In addition to these evidence-based recommendations, the guideline development group also identifies points of best clinical practice in the original guideline document.
Classification of evidence levels (1++ to 4) and grades of recommendations (A-D) are defined at the end of the "Major Recommendations" field.
Test for the Size of Fetomaternal Haemorrhage (FMH)
How Should the Size of FMH Be Quantified?
D - A Kleihauer screening test should be performed within 2 hours of delivery to identify rhesus D (RhD)-negative women with a large FMH who require additional anti-D immunoglobulin (anti-D Ig).
How Should Anti-D Ig Be Administered?
D - For successful immunoprophylaxis, anti-D Ig should be given as soon as possible after the potentially sensitising event but always within 72 hours. If it is not given before 72 hours, every effort should still be made to administer the anti-D Ig, as a dose given within 10 days may provide some protection.
Prophylaxis Following Miscarriage, Ectopic Pregnancy and Termination of Pregnancy
When Is Anti-D Ig Prophylaxis Required Following Miscarriage, Ectopic Pregnancy and Termination of Pregnancy?
When indicated, anti-D Ig is administered in a dose of 250 IU up to 19+6 weeks of gestation and in a dose of 500 IU thereafter. A test for the size of FMH should be performed when anti-D Ig is given at or after 20+0 weeks of gestation.
D - Anti-D Ig should be given to all non-sensitised RhD-negative women who have a spontaneous complete or incomplete miscarriage at or after 12+0 weeks of gestation.
D - Anti-D Ig is not required for spontaneous miscarriage before 12+0 weeks of gestation, provided there is no instrumentation of the uterus.
D - Anti-D Ig should be given to non-sensitised RhD-negative women undergoing surgical evacuation of the uterus, regardless of gestation.
D - Anti-D Ig should be considered for non-sensitised RhD-negative women undergoing medical evacuation of the uterus, regardless of gestation.
D - Anti-D Ig should be given to all non-sensitised RhD-negative women with a threatened miscarriage after 12+0 weeks of gestation. In women in whom bleeding continues intermittently after 12+0 weeks of gestation, anti-D Ig should be given at 6-weekly intervals.
D - Anti-D Ig should be considered in non-sensitised RhD-negative women if there is heavy or repeated bleeding or associated abdominal pain as gestation approaches 12+0 weeks.
D - Anti-D Ig should be given to all non-sensitised RhD-negative women who have an ectopic pregnancy, regardless of management.
Therapeutic Termination of Pregnancy
D - Anti-D Ig should be given to all non-sensitised RhD-negative women having a therapeutic termination of pregnancy, whether by surgical or medical methods, regardless of gestational age.
Prophylaxis Following Sensitising Events Before Delivery
Which Antenatal Sensitising Events Require Anti-D Ig Prophylaxis?
D - A minimum dose of 250 IU is recommended for prophylaxis following sensitising events up to 19+6 weeks of gestation. For all events at or after 20+0 weeks of gestation, a minimum dose of 500 IU anti-D Ig should be given and a test to identify FMH greater than 4 ml red cells performed; additional anti-D Ig should be given as required. [Evidence level 4]
D - In the event of recurrent vaginal bleeding after 20+0 weeks of gestation, anti-D Ig should be given at a minimum of 6-weekly intervals. [Evidence level 4]
Anti-D Ig should be given to all non-sensitised RhD-negative women after the following potentially sensitising events during pregnancy; this should be in addition to any already received:
- Invasive prenatal diagnosis (amniocentesis, chorion villus sampling, cordocentesis, intrauterine transfusion)
- Other intrauterine procedures (e.g., insertion of shunts, embryo reduction, laser)
- Antepartum haemorrhage
- External cephalic version of the fetus (including attempted)
- Any abdominal trauma (direct/indirect, sharp/blunt, open/closed)
- Fetal death
If there is concern about the frequency of recurrent bleeding, estimation of FMH using a Kleihauer test can be performed at 2-weekly intervals; if positive, an additional dose of anti-D Ig can be administered (500 IU or greater, depending on the size of the FMH). This dose is given irrespective of the presence or absence of passive anti-D.
Routine Antenatal Prophylaxis
How Should a Routine Antenatal Anti-D Prophylaxis (RAADP) Programme Be Put into Clinical Practice?
B - RAADP should be offered to all non-sensitised RhD-negative women. [Evidence level 2+]
C - The routine 28-week antibody screening sample must be taken before administration of the first dose of anti-D. This meets the British Committee for Standards in Haematology requirement for a second antibody screen during pregnancy. [Evidence level 2+]
What Are the Maternal and Fetal Effects of RAADP?
B - There is no evidence to suggest that RAADP is associated with adverse events that are of consequence for the mother or baby, other than the possibility of blood-borne infection, and procedures are in place to minimise these risks.
How Should Women Who Decline RAADP Be Managed?
C - In the event that RAADP is declined antibody screening should be performed at booking and at 28 weeks of gestation to identify cases where sensitisation has occurred. Sensitisation occurring in the third trimester is unlikely to cause significant fetal problems in that pregnancy. [Evidence level 2+]
Some women will decline RAADP, and certain subgroups can be identified:
- Women who object on religious grounds
- Women who will be sterilised after the birth
- Women who are certain they will have no more children
- Women who are in a stable relationship with the genetic father of their children and the father is known or found to be RhD-negative
Although it is desirable to avoid unnecessary RAADP, there are potential problems with the latter two groups: women may change their minds about a further pregnancy, and there are known complexities associated with paternal testing with potential for misidentification of the father.
Women should be given adequate information with which to make an informed choice about accepting or declining anti-D Ig. If a woman declines anti-D Ig, this decision should be acknowledged and the reasons for the decision documented in the case notes.
Who Should Receive Postnatal Anti-D Ig Prophylaxis?
A/B - At least 500 IU of anti-D Ig must be given to every non-sensitised RhD-negative woman within 72 hours following the delivery of an RhD-positive infant.
C/D - A test to detect FMH greater than 4 ml must also be undertaken so that additional anti-D Ig can be given as appropriate.
D - If the pregnancy is non-viable and no sample can be obtained from the baby, anti-D Ig should be administered to a non-sensitised RhD-negative woman. [Evidence level 4]
Some women who have received anti-D Ig during pregnancy may have detectable anti-D in their blood at delivery. Because it may be difficult or impossible to distinguish between such passive anti-D Ig and weak anti-D resulting from early immunisation, anti-D Ig should be given to any eligible woman with weak anti-D antibody at delivery unless it has been clearly confirmed that she is already sensitised.
Transfusion of RhD-Positive Blood Components
How Should Inadvertent Transfusion of RhD-positive Platelets Be Managed?
D - In the event that RhD-positive platelets are transfused, prophylaxis against Rh alloimmunisation should be given.
Each unit of platelets prepared according to the UK guidelines from one whole blood donation contains fewer than 1 x 109 (< 0.1 ml red cells). 250 IU (50 micrograms) anti-D Ig should be given following every three adult doses (i.e., derived from up to 18 routine donations) of platelets. Women who have marked thrombocytopenia should be given the anti-D Ig subcutaneously to avoid the possibility of a haematoma following intramuscular injection.
How Should Inadvertent Transfusion of RhD-positive Blood Be Managed?
D - Anti-D Ig should be given to RhD-negative women of reproductive capacity who inadvertently receive a transfusion of RhD-positive blood.
D - The dose should be calculated on the basis that 500 IU of anti-D Ig will suppress immunisation by 4 ml of RhD-positive red blood cells.
D - Exchange transfusion may be necessary for large volumes of transfused blood.
When less than 15 ml of RhD-positive blood has been transfused to an RhD-negative woman capable of childbearing, the appropriate dose of anti-D Ig should be given. When more than 15 ml has been transfused, it is preferable to use the larger anti-D Ig intramuscular preparation (2500 IU or 5000 IU).
When more than two units of RhD-positive blood have been transfused, consideration should be given to undertaking an exchange transfusion to reduce the load of RhD-positive red blood cells in the circulation and the dose of anti-D Ig required to suppress immunisation. In this situation, the woman should be counselled regarding the implications of both non-intervention (for future pregnancies) and of treatment, including any hazards from receiving donated blood, the exchange procedure itself and of larger doses of anti-D Ig including intravenous anti-D Ig.
Immediate exchange transfusion will reduce the load of RhD-positive red cells (a single-blood-volume exchange will achieve a 65%–70% reduction in RhD-positive cells, and a two-volume exchange 85%–90%). Following exchange transfusion, the residual volume of RhD-positive red cells should be estimated using flow cytometry or rosetting. Intravenous anti-D Ig is the preparation of choice, achieving adequate plasma levels immediately and being twice as effective microgram for microgram as intramuscular anti-D Ig at clearing red cells. The dose to be administered should assume that 600 IU of intravenous anti-D Ig will suppress immunisation by 10 ml of fetal red cells. Intravenous anti-D Ig is available for use in the UK on a named patient basis only as WinRho SDF or Rhophylac. Intramuscular anti-D Ig must not be given intravenously. An appropriate combined dose of intravenous and intramuscular anti-D Ig should be determined in discussion with a specialist in transfusion medicine. Follow-up tests for RhD-positive red cells should be undertaken every 48 hours and further anti-D Ig given until all RhD-positive red cells have been cleared from the circulation. Free anti-D in the woman's serum does not necessarily reflect adequate prophylaxis and anti-D Ig treatment should be continued until RhD-positive red cells are no longer detectable.
Passive anti-D Ig given in large doses may be detectable for up to 6 months or more and tests for immune anti-D may not be conclusive for 9–12 months.
Grades of Recommendations
A - At least one meta-analysis, systematic review or randomised controlled trial rated as 1++ and directly applicable to the target population; or
A systematic review of randomised controlled trials or a body of evidence consisting principally of studies rated as 1+ directly applicable to the target population and demonstrating overall consistency of results
B - A body of evidence including studies rated as 2++ directly applicable to the target population, and demonstrating overall consistency of results; or
Extrapolated evidence from studies rated as 1++ or 1+
C - A body of evidence including studies rated as 2+ directly applicable to the target population and demonstrating overall consistency of results; or
Extrapolated evidence from studies rated as 2++
D - Evidence level 3 or 4; or
Extrapolated evidence from studies rated as 2+
Good Practice Point - Recommended best practice based on the clinical experience of the guideline development group
Classification of Evidence Levels
1++ High-quality meta-analyses, systematic reviews of randomised controlled trials or randomised controlled trials with a very low risk of bias
1+ Well-conducted meta-analyses, systematic reviews of randomised controlled trials or randomised controlled trials with a low risk of bias
1– Meta-analyses, systematic reviews of randomised controlled trials or randomised controlled trials with a high risk of bias
2++ High-quality systematic reviews of case–control or cohort studies or high-quality case–control or cohort studies with a very low risk of confounding, bias or chance and a high probability that the relationship is causal
2+ Well-conducted case–control or cohort studies with a low risk of confounding, bias or chance and a moderate probability that the relationship is causal
2– Case–control or cohort studies with a high risk of confounding, bias or chance and a significant risk that the relationship is not causal
3 Non-analytical studies, e.g., case reports, case series
4 Expert opinion