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Anti-D Prophylaxis Guideline
Update
National Haemovigilance
Office Conference 2008
Overview
Causes of Residual Sensitisation
– Review NHO Anti-D errors
Evidence for RAADP
Implementation of RAADP in Ireland –
guideline for anti-D Ig in draft
Indications for Anti-D
Immunoglobulin
Prophylaxis following antenatal sensitising
events
Postnatal prophylaxis
Routine antenatal prophylaxis
Following transfusion of RhD positive platelets in
females of childbearing potential
Following transfusion of RhD positive red cells in
female of child bearing potential
Chronic ITP (RhD positive patients only-IV Anti-
D)
Causes of anti-D sensitisation
Failure to give anti-D for antenatal
sensitising event or following delivery of
RhD pos baby
Inadequate dose of anti-D (large FMH)
Silent FMH events ( estimated to account
for 50% of RhD alloimmunisations) which
occur mainly in the last 12 weeks of
pregnancy
Errors in Anti-D Administration
NHO & UK SHOT reports show that the most
common errors in respect to anti-D Ig
administration relate to: administering anti-D Ig
to the wrong patient (e.g, RhD positive woman)
or inappropriate administration (e.g. baby RhD
negative) due to failure to perform the necessary
pre administration checks of identity and
prescription.
Of significant concern are delays or omissions of
anti-D Ig which are associated with a lack of
knowledge or understanding of the indications
for anti-D Ig prophylaxis.
NHO 2006 IBCT Case Report :
Omission of Anti D
Rh D negative female presented to the hospital following
a fall onto her abdomen at 31 weeks gestation. A
Kleihauer test was used to estimate the foetomaternal
blood loss following the event. The result of the
Kleihauer test was negative and the doctor incorrectly
presumed that anti D was not required and discharged
the patient.
Error discovered 8 weeks later by the laboratory
following delivery.The cord DAT was positive and the
mother who was antibody screen negative at 31 weeks
now had anti-D present in her plasma
The baby suffered no sequelae as a result of the
omission however, the omission will have
implications for the mother in future
pregnancies.
The root cause was lack of understanding of the
guidelines. As a result of this incident there has
been an increased emphasis on anti-D
administration and the management of
sensitising events in local education sessions, in
addition to a review and update of the anti -D
guidelines.
Case in the Community
Patient under care of a community mid-wife
Anti-D was issued by the transfusion laboratory
but the community midwife failed to pick it up
Error noted and Anti-D was given 5 days post
delivery
CMs do not have patient’s charts and there was
no record on the home visit sheet.
Since then the mother’s blood group is now
documented on the home visit record.
Delay in anti-D administration
Post- natal anti- D not prescribed as
patient had anti-D prophylaxis given for PV
bleeding 10 days earlier- assumed that
patient was covered
– ? Lack of understanding of the guidelines
– ? Are the guidelines clear on this issue?
2007 IBCT associated with Anti D
(n=16)
Omission/Delay of Anti-D Ig =12
Omission 5
Delay 7
Unnecessary Treatment with Anti D = 4
Anti D given to mother of D neg infant 1
Anti D given to Rh pos Mother 2
Unnecessary Dose of Anti D given 1
Human Failures identified in
Anti D errors 2007 (n=16)
Human Failures identified in Anti-D errors
Knowledge, 2, 13%
Slip, 2, 13%
Co-
Failure to adhere to
ordination/Communica
policies/procedures, 6,
tion, 4, 24%
37%
Verification, 2, 13%
Knowledge Co-ordination/Communication Verification Failure to adhere to policies/procedures Slip
Findings from Anti D errors
Cause of Error
System failures identified = 3
Lack of polices highlighted in 2 cases
Design highlighted in 1 case
2007 Recommendations
Clear Procedures for Communication of the
requirement for anti-D prophylaxis should be
implemented and followed
– Clear notification of patient’s RhD negative status in
her files including hand-held/ shared care Card
– Patient should be advised of her RhD negative status
and situations requiring anti-D prophylaxis
– Consider issuing an RhD negative card (
recommended in BCSH guidance ) with listed
indications for prophylaxis
Implementation of RAADP in
Ireland
Irish Anti-D Guideline Working group established in 2006
To examine the feasibility of implementation of RAADP
in Ireland
To prepare a guidance / recommendation for RAADP
and also best practice for prevention of RhD HDN for
submission to the DOHC
Initiated by the Institute of Obstetricians and
Haematology - auspices of the RCPI. Chaired by
Obstetrician with representation from Foetal Medicine,
Haematology, Midwifery,Neonatology, Haemovigilance
Medical Laboratory Science, Public Health, National
Hospitals Office
Haemovigilance
Survey of Practice
13 units are using 1500 IU of anti-D post-partum
4 units using Rhesonativ (1250IU)
Transfusion Laboratory staff issue Anti-D in all
hospitals except 2 where the pharmacist does it
Approximately half of the units check the size of
the feto-maternal haemorrhage post-partum
using either by the Kleihauer-Betke test or flow
cytometry with some units using both methods.
Individual obstetricians are recommending
antenatal anti-D Ig currently.
Why RAADP?
Implemented in US, UK,Netherlands, Canada,
Australia and ? France
Anti-D Consensus Conference UK -
RCOG/BBTS recommendation 1997.
NICE Guidance on the use of routine antenatal
anti –D prophylaxis for RhD negative women.
Technology Appraisal 2002;41:1.
Guidelines for the use of prophylactic anti-D
immunoglobulin. British Committee for
Standards in Haematology 2006
RCOG Guideline – Use of anti – D Ig for prophylaxis
Routine antenatal prophylaxis
Evidence from clinical trials
- studies using historical controls (7)
- one quasi-randomised trial (Huchet et al. 1987)
→ Reduce rate of sensitisation from 1.5% to <0.2%
Evidence of cost effectiveness
- studies with some economic evaluation (9)
- one detailed analysis comparing programmes (Vick et al. 1996)
→ primigravid programmes more cost effective and should lead to
health care savings
Adequate supply of anti –D Ig
- Polyclonal (manufactured from non UK plasma)
- [Monoclonal]
NICE: Evidence for RAADP
Key study : involving 4700 women, included the
results of the two community-based UK studies
which used a regimen of 500 IU at 28 weeks and
34 weeks and which reported results for
primigravidae.
The rate of postnatal anti-D sensitisation was
0.95% (95% CI 0.18% to 1.71%) in the control
group and 0.35% (95% CI 0.29% to 0.40%) in
the antenatal treatment group.
NICE 2008
The Committee decided that it could not make
a firm recommendation for either the single-
dose or the two-dose regimen. (no apparent
difference in efficacy)
The Committee also concluded that, although
it was not possible to recommend a particular
product, individual purchasers should use
the product with the lowest cost available
locally, taking into account the acquisition cost
as well as the costs associated with
administration.
Uptake of RAADP UK
2005 survey- 328 maternity units : 75% were
offering RAADP; 81% using 2 dose regimen
Further NEQAS postal survey in 2007 of 173
hospitals; 90% implementation with the
transfusion lab responsible for issue of anti-D in
90% of cases.
81 centres have since switched to one dose
regimen but many are using 2 different products
(1500iu for RAADP and lower dose for PN &
antenatal sensitising events)
Draft Irish Guidance
The Irish Guidance is based on the 2002
Royal College of Obstetricians guidelines
on anti-D prophylaxis.
However as the 250iu and 500iu doses
preparations of anti-D Ig are not available
in Ireland the dose ranges advised are
based on the anti-D Ig preparations
currently licensed in Ireland.
Dose limitations of Anti-D
preparations marketed in Ireland
Rhophylac 1500 iu for iv or im administration
Rhesonativ : 1250iu for im use only
Winrho anti-D only stocked by IBTS -has a PA
through EMEA but not PL - is not licensed for
RAADP
– most maternity units use 1250-1500 iu
postnatal
– 50% of units do routine postnatal FMH screen
General Recommendations
Hospital blood banks not already involved with
the storage and issue of anti-D Ig should
consider taking over this function as not only can
they comply with traceability recommendations
but can also automatically link the information on
the provision of anti-D Ig prophylaxis to the
patient’s blood transfusion laboratory record.
Each hospital where anti-D Ig is used should
have an up to date standard operating
procedure for anti-D administration.
Procedures & Education
This procedure should cover the indications and
criteria for anti-D Ig, checking of laboratory
results prior to administration, details of dose
and administration, patient consent, verification
checks prior to administration and
documentation of anti-D Ig.
There should be regular multiprofessional
education updates on the use of anti-D Ig for
RhD prophylaxis.
BCSH /RCOG Guidelines – Use of anti – D Ig for Rh prophylaxis
Prophylaxis following sensitising events before delivery
Anti –D should be given to all non-sensitised women
after the following potentially sensitising events during
pregnancy:
- invasive prenatal diagnosis & other procedures
- spontaneous abortion after 12 wks
- ectopic pregnancy
- antepartum haemorrhage
- ECV
- closed abdominal injury
- intrauterine death
Up to 29% RhD- women will have potentially sensitising event after 12 w
*Anti –D omitted in 30-35% (Ghosh & Murphy 1994, Vinall et al. 1998).
*Kleihauer testing performed in 9% (Ghosh & Murphy 1994)
Prophylaxis following foetal loss
or threatened miscarriage
Anti-D is not required if a spontaneous
miscarriage occurs before 12 weeks’ gestation
Anti-D Ig is not routinely recommended for
prophylaxis following a threatened miscarriage <
12 weeks of pregnancy.
Anti-D Ig should be given to all non-sensitised
RhD negative women who have a medical or
surgical evacuation of the uterus regardless of
gestational age.
Before 20 weeks’ gestation 625iu of anti-D is
sufficient.
After 20 weeks’ gestation at least 1000iu anti-D
Ig should be given and blood should be taken for
the Kleihauer or other similar test to estimate the
size of the FMH
Anti-D Ig should be given for recurrent PV
bleeding at 6 weekly intervals.A test for FMH
must also be performed and repeated at 2
weekly intervals if recurrent bleeding after 20
weeks.
RAADP
Routine antenatal Anti-D prophylaxis (RAADP)
should be offered to all non-sensitized RhD
negative women at 28 weeks gestation as a
one-dose regimen. (1500iu)
A one-dose regimen is selected, as there is
evidence that compliance with the two-dose
regimen is less than ideal and there is no data to
suggest that the two-dose regimen is superior
Information (verbal and written) surrounding the
advantages and potential adverse effects of this
policy, should be provided to all RhD negative
women at their antenatal booking visit.
In some circumstances, women may choose not
to accept RAADP. Cases when treatment may
not be needed are:
– Women who are choosing to be sterilised following
delivery.
– Where the father is known to be RhD-negative.
– The woman is sure she will not have another child.
However, it may be difficult for the woman to be
certain about these factors and RAADP should
be recommended.
The provision of RAADP should not be affected
by previous anti-D administration for a
sensitising event earlier in the pregnancy.
Anti-D prophylaxis must still be given for any
subsequent sensitising events following the
administration of RAADP, irrespective of the
timing between the RAADP injection and the
event. Similarly postpartum anti-D prophylaxis is
administered in the event that the woman
delivers a RhD positive infant irrespective of the
RAADP
Implications for Laboratory Testing
Routine blood testing for antibodies should be
undertaken at booking, and again at 28 weeks
gestation prior to RAADP administration.
It is not necessary to wait for the results of the
28-week antibody screen before administering
the anti-D Ig. If however anti-D is detected in this
sample it should be referred for quantification
and the woman followed up appropriately.
Further routine screening of the mother’s
serum for antibodies in pregnancy should
not be performed if the result of the 28-
week baseline sample is negative. This is
because passive anti-D is detectable for
up to 3 months in the maternal circulation
following anti-D Ig administration and it is
not possible to differentiate between
passive and low levels of immune anti-D
on testing.
The blood transfusion laboratory must
always be informed about the
administration of anti-D Ig, to avoid
confusion should the woman present at a
later stage with anti-D detectable in her
serum.
If Anti-D is detected in a sample referred
for compatibility testing after 28 weeks
gestation and the 28 week sample was
negative then the patient should continue
to be regarded as eligible for anti-D
prophylaxis for any subsequent potentially
sensitising antenatal events and postnatal
administration.
Anti-D detected antenatally
If there is a record of anti-D injection within the past eight
weeks and the level is below 1iu/mL a further sample
should be tested at 28 weeks and prophylaxis should
continue.
If there is no record of anti-D injection the antibody
should be monitored as for immune anti-D i.e. at four
weekly intervals to 28 weeks and at fortnightly intervals
thereafter. If the anti-D level is falling, it is probably
passive whereas if it is steady or rising it is probably
immune.
Prophylactic anti-D should continue in either case unless
it is established that the anti-D is immune (BCSH c,
2006) (Level II b, Grade B).
Patients who miss their appointment for
RAADP should be offered an alternative
appointment as soon as is possible
afterwards, and
Should the woman decline RAADP, this
should be documented in her case notes.
Postnatal Prophylaxis
Maternal blood should be taken for repeat
ABO/D group prior to administration of anti-D
Ig
A further antibody screen on the maternal
sample at delivery is not advised
FMH if checked: maternal sample should be
taken after a gap of one hour following
delivery
ABO/ D group on cord sample
Role of FMH
The need for testing for FMH is
controversial and depends on the volume
of FMH being in excess of the volume
covered by the standard dose. Hence, the
lower the standard post-natal dose of Anti-
D administered, the greater the need to
quantify FMH.
Practice and recommendations differ between
North America, Australia, UK and continental
Europe.
In the UK and Australia where the recommended
standard postnatal dose of anti-D is 500 and
600iu respectively, a test for FMH is
recommended routinely.
Standard doses used in Ireland and most other
European countries are 1250-1500iu for
postnatal anti-D prophylaxis.This approach
would appear to make testing for larger
episodes of FMH less necessary
0.3% of pregnancies are associated with an
FMH in excess of 15mls which would not be
covered by 1500iu of anti-D Ig. This means that
up to 3 per 1000 RhD negative women could be
alloimmunised as a result.
Not all women will mount an immune response
to RhD positive blood (e.g.maternal:foetal ABO
incompatibility). Actual rate of sensitisation is
likely to be less than 0.07% of deliveries.
One approach is to perform an FMH
screen only where there is an associated
risk factor for large FMH. However up to
50% of large FMHs (>15mls fetal red cells)
occur in women without identifying risk
factors.
Risk factors for a large FMH are:
Risk Factors for large FMH
Abdominal trauma during the third trimester
Unexplained hydrops foetalis
Placental abruption
Cordocentesis
External cephalic version
Multiple pregnancies (at delivery)
Stillbirths and intrauterine deaths
Instrumental deliveries /caesarean section
Manual removal of the placenta
Recommendations
Where the standard postpartum dose of
anti-D is less than 1250iu, a test for FMH
should be employed routinely.
Conversely, if FMH testing is routinely
performed, the standard post-natal dose
could be reduced to 625iu. (if low dose
available )
FMH testing should always be performed,
irrespective of the anti-D Ig dose, where there
are associated risk factors for large FMH
present.
Where a quantitative test for FMH shows that
the FMH volume exceeds that covered by the
administered postnatal dose, then additional
anti-D Ig must be given to cover the magnitude
of the bleed (125 iu/ml fetal RhD positive cells or
as per manufacturer’s instructions).
As the cost benefit of adopting routine
postpartum FMH assessment and using a
lesser standard Anti-D Ig dose has not
been tested, there is insufficient evidence
to recommend implementation of routine
FMH testing in hospitals where it is not in
place.
RHD Foetal genotyping using
maternal sample
The Irish Anti-D Working Group recommends
the development of technology and assessment
of the feasibility of mass testing antenatally for
foetal blood group by analysis of circulating fetal
DNA in maternal plasma in Ireland.
If the foetal RhD type could be determined
before 28 weeks' gestation, RAADP would be
necessary only for pregnancies where the fetus
was RhD positive. (60%)
2007 NHO Report
Recommend that all new cases of anti-D
immunisation are investigated as to the
likely cause – silent FMH , treatment
failure and omission/ delays in treatment
and report to the NHO
This would facilitate a before and after
assessment of effect of RAADP
intervention
