30854 rh isoimmunisation

8/15/2019 30854 Rh Isoimmunisation

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Rh Isoimmunization

Professor Hassan A NasratChairman of the Department of Obstetrics and Gynecology

Faculty of Medicine

King Abdul A!i! "ni#ersity


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$%O& is a prefi' means similar( e)ual or uniform*

$soimmuni!ation& is the process of immuni!ing aspecies +ith antigen deri#ed from the same sub,ect*


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-he Antibodies Arise $n -he Mother As -he Direct .esult Of A/lood Group $ncompatibility /et+een -he Mother And Fetus

e*g* 0hen An .hD Negati#e Mother Carries An .hD Positi#eFetus*

$n -he Fetus& 1rythroblastosis Fetalis$n -he Ne+born& HDN*

Alloimmune Hemolytic Disease Of The Fetus / Newborn:

Definition:-he .ed Cells Of -he Fetus Or Ne+born Are Destroyed /y

Maternally Deri#ed Alloantibodies


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Antibodies That ay !e Detected Durin" #re"nancy:

Innocuous Antibodies &

Most Of -hese Antibody Are $gM -herefore Cannot Cross -he Placental /arrier1*G* -hose Directed Against %uch %pecificities As A( P234( 5e2a4( M( $( $H And%d2a4*

Antibodies $a%able Of $ausin" &i"nificant Hemolytic TransfusionReactions:

$gG antibodies ( -heir Corresponding Antigens Are Not 0ell De#eloped At /irth1*g* 5u 2b4( 6t 2a4( And 715 8

Antibodies That Are Res%onsible For HDN & Anti c( Anti d( Anti e( And Anti 9 2Kell4


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-he .H Antigen : /iochemical and Genetic Aspects

Mechanism of De#elopment of Maternal .h $soimmuni!ation

Natural History of Maternal isoimmuni!ation ;HD of the Ne+born

Diagnosis of .h isoimmuni!ation


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The Rh Anti"en' !iochemical As%ects:

-he .h Antigen $s A Comple' 5ipoprotein* $t Has A Molecular 0eight Of Appro'imately


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The RH Anti"en' (enetic As%ect

-he .h gene comple' is located on the distal end of theshort arm of chromosome one*

A gi#en .h antigen comple' is determined by a specific

gene se)uence inherited in a Mendelian fashion from theparents* one haploid from the mother and one from thefather*

-hree genetic loci( determine the .h antigen 2i*e* .hblood group4*

1ach chromosome +ill be either D positi#e or D negati#e2there is no >d> antigen4( C or c positi#e( and 1 or e positi#e*


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Grades Of ?Positi#ely@ Due -o 7ariation $n -he DegreeGenetic 1'pression Of -he D Antigen*

$ncomplete 1'pression May .esult $n A 0ea9ly Positi#ePatient e*g* Du 7ariant Of 0ea9ly .h Positi#e Patient2-hey May 1#en /e Determined As .h Negati#e4*

A Mother 0ith Du .h /lood Group 2Although GeneticallyPositi#e4 May /ecome %ensiti!ed From A D positi#e Fetus

Or -he Other 0ay Around May -a9e Place*

(enetic )*%ression + Rh &urface #rotein Anti"enicity,:


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$ncomplete 1'pression Of -he D Antigen .esult $n A 0ea9ly Positi#e Patiente*g* Du 7ariant Of 0ea9ly .h Positi#e Patient*

(enetic )*%ression + Rh &urface #rotein Anti"enicity,:

Du 7ariantFran9 D Positi#e


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Factors Affect -he 1'pression Of -he .h Antigen

-he Number Of %pecific .h antigen %ites& -he Gene Dose( -he .elati#e Position Of -he Alleles( -he Presence Or Absence Of .egulator Genes*

$nteraction Of Other Components Of -he .h /lood Group*1rythrocytes Of $ndi#iduals Of Genotype Cde;cde 1'press 5ess D Antigen-han Do -he 1rythrocytes Of $ndi#iduals Of Genotype cD1;cde*

-he 1'posure Of -he D Antigen On -he %urface Of -he.ed Cell Membrane*


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DcE

eCd

eCd/EcD

PhenotypeGenotype

D positive

Antigenicity of the Rh surface protein:

genetic expression of the D

allele. Number of specific Rh

antigen sites.

Interaction of componentsof the Rh gene complex.

Exposure of the D antigenon the surface of the red cell


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The echanism of De-elo%ment of the Rh Immune Res%onse:

Fetal R!$ with Rh .-e anti"en

aternal circulation of an Rh -e mother

+#rimary immune res%onse,

The Rh .-e anti"en will be cleared by macro%ha"es0 %rocessedand transferred to %lasma stem cell %recursors +De-elo% an almost

%ermanent immunolo"ic memory,

1ith subse2uent e*%osure the %lasma cell line %roliferate to %roducehumeral antibodies

+&econdary immune res%onse,3


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The #rimary Res%onse:

$s a slo+ response 2 +ee9s to months4*$gM antibodiesa molecular +eight of B==(=== that does not cross the

placenta*

The &econdary Res%onse:

$s a .apid response$gG antibodiesa molecular +eight of 3 =(=== that cross the placenta*


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1'posure to maternal antigen in utero ?the grandmother theory@&

-his theory e'plains the de#elopment of fetal isoimmuni!ation in a primigra#ida(+ho has no history of e'posure to incompatible .h blood* $f a fetus is .h negati#eand the mother is .h positi#e( the may be e'posed to the maternal .h antigenthrough maternal fetal transplacental bleed* $n such cases the fetus immunesystem de#elop a permanent template 2memory4 for the .h positi#e antigen*0hen the fetus becomes a mother herself and e'posed to a ne+ load of D antigenfrom her fetus 2hence the grandmother connection4 the immune memory isrecalled and a secondary immune response occur*


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0ithout treatment& less than = of .h D incompatible pregnanciesactually lead to maternal isoimmuni!ation

E


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The Risk of development of Fetal Rh-disease isaffected by:

The usband !henotype And "enotype #$% & 'f

Rh !ositi(e )en Are omo*ygous And +%& Areetero*ygous,.

The Antigen -oad And re/uency 'f Exposure.

A0' Incompatibility

4ess than 567 of Rh D incom%atible %re"nancies actuallylead to maternal alloimmunization


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-he Amount Of Fetal Cells $n Maternal /lood

1hy Not All the Fetuses of Isoimmunized 1omenDe-elo% the &ame De"ree of Disease8

-he Non responders&

A/O $ncompatibility&

Antigenic 1'pression Of -he .h Antigen&

Classes Of $gG Family


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Dia"nosis of Rh isoimmunization

The dia"nose is !ased on the %resenceof anti'Rh +D, antibody in maternal

serum3

The )nzymatic ethod The Antibody Titer In &aline9 In Albumin The Indirect $oombs Tests3

ethods of Detectin" Anti D Antibodies inaternal &erum:


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Antibody Titre in &aline &RhD'%ositi-e cells sus%ended insaline solution are a""lutinated by I" anti'RhD antibody9 but not

I"( anti'RhD antibody3 Thus9 this test measure I" 9 or recentantibody %roduction3

Antibody Titre in Albumin &Reflects the %resence of any anti'RhD I" or I"( antibody in the maternal serum *

The Indirect $oombs Test & o First &te%:RhD'%ositi-e R!$s are incubated with maternal serumAny anti'RhD antibody %resent will adhere to the R!$s3

o &econd &te% &The R!$s are then washed and sus%ended in serum containin"antihuman "lobulin +$oombs serum,3 Red cells coated with maternal anti'RhD will be a""lutinated bythe antihuman "lobulin +%ositi-e indirect $oombs test,3

Dia"nosis aternal Isoimmunization


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$s Done After /irth -o Detect -he Presence Of Maternal Antibody On -he Neonate s ./Cs*

-he $nfant s ./Cs Are Placed $n Coombs %erum*$f -he Cells Are Agglutinated -his $ndicate -he Presence OfMaternal Antibody

The Direct $oombs Test


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Inter%retation of aternal Anti'D Titer

Antibody Titer Is A &creenin" Test3

A Positive Anti-d Titer Means That The Fetus Is At Risk ForHemolytic Disease, Not That It Has Occurred Or ill

Develo!"

7ariation $n -iter .esults /et+een 5aboratories And$ntra 5aboratory $s Common*

A -ruly %table -iter %hould Not 7ary /y More -han OneDilution 0hen .epeated $n A Gi#en 5aboratory*


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#atho"enesis of The HD of the Fetus and Newborn


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Fetal Rhesus Determination

.HD -ype And ygosity 2$f .HD positi#e4 Of -he Father

Amniocentesis -o Determine -he Fetal /lood -ype "sing-he Polymerase Chain .eaction 2PC.4

Detection Of Free Fetal .HD DNA 2FDNA4 %e)uences $nMaternal Plasma Or %erum "sing PC.

Flo+ Cytometry Of Maternal /lood For Fetal Cells


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Pathogenesis of Fetal Hemolytic Disease


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ethods of Dia"nosis and )-aluation of Fetal RhIsoimmunization

easurements Of Antibodies in aternal &erum

Determination of Fetal Rh !lood (rou%

ltrasono"ra%hy

Amniocentesis

Fetal !lood &am%lin"


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-o 1stablish -he Correct Gestational Age*

$n Guiding $n#asi#e Procedures And Monitoring FetalGro+th And 0ell being*

"ltrasonographic Parameters -o Determine Fetal Anemia&o Placental -hic9ness*o "mbilical 7ein Diameter o Hepatic %i!e*o %plenic %i!e*o Polyhydramnios*o Fetal Hydrops 2e*g* Ascites( Pleural 1ffusions( %9in1dema4*

ltrasono"ra%hy :


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Anemic Fetus Preser#es O'ygen Deli#ery -o -he/rain /y $ncreasing Cerebral Flo+ Of $ts Already

5o+ 7iscosity /lood*

Do%%ler ;elocimetry Of The Fetal iddle $erebralArtery + $A,

-o Predict -he -iming Of A %econd $ntrauterineFetal -ransfusion*

For Predicting Fetal Anemia


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#re-ious &eriously Affected Fetus Or Infant 2e*g* $ntrauterine Fetal -ransfusion( 1arly Deli#ery( FetalHydrops( Neonatal 1'change -ransfusion4*

A $ritical Anti'D Titer:$*1* A -iter Associated 0ith A %ignificant .is9 For FetalHydrops* Anti D -iter 7alue /et+een And <

In-asi-e Techni2ues+ Amniocentesis and Fetal !lood &am%lin",:

Indications:


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Amniocentesis

Normally /ilirubin $n Amniotic Fluid Decreases 0ith Ad#anced Gestation*

$t Deri#es From Fetal Pulmonary And -racheal 1ffluents*

$ts 5e#el .ises in Correlation 0ith Fetal Hemolysis*

Determination Of Amniotic Fluid !ilirubin:

/y -he Analysis Of -he Change $n Optical Density Of Amniotic Fluid At IE= nm On -he %pectral Absorption Cur#e

2delta ODIE=4

Procedures Are "nderta9en At 3= 3E Days $nter#als "ntilDeli#ery Data Are Plotted On A Normati#e Cur#e /ased "pon

Gestational Age*


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)*tended 4iley "ra%h3


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Jueenan cur#e 2De#iation in amniotic fluid optical density at a +a#elength of IE=nm in .h immuni!ed pregnancies from 3I to I= +ee9s gestation4


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Inter%retation Of Amniotic Fluid !ilirubin:

A Fallin" $ur-e: $s .eassuring& i*e* An "naffected Or.hD negati#e Fetus*

A #lateauin" Or Risin" $ur-e & %uggests Acti#eHemolysis 2.e)uire Close Monitoring And May .e)uire

Fetal /lood %ampling And;Or 1arly Deli#ery4*

A $ur-e That Reaches To Or !eyond The one Of -he Jueenan Cur#e&

Necessitates $n#estigation /y Fetal /lood %ampling


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$s the gold standard for detection of fetal anemia*

.eser#ed for cases +ith& 0ith an increased MCA P%7 $ncreased OD IE=

$om%lications:

-otal .is9 of Fetal 5oss .ate *L 2Fetal death is 3*Ibefore +ee9s and -he perinatal death rate is 3*I after

+ee9s4* /leeding from the puncture site in < to E< of cases* /radycardia in


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Most polyclonal .h$g comes from male #olunteers +ho are intentionallye'posed to .hD positi#e red blood cells*

Potential Problems&infectious ris9sol#e supply problems*ethical issues

MONOCLONAL ANTI-D

anti D monoclonal antibody&

Although monoclonal anti D is promising( it cannot be recommended at thistime as a replacement for polyclonal .h$g*


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$om%lications of Fetal'Neonatal Anemia:

Fetal Hydro%s And &tillbirth

He%atos%lenome"aly

Neonatal >aundice

$om%ilations Of Neonatal ?ernicterus +4ethar"y9

Hy%ertonicity9 Hearin" 4oss9 $erebral #alsy And

4earnin" Disability, Neonatal Anemia


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Alloimmune Hemolytic Disease Of The Newborn +HDN,:

$auses Of Fetal Neonatal Anemia:

o Abnormal Placental %eparation 2Abruptio Placentae4 Or Placenta Pre#iao -raumatic -ear Of -he "mbilical Cordo Occult /lood 5oss $n "tero As A .esult Of Fetomaternal Hemorrhage*o A Chronic -+in to t+in -ransfusion $n $dentical -+ins

!lood 4oss:

Infections:

Anemia Due To $on"enital &%herocytosis

Nons%herocytic Hemolytic Anemias

Hemo"lobino%athies:


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-he .H Antigen


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Diagnostic algorithm for neonatal anemia* Note that the direct antiglobulin 2Coombs4


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&u""ested mana"ement of the RhD'sensitized %re"nancy

onthly aternal Indirect $oombs Titre

!elow $ritical Titre)*ceeds $ritical Titre

#aternal Rh Testin"

Rh #ositi-e Rh'ne"ati-e

Amniocentesis for RhD anti"en status Routine $are

Fetus RhD %ositi-e Fetus RH D Ne"ati-e

&erial Amniocentesis 1ee@ly $A'#&;

B3C6 O

$ordocentesis or Deli-er

B3C6 O


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%uggested management of the .hD sensiti!ed pregnancy

Monthly Maternal $ndirect Coombs -itre

/elo+ Critical -itre1'ceeds Critical -itre

Paternal .h -esting

.h Positi#e .h negati#e

Amniocentesis for .hD antigen status .outine Care

Fetus .hD positi#e Fetus .H D Negati#e

%erial Amniocentesis 0ee9lyl MCA P%7

3*E= MOM 3*E MOMCordocentesis or D

&erial Amniocentesis


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&u""ested mana"ement after amniocentesis for EOD C6

&erial Amniocentesis

4ily zone I4ower =one II

%%er =one II =one IIIHydramnios G Hydro%s

Re%eatAmniocentesis e-ery

5' wee@s

Deli-ery at or near term

Re%eat Amniocentesis in days or F!&

Hct 5C7 Hct 5C7

IntrauterineTransfusion

Re%eat &am%lin" to B days

C to J wee@sAnd Fetal lun"

immaturity

C to Jwee@s 4un"

maturity%resent

IntrauterineTransfusion

Deli-ery


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%uggested management after amniocentesis for OD IE=

%erial Amniocentesis

5ily !one $5o+er one $$

"pper one $$ one $$$Hydramnios Q Hydrops

.epeat Amniocentesise#ery I +ee9s

Deli#ery at or near term

.epeat Amniocentesis or F/%

Hct EHct E

$ntrauterine-ransfusion

.epeat %amplingL to 3I days


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A#erage regression lines for healthy fetuses 2 dotted line 4( mildly anemic fetuses 2 thin== 3 L&B< +ith permission*4


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%uggested management of the patient +ith antibody screen positi#e for antigenother than RhD *


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Incidence Of aternal Alloimmunization

-he o#erall incidence of maternal alloimmuni!ation to clinically significant ./Cantigens has been estimated to be E per 3=(=== li#e births


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.hD D negati#ity primarily occurs among Caucasians the a#erageincidence is 3E percent in this group* 1'amples of the blood groupdistribution in #arious populations are illustrated belo+& /as)ues 8


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Changes since introduction of Anti D


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S Chronic transplacental hemorrhage*S Failure to administer .h immune globulin +hen indicated*S or non detection of a large fetal bleed at deli#ery

#ATHO()N)&I&


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As an e'ample( in a study of 33= pregnant mothers +ith 333 at ris9fetuses( and maternal serum titers of 3&3 or greater( antibodies to D(

K( 1( and c +ere present in I( 3 ( ( and < fetuses( respecti#ely


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-he nature of the .h antigen comple' is determined by a specific genese)uence inherited in a Mendelian fashion from the parents( one haploid from

the mother and one from the father* $n 3BLI the location of the .h genecomple' +as pinpointed on the distal end of the short arm of chromosome one*-hree genetic loci( each +ith t+o possible alleles determined the .h antigen2i*e* .h blood group4*


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-he amount of fetal cells in maternal blood&

the Kleihauer /raun /et9e test


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The se-erity of fetal anemia is influenced:Primarily by antibody concentration(

Additional factors that are not fully understood*-hese include the subclass and glycosylation of maternal antibodies*-he structure( site density( maturational de#elopment and tissue distributionof blood group antigens*-he efficiency of transplacental $gG transport*-he functional maturity of the fetal spleen*Polymorphisms +hich affect Fc receptor function and the presence of H5Arelated inhibitory antibodies T 3


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DIA(NO&I&

/lood and .h2D4 typing and an antibody screen should al+ays be performed at the fir


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/elo+ the critical titer there is a ris9 of mild to moderate( but not se#ere( fetal orneonatal hemolytic anemia* Fetal assessment +ith in#asi#e techni)ues 2eg(

amniocentesis( fetal blood sampling4 is re)uired +hen a critical titer is presentor if the patient has had a prior significantly affected pregnancy 2eg( intrauterinefetal transfusion( early deli#ery( fetal hydrops( neonatal e'change transfusion4*-he purpose of these in#asi#e tests is to determine +hether se#ere fetalanemia is present*


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4i-er len"ths %lotted a"ainst "estation for B< fetuses with anemia withultrasono"ra%hic measurement durin" wee@ before deli-ery9 shown in

reference to normal -alues Open circles, $ord hemo"lobin le-el K6"/40 solid circles, cord hemo"lobin le-el K6 to B 6 43


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5i#er length measurements made +ithin I hours of fetal blood samplingin all fetuses +ith anemia at first fetal blood sampling( sho+n in reference

to normal #alues*


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"ltrasound image of amniocentesis at 3 +ee9s of gestation


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"ltrasound image of transabdominal chorionic #illus sampling*


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Do%%ler -elocimetry 8 Doppler assessment of the fetal middle cerebralartery 2MCA4


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Amniocentesis 8 Amniocentesis is performed +hen the critical titer is reachedor if there has been a pre#ious seriously affected fetus or infant*


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Fetal blood sam%lin" 8 "ltrasound directed fetal blood sampling 2ie(percutaneous umbilical blood sampling( cordocentesis( funipuncture4 allo+sdirect access to the fetal circulation to obtain important laboratory #alues such as

hematocrit( direct Coombs( fetal blood type( reticulocyte count( and total bilirubin


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ulti%le antibodies %ome +omen de#elop antibodies to more than one redblood cell antigen*


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"ltrasound image of cordocentesis +ith the needle tip located in a free loop of


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"ltrasound guided transabdominal fetocentesis


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"ltrasound image of bladder outlet obstruction +ith enlarged bladder( classic9eyhole appearance seen +ith posterior urethral #al#es( and anhydramnios


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Double pig tailed .oc9et catheter and trocar used for #esicoamniotic shunting*


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30854 rh isoimmunisation

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