<scp>BCSH</scp> guideline for the use of anti‐D immunoglobulin for the prevention of haemolytic disease of the fetus and newborn

Abstract

Prior to the availability of anti-D immunoglobulin (anti-D Ig), the incidence of Rh D alloimmunisation in D negative women following two deliveries of D positive, ABO-compatible, infants was approximately 16%, and haemolytic disease of the fetus and newborn (HDN) due to anti-D was a significant cause of morbidity and mortality (Urbaniak & Greiss, 2000). Following routine post-partum administration of anti-D Ig, the rate of alloimmunisation dropped to approximately 2%. A further reduction in the sensitisation rate ranging from 0·17 to 0·28% was achieved by introducing routine antenatal prophylaxis during the third trimester of pregnancy (Tovey et al., 1983a,b; Huchet et al., 1987; Mayne et al., 1997; MacKenzie et al., 1999). Associated with this reduction in sensitisation is a reduction in mortality associated with HDN, from 46/100 000 births to 1·6/100 000 births (Pilgrim et al., 2009). These findings contributed to the National Institute for Clinical Excellence (NICE) recommendation that all D negative pregnant women who do not have immune anti-D, should be offered additional routine prophylaxis with anti-D Ig during the third trimester of pregnancy (NICE, 2002, 2008). The objective of this guideline is to provide healthcare professionals with practical guidance on the use of anti-D Ig as immunoprophylaxis to prevent sensitisation to the D antigen during pregnancy or at delivery for the prevention of HDN. This guideline is an update of the 2006 BCSH guideline on the use of anti-D immunoglobulin for Rh prophylaxis (Parker et al., 2006), and takes into account the updated NICE guidance for routine antenatal anti-D prophylaxis (NICE, 2008). This revision also aims to ensure concordance with other BCSH guidelines including guidelines for estimation of fetomaternal haemorrhage (BCSH, 2009), blood grouping and antibody testing in pregnancy (BCSH, 2007) and recently published compatibility procedures in blood transfusion laboratories (Milkins et al., 2012) as well as professional guidelines produced by the Royal College of Obstetrics & Gynaecologists (RCOG Green Top No22, updated 2011). This guideline was developed in accordance with the standard British Committee for Standards in Haematology (BCSH) methodology for producing BCSH guidelines. The guideline group was selected to be representative of medical and scientific UK-based experts. A search of published literature was undertaken using the Cochrane Library, Pubmed, MedLine, Embase and internet searches using the following key words and relevant MeSH terms: anti D, anti-D Ig immune globulin, pregnancy, antenatal, prophylaxis, rhesus, Rh D, Rh D haemolytic disease, erythroblastosis fetalis. This search covered the period 1999 to March 2013 and was limited to the English language and humans. The papers included were subjected to critical reading by the authors using the CASP appraisal tool (CASP, 2004) and were ranked according to the hierarchy of evidence. This approach took account of the NICE systematic review undertaken in 2000 (Chilcott et al., 2003), and the NICE Health Technology Assessment report published in 2007. The writing group produced the draft guideline, which was subsequently revised by consensus by members of the Transfusion Task Force of the British Committee for Standards in Haematology. The guideline was reviewed by a sounding board of UK haematologists, the BCSH (British Committee for Standards in Haematology and the BSH Committee (British Society for Haematology) as well as representatives from the Royal College of Obstetrics and Gynaecology and the Royal College of Midwifery, with comments incorporated where appropriate. Criteria used to assign levels of evidence and grades of recommendations are as outlined by the Agency for Healthcare Research and Quality (AHRQ) at http:www.ahrq.gov (Appendix 1). Pregnant D negative women with no immune anti-D should be offered prophylactic anti-D Ig for potentially sensitising events listed in Table 1. A dose of anti-D Ig appropriate to the gestation (see 3–5) should be administered within 72 h of a potentially sensitising event. However if, exceptionally, this deadline cannot be met, some protection may still be offered if anti-D Ig is given up to 10 days after the sensitising event (Lee et al., 1999; RCOG, 2011). Following potentially sensitising events, anti-D Ig should be administered as soon as possible and always within 72 h of the event. If, exceptionally, this deadline has not been met some protection may be offered if anti-D Ig is given up to 10 days after the sensitising event (Grade 1C). A maternal blood group and antibody screen should be performed to determine or confirm the Rh D group and check for the presence of immune anti-D. The reagents used should conform to BCSH guidelines for pre-transfusion compatibility procedures (Milkins et al., 2012). Women with anomalous Rh D typing results should be treated as D negative until confirmatory testing is completed. A test for fetomaternal haemorrhage (FMH) is NOT required. 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 immunoglobulin is not necessary because the risk of FMH and hence maternal exposure to the D antigen is negligible. In cases of therapeutic termination of pregnancy, whether by surgical or medical methods, and regardless of gestational age, previously non-sensitised D negative women should receive a minimum dose of 250 IU prophylactic anti-D Ig within 72 h of the event (RCOG, 2011). There is a significant potential for sensitisation in cases of ectopic pregnancy (Hartwell, 1998). A minimum dose of 250 IU anti-D Ig should be administered to all cases of ectopic pregnancy in previously non-sensitised, D negative women regardless of the mode of management (RCOG, 2011). The authors note that the recent NICE guidance on the management of ectopic pregnancy and miscarriage (NICE, 2012) specifically recommends against offering anti-D Ig if ectopic pregnancy is solely managed medically but without any clear evidence to support this. The authors feel that this has potential for causing confusion resulting from inconsistency with established current practice based upon RCOG green top and BCSH guidelines and introduces complexity into decision making without strong evidence to support any such change. There is significant potential for sensitisation in cases of molar pregnancy. A minimum dose of 250 IU anti-D Ig should be administered to all cases of molar pregnancy in previously non-sensitised, D negative women (RCOG, 2010). Evidence that women are sensitised after uterine bleeding in the first 12 weeks of pregnancy, where the fetus is viable and the pregnancy continues, is scant (Ghosh & Murphy, 1994). Therefore anti-D Ig is not necessary in women with threatened miscarriage with a viable fetus where bleeding completely stops before 12 weeks gestation. However, 250 IU anti-D Immunoglobulin should be administered where bleeding is heavy or repeated or where there is associated abdominal pain particularly if these events occur as gestation approaches 12 weeks (Grade 2C recommendation). Gestational age should be confirmed by ultrasound. In pregnancies <12 weeks gestation, Anti-D Ig prophylaxis (minimum dose 250 IU) is only indicated following an ectopic pregnancy, molar pregnancy, therapeutic termination of pregnancy and in some cases of uterine bleeding where this is repeated, heavy or associated with abdominal pain. A test for FMH is not required (Grade 2C) A maternal blood group and antibody screen should be performed to determine or confirm the Rh D group and check for the presence of anti-D. The reagents used should conform to BCSH guidelines for pre-transfusion compatibility procedures (Milkins et al., 2012). If anti-D is identified, further history should be obtained and investigation undertaken to determine whether this is immune or passive (as a result of previous injection of anti-D Ig). If no clear conclusion can be reached as to the origin of the anti-D detected, then the woman should continue to be offered anti-D prophylaxis on the assumption that it may be passive. Women with indeterminate Rh D typing results should be treated as D negative until confirmatory testing is completed. A test for FMH is NOT required before 20 weeks gestation. For any potentially sensitising event listed in Table 1, confirmed D negative, previously non-sensitised, women should receive a minimum dose of 250 IU anti-D Ig within 72 h of the event (RCOG, 2011). D negative women presenting with continual uterine bleeding between 12 and 20 weeks gestation should be given at least 250 IU anti-D Ig, at a minimum of 6 weekly intervals (Grade For potentially sensitising events between 12 and 20 weeks gestation a minimum dose of 250 IU should be administered within 72 h of the event. A test for FMH is not required (Grade A maternal blood group and antibody screen should be performed to determine or confirm the Rh D group and check for the presence of immune anti-D. The reagents used should conform to BCSH guidelines for pre-transfusion compatibility procedures (Milkins et al., 2012). If anti-D is identified, further history should be obtained and investigation undertaken to determine whether this is immune or passive (as a result of previous injection of anti-D Ig). If no clear conclusion can be reached as to the origin of the anti-D detected, then the woman should continue to be offered Anti-D Ig prophylaxis on the assumption that it may be passive. Women with anomalous or indeterminate Rh D typing results should be treated as D negative until confirmatory testing is completed. A FMH test is required to in the maternal if to the of FMH to of additional anti-D required to clear the This should be performed according to BCSH guidelines for estimation of FMH If FMH is detected, are required at h following an dose of anti-D or 72 h following an dose to check for of (BCSH, 2009). For any potentially sensitising event listed in Table 1, D negative, previously non-sensitised, women should receive a minimum dose of IU anti-D Ig within 72 h of the event (RCOG, 2011). A minimum of IU anti-D Ig should be administered within 72 h for any potentially sensitising events regardless of whether the woman has at weeks (BCSH, 2009). of anti-D Ig be necessary if the of FMH that covered by the standard anti-D Ig dose in use RCOG, 2011). A blood should be at h following dose of anti-D and 72 h following dose of anti-D to check if have In the event of continual uterine bleeding which is to the sensitising with no of a or a significant in the or of such as the presence of abdominal pain or a minimum dose of IU anti-D Ig should be given at weekly In the event of further uterine estimation of FMH should be at two weekly In this typing using maternal be to blood and repeated administration of of anti-D, against the risk of et al., et al., of D typing by this If the two weekly FMH test the presence of additional anti-D Ig should be administered to the of The additional dose should be as IU if administered or IU if administered for of (minimum The additional dose should be offered regardless of the presence or of passive anti-D in maternal and FMH should be after h if anti-D Ig has been given or 72 h if given (Grade If of a sensitising event in to continual uterine bleeding abdominal pain associated with a significant in the or of then it should be managed as an additional sensitising event with an appropriate additional dose of anti-D and estimation of sensitising event should be managed with an appropriate additional dose of anti-D Ig regardless of the or dose of anti-D Ig administered for a previous event. For potentially sensitising events after 20 weeks gestation a minimum D Ig dose of IU should be administered within 72 h of the event (Grade for FMH should be for all D negative, previously non-sensitised, pregnant women who have a potentially sensitising event after 20 weeks of gestation, and additional of anti-D Ig should be administered as necessary (Grade 1C). This takes account of the of the NICE which recommends that be offered to all D negative, non-sensitised, pregnant women (NICE, 2002, 2008). A should be for the routine antenatal blood group and antibody screen as in the BCSH guidelines for blood group and antibody testing in pregnancy before is If anti-D is in this further should be undertaken to determine whether this is immune or passive previous administration of anti-D Ig). If no clear conclusion can be reached as to the origin of the anti-D detected, then the woman should continue to be offered anti-D Ig prophylaxis, and should continue to be until weeks gestation and There is evidence that antenatal anti-D Ig prophylaxis using a dose at weeks gestation, et al., et al., MacKenzie et al., or two given at and weeks, (Tovey et al., 1983a,b; Mayne et al., 1997; MacKenzie et al., a significant reduction in the incidence of maternal sensitisation to However, no is to an of the of dose NICE guidelines (NICE, that the with the associated should be This should into account the and associated with If using the a minimum dose of anti-D Ig IU is at and a dose of anti-D Ig, IU should be administered between and The dose may be (Pilgrim et al., 2009), potentially and of routine antenatal anti-D Ig prophylaxis should not be by previous anti-D Ig prophylaxis administered for a sensitising event in the pregnancy. D negative pregnant women who have not been previously sensitised should be offered routine antenatal prophylaxis with anti-D Ig with a dose given weeks, or two dose given at and weeks (Grade is that the for blood group and antibody screen is to the first routine prophylactic anti-D Ig injection This the screen required in pregnancy as in the BCSH for and during pregnancy NICE (Grade The should be as to any anti-D Ig administered for sensitising listed in Table (Grade the administration of the transfusion this is should a pregnant woman pre-transfusion This is because if anti-D is a of anti-D Ig administration in the of whether this is immune or the of which management of the pregnancy. of women for and of This be to ensure that all women are and should be to pregnant women to with the (RCOG, 2011). for the with of the should be in a to the for the Following a blood should be to the and Rh D of the If a blood is not for any a from the should be obtained as soon as possible (BCSH, The reagents used should conform to the BCSH pre-transfusion compatibility procedures (Milkins et al., 2012). or indeterminate Rh D should be treated as D until confirmatory testing is completed. If a cannot be the should be to be D for the of administration of anti-D A test on the blood is not performed it may be in a of cases because of antenatal prophylaxis with anti-D However, a should be performed if haemolytic disease of the newborn is or because of a blood the presence of maternal immune for confirmatory and Rh D and FMH testing should be after has for any FMH to be in the maternal A period of is et al., and the should be within h of delivery to ensure that the is to from the (RCOG, 2011). FMH testing should be undertaken on all D negative women D infants to determine if additional of anti-D Ig are required. If an FMH is detected, are required at h following an dose of anti-D or 72 h following an dose to check for the of 2009). If the blood group is D positive, a minimum of IU anti-D Ig should be administered to previously non-sensitised D negative within 72 h of the delivery & of anti-D Ig prophylaxis should not be by previous routine antenatal anti-D Ig prophylaxis or by antenatal anti-D Ig given for a potentially sensitising event. A dose of is to a FMH of up to it is necessary to additional of anti-D Ig, as by for the dose is based on IU anti-D for However, healthcare professionals should to guidance on which is used (see In cases of and particularly if FMH is in of a of anti-D Ig should be for injection be given should be given to but this should not the of anti-D is used for blood may literature using and of blood that the of in blood from to 20 et al., 1999; et al., 1999; et al., 2008). the of in blood is and can be it is that a minimum anti-D Ig dose of IU be administered after of if the blood group is D if the group cannot be established for should be for estimation of FMH after the of and additional of anti-D administered if and appropriate FMH testing is that the transfusion if has been used to ensure that dose of anti-D Ig is Following and Rh D typing should be performed on blood and if the is confirmed to be D positive, all D negative, previously non-sensitised, women should receive at least IU of anti-D Ig within 72 h following should be for FMH and additional given as by FMH (Grade If there is an and hence no can be obtained from the prophylactic anti-D Ig should be administered to previously non-sensitised A minimum of IU of anti-D Ig should be administered within 72 h following the of should be for FMH and additional given as by FMH should be that the of is the sensitising event delivery and hence anti-D Ig should be administered within 72 h of (Grade If blood cannot be obtained or if blood group cannot be established for any at least IU anti-D Ig should be administered to D negative, previously non-sensitised women (Grade is used during in D negative, previously non-sensitised and where blood group is confirmed as D a minimum dose of IU anti-D Ig should be administered following the of and a maternal should be for estimation of FMH after in anti-D Ig is is that the transfusion if has been used to ensure that dose of anti-D Ig is (Grade D negative should be to D negative or women of who a if the appropriate is not or availability cause it may be necessary to D In these prophylaxis against possible sensitisation to the D antigen by the should be given A dose of 250 IU anti-D immunoglobulin should be to up to therapeutic of D given within a period (Grade In with of anti-D Ig should be given or if a or is to the risk of following is not necessary to anti-D Ig to D negative without or who receive D have been the appropriate dose of anti-D Ig may be given (see have been it is to use the anti-D immunoglobulin or anti-D immunoglobulin is the of levels only of anti-D immunoglobulin not be given The of D should be performed by after h if an dose of anti-D has been given or 72 h if an dose has been given (Grade and further anti-D Ig given until there are no D in of D blood has been a transfusion should be to the of D in the and the dose of anti-D Ig required to prevent In this should be from a in Transfusion and the should be the of and of including any from the and of of anti-D Ig, including anti-D Ig (RCOG, A transfusion a reduction in D a an after the the of D should be using anti-D Ig given in may and for immune anti-D may not be for the of writing this guideline, the recommendation in the UK is that all previously non-sensitised, D negative, pregnant women are offered However, the of this approach is that approximately of D negative women who are an D negative be given routine prophylactic anti-D Ig This to approximately 000 women in the UK who are prophylaxis In recent in blood group using from maternal blood at gestation, have it possible to determine D with a of et al., et al., et al., 2009). The risk of a negative result an D blood by this is and to be to et al., et al., 2012). blood group can also be for Rh and using from maternal typing for all D negative pregnant women has been in and The to use of this has not been in the UK et al., 2012). of practice should to be undertaken on a to ensure with these guidelines where identified, or in to should be 1997; 1998). The UK of Transfusion is a at women who have produced an immune anti-D that is for the first in the current pregnancy, whether at weeks, delivery or at any other within the pregnancy. For any woman identified, there be previous sensitising events, anti-D prophylaxis and This in Transfusion laboratories are to report any cases of immune anti-D. anti-D Immunoglobulin (anti-D used in the UK is from from blood who have levels of anti-D Ig due to previous sensitisation or is for and In the in to further the risk of The risk of of disease is to be by to National Institute of Health and Clinical Excellence appraisal guidance (NICE, 2002, a rate of a or possible event (Pilgrim et al., 2009), to be event 000 of anti-D The of events were not There is no evidence to that anti-D Ig administered to women during pregnancy is to the are but including may Anti-D may of and hence with to have a risk of potentially and If of or of of the and administration of anti-D be and appropriate for recommends that such as should be for of The by which anti-D Ig alloimmunisation is of anti-D D by and of et al., The following anti-D Ig are in the UK at the of writing this as and IU for use as IU for or should be that due to the of the are for and not be administered because of the risk of due to the presence of of and other However, by is a and is for and a dose of anti-D Ig is in this guideline, it is as the minimum dose for a The dose given on the and of anti-D Ig in and may be is The dose of anti-D Ig is as and of anti-D Ig is of A dose of is to a FMH of up to it is necessary to additional of anti-D Ig, as by for the dose is based on IU Anti-D or D for However, healthcare professionals should to guidance on the The for based upon at least IU of or D or There is some evidence from et al., et al., 2004) that is associated with levels of anti-D Ig following However, it is whether this to a sensitisation rate in the of the a recommendation cannot be a dose or of administration in women with or of anti-D Ig are should be given to exposure for the anti-D Ig for and the but this should not in any the of anti-D The is an appropriate and for administration of anti-D Ig et al., If the is should be to ensure that the injection is given into as may be if it only the In women with or a history of a bleeding such as disease, anti-D Ig should be administered or on whether a for use is Women with significant bleeding such as disease should be managed with a The on practice recommends that there is clear and to ensure of all blood anti-D from to 2000). The Health Transfusion 2007) also the for for anti-D There are in the transfusion in the and administration for anti-D Ig, as the be in the However, it is that may and other may be for the and of anti-D In any it is that complete of and administration are in to of anti-D Ig to of the injection including the and the and or and of administration should be in the and is also that these are in the transfusion that this is should pre-transfusion testing be required. of and administration should be to of anti-D immunoglobulin (Grade pregnant women be offered and anti-D Ig to decision anti-D be obtained to anti-D Ig, and the decision to or the injection should be by the healthcare in the and (RCOG, 2011). NICE guidance recommends that is offered at the of blood group in antenatal healthcare This is required an D negative woman a potentially sensitising event after 20 weeks gestation, and after the of an D to determine whether the standard dose of anti-D Ig administered has been to all from the maternal (RCOG, BCSH 2009). FMH testing of and should be undertaken according to BCSH guidelines for the estimation of FMH 2009). the FMH result that anti-D Ig has been given to the an additional dose of anti-D Ig should be administered within 72 of the sensitising event. The additional dose of anti-D Ig should be as for and should into account any anti-D Ig if but not any dose given as A FMH should be 72 if the additional anti-D Ig is given or after if given to check for of of anti-D Ig and be necessary if A FMH confirmed by as or to is to be and if such a is covered by the standard anti-D dose a FMH is still required to confirm that anti-D Ig has been administered and to check for of The presence of anti-D in maternal not prophylaxis and additional of anti-D Ig should be until D are no RCOG, on maternal pre-transfusion may be following injection of anti-D anti-D may be passive or immune and there is no for between the if at the passive anti-D IU IU has been given The is and following anti-D and IU following The with et al., MacKenzie et al., There have been cases in the UK where immune anti-D has been to be prophylactic without a of the of or into account an history is that regardless of any administration of anti-D Ig, any anti-D at weeks should be and the results in the and anti-D is in a from a pregnant further history should be obtained and undertaken to whether this is immune or passive. If no clear conclusion can be reached as to the origin of anti-D, then prophylaxis should continue to be administered in accordance with guidelines for D negative women who have not immune anti-D (Grade of the authors have a of authors contributed to writing the BCSH & additional at the of by a systematic search of published literature for these guidelines. members of the BCSH transfusion and sounding board reviewed the and comments and recommendations are there is that the do or do not and recommendations can be to as the of or is a recommendation is recommendations to as