Anti-D immunoglobulin administration for the prevention of maternal anti-D sensitisation

Introduction

Maternal sensitisation with anti-D antibodies remains a significant cause of haemolytic disease of the fetus and newborn (HDFN). The development of anti-D antibodies most often occurs as a result of feto-maternal haemorrhage (FMH) between a woman with a D negative blood type and a D positive fetus. Although sensitisation is permanent and irreversible, it can usually be prevented by appropriate administration of prophylactic anti-D immunoglobulin (Ig).

Statement of intent and aim of the guideline

The objective of this guideline is:

• Improve patient safety and reduce potential risks during the transfusion process.
• Provide guidance on the management of women who are of child bearing age and D -ve.
• Ensure all patients are fully informed and involved in the decision to receive anti-D.
• To provide healthcare professionals within NHS Borders with practical guidance in the use of prophylactic anti-D Ig to prevent sensitisation to the D antigen during pregnancy or around the time of delivery, in order to prevent HDFN.
• Incorporate evidenced based practice as part of local service provision.

This guideline mirrors the following national guidelines: National Institute for Clinical Excellence (NICE 2008, 2012, 2015), British Society in Haematology (BCSH, 2014) and Royal College of Obstetricians and Gynaecologists (RCOG, 2011).

The guideline is developed by the Hospital Transfusion Team (HTT) on behalf of the NHS Borders Transfusion Committee (TC) and NHS Borders Maternity Services. Guideline is approved by the NHS Borders Transfusion Committee and Clinical Executive Group. The guideline is based on evidence-based practice (National Institute for Clinical Excellence (NICE 2008, 2012, 2015), British Society in Haematology (BCSH, 2014) and Royal College of Obstetricians and Gynaecologists (RCOG, 2011), Norfolk (2014).

The guideline is distributed to all internal stakeholders within NHS Borders. NHS Borders Transfusion Committee members will initiate the cascade and the distribution of the protocol to clinical areas. It is the responsibility of the individual Heads of Clinical Services and Senior Sisters/Charge Nurses to oversee the distribution of the policy within their own departments/services. The policy is available on the intranet.

The HTT on behalf of the NHS Borders TC will facilitate the collaboration, co-ordination and maintenance of the protocol by:

• Engage with policy lead.
• Reviewing and updating policy based on evidence based practice and service provision every two years unless otherwise indicated.
• Continually reviewing the effectiveness of the policy based on any adverse events and clinical incidents.

Nurses, Midwifes, Doctors, Biomedical Scientists and Phlebotomists are all accountable to their respective professional bodies, to their patients and to the NHS as their employer to provide safe and appropriate care (General Medical Council 2013, Health Professional Council 2008, Nursing and Midwifery Council 2015).

ALL staff involved in the transfusion process must complete the Learnbloodtransfusion, Safe Transfusion Practice module or the equivalent if working in paediatric practice. Additionally, staff
are required to complete the anti-D clinical or laboratory module appropriate to their role. This can be accessed via Learnpro or http://www.learnbloodtransfusion.org.uk. It is the responsibility of the
staff member to ensure training and education is updated every 2 years. All health care professionals are legally required to evidence training and care provided.

PLEASE NOTE: It is the responsibility of the midwife to communicate with the transfusion laboratory regarding the results of blood tests and the requirement for anti-D. In the BGH setting it is the responsibility of the midwife to arrange for the collection and delivery of anti-D from the
transfusion laboratory to the clinical area, which includes the immediate post natal care period. Please refer to section 10.1 for issuing of anti-D to a patient in the community setting.

All pregnant women will have access to a national single unified record for recording all aspects of maternity care during the pregnancy.

Please refer to the NHS Borders Transfusion Policy (2019) and NHS Borders Patient Identification policy (2017) for further information on the minimum data set required for transfusion at any point of the transfusion process.

A blood sample for blood group (A, B, O and D) and antibody screen should be obtained at the booking appointment. The results of this test will be returned to the midwife for recording and documenting in the maternal record. The woman should be informed of her blood group as soon as is practical, usually at her next antenatal appointment.

NB: Prophylactic anti-D Ig given to prevent sensitisation is indistinguishable from an immune anti-D antibody. If a woman has received any prophylactic anti-D Ig during her pregnancy the date, time and dose should be stated on the group and screen sample request form. This will help with the laboratory interpretation as to whether any anti-D
antibody identified is likely to be maternal immune antibody or passive anti-D Ig recently administered to reduce the risk of sensitisation. In some instances this differentiation between immune and passive anti-D may not be immediately possible and the woman would need monitoring over time to distinguish between the two.

1. Women who are D positive 

Women who are D positive, and have no red cell antibodies, should have a further blood sample taken for routine antibody screen at 28 weeks gestation. This coincides with routine blood sampling for full blood count estimation.

Women who are D positive and have red cell antibodies should receive care in line with the Scottish National Guidance for Pregnant Women with Red Cell Antibodies (3rd ed., SNBTS, 2020).

2. Women who are D negative

Women who have a D negative blood group and who have not formed anti-D antibodies:

As per local agreement, the hospital transfusion laboratory will send the ‘record card’ to the midwife for recording and filing in the maternal record. At the first antenatal appointment following availability of the results, usually around 15 weeks gestation, the ‘record card’ information letter should be given to the woman. The woman should be given an opportunity to discuss her blood group and anti-D Ig prophylaxis.

3. Women who are D negative and have an D negative partner

Women who have a D negative partner which has been confirmed by the Blood Transfusion Department do not require anti-D. However, patient information and informed consent must be clearly documented in the maternal record to ensure a multidisciplinary approach to care during the pregnancy is delivered.

4. Women who have an D negative blood group and who have formed red cell antibodies

If a woman with D negative blood develops red cell antibodies at any time during her pregnancy, she should receive care in line with the Scottish National Guidance for Pregnant Women with Red Cell Antibodies (SNBTS, 2020).

D negative women who develop immune anti-D antibodies should not be given anti-D immunoglobulin. If there is any doubt whether the anti-D being detected is immune or prophylactic in nature please discuss with a haematology/transfusion specialist for advice on further management and follow up. D negative women, who have red cell antibodies
other than anti-D, should be offered anti-D immunoglobulin prophylaxis to prevent formation of anti-D antibodies.

Women should always be involved in the decision to administer prophylactic anti-D Ig. Written and verbal information should be provided in order to allow them to make a fully informed decision. Women must also be made aware of the significance of potentially sensitising events (PSE), and know how to report them in order to maximise the chance of
receiving prophylactic anti-D Ig within 72 hours.

It is important to acknowledge that there are some circumstances where prophylactic anti-D Ig has little or no benefit for women, for example if they feel certain that they will not have another pregnancy, or if the father of this baby has been confirmed as having a D negative blood type. Any decision to decline prophylactic anti-D Ig should be respected.

In all cases the decision to accept or decline prophylactic anti-D Ig, at any time during pregnancy or the postnatal period, should be clearly documented in the maternity record.

1. Following a Potentially Sensitising Event during Pregnancy

Any woman who experiences a potentially sensitising event (PSE) during pregnancy should be offered prophylactic anti-D immunoglobulin (Ig).

In order to be effective, prophylactic anti-D Ig should be administered as soon as possible, and always within 72 hours of a PSE. If it is not possible to administer prophylactic anti-D Ig within 72hours, it may still be effective when administered within 10 days. The decision to administer prophylactic anti-D Ig in this instance should be made by an obstetrician following consultation with a haematologist/transfusion specialist.

Prophylactic anti-D Ig offered following a PSE during pregnancy should be administered regardless of proximity to administration of routine antenatal anti-D prophylaxis. Anti-D required as a result of a PSE is covered as part of the midwives exemption and can be administered as detailed.

Potentially Sensitising Events:

• Ectopic pregnancy: at any gestation and regardless of method of management.
• Termination of pregnancy: offer anti-D prophylaxis to women who are D negative and are having a termination after 10+0 weeks gestation. Do not offer anti-D prophylaxis to women who are D negative and having a medical termination up to and including 10+0 weeks gestation. Consider anti-D prophylaxis for women who are D negative and are having a surgical termination up to and including 10+0 weeks gestation.
• Miscarriage prior to 12 weeks: only when managed medically or surgically or where there is unusually severe pain and/or bleeding. In cases of spontaneous complete miscarriage confirmed by scan where the uterus is not instrumented, or where mild painless vaginal (PV) bleeding occurs before 12 weeks, prophylactic Anti-D is not required.
  
• Miscarriage after 12 weeks gestation: any miscarriage whether complete or incomplete and regardless of method of management.
• Invasive intra-uterine procedures: regardless of gestation. Examples include amniocentesis, chorionic villus sampling, fetal blood sampling and laparotomy.
• Antepartum haemorrhage after 12 weeks gestation: regardless of size or cause
• Blunt abdominal injury after 12 weeks gestation: examples include seat belt injury, falling directly onto the abdomen, punch or kick to abdomen.
• Intra-uterine death: a Kleihauer should be sent and a minimum of 500IU anti-D Ig (D-GAM) should be given as soon as possible after diagnosis of fetal death, even if this is before delivery. Further Kleihauer should be sent and further 500IU anti-D given at time of delivery. Yet more Anti-D may be required depending on results. If immediate Kleihauer result is available then 500IU (D-GAM) may be adequate but where this is not the case it is better to give 500IU (Rhophylac) rather than risk under estimating dose. Anti-D Ig is not required if the fetus is confirmed, through formal blood testing, as RhD negative.
• External Cephalic Version (ECV): anti-D Ig should be offered regardless of success or failure of ECV.

If a PSE occurs at 20 weeks gestation or later, at least 500IU (D-GAM) of prophylactic anti-D Ig should be administered as soon as possible and a blood sample should be sent for fetomaternal haemorrhage quantification (Kleihauer).
NB: do not wait for the Kleihauer test result before giving anti-D Ig.

The standard dose, 500IU (D-GAM), of prophylactic anti-D Ig is effective for any fetomaternal haemorrhage (FMH) up to 4mls. The Kleihauer test is used to identify FMH greater than 4mls, and in this instance further prophylactic anti-D Ig will be recommended. The dose of any additional prophylactic anti-D Ig will be advised by the hospital transfusion laboratory. Communication with the transfusion laboratory is critical to
ensure the appropriate dose is issued and administered.

In the event of recurrent intermittent antepartum haemorrhage at 20 weeks gestation or later, prophylactic anti-D Ig should be given at least at 6 weekly intervals, and FMH quantification (Kleihauer testing) carried out at least every 2 weeks. More frequent treatment and Kleihauer testing may be required depending on the Kleihaeur test results
and clinical picture respectively; discuss as necessary. If new symptoms develop that are suggestive of a sensitising event in addition to the original recurrent bleeding, for example abdominal pain or significant change in the pattern or severity of bleeding, this should be managed as an additional sensitising event with an appropriate additional dose of
prophylactic anti-D Ig administered and estimation of FMH (Kleihauer test).

2. Routine antenatal anti-D prophylaxis (RAADP)

1500IU (Rhophylac) prophylactic anti-D Ig should be offered to all pregnant women with an RhD negative blood group and no immune anti-D antibodies at 28-30 weeks gestation (27 + suitable if falls at appointment time). If anti-D is out with the specified time period a
medical prescription is required as detail in the midwifery exemption.

Requesting of anti-D must be clearly documented on the transfusion request form. A blood sample for routine antibody screening is taken at the 28 week appointment. As prophylactic anti-D Ig is indistinguishable from maternal immune anti-D antibody, this blood sample should always be taken prior to administration of prophylactic anti-D Ig.

Please note: If a woman has received any prophylactic anti-D Ig during her pregnancy the date, time and dose should be stated on the sample request form. This helps the laboratory to determine whether any anti-D identified is likely to be maternal immune antibody or passive anti-D Ig administered to prevent sensitisation, although this distinction may not be possible immediately.

RAADP should be administered regardless of proximity to administration of prophylactic anti-D Ig offered following a PSE during pregnancy.

D negative pregnant women who have reached 30 weeks gestation or later without receiving RAADP should be offered a single dose of 1500IU (Rhophylac) prophylactic anti-D Ig following discussion with an obstetrician. In this instance the prophylactic anti-D
Ig should be prescribed by the obstetrician as detailed in the midwifery exception.

The transfusion laboratory is responsible for issuing anti-D to the GP practice/clinical area as per detail on the transfusion request form. The midwife exemption should be used by midwives for administration of RAADP.

3. Postnatal administration of anti-D Ig

An umbilical cord blood sample should be obtained as soon as is practical following delivery of a baby to a D negative woman, and sent for blood group testing.

In addition, two maternal blood samples should be taken for Kleihauer testing and group and screen. These samples should be taken as soon as possible, but at least 30-45 minutes after placental separation to allow any fetal cells to become apparent in maternal circulation.

The baby’s blood type should always be confirmed to be D positive by the hospital transfusion laboratory prior to administration of prophylactic anti-D Ig to the woman in the immediate postpartum period. It is however acceptable to administer prophylactic anti-D Ig to the mother if the baby’s blood type cannot be confirmed within 72 hours of delivery,
for example in cases of intrauterine death or stillbirth.

All women who deliver a D positive baby should be offered a 500IU (D-GM) of prophylactic anti-D Ig, to be administered as soon as possible and always within 72 hours of delivery.

The standard dose of 500IU (D-GAM) prophylactic anti-D Ig is effective for any fetomaternal haemorrhage (FMH) up to 4mls. The Kleihauer test, taken at delivery, is used to identify FMH greater than 4mls and in this instance further prophylactic anti-D Ig will be recommended. The dose of any additional prophylactic anti-D Ig will be calculated by
the hospital transfusion laboratory. In this situation any additional prophylactic anti-D Ig should be prescribed by an obstetrician.

Should prophylactic anti-D Ig not be administered within 72 hours of delivery it may still be effective when administered within 10 days. The decision to administer prophylactic anti-D Ig in this instance should be made by an obstetrician following consultation with a haematologist/transfusion specialist.

The midwife exemption should be used by midwives for administration of routine postnatal prophylactic anti-D Ig.

Please note: if FMH result is >2mls, samples are sent to Gartnaval Hospital in Glasgow for flow cytometry. At weekends results may not be available within 72 hours.
The dose of anti-D will be issued based on the initial FMH result. Further anti-D will be issued if required for the patient based on the flow cytometry result once received. Blood Bank will contact clinical area as required.

The Midwife Exemption applies for administration of the increased dose of routine postnatal prophylactic anti-D Ig during the interim change.

1. Administration of Anti-D Ig

Prophylactic anti-D Ig should never be administered to a woman who is D positive or is who known to have immune anti-D antibodies. Postnatal prophylactic anti-D Ig should only be administered to women who have delivered a D positive baby, or those in whom the baby’s blood group is unobtainable.

Blood group and antibody screening should always be confirmed through formal, blood bank report prior to administration.

The following checks should be completed prior to administration of prophylactic anti-D Ig:

• Confirm reason for administration.
• Formal confirmation of blood type (maternal and baby where appropriate) and antibody screen, using laboratory reports or telephone confirmation with laboratory staff. If a telephone communication takes place lease ensure the conversation and actions are clearly documented by laboratory and midwifery staff.
• Confirm dose to be administered against prescription or midwife exemptionary, this guidance and any instructions from hospital transfusion laboratory.
• Confirm correct product and check expiry date.
• Confirm correct woman by ID band and/or verbal check with the woman, against traceability tag attached to anti-D and prescription.

It is good practice that the midwife should complete these checks alongside another healthcare professional. If this is not possible a single person check is acceptable. The woman should always be involved in this process by verbally confirming her name and date of birth and that she understands why prophylactic anti-D Ig is being offered and agrees to receive it.

The date, time and dose of prophylactic anti-D Ig administered should be clearly documented in the patient’s record. Discussion with the woman and her decision to accept, or decline, prophylactic anti-D Ig should also be documented.

Prophylactic anti-D Ig should be used immediately upon opening. If the contents of the vial(s) or prefilled syringe are cloudy or contain deposits they should not be used. This should be reported to the hospital transfusion laboratory.

Prophylactic anti-D Ig should be given as an intramuscular injection. The deltoid muscle is the site of choice, but the gluteal muscle may be acceptable if the person giving the injection is confident of achieving intramuscular, as opposed to subcutaneous, administration.

2. Adverse events associated with administration of prophylactic anti-D Ig

Serious adverse and near miss events associated with anti-D must be reported to the Serious Adverse Blood Reactions and Events (SABRE) and the Serious Hazards of Transfusion (SHOT) reporting scheme (via SABRE) as part of a national haemovigilance requirement.

Any associated adverse events with the administration of anti-D must be reported via Adverse Event Recording system. The Hospital Transfusion Team will review all transfusion related incidents and report to SABRE/SHOT accordingly. These include:

• Omission or late administration of anti-D immunoglobulin (Ig) within the 28 – 30 weeks for RAADP or >72 hours for PSE.
• Anti-D Ig administered to an D positive woman.
• Anti-D Ig administered to a woman with immune anti-D.
• Anti-D Ig administered erroneously to a mother of an D negative infant.
• Anti-D Ig given to the wrong woman (failure of bedside ID check).
• Incorrect dose of anti-D Ig given according to local or national policy, due to erroneous selection of wrong dose or misinterpretation of Kleihauer results.
• Handling and storage errors associated with anti-D Ig, including issue of expired anti-D, inappropriately stored anti-D, where batch numbers on the vials do not match with issue paperwork, or inappropriate route of administration.

Additionally, any events relating to the administration of D positive mismatched platelets to women who are D negative must be reported.

SHOT have defined late administration of RAADP as after 34 weeks gestation. Any event at or after 34 weeks must be reported to SHOT.

If the primary reason for the late administration of anti-D is patient non-compliance there is no requirement to report to SHOT. However a local adverse event report is still required.

Please follow the process detailed in Appendix B for any anti-D event associated with D negative women. In the event a D negative woman delivers a D positive baby in this situation, there is a requirement for a follow up 6 months post natal sample to check for sensitisation. A standard letter will be issued to the woman offering the follow up sample as detailed in Appendix C.

Allergic reactions associated with prophylactic anti-D Ig are very rare but severe hypersensitivity including anaphylaxis may occur. Any allergic reaction is reportable via the ‘yellow card system’ for medicines which can be accessed at https://yellowcard.mhra.gov.uk/.

Guidance for the management of anaphylaxis is contained in the NHS Borders anaphylaxis protocol. Further information can be found at:
https://www.resus.org.uk/anaphylaxis/emergency-treatment-of-anaphylactic-reactions/

3. Administration of prophylactic anti-D Ig alongside live vaccines

Prophylactic anti-D Ig may inhibit immune response to live vaccines such as Measles, Mumps and Rubella (MMR). For this reason:

Live vaccines, such as MMR, may be given simultaneously alongside prophylactic anti-D Ig provided that separate syringes are used and the products are administered into different limbs. If not given simultaneously, the live vaccine should be given 3 months after
prophylactic anti-D Ig.

If MMR is administered alongside, or within 3 months of, prophylactic anti-D Ig MMR antibody response should be checked 8 weeks following administration.

Administration of prophylactic anti-D Ig should never be delayed beyond 72 hours following a PSE of delivery of an RhD positive baby.

1. Issue of anti-D

The transfusion laboratory is responsible for issuing the correct dose of anti-D as per transfusion request or Kleihauer result. Product will be issued on a named patient basis only. There are no stocks held in ward fridges in the BGH.

Anti-D sent to a GP practice will be appropriately packed and transferred as per details on the transfusion request form. Receipt of anti-D by the GP Practice will check the envelope containing anti-D and will check If the patient has an appointment. The midwife will collect the anti-D prior to the appointment for administration. If no appointment is made, the midwife will contact patient.

2. Storage of anti-D Ig

Prophylactic anti-D Ig should be stored in a validated clinical fridge at temperature 2◦C to 8◦C and protected from sunlight.

3. Product Safety

Please refer to product insert for further information

Appendix A: Information for D negative women - PDF

Appendix B: Flowchart for the follow up process for D-ve women following the late administration or omission of Anti-D during pregnancy or post delivery - PDF

Appendix C: Anti-D 6 month blood test - letter template - PDF