Management of Rh negative pregnancy

MANAGEMENT OF RHESUS
NEGATIVE PREGNANCY
OBIOKONKWO AC
(MBBS, U.PHACOURT)
DEPARTMENT OF OBSTETRICS & GYNAECOLOGY
FEDERAL MEDICAL CENTRE, BIRNIN
KEBBI

02/09/16 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


... 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 ...


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)


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

− 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


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


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


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 ...

... 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 ...

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 ...

... 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 ...

... 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
Queenan
Liley
Not accurate before 26 weeks GA
Can be used from 14th
to 40th
week GA
Sensitivity 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

... 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

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