Rh Iso Immunization - Dr. Malak

8/3/2019 Rh Iso Immunization - Dr. Malak

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Rh ISOIMMUNIZATION

By: DR. MALAK AL-HAKEEMAssociate Professor &

consultant



What is isoimmunization? Why is it a concern duringpregnancy?

Isoimmunization refers to the maternaldevelopment of antibodies to fetal red blood cell(RBC) antigens. During normal pregnancy a smallnumber – and in some situations a large number –of fetal RBCs cross the placenta and enter thematernal circulation. When the fetal RBC antigensdiffer from those of the mother, a maternal immuneresponse is generated. Although this response may

be relatively small at first exposures, elicit a largerand quicker response of IgG. This maternal IgG,directed at the fetal RBC antigen, is capable of traversing the placenta into the fetal circulation,causing hymolysis.



What is hemolytic disease of the

newborn?

Most often secondary to isoimmunization to

the Rh (rhesus) antigen, fetal RBCs, thatcontain an antigen foreign to the mother (suchas an RhD-positive fetus with an RhD –negative mother) become a site of binding for

the maternal IgG. Once the maternal IgGbinds to the RhD antigen on the fetal RBCs,these cells are destroyed. Depending on theseverity of this hemolysis, the fetus may

become anemic and hydropic, ultimately



Why does the severely anemic fetusbecome hydropic?

Severe fetal anemia results in extramedullaryproduction of RBCs (primarily in the fetal liver

and spleen). Extensive hepatic erythropoiesisdistorts the portal venous circulation, leadingto obstruction and finally to hepatomegaly,ascites, and placental edema.

Hypoalbuminemia secondary to liverdysfunction also may contribute to thisgeneralized edema.



In addition to anemia, what are therisks to the RhD-positive newborn

whose mother is sensitized?

Marked hyperbilirubinemia, which, if

untreated, may lead to central nervoussystem damage.



How many red blood cell (RBC)

antigens are there?

More often 400 antigens have been

identified on the red blood cell surface.However, only a few are clinicallyimportant as causes of hemolytic

disease of the newborn. In addition tothe Rh antigen, others include A, B, Kell(k), Duffy (Fy), Kidd (Jk), M,N,S, Lutheran(Lu), Diego (Di), and Xg.



What is the most commoncause of hemolytic disease of

the newborn?Rh antigen isoimmunization



How many antigens comprise the Rh

system on the human red blood cell?

Five: CDE and c,e. Small d has not

been identified. There are three closelylinked loci within the Rh complex(D,C,E) with allelic forms (d,c,e). Some

consider each antigen to be a separategene. These three sites tend to beinherited intact with little crossoverand rearrangement



In which population is RhD – negativetrait most common? In whichpopulation is it rarely encountered

Basque people are 95% RhD –negative, whereas approximately 15%of Caucasians are RhD – negative. Less

than 5% of Asians and North AmericanIndians are RhD – negative.



Define “D”

D” refers to the situation in which “D” is notdetected by anti-D sera at a level that types theperson as RhD – positive. This situation can occurby two mechanisms. First, the person may

genetically contain the D sequence, but itsexpression is decreased (or masked) by thepresence of C at the rhesus loci on the otherchromosome. These genetic RhD – positiveindividuals are not at risk for isoimmunization. Less

often, however, “D” is the result of genetic absenceof a portion of the D antigen. Such women are atlow risk for isoimmunization. RhoGAM should begiven to the “D” mother unless the “environmental”(C allele) can be differentiated from the “genetic”

variety.



What is the difference between adirect and indirect Coombs’ test inthe fetus?

A direct Coombs’ test detects thepresence of attached immunoglobulinin red blood cells; an indirect Coombstest detects the presence of freeimmunoglobin in sera.



What is immunoglobulin prophylaxis

for RhD-negative, nonsensitizedmothers? Why is it helpful?

It is RhD immune globulin (RhoGAM)prepared from subjects previouslysensitized to RhD. It absorbs the fetalRhD-positive antigen thus blocking

formation of maternal Rh antibody at thetime of exposure, usually at delivery. Analternative theory is that RhoGAM worksat the cellular level of IgG production.



The standard dose (300 µg) of RhoGAM

given after delivery provides coveragefor how large of a fetomaternalhemorrhage?

30 ml of fetal whole blood or15 ml of fetal packed red bloodcells.



What percentage of women haveevidence of fetomaternal hemorrhageafter delivery? In what percentage isthis bleeding considered excessive (>

5ml of fetal blood)?

Seventy – five percent have

evidence of fetomaternalhemorrhage. It is > 5 ml in < 1%.



In what circumstances may a woman

at delivery have experiencedfetomaternal hemorrhage of > 15 ml( 30 ml of fetal whole blood)?

- Placental abruption

- Placenta previa associated with bleeding

- Manual removal of the placenta- Multifetal gestations



Which test can be used to estimate the

amount of fetomaternal hemorrhage?

Kleihauer – Betke test. A maternalblood sample can be treated with anacid dilution procedure, allowing

identification and quantification of fetal red blood cells.



After a first pregnancy in a woman who

is RhD – negative with an RhD –positive fetus and who does notreceive RhoGAM, what is the risk that

she will become sensitized?

Approximately 18%



What is sensibilization?

Approximately one-half of women who areRhD-negative, do not receive RhoGAM aftertheir first RhD – positive pregnancy, and

become sensitized to the RhD antigenrespond immediately with immunoglobinproduction to the RhD antigen. The otherhalf mount a small, often undetectableresponse and may quickly mount an

immune response with subsequent exposureto the antigen.



After evacuation of a molar gestation,

do women who are RhD – negativeneed RhoGAM?

With complete molar gestation, there is

theoretically no production of fetal redblood cell, the only cells that expressesRh antigen. However, the distinction of acomplete mole with no fetal red blood

cells in often not available at the time thedecision for RhoGAM is needed. For thisreason, many advocate RhoGAM evenafter evacuation of a complete mole.



How should pregnant women befollowed to avoid fetal complications

from Rh antibodies?At their first prenatal visit, all pregnant women

should be typed according to blood group, withserum screening for antibodies (indirect Coombs)

to all RBC antigens associated with hemolyticdisease of the newborn. For RhD-negativemothers without antibodies, antibody statusshould reevaluated at least once duringpregnancy, generally at 26-28 weeks. Some

recommend reevaluation of antibody status eachtrimester. RhoGAM is administered to RhD-negative women at 26-28 weeks to prevent thesmall risk of sensitization in the third trimester.



For RhD – negative women withevidence of antibodies, serial antibody

titers are obtained on a monthly basis.Further evaluation of the fetus isinitiated when the antibody titers

reach a critical level (≥ 1:16 in mostlaboratories). If there is a history of apreviously affected sibling in utero,many initiate further testing of the

fetus at 4-6 weeks before thegestational age at which the sibling

was affected.



How is amniocentesis used in the

management of Rh isoimmunization?

Amniocentesis can serve two purposes:

1. Assessment of fetal Rh status byDNA-based molecular studies of theamniocytes and

2. Measurement of bilirubin pigments inthe amniotic fluid.



Amniotic bilirubin reflects ongoing erythrocyte destruction. It can be quantitated by measuring the

absorbance of amniotic fluid on a continuouslyrecording spectrophotometer at the 450-nm wavelength (∆ OD450). The ∆OD450 is determined bymeasuring the absorbance of amniotic fluid at365nm and 535nm and drawing a straight line. The

∆OD450 is then determined by subtracting theactual value from the expected 450nm value. Lileydefined three zones that relate the fetal health tothe bilirubin level and the suggested course of

action for each zone. For the premature fetus withevidence of significant hemolysis based on amnioticfluid bilirubin analysis, assessment of the fetalhematocrit by percutaneous umbilical blood sample(PUBS) is the next step.



What is the risk that after amniocentesis aRHD – negative mother will become

sensitized if she does not receive RhoGAM?

Even with placental localization by ultrasoundand avoidance of the transplacental passage of

the needle, amniocentesis is associated with a 1-2% risk of fetomaternal hemorrhage of ≥ 1.0 mlfetal RBC. This risk is similar for amniocentesisperformed in the second trimester for geneticindications and in the third trimester. Given

these risks, RhoGAM should be administered tounsensitized Rh-negative women afteramniocentesis. Of note, in the previously Rh-sensitized woman, even this small degree of fetomaternal hemorrhage can be associated with

a marked increase in antibody titers.



What factors are considered intransfusing an anemic fetus?

In general, a fetal hematocrit below25% warrants transfusion if gestational

age is remote from term. To determine theamount of RBCs to transfuse, thegestational age and weight of the fetus,total vascular volume of both fetus and

placenta, and desired final hematocrit areincorporated into the calculation. Fortransfusion, O-negative, CMV-negative,irradiated blood is used.



How are in utero fetal transfusion

performed?

Either intravascularly orintraperitoneally. The technique isessentially similar, with ultrasoundvisualization of placement of a 20-gauge spinal needle within the amnioticsac and further advancement of theneedle into either the umbilical vein(intravascular transfusion) or theperitoneal cavity of the fetus

(intraperitoneal).



What are the advantages and

disadvantages of intravasculartransfusion?

The advantages of intravasculatransfusion are the ability to obtain a fetal

hematocrit before and after procedure anddirect placement of the transfused packed redblood cells into the fetal vascular system withmore rapid correction of the fetal hematocrit.

Disadvantages include technical constraintsdue either to vessel size at early gestationalage or posterior placentation and dislodgmentof the needle from the umbilical vein bymovement during the procedure.



Can a fetus still be transfused if it ishydropic?

Yes. If an intraperitoneal transfusionis needed, the ascitic fluid may beremoved before transfusion.



What are the risks of fetal transfusion

and the anticipated complications?

The risk of procedure – relatedmortality is 4-9%. In addition, significantmorbidity may include fetal bradycardia,abruption, preterm rupture of

membranes, and emergent delivery dueto fetal distress.



When are fetuses who have

required intrauterine transfusiondelivered?

Once fetal lung maturity has beenobtained, the risk of intrauterinetransfusion outweighs the risk of delivering the infant with transfusion

performed in the neonatal intensivecare unit.



Why do the lungs in infants with Rh

sensitization generally mature at aslightly later gestational age?

The cause is unknown but maybe related to hydropic changes inthe placenta with increased insulin

production, an etiology similar todelayed fetal lung maturation ininsulin – dependent diabetics



Can the Rh type of a fetus bedetermined early in pregnancy?

For several of the Rh antigens it is nowpossible to determine the Rh antigens status

of a fetus through DNA molecular probeswith chorionic villus sampling oramniocentesis. This technique allows theopportunity to determine RhD-antigen statusof a pregnancy early in gestation and may be

considered by couples who have had priorpregnancies complicated by intrauterinetransfusion or fetal demise. The expectationis that subsequent pregnancies would besimilarly or more severely affected.



Because RhD immunoglobulin

(RhoGAM) has prevented much of theisoimmunization problem, whatremains?

The Kell antigen, Kell type is notdetermined before blood transfusion.Approximately 10% of people are Kell –positive, suggesting that the risk of sensitization to Kell after a bloodtransfusion is approximately 10%.



How does ABO sensitization differfrom RhD sensitization?

Although successive pregnancieswith fathers homozygous for RhDusually become more severe, ABOsensitizations are the opposite: thefirst pregnancy is usually the worst.



What are the private antigens?

In rare instances, a fetus may haveinherited a rare red blood cell surface antigenfrom the father. As the red blood cells of themother in all likelihood do not contain thisantigen, during her first pregnancy she maybecome sensitized to this “private” antigen.Subsequent pregnancies, depending on theantigen’s ability to elicit an antibodyresponse, are at variable risk forisoimmunization.



END OF LECTURE

GOOD LUCK!

Rh Iso Immunization - Dr. Malak

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