management of rh negative pregnancy

MANAGEMENT OF RHESUS NEGATIVE PREGNANCY

OBIOKONKWO AC(MBBS, U.PHACOURT)

DEPARTMENT OF OBSTETRICS & GYNAECOLOGY

FEDERAL MEDICAL CENTRE, BIRNIN KEBBI

01/05/23 http://www.facebook.com/imezi 2

Outline Introduction Epidemiology Pathophysiology Management Problems in our setting Recommendations Conclusion References


Introduction

The Rhesus (Rh) blood group system is one of the 35 current human blood group systems

It's the second most important system after the ABO system

At present, the Rh system consists of 50 defined blood group antigens (Ag), among which the five Ag D, C, c, E, e are the most important


... Introduction ...

The D Ag, also called the Rh factor is the most immunogenic[1] of them though the others are still clinically relevant

The Rh factor is a red cell surface antigen named after the rhesus monkey in which it was first discovered.[1]

An individual either has or does not have the D antigen on the surface of their red blood cells (RBCs)



The status is usually indicated by the suffices Rh+ for those that have, or Rh- for those who lack the D antigen

These suffices are attached to the ABO blood type An Rh-negative pregnant woman is one who lacks

this antigen on the surface of their red cells.



Historical time line 1937: Rh blood type discovery by Karl Landsteiner &

Alexander Wiener, and noted to be distinct from ABO blood type

1939: The D antigen was incidentally discovered but yet unnamed. This followed a case of haemolytic disease of the newborn observed in a the infant of a 25 year old G2 P1 woman, blood group O who received O type blood

This case was subsequently published[2] by Philip Levine and Rufus Stetson


... Introduction ... ... Historical time line ...

1940: This unnamed factor was realised to be similar to the earlier discovered blood type and a connection was made to it[3]

1946: Exchange transfusion created by Wiener for treatment of Rh disease

1960: The concept of anti-RhD for the prevention of Rh disease was proposed by Ronald Finn

1963: First successful intrauterine transfusion for treatment of Rh disease was carried out by Sir William Liley


... Introduction

... Historical time line 1964: First prophylactic injection for Rh disease was given 1968: Immunoglobulin G antibody was first approved for use

in USA (as RhoGAM) and UK @300 mcg within 3 days postpartum

1973: Reports in the USA said 50,000 babies' lives had been saved since approval

1981: Rh IgG approved for routine postpartum and antepartum administration by the US Food and Drug Administration


Epidemiology

Globally, the Basque population (of Spain) has the highest incidence of Rh negativity (30-35%)[4]

Otherwise, Whites: 15-16% African Americans: 8% Black Africans: 4% Asians and others, 2% or less


... Epidemiology

Nigerian studies 4.5% prevalence rate at Enugu,[5] Southeast 0.7% incidence rate at Kaduna,[6] North 5.5% prevalence rate at Ogbomosho,[7] Southwest


Pathophysiology Two commonest systems for blood group classification:[8]

ABO system Rhesus system

ABO system: Groups A, B AB, O antigen (Ag) Rhesus system: C, c, D, E, e and G.[4]

There's no 'd' Ag. The letter represents absence of 'D' Ag The D antigen is considered to be the most immunogenic

(aka Rh factor)


... Pathophysiology ...


... Pathophysiology ... There are two possible alleles for each of the c or C, D

and e or E An individual inherits one haplotype from each parent Rh positive: presence of at least one of either C, D or E

antigens regardless of the combination (ie, homozygous or heterozygous)

Rh negative: cde/cde genotype (always homozygous)


... Pathophysiology ... The D antigen

The Rh-positive father may be homozygous (45%) or heterozygous (55%) for D

If homozygous for D, all children will test positive If heterozygous, his children will have a 50% chance of being

RhD-positive Thus if 'D' antigen is specifically tested, its absence will

give a negative result regardless of the presence of the other antigens (C, E)



The amount of foetal blood necessary to produce Rh incompatibility varies, but as little as 0.1 mL of Rh+ cells have been documented.[4]

Studies have suggested that up to 30% of persons (non-responders) with Rh- blood never develop Rh incompatibility even when challenged with large volumes of Rh+ blood[1]

Rh alloimmunisation occurs by 1 of 2 mechanisms After incompatible blood transfusion


... Pathophysiology ... After foeto-maternal haemorrhage between mother and an

incompatible foetus Foeto-maternal haemorrhage may occur during pregnancy

(10%) or delivery (90%)[1]

Notwithstanding, foetal RBCs have been detected in the maternal blood in all three (7, 16, 29%) trimesters without an apparent predisposing factor[4]

The initial maternal response to Rh sensitisation is low levels of immunoglobulin (Ig) M antibodies (Ab)



These are confined to maternal circulation being unable to cross the placental barrier

Within 6 weeks to 6 months, IgG Ab are formed These are able to cross the placenta and destroy foetal Rh-

positive cells Therefore, first-born infants with Rh-positive blood type

are not affected The short period of 1st exposure of mother to foetal RBCs is

insufficient for production of significant IgG Ab response



Subsequent pregnancies may trigger a rapid & robust Ab response - Anamnestic response

Anamnestic theories:– Grandmother theory– “Sensibilization” theory

Maternal O blood type appears particularly protective


... Pathophysiology ... Sequence of inutero events

Maternal IgG enters foetal circulation via placenta Destruction of foetal red cells occur - foetal anaemia [HCT<30%] Haem is formed and converted to bilirubin – foetal

hyperbilirubinaemia Both are neurotoxic, but effectively cleared by placenta and

metabolised by the mother Extramedullary erythropoeisis is stimulated Immature erythroblasts are produced


... Pathophysiology ... When cell destruction exceeds production

Severe anaemia occurs More demand on extramedullary sites to produce more red cells

– hepatosplenomegaly Heart failure eventually results, with ascites, oedema and

pericardial effusion – erythroblastosis foetalis Hydrops foetalis, occurs when the haematocrit falls below 15%.

Often results in foetal death shortly before or after birth• Male to Female foetus = 13.1 to 1


... Pathophysiology ... The risk and severity of sensitisation response increases

with each subsequent pregnancy involving an ABO-compatible foetus with Rh-positive blood

Without prophylaxis, this risk is 16% after two deliveries;– 1.5-2% occur antepartum– 7% within 6 months of delivery– 7% manifest early in 2nd pregnancy

With prophylaxis, the risk drops to 0.1%


... Pathophysiology The aforementioned risk depends on the 3 main factors

Volume of transplacental haemorrhage Extent of the maternal immune response Concurrent presence of ABO incompatibility (protective –

risk drops to 1.5-2%)[4]

Rh incompatibility is only of medical concern for females who are pregnant, or plan to get pregnant in future


Management

This includes history taking, clinical examination, appropriate investigations, and treatment

Two groups of women are catered for– Unsensitised Rh-negative women– Sensitised Rh-negative women

There is usually no specific finding on the history and clinical examination for the woman that is not sensitised


... Management ...

For the sensitised woman, her presentation would depend on whether or not she has a previously affected infant. This also guides management.

Some events have been found to increase the chances of formation of anti-D antibodies in Rh-negative women

The goal of the history therefore, is to establish or exclude the occurrence of such events


... Management ... Potentially sensitising events

Abortion Invasive procedures (amniocentesis, chorionic villus sampling) Abdominal/pelvic trauma Antepartum haemorrhage (placenta praevia, abruptio) Intrauterine foetal demise Multiple gestation Manual removal of the placenta Ectopic pregnancy Caesarean delivery


... Management ... Other aspects of the history to be explored include

Prior blood transfusion Rh blood type of patient and spouse All previous pregnancies, outcomes, interventions

• History of hydrops = 90% chance recurrence Previous administration of Rh IgG Mechanism of injury in cases of maternal trauma during pregnancy Presence of vagina bleeding Prior invasive procedure


... Management ...

The objective of antenatal management is– Prevention of Rh alloimmunisation in the Rh-

negative unsensitised woman– Early detection and treatment of foetal anaemia in

the sensitised woman Sensitisation is determined via the indirect

Coombs test, otherwise called antibody screen


... Management ...

The unsensitised Rh-negative woman History may be uneventful with patient hearing for

the first time of her Rh-negative group First, determine husband's ABO and Rh group. If negative, manage as any other pregnancy. No

further investigation required If positive, screen woman for alloimmunisation at

contact.


... Management ...

... The unsensitised Rh-negative woman If the antibody screen is negative, repeat at 20, 24 & 28

weeks If still negative by 28 weeks, 300 mcg of Rh IgG is given A repeat dose is given after each invasive procedure, or

after 12 weeks of last dose if pregnancy lasts that long If a positive result is recorded at any time, the patient is

managed as a sensitised Rh-negative woman


... Management ... Precautions during delivery

– Ensure consultation with neonatologist– Don't give oxytocics at delivery of anterior shoulder– If manual removal of placenta is required, do so gently– If blood transfusion is indicated, use Rh-negative blood

only– Early clamping of umbilical cord is indicated– Leave a long length of cord, about 15 to 20 cm


... Management ...

Postpartum management Involve the neonatologist Send cord samples for ABO/Rh typing, DCT, Hb,

bilirubin levels, peripheral smear If foetus is Rh-negative, no further intervention If foetus is Rh-positive, determine the dose of Rh IgG to

be administered by a 4-step laboratory procedure


... Management ...

The 4-step laboratory procedure– Rosette foetal RBC screen for FMH. If positive,– Acid elution (Kleihauer-Betke) test to quantify the

RBCs in maternal circulation– Estimate the volume of FMH (50 x % foetal RBCs)– Calculate the dose of Rh IgG to be given within 72

hours of delivery


Rosette Test

Positive rosetteNegative rosette


Acid Elution Test


... Management ...

For sensitised women, management is guided by the following

– Presence or absence of history or affected foetus in previous pregnancy (e.g. with severe anaemia or hydrops)

– Maternal antibody titres (where no prior history) Sensitisation may be determined by doing an

antibody screen using indirect Coombs test


Direct Coombs Test


Indirect Coombs Test


... Management ...

The sensitised Rh-negative woman No previous history of affected foetus

– The history might include some of the previously mentioned sensitising events

– Risk of foetal anaemia is proportional to maternal anti-Rh antibody titre

– This relationship is lost in subsequent pregnancies– Obtain the ABO and Rh group of the husband. If

negative, no further testing is needed. If positive,


... Management ...... The sensitised Rh-negative woman ...

... No previous history of affected foetus...– Screen for alloimunisation. If positive, obtain Ab titres– If below the critical titre, obtain monthly titres– If still below critical level by 36th week, pregnancy

may continue to term, but not allowed to be postdated– If it rises beyond critical value after 34 weeks, deliver

immediately


... Management ...

... The sensitised Rh-negative woman ... ... No previous history of affected foetus

– If it rises before 34 weeks, further testing includes• Peak systolic velocity of the middle cerebral arteries

using Doppler• Amniocentesis for analysis and spectrophotometry• Ultrasound examination of foetus• Percutaneous umbilical cord blood sampling

(cordocentesis) for HCT, Rh


... Management ...

... The sensitised Rh-negative woman ... Previously affected foetus

– The history may include, amongst others, that of a stillborn neonate, one admitted for phototherapy or exchange blood transfusion.

– One needs to be proactive to prevent recurrence, and have a high index of suspicion

– Her Rh type should be established as well as sensitisation


... Management ...

... The sensitised Rh-negative woman ... ... Previously affected foetus

– Evaluation should start early – at least 4 weeks to anniversary of prior affected foetus

– The anti-D titres cannot predict the development of foetal anaemia, thus other tests are indicated

– Cordocentesis may be indicated to determine foetal HCT, and Rh genotype if father is heterozygous for D

– If the foetus is determined to have the D Ag, there is a risk of haemolytic disease and sequelae


... Management ...

... The sensitised Rh-negative woman ... ... Previously affected foetus

– Amniocentesis may be done for amniotic fluid spectrophotometry and assay

– Initiate middle cerebral artery Doppler (MCAD) surveillance from 18 weeks


... Management ...


... Management ...

Middle Cerebral Artery Doppler (MCAD) Velocimetry Accurate & non-invasive screening tool for detecting

moderate to severe foetal anaemia A sensitivity of 100% and a 12% false positive rate for

anaemia Use has resulted in up to 80%[9] reduction in invasive

testing (i.e., amniocentesis, cordocentesis)


... Management ...

Middle Cerebral Artery Doppler (MCAD) Velocimetry Not useful before 18 weeks of gestation – RES too

immature to haemolyse enough cells to cause significant anaemia[9]

Not a reliable predictor of severe anaemia after 35 weeks GA[10]

Found to be similar[11] or better[12] than amniotic fluid OD450 in prediction of anaemia


Normal vs abnormal MCA-PSV

Normal MCA Doppler


... Management ...

Results MCAD Velocimetry[4]

Unaffected/mildly affected foetus– Normal MCAD. Doppler is repeated monthly. Deliver at or near term after

lung maturity. Low risk of IUFD

Moderately affected– MCAD about 1.5 multiples of median (MoM). Repeat 1-2 weekly. Deliver

after lung maturity. Enhancement of lung maturity may be necessary

Severely affected– MCAD >1.55 MoM or has frank evidence of foetal hydrops. Foetus needs

help to attain lung maturity before delivery. High risk of IUFD


Spectrophotometry charts

QueenanLiley

Not accurate before 26 weeks GA Can be used from 14th to 40th week GASensitivity 10% superior to Liley curve


... Management ...


... Management ...

Intrauterine Blood Transfusion[8]

Recommended treatment for severe (haemolytic) anaemia inutero

Typically carried out between 18 and 35 weeks GA May be given intraperitoneal or intravascular O RhD negative packed cells with HCT of 80% is used Amount to be transfused in mL is (GA-20) x 10 where GA>

20 weeks


Intravascular IUBT


... Management ...

... The sensitised Rh-negative woman Postpartum management of the neonate

– Baby, if alive should be admitted into the neonatal intensive care unit

– An urgent exchange blood transfusion is indicated in moderate to severely affected neonates

– Phototherapy for mild affectation.


... Management ... Special foeto-maternal risk states[4]

Abortion: Up to 5% chance of sensitisation. Fifty microgram is recommended

Invasive foetal procedure: Up to 11% of sensitisation. A dose of 300 mcg is recommended

Antepartum haemorrhage: 300 mcg stat, to be repeated 12 weeks later if pregnancy lasts that long

External cephalic version: Up to 6% chance of sensitisation. Dose is 300 mcg


... Management

– Delivery with foeto-maternal haemorrhage• The normal amount of foetal blood that enters the

maternal circulation is <0.5 mL.[13]

• Dose of Rh IgG given @ 300 mcg will neutralize nearly 30 mL whole foetal blood (or 15 mL Rh+ foetal RBCs)

• Management is guided by the estimated volume of FMH determined by the 4-step lab tests

• Dose of Rh IgG given after sensitisation is at least 20 mcg/mL of foetal RBCs[1]


Recent Advances

Non-invasive foetal RhD genotyping (from foetal cell-free DNA in maternal circulation)[14]

Point-of-care-tests (POCT), i.e., rapid tests for determining Rh status[15]

A lower 50 mcg dose preparation of Rh IgG for use following first trimester abortions[1]

Concept of partial D and weak D antigens (usually test positive, but can also form anti-Rh antibodies)[16]


Take home points

1. Every woman of childbearing age should have her ABO and Rh types done at first contact

2. Obtain the ABO/Rh types for husbands of women found to be Rh-negative

3. Ensure ICT is done at 20, 24 and 28 weeks of pregnancy with appropriate prophylaxis

4. A single postpartum dose may be inadequate in cases of severe foeto-maternal haemorrhage


Problems in our setting

High cost of the immunoglobulin Lack of resources to adequately investigate and

monitor foetus inutero Low turnout for antenatal clinics – missed cases Poor documentation of prior sensitising events –

some are yet to fully grasp the import Loss of case notes


Recommendations

Advocacy for partnership by Government and NGOs to help subsidize the cost of the immunoglobulin

Special insurance cover for Rh-negative women to ensure ease of procurement when needed

Involvement of clergy as part of premarital counsellors Creation of special fora/groups for Rh-negative people

where potential Rh-negative spouses can be met


Conclusion

Rhesus alloimmunisation is a real problem and real efforts need to be made to mitigate its impact

Although its incidence has decreased dramatically, yet the consequences of haemolytic disease of the newborn remain

Great advancements have been made in the detection and management of this condition, and many of our Rh-negative women can now have a happy obstetric career.


THANK YOU FOR LISTENING


References

1. Salem L, Singer KR. Rh Incompatibility. [Updated: Feb 06, 2014]. Available from http://emedicine.medscape.com/article/797150

2. Levine P, Stetson RE. An unusual case of intragroup agglutination. JAMA. 1939. 113:126-7.

3. Landsteiner K, Wiener AS. An agglutinable factor in human blood recognised by immune sera for rhesus blood. Proc Soc Exp Biol Med. 43: 223-4.

4. Roman AS. Late pregnancy complications. In: Decherney AH, Nathan L, Laufer N, Roman AS, editors. Current Diagnosis & Treatment: Obstetrics & Gynaecology. 11th ed. United States: McGraw-Hill Companies Inc; 2013: 250-266.

5. Okeke TC, Ocheni S, Nwagha UI, Ibeghulam OG. The prevalence of Rhesus negativity among pregnant women in Enugu, Southeast Nigeria. Niger J Clin Pract. 2012 Oct-Dec; 15(4): 400-2

http://emedicine.medscape.com/article/797150


... References ...

6. Onwuhafua JA. Pregnancy in Rhesus Negative Women in Kaduna, Northern Nigeria. Trop J Obstet Gynaecol. 2004; 21(1): 21-23

7. Adeyemi AS, Bello-Ajao HT. Prevalence of Rhesus D-negative blood type and the challenges of Rhesus D immunoprophylaxis among obstetric population in Ogbomosho, Suthwestern Nigeria. Ann Trop Med Public Health. 2016; 9(1):12-15.

8. Saxena R, editor. Bedside Obstetrics and Gynaecology. 1st ed. New Delhi: Jaypee Brother Medical Publishers (P) Ltd; 2010: 105-120.

9. Scheier M, Hernandez-Andrede E, Carmo A, Dezerenyz V, Nicholaides KH. Prediction of fetal anemia in rhesus disease by measurement of fetal middle cerebral artery peak systolic velocity. Ultrasound Obstet Gynecol. 2004; 23: 432-436.


... References ...

10. Zimmermann R, Durig P, Carpenter RJ, Jr, Mari G. Logitudinal measurement of peak systolic velocity in the fetal middle cerebral artery for monitoring pregnancies complicated by red cell alloimmunization: A prospective multicentre trial with intention to treat. Br J Obstet Gynaecol. 2002; 109: 746-752

11. Bullock R, Martin WL, Coomarasamy A, Kilby MD. Prediction of fetal anemia in pregnancies with red-cell alloimmunization: comparism of middle cerebral artery peak systolic velocity and amniotic fluid OD450. Ultrasound Obstet Gynecol. 2005;25:331-334

12. Pereira L, Jenkins TM, Berghalla V. Conventional management of maternal red cell alloimmunization compared with management by Doppler assessment of middle cerebral artery peak systolic velocity. Am J Ostet Gynecol. 2003;189:1002-1006


... References

13. Pessel C, Tsai MC. The Normal Pueperium. In: Decherney AH, Nathan L, Laufer N, Roman AS, editors. Current Diagnosis & Treatment: Obstetrics & Gynaecology. 11th ed. United States: McGraw-Hill Companies Inc; 2013: 190-213

14. Kolialexi A, Tounta G, Mavrou A. Noninvasive fetal RhD genotyping from maternal blood. Expert Rev Mol Diagn. 2010 Apr; 10(3): 285-96

15. Rapidtest® Rh Test kit. Available from http://nbi-sa.co.za/index.php/products/30-products/71-diagnostics

16. Gonsorcik VK, Zhou L. Rh Typing. [Updated: Nov 06 2013]. available from http://emedicine.medscape.com/article/1731224

http://nbi-sa.co.za/index.php/products/30-products/71-diagnostics

http://emedicine.medscape.com/article/1731224

management of rh negative pregnancy

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