Recommendations for the prevention and treatment of haemolytic disease of the foetus and newborn

Recommendations for the prevention and treatment of haemolytic disease of the foetus and newborn Francesco Bennardello,1 Serelina Coluzzi,2 Giuseppe Curciarello,3 Tullia Todros,4 and Stefania Villa5, as Italian Society of Transfusion Medicine and Immunohaematology (SIMTI) and Italian Society of Gynaecology and Obstetrics (SIGO) working group Author information Copyright and License information Disclaimer This article has been cited by other articles in PMC. Go to: Introduction The publication of the second edition of the “Recommendations for the prevention and treatment of haemolytic disease of the foetus and newborn” is the result of collaboration between the Italian Society of Transfusion Medicine and Immunohaematology (SIMTI, Società Italiana di Medicina Trasfusionale e Immunoematologia) and the Italian Society of Gynaecology and Obstetrics (SIGO, Società Italiana di Ginecologia e Ostetricia). The recommendations published in 20061 have been revised in the light of current scientific evidence: the immunohaematological and instrumental investigations that should be performed in the antenatal and perinatal periods, the immunoprophylaxis (IP) to prevent the haemolytic disease of the foetus and newborn (HDFN due to RhD incompatibility and the treatment to use if HDFN develops are described. The recommendations are focused on the prevention and management of HDFN, in particular that one due to RhD incompatibility, the most serious form of this condition. Although IP has dramatically reduced the number of cases of HDFN, this disease continues to occur and engage specialists in Transfusion Medicine, Obstetrics and Neonatology. The recommendations are aimed at Transfusion Structures (TS) and all public facilities pertaining to Mother and Child Departments, Family Planning Clinics and private structures managing pregnancies, including those in which the woman gives birth at home. The prevention of HDFN must be guaranteed, through organisational models adapted to local circumstances, to all pregnant women for whom it is deemed necessary and the women must also be ensured adequate information. Besides HDFN due to RhD incompatibility, the recommendations also cover less frequent forms of the disease, caused by immunisation to other blood group antigens, and by ABO incompatibility, which is a more frequent laboratory finding, although of less importance from a clinical point of view. These recommendations will be periodically reviewed in the light of evolving scientific knowledge, technology and clinical practice. They were developed on the basis of an analysis of current scientific literature (identified through bibliographic searches of Medline/PubMed and Ovid databases) and were submitted to the consensus of experts from SIMTI and SIGO. Protocols jointly agreed upon by the Transfusion Medicine and Immunohaematology Services (SIMT, Servizio di Immunoematologia e Medicina Trasfusionale) and Obstetricians-Gynaecologists working in the same territory, including at a regional level, should be drawn up to promote compliance among pregnant women. Go to: Purpose of the recommendations The purpose of this document is to give correct guidance on the management and prevention of HDFN with the aim of promoting homogeneous practices throughout Italy, ensuring a minimum common denominator of quality that can be achieved in all health care structures2 used by pregnant women or females of childbearing potential*. The dual value of these recommendations is that besides being a technical and scientific support for doctors making clinical decisions regarding the management of HDFN, they also provide updates on the risks associated with immunisation in females of childbearing potential. The recommendations are not intended in any way to replace either the physician’s clinical evaluation of individual cases or the doctor’s personal experience; they are, rather, a reference tool that can also be used to check the correctness of treatment. The final decision on a given treatment must always be taken by the doctor in the light of the clinical picture and resources available; however, substantial deviations from these recommendations should be documented and justified in the patient’s clinical records. For this purpose specific indicators for monitoring and evaluation have been identified to use in clinical audits. Go to: Expected benefits The expected benefits of the dissemination of these recommendations for the prevention and management of HDFN are as follows: - a decrease in the incidence of HDFN; - a decrease in the incidence of alloimmunisation; - an increase in appropriate clinical use of blood components in the foetal and neonatal periods; - an increase in the appropriate clinical use of blood components in females of childbearing potential; - an increase in the appropriate clinical use and dosages of anti-D immunoglobulin (Ig); - greater involvement of patients in decisions related to the prevention and management of HDFN. Go to: Intended users of the recommendations Doctors and healthcare workers involved in the prevention, diagnosis and treatment of HDFN. Go to: Applicability These recommendations are applicable to females of childbearing potential, pregnant women at risk of HDFN and foetuses/neonates affected by haemolytic disease caused by materno-foetal alloimmunisation. Go to: Methodology of the Working Group and grades of recommendation The process of developing these recommendations, in accordance with the indications contained in the methodology manual of the National Guidelines Programme3, was based on systematic reviews of the literature and updating of already existing recommendations on the subject. For most of the recommendations there is an explicit evaluation of the quality of the proof leading to the recommendation and the strength with which the recommendation is made. In the absence of clear proof, the recommendations are based on a consensus of published opinions of experts and that of the Working Group. The methodology used to derive the grades of recommendation was based on that used by the Grading of Recommendations Assessment, Development and Evaluation (GRADE) Working Group4–6. According to the GRADE system, recommendations are classified by grades, expressed in Arabic numbers (1, 2), depending on their strength, and by letters (A, B, C) depending on the quality and type of evidence provided by the studies on which the recommendations are based. In detail: - Grade 1: the authors are confident that the benefits for health clearly outweigh the undesirable effects, in terms of both risk and economic cost. This is, therefore, a strong recommendation. - Grade 2: the authors are less certain and the difference between desirable and undesirable effects is less clear. This is, therefore, a weak recommendation. As to the quality and type of evidence provided by the studies in support of the recommendations, there are three levels of classification: - Grade A: high level of evidence. The evidence derives from the analysis of numerous, substantial randomised studies without major limitations. It is unlikely that further research would alter the conclusions reached by these studies. - Grade B: moderate level of evidence. The evidence is derived from randomised clinical trials but with important limitations (for example, inconsistent results, wide confidence intervals, methodological problems). Grade B is also attributed to recommendations derived from strong evidence collected in observational studies or case series (for example, treatment effects or the demonstration of a dose-response effect). Further research could change the conclusions of these studies. - Grade C: low or very low level of evidence. The evidence is derived from an analysis of observational clinical studies with less consistent results or from the clinical experience/opinions of experts. Further research is required to consolidate or change the conclusions presented. Generally speaking, it can be assumed that for all recommendations other than Grade 1A the authors recognise that other interpretations of the available evidence and other “clinical policies” are reasonable. The conventional classification of evidence is based on mathematical and statistical criteria, with the “strength” of the evidence being assigned, in order, to: meta-analyses, randomised controlled trials, retrospective analyses, prospective follow-ups, cross-sectional population studies, reviews, anecdotal reports. This is correct as far as regards strictly clinical studies, especially if they are investigations of therapies and focused on objective evaluations of outcome. Nevertheless, the recommendations in some fields are weak; in contrast, in other areas the availability of clinical studies carried out with rigorous methodology in large groups of subjects has enabled specific recommendations to be made with more confidence. It was not always possible to use aggregate data from meta-analyses: these variables increase the margins for individual decisions by each doctor and for each patient. As to transfusion support for HDFN in the antenatal and postnatal periods (intrauterine transfusion, exchange transfusion [ET], neonatal transfusion), the fundamental principles taken from the “Recommendations for transfusion therapy in neonatology”7 and subsequent amendments are reported in the appendix. The appendix also contains some recommendations to be followed in order to avoid the risk of immunisation when transfusing females of childbearing potential, a summary of the investigations to carry out during pregnancy and the puerperium to enable the correct prevention of HDFN, and a flow-chart describing the immunohaematological monitoring of women during pregnancy and at delivery. Finally, the recommendations are summarised and reported with their classification at the end of the appendix. Each member of the Working Group has signed a statement, which conforms with the one adopted by the National Guidelines Programme, declaring that they have no conflicts of interest3. Go to: Haemolytic disease of the foetus and newborn due to maternal-foetal RhD incompatibility The anti-D alloantibody is the antibody most frequently responsible for HDFN8,9. Before the introduction of anti-D IP, HDFN secondary to anti-D immunisation affected 1% of neonates and was the cause of death of one in every 2,200 babies born10. Although the introduction of post-partum IP in RhD negative pregnant women drastically reduced the incidence of cases of HDFN11, HDFN due to anti-D continues to occur in 0.4 of every 1,000 births12–13 and red blood cell alloimmunisation still remains the most common cause of foetal anaemia14. There are various reasons for the continued occurrence of this disease: (i) the possible development of anti-D immunisation during a pregnancy as a result of an occult foetal-maternal haemorrhage (FMH), usually after the 28th week of gestation, which affects about 1% of RhD negative mothers of a RhD positive foetus15; (ii) lack of administration of IP; (iii) ineffective IP because the amount administered was not sufficient for the volume of the FMH; (iv) possible errors in the typing of the pregnant woman, puerpera or neonate; and (v) possible errors in the transfusion treatment of females of childbearing potential (transfusion of red blood cell concentrates with mismatched RhD antigen). The fundamental cause of HDFN is the reaction between class IgG maternal antibodies and antigens on foetal red blood cells, leading to the destruction of these cells, mainly in the spleen. HDFN rarely occurs during a first pregnancy, unless the mother has been previously sensitised by transfusions. Usually, during the first pregnancy primary immunisation takes place; this immunisation is characterised by the production of a small amount of IgM antibodies, immunoglobulins which do not cross the placenta. In subsequent pregnancies, and after further exposure to the antigen, as a result of the secondary immunisation, IgG antibodies, which can cross the placenta and cause haemolysis, are produced. The immune response depends on the entity of the FMH, the number of immunising events and the capacity of the woman’s response. ABO incompatibility between mother and foetus partially protects against immunisation. In the natural history of HDFN, without any kind of intervention, in 50% of cases the foetus has only mild signs of the disease and recovers without any treatment; in 25% of cases the foetus develops haemolysis and kernicterus, if not treated adequately at birth; and in the remaining 20–25% of cases, HDFN due to anti-D may present in its most severe form (hydrops foetalis and death) before the 34th week of gestation16. However, with the improvement of maternal and foetal monitoring and the current possibility of in utero treatment, the incidence of severe cases (hydrops and death) has now been reduced to about 10. Go to: Haemolytic disease of the foetus and newborn due to incompatibility for other red blood cell antigens Besides the RhD antigen, other antigens belonging to the Rh system and other known blood group systems (with the possible exclusion of those of the Lewis, Chido and Rodgers, and Knops systems and of the I/i collection) can also induce the production of IgG antibodies and, therefore, provoke HDFN if a person lacking an antigen comes into contact with that antigen as a result of a pregnancy or transfusion. As a general rule, the forms of HDFN not due to RhD incompatibility are clinically benign, such that only 10% of them are clinically severe enough to require transfusion therapy; nevertheless, there are descriptions of fatal cases in the literature18. The order of frequency of HDFN, after the forms due to RhD incompatibility and ABO incompatibility, are those caused by incompatibility for the c antigen (r′), the Kell antigen (K1), the C antigen and the antigens of the Duffy system19–20. Still in strict order of frequency, there are the forms of HDFN due to incompatibility for antigens of the Kidd, MNS, and Dombrock systems and others, which are all very rare. Anti-Cw, -Fyb, -Jka, -Jkb, -Jk3, -S, and -s usually only cause a positive direct antiglobulin test (DAT) in the neonate and treatment, if necessary is almost always limited to phototherapy21. Anti-M, which may also be of the IgG class, rarely cause HDFN. The same applies for warm autoantibodies. Antibodies such as anti-I, -P, -Lea and -Leb can be ignored because the corresponding antigens are scarcely present at birth. Various studies22–25 have shown that HDFN caused by anti-K differs from that due to anti-D in a number of ways. In women with anti-K, the obstetric history is not usually predictive of the severity of the disease; there is only a weak correlation between antibody titre and the severity of the disease, haemolysis and the consequent hyperbilirubinaemia are not dominant features of the disease and the suppression of foetal erythropoiesis, rather than haemolysis, is the most important pathogenic mechanism in causing foetal anaemia. Pregnancies in which anti-K maternal-foetal alloimmunisation has occurred, even when the antibody titre is low (1:8 or greater), must, therefore, be considered at risk, given the severity of the foetal and/or neonatal clinical manifestations. The recent increase in migration to Italy has led to the diagnosis of other forms of HDFN due to antigens rarely observed in the Italian population. The search for irregular antibodies in these forms of HDFN is often falsely negative because of the lack of the relevant antigens in the test red cell panels commonly used, which are prepared with red blood cells from Caucasians. In these cases, the alloantibody involved can be detected and identified by using the father’s red cells (if ABO compatible with the mother’ ones), or, after delivery, the neonate’s cells. The protocols regarding investigations to carry out during pregnancy and in the perinatal and postnatal periods, as well as the treatment, are not different from those recommended for HDFN due to RhD incompatibility, to which the reader is referred. Once an antibody specificity has been identified, the test red cells to use in controls, in determining the titre and in studies of the eluate of neonatal erythrocytes must express the antigen in question. In contrast, the red cells to use for a possible ET or for transfusion into the neonate must not carry the antigen involved. Go to: Haemolytic disease of the foetus and newborn due to maternal-foetal ABO incompatibility HDFN due to ABO incompatibility is currently the most common neonatal haemolytic disease in the western world; indeed, in 15–20% of pregnancies in the white population there is incompatibility between a group O mother and a group A or B child; in 10% of these pregnancies, HDFN develops as a result of destruction of the foetal red blood cells, caused by IgG class anti-A and/or anti-B antibodies in the maternal serum. The mother-child serological combination in which a clinically relevant ABO HDFN develops most readily is a group O mother and a group A neonate. However, only in about 1.5–2% of cases does the haemolytic disease require transfusion support26,27. There are various reasons for the prevailing modest clinical expression of HDFN due to ABO incompatibility: - the expression of A and B antigens on foetal and neonatal red blood cells is low; - the A and B substances, ubiquitously present on endothelial and epithelial cells, including placental ones, adsorb some of the maternal IgG that crosses the placenta; - anti-A and anti-B IgG are predominantly IgG2, a subclass of Ig with a lesser capacity to cross the placental barrier actively. Nevertheless, there are occasional reports in the literature of severe cases of haemolytic disease that have required ET and complex management28,29. The incidence of HDFN due to ABO incompatibility is higher in African and Arab populations because of the more frequent expression of A and B genes in these populations. Given the migratory phenomena involving Italy (the 2013 CEDAP report [analysis of Birth Support Certificates] described that, in 2010, 18.3% of births were to women of non-Italian citizenship, with the peak being 28% in the region of Emilia Romagna), it can be predicted that the incidence of this type of HDFN will increase in the future30. The incidence of HDFN due to ABO incompatibility is the same in first pregnancies as it is in subsequent pregnancies; the disease is, therefore, neither preventable nor predictable. The search for anti-A and/or anti-B IgG during a pregnancy is of little use for predicting the development of ABO HDFN in the unborn child. In fact, most pregnant women, especially those with group O blood, have anti-A and/or anti-B (and anti-A,B) IgG in their serum, whereas relatively few neonates are affected by haemolytic disease, particularly clinically important forms. Go to: Investigations during pregnancy to prevent and manage haemolytic disease of the foetus and newborn Immunohaematological tests to perform in all women (Table I) Table I Recommendations on immunohaematological tests to perform in all women. Rec. n. Recommendation GoR 1 It is recommended that the ABO group and RhD factor are determined and a search for irregular antibodies is carried out with an IAT in all pregnant women, independently of their RhD status, within the first trimester of pregnancy in a Transfusion Structure. 1B 2 It is suggested that the samples for immunohaematological investigations are identified as samples for pre-transfusion tests and carry the surname, name and date of birth of the patient and the signature of the person who took the sample. 2C 3 It is suggested that all pregnant women are notified of their RhD status because of the possible need for prophylaxis with anti-D Ig. 2B 4 It is suggested that the search for irregular antibodies is repeated in all pregnant women at 28 weeks of gestation, regardless of their RhD status. In RhD negative women receiving antenatal prophylaxis at 28 weeks of gestation, the IAT should be performed before the IP is administered. 2B 5 If the search for antibodies is positive, for the purpose of evaluating the risk of HDFN, it is suggested that the specificity, titre and origin of the antibodies are determined and that a careful immunohaematological and obstetric history of the woman is taken. 2B 6 It is suggested that RhD typing and screening and identification of irregular antibodies is performed using methods in line with those set out in the SIMTI Standards. 2C 7 It is recommended that anti-A and anti-B immune antibodies are not searched for or monitored in pregnant women. 2B - ABO blood group and RhD factor must be determined in all pregnant women, preferably within the first trimester of pregnancy. The tests must be performed in a TS using validated methods9,31–32. - Samples of blood from pregnant women must carry the surname, name and date of birth of the patient and the signature of the person who took the sample33,34. The patient’s personal data must be transcribed in the presence of the patient herself, who must confirm the data. - Two different monoclonal anti-D reagents, which must not recognise the DVI variant of the RhD antigen, must be used to determine the RhD type32,33. Determination of weak D antigen is not recommended since this is not useful and could lead to a dangerous omission of IP in the absence of in depth investigations, which cannot be carried out in all immunohaematology laboratories. - All pregnant RhD negative women should be given

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