ALLOIMMUNIZATION IN PREGNANCY

ALLOIMMUNIZATION IN ALLOIMMUNIZATION IN PREGNANCYPREGNANCY

Erythroblastosis FetalisErythroblastosis Fetalis (Red Cell Alloimmunization) (Red Cell Alloimmunization)

the first description of erythroblastosis fetalis the first description of erythroblastosis fetalis (hemolytic disease of the newborn) dates (hemolytic disease of the newborn) dates back to 1609back to 1609

until the early 1900s that the role of until the early 1900s that the role of alloimmunization in the pathogenesis of alloimmunization in the pathogenesis of erythroblastosis was establishederythroblastosis was established

In the past, Rh alloimmunization also has In the past, Rh alloimmunization also has been referred to as Rh sensitization or Rh been referred to as Rh sensitization or Rh isoimmunization.isoimmunization.

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ERYTHROBLASTOSIS FETALISERYTHROBLASTOSIS FETALIS

Genetics of the Rh AntigenGenetics of the Rh Antigen

three genetic loci, each with two major alleles, three genetic loci, each with two major alleles, lettered C, c, D, E, and e. lettered C, c, D, E, and e.

The Rh gene complex is described by the three The Rh gene complex is described by the three appropriate letters with eight possible appropriate letters with eight possible combinations (listed in decreasing order of combinations (listed in decreasing order of frequency among whites): CDe, cde, cDE, cDe, frequency among whites): CDe, cde, cDE, cDe, Cde, cdE, CDE, and CdE.Cde, cdE, CDE, and CdE.

Rh positive indicates the presence of the D antigenRh positive indicates the presence of the D antigen Rh negative indicates the absence of D antigen on Rh negative indicates the absence of D antigen on

erythrocytes.erythrocytes.

Pathophysiology of Rh AlloimmunizationPathophysiology of Rh Alloimmunization

Rh D alloimmunization can occur only in the Rh D alloimmunization can occur only in the presence of three conditions: presence of three conditions:

(a)(a) the fetus must have Rh-positive erythrocytes, and the fetus must have Rh-positive erythrocytes, and the mother must have Rh-negative erythrocytes; the mother must have Rh-negative erythrocytes;

(b)(b) the mother must have the immunogenic capacity the mother must have the immunogenic capacity to produce antibody directed against the D to produce antibody directed against the D antigen;antigen;

(c)(c) a sufficient number of fetal erythrocytes must gain a sufficient number of fetal erythrocytes must gain access to the maternal circulation.access to the maternal circulation.

Incidence of Rh D Incompatibility and Incidence of Rh D Incompatibility and Subsequent AlloimmunizationSubsequent Alloimmunization

About 10% of pregnancies are Rh incompatibleAbout 10% of pregnancies are Rh incompatible– fewer than 20% of Rh-incompatible pregnancies result in fewer than 20% of Rh-incompatible pregnancies result in

alloimmunizationalloimmunization

About 16% of untreated Rh-negative women become About 16% of untreated Rh-negative women become alloimmunized in their first Rh-incompatible (ABO-alloimmunized in their first Rh-incompatible (ABO-compatible) pregnancycompatible) pregnancy– Half produce detectable anti-D antibody within 6 months of delivery, Half produce detectable anti-D antibody within 6 months of delivery,

– rest have undetectable amounts until early in the next incompatible rest have undetectable amounts until early in the next incompatible pregnancypregnancy

before the introduction of Rh immune globulin prophylaxis, before the introduction of Rh immune globulin prophylaxis, only about 1% of pregnant women had anti-D antibodyonly about 1% of pregnant women had anti-D antibody

Maternal Immunologic ResponseMaternal Immunologic Response::

30% of Rh-negative individuals appear to 30% of Rh-negative individuals appear to be immunologic “nonresponders”who will be immunologic “nonresponders”who will not become sensitizednot become sensitized

ABO incompatibility diminishes the risk of ABO incompatibility diminishes the risk of alloimmunization to about 1.5% to 2.0% alloimmunization to about 1.5% to 2.0% after the delivery of an Rh-positive fetusafter the delivery of an Rh-positive fetus– The effect is most pronounced if the mother is The effect is most pronounced if the mother is

type O and the father is type A, B, or AB.type O and the father is type A, B, or AB.

Fetomaternal HemorrhageFetomaternal Hemorrhage

Fetal red cells may gain access to the Fetal red cells may gain access to the maternal circulation :maternal circulation :– during pregnancy,during pregnancy,– During delivery:During delivery:– the immediate postpartum periodthe immediate postpartum period


During delivery :During delivery :– 15-50% of births15-50% of births– The amount of fetal blood entering the maternal The amount of fetal blood entering the maternal

circulation is usually less than 0.1 mL but may circulation is usually less than 0.1 mL but may be greater than 30 mL in 0.2% to 1.0% of cases.be greater than 30 mL in 0.2% to 1.0% of cases.


immediate postpartum period :immediate postpartum period :– Risk factors :Risk factors :

» cesarean deliverycesarean delivery

» multiple gestations,multiple gestations,

» bleeding placenta previa or abruption,bleeding placenta previa or abruption,

» manual removal of the placenta, manual removal of the placenta,

» intrauterine manipulation. intrauterine manipulation.

However, the majority of cases of excessive However, the majority of cases of excessive fetomaternal hemorrhage occur after fetomaternal hemorrhage occur after uncomplicated vaginal delivery.uncomplicated vaginal delivery.

Rh D Immune Globulin and the Rh D Immune Globulin and the Prevention of Rh D AlloimmunizationPrevention of Rh D Alloimmunization

antibody-mediated immune suppression the amount of Rh D immune globulin necessary to the amount of Rh D immune globulin necessary to

prevent alloimmunization varies according to the prevent alloimmunization varies according to the size of fetomaternal hemorrhage:size of fetomaternal hemorrhage:– 300 Âµg of Rh D immune globulin for exposure to 10 300 Âµg of Rh D immune globulin for exposure to 10

mL of fetal bloodmL of fetal blood

– 20 Âµg of Rh D immune globulin for exposure to 1 mL 20 Âµg of Rh D immune globulin for exposure to 1 mL of fetal erythrocytesof fetal erythrocytes

– 10 Âµg of Rh D immune globulin for 1 mL of whole 10 Âµg of Rh D immune globulin for 1 mL of whole fetal bloodfetal blood

Postpartum Alloimmunization ProphylaxisPostpartum Alloimmunization Prophylaxis

administration of Rh D immune globulin administration of Rh D immune globulin – a dose of 100 Âµg to 150 Âµga dose of 100 Âµg to 150 Âµg– within 72 hours of deliverywithin 72 hours of delivery

Postpartum Alloimmunization ProphylaxisPostpartum Alloimmunization Prophylaxis

Rh D immune globulin should be given as soon as possible Rh D immune globulin should be given as soon as possible after exposure to Rh D-positive blood (delivery or other after exposure to Rh D-positive blood (delivery or other event associated with fetomaternal hemorrhage) and before event associated with fetomaternal hemorrhage) and before the primary immune response is establishedthe primary immune response is established

if for some reason Rh D immune globulin prophylaxis if for some reason Rh D immune globulin prophylaxis does not occur within 72 hours after exposure, susceptible does not occur within 72 hours after exposure, susceptible Rh D-negative women should be treated up to 14 to 28 Rh D-negative women should be treated up to 14 to 28 days.days.

if the neonatal Rh status is unknown 3 days after delivery, if the neonatal Rh status is unknown 3 days after delivery, Rh D immune globulin should be given rather than waiting Rh D immune globulin should be given rather than waiting for the neonatal results.for the neonatal results.

Antepartum Alloimmunization Antepartum Alloimmunization ProphylaxisProphylaxis

Prophylactic administration of Rh D Prophylactic administration of Rh D immune globulin at 28 weeks gestation immune globulin at 28 weeks gestation reduces the incidence of alloimmunization reduces the incidence of alloimmunization from 1.8% to 0.1%from 1.8% to 0.1%

Management of the Unsensitized Rh-Management of the Unsensitized Rh-Negative Pregnant WomanNegative Pregnant Woman

Every woman should have her ABO blood Every woman should have her ABO blood group, Rh type, and antibody screen group, Rh type, and antibody screen checked at the first prenatal visit of all checked at the first prenatal visit of all pregnanciespregnancies

If she is Rh-negative or weak D-negative If she is Rh-negative or weak D-negative and has no demonstrable antibody,and has no demonstrable antibody,– she is a candidate for 300 Âµg Rh D immune she is a candidate for 300 Âµg Rh D immune

globulin prophylaxis at around 28 weeks globulin prophylaxis at around 28 weeks gestation and again immediately postpartumgestation and again immediately postpartum


obtaining another antibody screen before obtaining another antibody screen before administration of Rh D immune globulin, inadministration of Rh D immune globulin, in

After delivery, another antibody screen is After delivery, another antibody screen is routinely performed. If negative and the routinely performed. If negative and the newborn is Rh D positive or weak D newborn is Rh D positive or weak D positive, women should be given 300 Âµg positive, women should be given 300 Âµg of Rh D immune globulincluding of Rh D immune globulincluding antepartum prophylaxisantepartum prophylaxis

Management of the Unsensitized Management of the Unsensitized Rh-Negative Pregnant WomanRh-Negative Pregnant Woman

because a small number of deliveries (0.1% to because a small number of deliveries (0.1% to 1.0%) result in a fetomaternal hemorrhage 1.0%) result in a fetomaternal hemorrhage greater than 30 mL :greater than 30 mL :– a screen for “excessive” fetomaternal hemorrhage a screen for “excessive” fetomaternal hemorrhage

should be performed routinelyshould be performed routinely» use the erythrocyte rosette testuse the erythrocyte rosette test

If positive :the volume of fetal red cells in the maternal If positive :the volume of fetal red cells in the maternal circulation can be calculated by using the Kleihauer-Betke circulation can be calculated by using the Kleihauer-Betke test ,if >30 ml :test ,if >30 ml :

– an additional 10 Âµg of Rh D immune globulin should be an additional 10 Âµg of Rh D immune globulin should be administered for each additional milliliter of fetal blood.administered for each additional milliliter of fetal blood.



A weak D-“positive mother who delivers an A weak D-“positive mother who delivers an Rh-positive infant is not at significant risk of Rh-positive infant is not at significant risk of Rh alloimmunizationRh alloimmunization

Occasionally, a woman previously typed as Rh Occasionally, a woman previously typed as Rh negative is unexpectedly found to be weak D negative is unexpectedly found to be weak D positive during pregnancy or after deliverypositive during pregnancy or after delivery– if fetomaternal hemorrhage is found :if fetomaternal hemorrhage is found :

» the mother should be treated with Rh D immune the mother should be treated with Rh D immune globulin.globulin.


First-trimester complications result in First-trimester complications result in fetomaternal hemorrhage sufficient to fetomaternal hemorrhage sufficient to alloimmunization :alloimmunization :– spontaneous miscarriage, spontaneous miscarriage, – elective abortionelective abortion– ectopic abortionectopic abortion

women with threatened first-trimester women with threatened first-trimester miscarriage miscarriage – only occasionally is associated with alloimmunizationonly occasionally is associated with alloimmunization


patient who has antepartum bleeding or patient who has antepartum bleeding or suffers an unexplained second- or third-suffers an unexplained second- or third-trimester fetal death:trimester fetal death:– should receive Rh D immune globulin should receive Rh D immune globulin

prophylaxis prophylaxis – be evaluated for the possibility of massive be evaluated for the possibility of massive

fetomaternal hemorrhage. fetomaternal hemorrhage.


Several procedures also may result in Several procedures also may result in fetomaternal hemorrhage sufficient to cause fetomaternal hemorrhage sufficient to cause alloimmunization :alloimmunization :– chorionic villus sampling (CVS)chorionic villus sampling (CVS)– amniocentesisamniocentesis– external cephalic version.external cephalic version.


For first-trimester pregnancy complications For first-trimester pregnancy complications and procedures :and procedures :– 50 Âµg of Rh D immune globulin is protective. 50 Âµg of Rh D immune globulin is protective. – Beyond 12 weeks, a full 300-Âµg dose is Beyond 12 weeks, a full 300-Âµg dose is

indicated, even in the absence of detectable indicated, even in the absence of detectable hemorrhage. hemorrhage.

– In second & third trimester: an assessment of the In second & third trimester: an assessment of the volume of fetal whole blood should be volume of fetal whole blood should be performed, and the appropriate amount of Rh D performed, and the appropriate amount of Rh D immune globulin should be givenimmune globulin should be given


Failure to administer Rh D immune Failure to administer Rh D immune globulin when indicated may due to:globulin when indicated may due to:– Failure to type the patient's blood at the first Failure to type the patient's blood at the first

prenatal visit or to order Rh D immune globulin prenatal visit or to order Rh D immune globulin when indicatedwhen indicated

– Error in transmitting the proper blood type to Error in transmitting the proper blood type to the mother's chart and to the physicianthe mother's chart and to the physician

Management of the Unsensitized Management of the Unsensitized Rh-Negative Pregnant WomanRh-Negative Pregnant Woman– ......– Error in typing the mother, father, or baby's bloodError in typing the mother, father, or baby's blood– Failure to administer Rh D immune globulin Failure to administer Rh D immune globulin

when orderedwhen ordered– Unrecognized fetomaternal hemorrhage during Unrecognized fetomaternal hemorrhage during

pregnancypregnancy– Inadequate Rh D immune globulin for the volume Inadequate Rh D immune globulin for the volume

of fetomaternal hemorrhageof fetomaternal hemorrhage– Patient refusalPatient refusal

Management of the Rh D-Management of the Rh D-Alloimmunized PregnancyAlloimmunized Pregnancy

mildly affected fetuses:mildly affected fetuses:– can be allowed to remain in utero until they can be allowed to remain in utero until they

have achieved pulmonary maturationhave achieved pulmonary maturation moderately to severely affected fetuses:moderately to severely affected fetuses:

– may need intrauterine treatment (transfusion) may need intrauterine treatment (transfusion) and very likely will require delivery prior to and very likely will require delivery prior to pulmonary maturation.pulmonary maturation.

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ALLOIMMUNIZATION IN PREGNANCY