AntiD Prophylaxis Guideline Update

1
Anti-D Prophylaxis Guideline Update

• National Haemovigilance
• Office Conference 2008

2
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

3
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)

4
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

5
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.

6
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

7

• 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.

8
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 patients charts and there was no
  record on the home visit sheet.
• Since then the mothers blood group is now
  documented on the home visit record.

9
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?

10
2007 IBCT associated with Anti D (n16)

• 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

11
Human Failures identified in Anti D errors 2007
(n16)
12
Findings from Anti D errors

• Cause of Error
• System failures identified 3
• Lack of polices highlighted in 2 cases
• Design highlighted in 1 case

13
2007 Recommendations

• Clear Procedures for Communication of the
  requirement for anti-D prophylaxis should be
  implemented and followed
• Clear notification of patients 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

14
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

15
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.

16
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 2002411.
• Guidelines for the use of prophylactic anti-D
  immunoglobulin. British Committee for Standards
  in Haematology 2006

17
RCOG Guideline Use of anti D Ig for
prophylaxisRoutine 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
  lt0.2
• 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

18
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.

19
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.

20
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)

21
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.

22
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

23
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
  patients 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.

24
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.

25
BCSH /RCOG Guidelines Use of anti D Ig for
Rh prophylaxisProphylaxis 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)
26
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 lt
  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.

27

• 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.

28
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.

29

• 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.

30

• 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

31
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.

32

• Further routine screening of the mothers 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.

33

• 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.

34

• 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.

35
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).

36

• 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.

37
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

38
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.

39

• 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

40

• 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.maternalfoetal ABO
  incompatibility). Actual rate of sensitisation is
  likely to be less than 0.07 of deliveries.

41

• 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
  (gt15mls fetal red cells) occur in women without
  identifying risk factors.
• Risk factors for a large FMH are

42
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

43
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 )

44

• 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 manufacturers instructions).

45

• 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.

46
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)

47
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