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We'd like to understand how you use our websites in order to improve them. Register your interest. Rhesus Rh isoimmunization is an important clinical entity in India and other developing countries, which is responsible for fetal anemia and hydrops fetalis, and if not treated, it can result in intrauterine fetal demise. Rh isoimmunization is responsible for severe jaundice in neonates, which can be severe enough to cause kernicterus with debilitating consequences, if not treated adequately.

It can be prevented with simple measures and treated if recognized in time. Isoimmunization is defined as the development of antibodies against the antigens of another individual of the same species.

The presence of particular antigens on RBCs confers an individual a specific blood group status. Rh isoimmunization is the development of antibodies against the Rh antigens present on the surface of RBCs [ 1 ].

The important Rh antigen responsible for majority of cases of severe Rh isoimmunization is Rhesus D antigen. The other atypical Rh antigens with a potential to cause severe isoimmunization are c, E and Kell antigens. Data on frequency of Rh typing from India are limited. The frequency of Kell antigen was found to be 2.

Kidd antigen was not tested due to financial constraints. The ABO blood group antigens may also sometimes cause isoimmunization in a mother having O positive blood group and carrying an A, B or AB positive fetus. But for practical purposes these antigens do not cause significant fetal hemolysis and fetal anemia.

An individual lacks the antibodies against the antigens, which are present on his own RBCs. However, if RBCs coated with different antigens from another individual gain entry into the circulation, the reticuloendothelial system RES of the recipient identifies these antigens on RBCs as foreign and mounts immune response to eliminate these cells.

A similar phenomenon occurs during Rh isoimmunization. The Rh positive RBCs of the fetus gain entry into Rh negative maternal circulation via fetomaternal hemorrhage FMH resulting into formation of anti-D antibodies, which in turn pass to the fetus through placental circulation and destroy fetal RBCs to produce fetal anemia.

FMH occurs throughout pregnancy and the amount of this hemorrhage increases with increasing gestation. Kleiheur—Betke test can detect fetal blood cells into maternal circulation by acid elution test. It has been found that the amount of FMH is very minute around 0. It is the standard method to quantitate FMH [ 6 ]. The fetal blood has differential resistance to acid as compared to adult hemoglobin. A blood smear is prepared from the maternal blood and treated with the acid. This removes adult hemoglobin whereas fetal hemoglobin persists in the red cells.

On subsequent staining, fetal cells appear rose-pink in color whereas adult RBCs appear as ghost cells. Two thousand cells are counted in the microscope and percentage of fetal to maternal cells is calculated.

The Rh-D antigen on fetal cells, which is circulating in maternal blood, is recognized by maternal RES as foreign antigen. When there is second time exposure to this foreign antigen during second pregnancy with an Rh-D positive pregnancy , the previously primed memory B cells respond more strongly with the formation of IgG antibodies booster response. Sometimes sensitization of an Rh-D negative mother may be because of the mismatched blood transfusion Rh-D negative mother transfused with Rh-D positive blood.

The initial response could be prevented if the fetal RBCs entering the maternal circulation are removed before they are detected by the maternal RES. This can be achieved by giving anti-D immunoglobulins to the mother so as to counteract appropriately for the FMH. This prophylaxis has drastically brought down the cases of isoimmunization throughout the globe.

The IgM antibodies formed due to initial response cannot cross the placenta and gain entry into the fetal circulation and therefore do not affect the first sensitizing pregnancy.

During the next pregnancy with Rh-D positive fetus, the IgG antibodies cross the placenta by binding on the Fcy receptors present on the syncytiotrophoblasts. These antibody-coated RBCs are trapped in the fetal spleen and are destroyed. This results in fetal anemia, the severity of which depends upon the amount of FMH and amount of antibody formation.

The Rh gene locus is located on chromosome 1pp There are two isoforms for two antigens Cc and Ee but there is no isoform for D antigen and either absence or partial deletion of RHD gene is denoted as d in the genotype. One group of antigens would be inherited by the paternal chromosome and another group by the maternal chromosome which will result in one of the various possible combinations of genotypes.

Since the introduction of prophylactic anti-D immunoglobulin given to all unsensitized Rh-D negative women after termination of pregnancy or delivery with an Rh-D positive fetus, there has been a dramatic decrease in the rate of Rh isoimmunization.

In UK, prophylactic anti-D immunoglobulin has been in use since The stillbirths or neonatal death rate due to Rh-D isoimmunization reduced from per , births in to 1. Still there are around — new cases of Rh-D isoimmunization happening every year in UK. The reason suggested is either due to insufficient dose or failure to cover a potentially sensitizing event.

Incidence of hemolytic disease due to antibodies against the other Rh antigens like Kell, Duffy and kidd is around six cases per year in the UK [ 8 ]. In North America, there is policy of prophylactic immunization to all Rh-D negative women and there has been much more decline in the number of cases of Rh-D isoimmunization [ 9 ].

Unfortunately there are no reports regarding the real magnitude of Rh isoimmunization from India. In , Bhatnagar et al. Gupta et al. A recent hospital-based study from New Delhi reported overall incidence of isoimmunization to be 1. The isoimmunization rate was Thakral et al. The newborn babies had features of hemolytic disease of newborn with Rh positive status of mother. A positive direct Coombs test led to suspicion which was confirmed by definitive testing for atypical antigens.

Rh isoimmunization of a pregnant mother may be responsible for varying severity of anemia in the fetus and newborn. Usually it is in the second or subsequent pregnancies that the fetus is affected. Such a fetus will initially have fetal anemia, this may manifest clinically as decreased fetal movements.

If the condition persists and becomes more serious there would be extramedullary erythropoiesis in the liver and spleen.

This can be seen on ultrasound as hepatosplenomegaly. In a profoundly anemic fetus initially there is increased cardiac output but the hypoxic heart can no longer sustain and finally culminates in heart failure.

This is manifested sonographically as hydropic changes like pleural effusion, pericardial effusion, ascites, subcutaneous edema and scalp edema.

To compensate for the reduced oxygen supply, the placenta also enlarges which could be seen as placentomegaly on ultrasonography [ 1 , 7 ]. By the time these hydropic changes are evident on ultrasound, it is quite late and fetus is very sick with a high fetal mortality.

Therefore our aim remains to identify fetal anemia much before this terminal stage [ 1 , 7 ]. An algorithm for management for Rh isoimmunization is depicted in Fig.

Blood grouping and crossmatching is performed in all pregnant women at the first visit. If the woman is Rh-D positive no further testing for blood groups is required. In western countries testing for antibodies against all the Rh red cell antigens D, Ee, Cc, Kell, Duffy, Kidd, Jka, Jkb and M is also performed irrespective of the blood group and if a woman is positive for these antibodies she is managed as a case of isoimmunized pregnancy.

However because of the high cost, this test is not routinely performed in India. It is reserved for pregnant women, who are Rh positive or Rh-D negative with negative indirect Coombs test ICT for Rh-D antibodies, with a past obstetric history suggestive of isoimmunization birth of a baby with features of hydrops, neonatal jaundice or history of postnatal exchange transfusion.

If the husband is Rh positive, virtually all guidelines [ 18 — 21 ] recommend performing genotype of the father for Rh-D coding gene. A homozygous father will inherit Rh-D gene to all his offspring and all the pregnancies will have potential for sensitization. Most of the western guidelines recommend finding the fetal blood group from circulating cell free fetal DNA in maternal blood. When fetus is Rh-D negative no further testing required.

If fetus is Rh-D positive, further follow- up is done. However in India, the facilities for testing of zygosity for Rh-D gene and fetal blood group from circulating cell-free fetal DNA in maternal circulation are available only in few centers. Therefore a pregnancy, when mother is Rh-D negative and father is Rh-D positive, is considered potentially at risk of immunization.

To detect sensitization of mother, presence of anti-D antibodies in maternal circulation is usually detected by ICT. It involves incubation of maternal serum with the RBCs carrying the particular Rh antigen against which the antibodies are being tested.

Anti-human immunoglobulin is then added. It will cause agglutination of RBCs if they have adsorbed the antibodies. The serial dilutions of maternal serum are mixed with the RBCs carrying D antigen and the reverse of maximum dilution which causes clumping of RBCs is denoted as the titer.

Mostly or is considered as the critical titer potential to cause significant fetal anemia which may vary with the laboratory. Separate tests using specific Rh allele are required for detecting antibody to minor alleles. In some women, the test for Rh-D typing may be weak Rh-D positive.

These women are genetically Rh-D positive and are at low risk of producing anti-D antibodies. These women are given status of weak D positive and Rh typing is represented by Rh-D u. There are no clear recommendations for management of these women and at present these women are not given any anti-D prophylaxis. For women who are not yet isoimmunized the aim is to prevent sensitization.

It can be achieved by giving prophylactic dose of anti-D immunoglobulins to cover for the spontaneous fetomaternal hemorrhages and also any antepartum event which has potential to cause additional FMH. The most effective strategy to reduce the incidence of Rh isoimmunization has been the introduction of antenatal and at birth anti-D prophylaxis. The occurrence of Rh-D sensitization in last few week of an uncomplicated pregnancy has been stated to be the single most reason for remaining cases of isoimmunization.

It may be due to either the inability to cover the potential events causing FMH or inadequate dose of anti-D. Therefore, clear instructions regarding the event-specific doses and timing could almost eliminate this condition. Also transfusion of Rh-D positive blood to Rh-D negative woman should be avoided and blood should be properly crossmatched before transfusion so as to avoid possibility of isoimmunization against other minor red cell antigens.

This will take care of the small amount of FMH and prevent isoimmunization. Since anti-D injection is a human blood product obtained from plasma, a written informed consent should be taken before its administration.


[Mechanism of Rhesus Iso-Immunisation and of Its Prevention]

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Rh isoimmunisation and Anti-D

Oxford University Press makes no representation, express or implied, that the drug dosages in this book are correct. Readers must therefore always check the product information and clinical procedures with the most up to date published product information and data sheets provided by the manufacturers and the most recent codes of conduct and safety regulations. The authors and the publishers do not accept responsibility or legal liability for any errors in the text or for the misuse or misapplication of material in this work. Except where otherwise stated, drug dosages and recommendations are for the non-pregnant adult who is not breastfeeding. Rhesus hemolytic disease of the fetus and newborn, while by no means the frequent condition that it once was, remains a problem that requires constant vigilance and attention. Although effective prophylaxis is available it must be properly used. Postpartum prophylaxis with anti-D immunoglobulin should be given within 72 hours of birth to all RhD-negative women who give birth to a RhD-positive baby, or a baby whose RhD status cannot be determined, irrespective of their ABO status.

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