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International Journal of Medical Sciences and Health Care

Vol-1 Issue-8 (Ijmshc 803)

Medical Sciences and Health Care Vol-1 Issue-8 (Ijmshc 803) Suboptimal testing for alloantibodies in sub Saharan

Suboptimal testing for alloantibodies in sub Saharan Africa: Bane to effective Immunohaematological services delivery.

ADIAS Teddy Charles 1* ERHABOR Osaro 1

1. Department of Haematology Faculty of Medical Laboratory Science, Usmanu Danfodio University, Sokoto, Nigeria

All Correspondence To Dr Teddy Charles Adias Associate Professor of Immuno-HaematologyUsmanu Danfodio University, Sokoto State, Nigeria

Abstract:

Alloimmunization to clinically significant red cell antigen is a major complication associated with immunohaematological services in developing countries. The aim of this review is to highlight the challenges associated with effective immunohaematological service delivery in sub Saharan Africa. There are several daunting challenges militating against effective immunohaematological services; absence of phenotyped units in multiply transfused patients that have developed clinically significant alloantibodies, reliance on family replacement blood donors and commercial remunerated blood donors rather than safer voluntary donors, absence of universal alloantibody testing among antenatal women and in patients in whom red cell transfusion is indicated, suboptimal management of clinically significant antibodies in pregnancy that is associated with HDN, absence of universal access to routine Antenatal Anti-D Prophylaxis (RAADP) in Rhesus negative women and suboptimal management of Feto-Maternal Haemorrhages (FMH) in Rhesus negative pregnant women. There is need for additional testing of blood donors for clinically significant red cell antigens as well as alloantibody screening of all recipients for which red cell transfusion is indicated. The collection of blood from family replacement and commercial remunerated donors should be discouraged. It is best practice to screen all antenatal women for alloantibodies in early pregnancy to enable remedial action to be taken if the women if found positive for a clinically significant antibody that has the potential to cause HDFN. There is also the need for the availability of FMH measurements following potentially sensitizing events in Rh negative pregnant women. Knowledge of anti-D prophylaxis among obstetricians, biomedical scientist, midwives, traditional birth attendants, pharmacists, and nurses in Africa needs to be optimized. Countries in sub Saharan Africa need to urgently implement these evidenced based best practices to facilitate the delivery of effective immunohaematological services in sub Saharan Africa.

Introduction

The development of red cell alloantibodies complicates transfusion therapy particularly among transfusion- dependent patients. Alloimmunization to clinically significant red cell antigen is a major complication observed in multiply transfused patients making it difficult to source for compatible units for transfusion. Differences exist in the blood group phenotype of individuals of various ethnic groups [1]. Immigration of humans from one part of the world to the other has resulted in a genetic mix of most populations with attendant risk of development of alloantibodies in patients who are transfused with ABO and Rhesus compatible units that contain clinically significant red cell antigens which the recipient lacks [2].

determine the frequency of occurrence of alloantibodies among pregnant women in Port Harcourt, Nigeria identified alloantibodies in the serum of (3.4%) of pregnant women studied. The specificity of the antibodies was as follows; anti-C (1.2%), anti-E (0.6%), anti-Jsb (0.6%) and anti-K (1.0%). No anti-D was identified despite 8.6% of the study population being Rhesus D (Rh D) negative. Also, a previous report [6] involving a total of 214 transfused Ugandans indicated that 6.1% of subjects possessed RBC alloantibodies

whose specificities including anti-E, anti-S, anti-D, anti -

K and anti -Le(a). Antenatal screening of 3,000 patients

who were grouped and screened in Zimbabwe indicated an overall antibody incidence of 1.7%. Antibodies identified from patients were; anti-D 13.3% , anti-E 6.7% , anti-Jsb 3.2% , anti-Lea 23.3% and anti-Leb 20%

[7].

Red blood cell (RBC) alloimmunization results from genetic disparity of RBC antigens between donor and recipients. Alloimmunizations are significant especially when it involves a clinically significant alloantibody that

Alloantibody testing of transfusion recipients to ensure that they receive red cells negative to alloantibody they may have developed is often lacking in most settings in Africa; there is absence of universal access to

Feto-Maternal-Haemorrhage (FMH) in many African

causes haemolytic transfusion reactions and haemolytic disease of the newborn (HDN). It is very important that they be correctly, and some of them routinely, typed in

prophylactic immunoglobulin D for the prevention of Rh isoimmunization in Rh negative [8] women coupled with the absence of cost - effective means of estimating

settings. These factors all complicate transfusion practice

blood donors as well as in patients [3]. The development of red blood cell (RBC) isoimmunization with

in

this region.

alloantibodies and autoantibodies complicate transfusion

It

is obvious that the additional testing of blood donors

therapy particularly in multiply transfused patients [4].

for clinically significant red cell antigens as well as

Alloantibodies of clinical importance can cause transfusion reactions or HDN. A previous report [5] to

alloantibody screening of all transfusion recipients as well as other patients in which red cell transfusion is

of all transfusion recipients as well as other patients in which red cell transfusion is http://www.ijmshc.com
of all transfusion recipients as well as other patients in which red cell transfusion is http://www.ijmshc.com

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Vol-1 Issue-8 (Ijmshc 803)

Medical Sciences and Health Care Vol-1 Issue-8 (Ijmshc 803) indicated should be implemented as a routine

indicated should be implemented as a routine to prevent

as far as possible the incidence of alloimmunization [9-

10]. It would also be cost-effective, bearing in mind the

fact that there are laborious and expensive laboratory testing necessary to provide compatible blood for alloimmunized patients. Extended blood typing should

be implemented for some categories of poly-transfused

patients as well. This strategy is another step forward to improving the safety of blood transfusion in Africa. Alloimmunization to red cell antigens is still a current problem in many settings in sub Saharan Africa.

In most hospitals, alloantibody screening of recipient

plasma is not available. Although the implementation of

a program of routine antenatal anti-D prophylaxis

(RAADP) has led to a significant decline in the residual numbers of women becoming sensitized in most developed countries, a significant number of women are not fortunate enough to have access in Sub-Saharan Africa and thus continue to be affected. The aim of this review is to highlight the challenges associated with the management of Rh-negative pregnancy, significance of alloantibody screening of all transfusion dependent patients particularly women of child bearing ages in

which transfusion is indicated and to advocate for the inclusion of a universal alloantibody screen in the transfusion and antenatal protocol in sub Saharan Africa.

Absence of phenotyped unit in multiply transfused patients that have developed clinically significant alloantibodies

Transfusion-dependent patients are individuals who require regular red cell transfusion and on long-term basis to manage anaemia, sustain life and support a good quality of life [11]. Many transfusion dependent patients have anaemia and require red cell transfusion which has significant cost implications [12]. Alloimmunization is a major risk in multiply transfused patients and often complicated red cell transfusion in these patient groups. Multiply transfused patients includes patients with hereditary haemoglobinopathies (thalassaemia, sickle cell anaemia, dyserythropoietic anaemia, congenital spherocytosis, congenital non-spherocytic haemolytic anaemia (G6PD and Pyrukave Kinase deficiency and sideroblastic anaemia), Acquired disorders (bone marrow failure, severe aplastic anaemia (SAA), autoimmune haemolytic anaemia, paroxysmal norcturnal haemoglobinuria), Myelodysplastic syndroms (Chronic Myelo Monocytic Leukaemia (CMML), Refractory Anaemia (RA), Refractory Anaemia with Ringed Sideroblast (RARS), Refractory Anaemia with excess blast in transformation (RAEB-T), Refractory Cytopenias with multilineage and 5 q syndrome). Previous reports on the frequency of alloimmunization in multiply transfused sickle cell and thalassemia in different countries had indicated a 22.06% in Saudi Arabia [13], 76% in the UK [2], 47% in the United States of America [14], 37% in Taiwan [15], 30% in Kuwait [16] and 21.1% in Greece [17]. Frequently detected alloantibodies include anti-K, anti-E and anti-c, anti-M, anti-S and anti-Fya [13, 18- 20].

There are several daunting challenges associated with the management of transfusion dependent patients

particularly in developing countries. Apart from the risk

of development of alloantibodies, other complications

includes risk of immunologic complications, difficulty of getting compatible red cell units, risk of development of

autoantibodies, risk of haemolytic transfusion reaction (immediate or delayed) and risk of haemolytic disease of newborn in transfusion dependent female patients that of child bearing age. These complications poses a significant challenges to the effective management of transfusion dependent patients in sub-Saharan Africa- a continent associated with lack of national blood transfusion services and necessary policies to support an effective blood transfusion service, necessary infrastructure as well as trained biomedical personnel and financial resources are often suboptimal to support the effective running of a blood transfusion service. Most developed countries have guidelines for the universal testing of all patients in whom transfusion is indicated including multiply transfused patients. The aim is to ensure that patients with clinically significant red cell antibodies receive red cells negative for those antigens to which the alloantibody is specific.

Red cell alloantibody screening is of necessity a routine component of pre-transfusion compatibility protocol in most developed countries. However it is sad to note that in most settings in sub Saharan Africa, this has not become a routine practice. This failure in stewardship by government, policy makers and head of health departments in most African Countries needs to be urgently addressed to ensure that patients who require red cell transfusion get the best standard of transfusion- related care like their counterparts in the West. This is possible if Africa leaders are committed to implementing evidenced based best practices in blood transfusion practices in the region. Africa faces several daunting challenges with regards to access to basic health services like their counterparts in most developed countries of the world. The healthcare system and infrastructure are suboptimal. This is often due to fundamental limitations in funding, lack of adequate qualified healthcare professionals and equipment as well as deep- rooted, institutionalized and chronic corruption among the political class and bureaucratic compensation and corruption among civil servants [21]. Africa remains the world's most corrupt continent. Corruption is the abuse of entrusted power for private gain, in public and private sectors [22]. This vice has contributed to a large extent to the stunted development and impoverishment seen in many African states. Corruption is a cankerworm that continues to weaken societies, ruins lives, and impedes development in the African continent. The African union estimates that corruption among the political class is costing the continent more than $150 billion dollars per year. These are funds that could be used to improve the health infrastructure and quality of life of people in the continent, reduce the incidence of maternal and child mortality and provision of pipe borne water and sanitation services but rather are laundered out of developing countries to banks in the developed world thus perpetrating poverty among African people. Industrialized countries have continue to encourage corruption in Africa and perpetuation of poverty among people in the African continent by providing crooked African leaders with a safe haven for their looted funds rather than repatriating such funds back and ensuring that they are used to enhance the infrastructural development of the continent. Corruption is endemic and continues to thrive in the African continent for several reasons; institutional weakness and criminal collaboration between the executive, the legislative and judicial arms of government, non-existence of the principle of rule of law, political god-fatherism,

arms of government, non-existence of the principle of rule of law, political god-fatherism, http://www.ijmshc.com Page 14
arms of government, non-existence of the principle of rule of law, political god-fatherism, http://www.ijmshc.com Page 14

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Medical Sciences and Health Care Vol-1 Issue-8 (Ijmshc 803) institutional failure and criminal collaboration between

institutional failure and criminal collaboration between civil servants and politicians.

Challenge of reliance on family replacement blood donors

The collection of blood only from voluntary, non- remunerated blood donors is the only evidenced-based measure for ensuring the safety, quality, availability and accessibility of blood transfusion. Countries in sub Saharan Africa needs to objectively seek innovative ways to possibly recruit and retain voluntary donors such as; celebration of the gift of blood donation, recognition of voluntary blood donors, increasing public awareness of voluntary non - remunerated blood donation, educating the public on the importance of regular voluntary non- remunerated blood donation, educating the public on the benefits of voluntary non- remunerated blood donation to recipients, promoting healthy living nutrition, exercise and lifestyle and provision of non- cash motivation to encourage people to donate blood. Blood safety remains an issue of major concern in transfusion practice in many settings in SSA. Despite recommendations that all blood donors should be voluntary and non-remunerated, family replacement blood donors continues to predominate rather than regular benevolent, non-remunerated donors who give blood as a result of altruism. Blood donated by voluntary non-remunerated blood donors are considered safer than family replacement donors and, in particular, commercial or professional donors. Establishing a panel of regular, voluntary non-remunerated blood donors remains the most effective way of ensuring adequate supplies of safe blood and on a continuing basis. The African continent faces considerable obstacles to ensuring a safe blood supply and safe blood transfusions. There is a tendency for developing countries not to have enough available blood so thus continue to depend on family blood donors [23]. Family replacement donors are a class of donor who offer to donate blood when a member of their family or community is admitted in hospital in need of a blood transfusion. The disadvantages of this method of blood donation include; it puts patients and their family members under pressure to donate blood. Such donors can sometimes offer to donate blood even when that such donation put them at risk and increases the potential of transmission of transfusion-transmissible infection to their patient [24]. It is extremely difficult the transfusion need of a nation to be met solely relying on these class of blood donors [25]. The World Health Assembly recommended that reliance on replacement donations should be phased out due to their association with an increased risk of transfusion-transmitted infections [26-27]. There is often the challenge of the transfusion needs of the recipient not being met because blood donated by relations may not be of the same blood group as the patients coupled with the fact that relations may not be able to donate the quantity required for the effective management of the patient [28]. When patients are unable to meet the transfusion requirements of their patients, they are often left with no other option than to seek commercially donated high risk blood. Also, blood donated by family members (spouse) of women who are of child bearing age can potentially put partners at risk of being sensitized to produce alloantibodies to clinically significant antigens which the husband may have and which his partner lacks. The developing foetus can sometimes be positive for a red cell antigen to which the

mother has developed alloantibodies. These alloantibodies are often immune antibodies with low molecular weight and can potentially cross the placenta barrier into the foetal circulation and cause the destruction of the foetal red cells resulting in HDN in subsequent pregnancies associated with the same antigen.

Absence

antenatal women

of

universal

alloantibody

testing

among

Red cell immunization during pregnancy remains a major challenge to obstetricians and transfusion practitioners in developing countries five decades after the introduction of Rhesus (Rh) D prophylaxis. It is recommended that all women in most developed countries should have a blood group and antibody screening at first antenatal visit. Alloimmunization in pregnant women has been found to range from 0.4% to 2.7% worldwide [29-31]. It has been reported that 1.5%2% of pregnant women shows atypical blood group sensitization [32]. Most developed countries have guidelines for screening of all pregnant women for atypical antibodies. The British Committee for Standards

in Haematology (BCSH) recommends that all pregnant

women should be ABO and D antigen typed and screened for the presence of red cell antibodies early in pregnancy and at least at the 28 weeks gestation [33]. The Netherland has had a policy for the universal screening for the presence of atypical antibodies in the first trimester of pregnancy since 1998 [34]. Opinion is divided as to the clinical importance of a repeat anti-D

antibody screen at 28 weeks’ gestation. Those in support

of 28 weeks’ testing argue that there is the potential

advantage of being able to identify about 0.18% or fewer

women particularly Rh-negative who become alloimmunized after their first antenatal screen possibly

as a result of potential sensitizing event occurring after

the first antenatal visit [35]. The American Society of Clinical Pathology recommends that testing for unexpected antibody be carried out before antenatal anti-

D is given to Rh-negative pregnant women and that

repeat Rh testing be omitted if two documented test results confirming the Rh-negative status of the woman are on her record [36]. Prior to 1970, HDFN due to anti- D was a significant cause of morbidity and mortality. By 1990, a reduction in mortality from 1.2 per 1000 births to 0.02 per 1000 births had been achieved in response to the introduction of immunoprophylaxis with anti-D

immunoglobulin [37]. At that time the sensitization rate dropped to about 1.2%. A further reduction to between 0.17% and 0.28% was achieved by introducing prophylaxis during the third trimester of pregnancy [38]. The National Institute for Clinical Excellence (NICE) recommends that all D-negative pregnant women who do not have alloantibody-D should be offered anti-D immunoglobulin routinely during the third trimester of pregnancy [39]. Previously anti-D immunoglobulin was only administered antenatally only when sensitizing events occurred that puts the mother at risk of producing alloantibodies. NICE recommendation is that all RhD negative pregnant women be offered anti-D immunoglobulin at 28 and 34 weeks’ gestation. It is worth noting that in Caucasian populations, about 38%

of women are likely to carry an RhD-negative foetus and

thus do not carry a risk of isoimmunisation but yet would have received anti-D prophylaxis unnecessarily. Consequently, NICE also endorsed studies into the feasibility of mass foetal blood group by analysis of

NICE also endorsed studies into the feasibility of mass foetal blood group by analysis of http://www.ijmshc.com
NICE also endorsed studies into the feasibility of mass foetal blood group by analysis of http://www.ijmshc.com

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Medical Sciences and Health Care Vol-1 Issue-8 (Ijmshc 803) foetal DNA in maternal plasma to determine

foetal DNA in maternal plasma to determine pregnancies that involve Rh-negative foetuses to prevent such mothers from receiving prophylactic anti-D which is not indicated. This strategy is also enable obstetricians determine foetuses that are at risk of HDN among the 4% of African women of reproductive age who have developed alloantibody-D [40]. To prevent HDFN in most developed countries, RhD negative women receive prophylactic anti-D between 28 and 34 weeks of gestation, following a potentially sensitizing event during pregnancy and within 72 hours after delivery of a Rhesus positive baby. At delivery, RhD phenotype of the new-born should be determined even if RhD foetal genotype is known. Maternal blood is drawn for quantification of fetomaternal transfusion within 72 hours of delivery of an Rh-positive baby to enable the administration of an optimum amount of anti-D immunoglobulin [41]. Anti-D prophylaxis has significantly reduced the incidence of erythroblastosis foetalis caused by sensitization to the D-antigen. Perinatal deaths from alloimmunization have fallen dramatically by a 100-fold in the developed world [42- 43]. The anti-D immununoglobulin is prepared from the plasma of immunized human donors and therefore exists in limited supply. The principle of action of monoclonal and polyclonal anti-D is based on their ability to clear Rhesus positive foetal red cells from the maternal circulation [44-45]. A previous report [46] observed a clinically significant case of severe Rh (D) alloimmunization can be treated by intensive plasma exchange and high-dose intravenous immunoglobulin. The alloimmunisation rate recorded by De Vrijer and colleagues [47] who studied 2392 women and found alloimmunization prevalence of 2.71%. It is sad to note that despite the implementation of evidenced- based best practice of universal testing of all pregnant women in the West for atypical alloantibodies, such guidelines are not being implemented in many developing countries. This has negative implications on the effective immunohaematological management of pregnant women in developing countries. The attendant effect of this failure in the effective management if pregnant women in developing countries is that the incidence of HDN in these countries are significantly higher than it is in the developed world.

Suboptimal management of clinically significant antibodies in pregnancy that is associated with HDN

HDN (erythroblastosis foetalis) is an alloimmune disease that often results when immune antibodies produced by a mum (resulting from feto- maternal haemorrhage or previous incompatible blood transfusion) passes through the placenta barrier and destroy foetal red cells resulting in jaundice, reticulocytosis and anaemia. The resulting anaemia may be severe enough to result in hydrops foetalis (heart failure). The bilirubin level may be highly elevated and can cross the blood brain barrier and result in chronic kernicterus (brain damage). The 3 most clinically significant alloantibodies that causes haemolytic disease of the newborn include the ABO, Rhesus (D, E c, e, C) and the Kell (K1-K4) antibodies. ABO- HDN can often range from mild to severe with a significant number being mild. Other blood group antibodies that can potentially cause HDN includes; Kidd (anti-Jka and anti Jkb), Duffy (anti-Fya), MNS, s, Lewis and P). The P and Lewis blood group antibodies are seldom associated with HDN. To reduce the incidence of HDN resulting from these antibodies

particularly anti-Kell, most developed countries transfuse all women of child bearing age (< 50 years) who require a red cell transfusion with ABO, RhD compatible Kell negative red cells units. This to a large extent will prevent these women from developing immune anti-K.

Absence of universal access to Routine Antenatal

Anti-D

Prophylaxis

(RAADP)

in Rhesus

negative

women

The human red blood cell (RBC) membrane is complex and contains a variety of blood group antigens, the most clinically significant being the ABO system followed by the Rh system. The Rh system consists of two related proteins, RhD and RhCE, which express the D and CE antigens, respectively. People who have the D antigen on their RBCs are said to be RhD-positive, whereas those who do not are said to be RhD-negative. If the mother is RhD-negative and the foetus is RhD-positive, the mother may react to foetal blood cells that enter her circulation by developing anti-D antibodies, a process known as RhD sensitization. Sensitization is unlikely to affect the first pregnancy but may result in HDN during the second and subsequent RhD-positive pregnancies. In its mildest form the infant has sensitized RBCs, which are detectable only in laboratory tests; however, HDN may result in jaundice, anaemia, developmental problems, or intrauterine death [48]. The frequency of RhD-negative phenotype has been determined in previous studies in sub Saharan Africa; Nigeria 4.44% [49]; Kenya 3.9% [50] Guinea 4.06% [51] and Cameroon 2.4% [52]. These findings are much lower than the 14% prevalence of Rh-negative phenotype observed in studies among Caucasians [53]. In most sub-Saharan African countries, there are several challenges associated with Rh pregnancies [54]. A previous report on the utilization rate of anti-Rh antiserum in South African population groups for the years 19831985 indicated the effectiveness of anti-D prophylaxis in the prevention of HDN [55]. The crude utilization rate of anti-Rh antiserum was 41%44% for all population groups combined. The rate for Blacks, Whites, Indians, and Coloreds was 14%20%, 89%94%, 59%64%, and 45%51%, respectively. The potential risk of Rhesus alloimmunization and the ensuing risk of foetal death with increasing parity were investigated in two groups of parturients: primiparous and grand multiparous Mozambican parturients. The difference did not reach statistical significance [56]. A previous report from Zimbabwe indicated that anti-D immunoglobulin remains the most important alloantibody causing HDN, regardless of the availability of anti-D immunoglobulin for prophylaxis and suggests that all patients at booking should have an antibody screen [22]. A report from Nigeria has shown that isoimmunization due to Rh incompatibility is poorly studied among Nigerian women and indicates the urgent need for a management protocol for anti-D immunoglobulin for prophylaxis [57]. Care management with anti-D prophylaxis in patients presenting with severe alloimmunization is difficult to access in Sub-Saharan Africa [58]. Beyond the challenge of access to anti-D prophylaxis, there is lack of a policy on alloimmunization prevention policy during illegal abortions and poor documentation of important information in patients’ medical notes. These factors are highly responsible for the difficulty observed in the management of Rh-negative pregnancies particularly in developing countries [59]. A cross-

management of Rh-negative pregnancies particularly in developing countries [59]. A cross- http://www.ijmshc.com Page 16
management of Rh-negative pregnancies particularly in developing countries [59]. A cross- http://www.ijmshc.com Page 16

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Medical Sciences and Health Care Vol-1 Issue-8 (Ijmshc 803) sectional retrospective study to determine the prevalence

sectional retrospective study to determine the prevalence of fetomaternal haemorrhage among Kenya women indicated a 32.2% prevalence among antenatal patients [60]. To prevent HDN in most developed countries, RhD negative women are given anti-D immununoglobulin (IgG) after delivery and often also between 28 and 34 weeks of gestation. At delivery, RhD phenotype of the

newborn is determined even if RhD foetal genotype is known. Maternal blood is often tested and quantified for the presence of foetal red cell within 72 hours of delivery of a Rh-positive baby to enable the administration of an optimum amount of anti-D immunoglobulin [61]. Anti-D prophylaxis has significantly reduced the incidence of erythroblastosis foetalis caused by sensitization to the D- antigen and perinatal deaths from alloimmunization have fallen 100-fold in the developed world [62]. The anti-D immununoglobulin is prepared from the plasma of immunized human donors and therefore exists in limited supply. Monoclonal anti-D antibodies have been developed to replace polyclonal anti-D and in vivo assays for these have been predominantly based on their ability to clear erythrocytes from the maternal circulation [63]. Although the implementation of a program of routine antenatal anti-D prophylaxis (RAADP) has led to

a significant decline in the residual numbers of women

becoming sensitized in most developed countries, a significant number of women are not fortunate enough to have access in sub-Saharan Africa and thus continue to be affected. This is an ethical issue of utmost public health importance. It is recommended that all women in most developed countries should have a blood group and antibody screening at first antenatal visit. It has been reported that 1.5%2% of pregnant women shows atypical blood group sensitization [64]. Opinion is divided as to the clinical importance of a repeat anti-D antibody screen at 28 weeks’ gestation. Those in support of 28 weeks’ testing argue that there is the potential advantage to identify about 0.18% or fewer women particularly Rh-negative who become alloimmunized after their first antenatal screen possibly as a result of potential sensitizing event occurring after the first

antenatal visit [65]. The American Society of Clinical Pathology recommends that testing for unexpected

antibody be carried out before antenatal anti-D is given to Rh-negative pregnant women and that repeat Rh testing be omitted if two documented test results confirming the Rh-negative status of the woman are on her record [66]. Prior to 1970, HDFN due to anti-D was

a significant cause of morbidity and mortality. By 1990,

a reduction in mortality from 1.2 per 1000 births to 0.02

per 1000 births had been achieved in response to the introduction of immunoprophylaxis with anti-D immunoglobulin [67]. At that time the sensitization rate dropped to about 1.2%. A further reduction to between 0.17% and 0.28% was achieved by introducing prophylaxis during the third trimester of pregnancy [68]. These findings was a justification for the National Institute for Clinical Excellence (NICE) to recommend

that all D-negative pregnant women who do not have immune anti-D be offered anti-D immunoglobulin routinely during the third trimester of pregnancy. In 2002 the NICE (National Institute for Clinical Excellence) in the United Kingdom assessed the cost effectiveness of routine antenatal anti-RhD prophylaxis with anti-D immunoglobulin [69]. Previously anti-D immunoglobulin had been administered antenatally only when sensitizing events occurred that would be associated with a feto-maternal haemorrhage. NICE recommended that all RhD negative pregnant women

should be offered anti-D immunoglobulin at 28 and 34 weeks’ gestation. In a predominantly White population, however, about 38% of these women are likely to be carrying an RhD-negative foetus and would receive the treatment unnecessarily. Consequently, NICE also endorsed studies into the feasibility of mass foetal blood group by analysis of foetal DNA in maternal plasma. The benefits of this testing would be twofold. Firstly, there would be a substantial reduction in the use of anti- RhD immunoglobulin, an expensive blood product in short supply. Secondly, women with an RhD-negative foetus would be spared unnecessary exposure to this pooled human blood product with its associated discomfort and possible risk of viral contamination [70].

Suboptimal management of Feto-Maternal Haemorrhages (FMH) in Rhesus negative pregnant women. Transplacental or fetomaternal haemorrhage (FMH) may occur during following a potentially sensitizing events during pregnancy or at delivery and lead to immunization to the D antigen if the mother is Rh- negative and the baby is Rh-positive. This can result in HDN in subsequent D-positive pregnancies. In most Sub-Saharan African countries, there is poor and sometimes no alloimmunization prevention following potentially sensitizing events and during medical termination of pregnancy in Rh-negative women. Information about previous pregnancies and termination are often lacking in patients’ medical notes due to poor data management. These issues have made the management of Rh-negative pregnancy a huge challenge. Despite the fact that the prevalence of Rh- negative phenotype is significantly lower among Africans than Caucasians, Rh alloimmunization remains a major factor responsible for perinatal morbidity in sub- Saharan Africa and may compromise obstetric care offered to pregnant Rh-negative African women due to the unaffordability of anti-D immunoglobulin. There is the urgent need for the implementation of universal access to anti-D immunoglobulin for the Rh- negative pregnant population in Africa. Anti-D immunoglobulin should be available in cases of potentially sensitizing events such as amniocentesis, cordocentesis, antepartum haemorrhage, vaginal bleeding during pregnancy, external cephalic version, abdominal trauma, intrauterine death and stillbirth, in utero therapeutic interventions, miscarriage, and therapeutic termination of pregnancy.

Testing for FMH

The KB test is a diagnostic test that is used to determine the amount of foetal red cells that has entered the maternal circulation [71]. It is rotinely performed on all Rh-negative mothers particularly in developed countries to identify women with a large fetomaternal haemorrhage (4 mL of packed foetal RBCs) who are at risk of being sensitized to produce alloantibody-D. Such women may need additional anti-D immunoglobulin to ensure complete clearance of all foetal RBCs from maternal circulation and thus prevent them from being sensitized to produce alloantibody-D against D- antigen on the surface of the foetal RBCs. A standard dose of 125 IU is the required dose of prophylactic anti-D immunoglobulin required to inhibit 1 mL bleed of foetal RBCs and thus prevent the formation of Rh- antibodies in the mother and prevent HDN in subsequent Rh- positive children. This test is based on the ability of red

prevent HDN in subsequent Rh- positive children. This test is based on the ability of red
prevent HDN in subsequent Rh- positive children. This test is based on the ability of red

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Medical Sciences and Health Care Vol-1 Issue-8 (Ijmshc 803) cells containing foetal haemoglobin to resist acid

cells containing foetal haemoglobin to resist acid elution. The test involves preparing a blood film from the mother’s EDTA anticoagulated blood and exposing to an acid bath. This removes adult haemoglobin, but not foetal haemoglobin, from the RBCs. Subsequent staining with eosin stains foetal cells (containing foetal haemoglobin) pink while adult RBCs are eluted and do

not take up the eosin stain thus appearing as ‘ghosts’. For effective counting, it is recommended that about 5000 cells are counted under the microscope and that a ratio of foetal to maternal cells is generated. Patients with a positive tests, should have the FMH quantified and the optimum amount of anti-D administered. A follow-up testing should be carried out as a postpartum check to ensure the complete eradication of foetal red cells from maternal circulation and to rule out the possibility of a false positive. False positive reaction can occur if there is persistent elevation of foetal haemoglobin in the mum. Patients with hereditary persistence of foetal haemoglobin (HPFH) can often present with a false positive reaction. There is evidence which indicates that results from KB test is inexpensive buy yet comparable to results from other more expensive and technologically advanced methods such as flow cytometry. Performance indicators for the KB test during antepartum period in most developed countries include; unexpected/unexplained still birth, significant maternal abdominal trauma, post 20 weeks’ gestation vaginal bleed, post 20 weeks’ therapeutic termination of pregnancy, miscarriage, in utero therapeutic interventions, external cephalic version, and antepartum haemorrhage [72]. Testing at the time of birth and postpartum is indicated if baby is Rh-positive. A cord sample is collected from all babies born of Rh-negative mothers. Where the cord sample is Rh (D)-positive, a KB or flow cytometric determination of FMH is carried out and anti-D immunoglobulin optimal to clear the volume of FMH is administered preferably within 72 hours of delivery [73]. If recurrent uterine bleeding occurs in a D-negative woman after 20 weeks’ gestation, anti-D immunoglobulin will be required at a minimum

of 6-weekly intervals. A FMH test should be performed

every 2 weeks and if FMH is detected, additional anti-D

will be required [74]. The KB technique, based on acid elution of maternal RBCs, is the most widely used technique in the developed world for estimating the volume of FMH and for determining the need for additional doses of anti-D immunoglobulin to prevent

maternal alloimmunization [75]. False positive results is often associated with the persistence of foetal haemoglobin in maternal blood, in certain haemoglobinopathies such as sickle cell trait. The KB test has been used worldwide since the 1950s to quantify the FMH and to ensure that an appropriate dose of anti-

D immunoglobulin is administered both antenatally and

postnatally to RhD-negative women to prevent Rh alloimmunization. Although apparently a simple and an inexpensive test to perform, recent reports suggest that

unless meticulous attention is paid to both technique and interpretation, the accuracy of the test cannot be guaranteed and that it should be replaced with a flow cytometric test which would give more relevant and accurate results [76]. Flow cytometers are expensive and often times are unavailable in laboratories performing estimations of FMH particularly in developing countries.

A previous report compared the results of 957 patients

obtained from standardized KB technique with flow cytometry. Results suggest that if careful attention is paid to performing a standardized KB test, then it is of

value in estimating the size of FMH, and that flow cytometry may offer additional value for cases in which the Kleihauer result is equivocal or indicates that a large FMH has occurred which requires the administration of additional anti-D immunoglobulin [77]. Similarly Johnson and colleagues [78] evaluated an indirect immunofluorescence flow cytometry technique in a series of patients with large FMH. Patient samples identified by KB testing as having FMH of > 4 mL were sent for flow cytometric analysis. The report indicated that flow cytometry is helpful for the accurate quantification and management of patients with large FMH, in patients where the presence of maternal haemoglobin F-containing cells renders the KB technique inaccurate and produces a reduction in the use of anti-D.

Absence of alloantibody testing of all patients in whom red cell transfusion is indicated

Patients with a clinically significant alloantibody are asymptomatic. The alloantibody is discovered at the time of pre-transfusion testing. It is compulsory in the developed world to carry out ABO, Rh group and indirect antihuman Globulin (IAT) alloantibody screening on all patients in whom transfusion of red cells is indicated. All patients found positive should have their plasma tested against a panel of cell of known antigen status to identify the alloantibody present. Antibody identification is carried out on serum employing commercial two-cell panel (APAN and EPAN).However when test with the two-cell panel using standardized blood bank methods is inconclusive, a third cell panel (B Panel) may be used to facilitate the identification. Alloimmunization significantly concerns the Rhesus, Kell, Duffy and Kidd system which are clinically significant. They can cause haemolytic transfusion reactions and limit the ability of safer transfusion. Factors responsible for immunization are complex and involve at least three main contributing elements; RBC antigenic difference between the blood donor and the recipient, the recipient's immune status and the immunomodulatory effect of the allogenic blood transfusions on the recipient's immune system. There is relatively high risk of alloimmunization in transfusion- dependent patients. Red cell alloimmunization should not be overlooked in transfusion-dependent and multi- transfused patients. Alloimmunization must always be considered in certain patients; those who repeatedly suffer from haemolytic transfusion reaction and those who are not able to maintain haemoglobin at a desired level despite having regular transfusions. Regular screening for red cell alloantibodies is associated with better management of these patients. Antibody identification can also be used as a follow-up test to a positive indirect antiglobulin test (IAT). The IAT is typically performed on all patients that require red cell transfusion and during each pregnancy to determine whether the patient and mother have developed any red blood cell (RBC) antibodies as part of a "Group and Screen" or "Group and Crossmatch request." The antibody identification test involves the reaction of patient plasma against a panel cell of known antigenic status. Antigen and antibody reaction are specific. If there are antigens on the panel cells and the patient serum contain the group specific antibody, antigen- antibody reaction results with an observable agglutination reaction. The clinical significance of a detected alloantibody depends on two factors; ability to

The clinical significance of a detected alloantibody depends on two factors; ability to http://www.ijmshc.com Page 18
The clinical significance of a detected alloantibody depends on two factors; ability to http://www.ijmshc.com Page 18

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Medical Sciences and Health Care Vol-1 Issue-8 (Ijmshc 803) cause a transfusion reaction and ability to

cause a transfusion reaction and ability to cause haemolytic disease of the foetus newborn (HDFN). Some RBC antibodies are known to cause moderate to severe reactions while other less significant ones may cause a positive IAT but few or no symptoms or complications in the blood transfusion recipient or pregnant woman. If one or more clinically significant RBC antibodies are identified, it becomes imperative that donor blood that lacks the corresponding RBC antigens must be used for transfusion. Patients diagnosed with a disease condition that requires recurrent transfusions, stands the risk of exposure to many foreign RBC antigens and are potentially more at risk of developing multiple RBC alloantibodies over time thus making the process of finding compatible blood increasingly challenging. Alloimmunisation to the D and K (Kell) antigens is prevented by the provision of Rh (D) negative and Kell negative blood for Rh (D) negative, Kell negative patients. This is particularly important for females with child-bearing potential as these antibodies can cause severe haemolytic disease of the newborn during pregnancy. Patients with sickle cell disease or other major haemoglobinopathy syndromes (thalassaemia) and haematological oncology patients who are chronically transfused are at greatest risk of alloantibody formation. Prior to commencing transfusion, patients with these conditions should have extended red cell phenotyping performed to enable the selection of blood that matches the patient's Rhesus and Kell antigens. The development of red blood cell (RBC) isoimmunisation with alloantibodies and autoantibodies complicate transfusion therapy particularly in multiply transfused patients. Alloimmunization to red cell antigens is still a current problem in many settings in sub Saharan Africa for several reasons; alloantibody testing for antenatal women and patients who require red cell transfusion is often lacking, alloantibody testing of transfusion recipients to ensure that they receive red cells negative to alloantibody they may have developed is often lacking in most settings, there is absence of universal access to prophylactic immunoglobulin D for the prevention of Rh isoimmunisation in Rh negative women, absence of cost effective means of estimating Feto Maternal Haemorrhage (FMH) in Rhesus negative mothers delivered of Rhesus positive babies and following any potentially sensitizing events during pregnancy.

Conclusion

It is obvious that the additional testing of blood donors for clinically significant red cell antigens as well as alloantibody screening of all recipients for which red cell transfusion is indicated should be implemented as a routine in all sub Saharan African countries to prevent as far as possible the incidence of alloimmunization. It would also be cost-effective, bearing in mind the fact that there are laborious and expensive laboratory testing necessary to provide compatible blood for alloimmunized patients. Transfusion-dependent patients are individuals who require regular red cell transfusion and on long-term basis to manage anaemia, sustain life and support a good quality of life. In the developed world, it is vital to carry out alloantibody screening on such patients to determine if they have produced any clinically significant antibody to enable the determination of the specificity of the alloantibody to facilitate the selection of antigen negative red cells for such patient. This evidenced-based best practice is

important to prevent blood transfusion reaction and to ensure that transfusion produces the desired increment in the haemoglobin of the patient as well as ensure that transfused red cells survive optimally in the patient. Developing countries particularly sub Saharan African countries will need to urgently implement this evidenced based best practice.

The collection of blood only from voluntary, non- remunerated blood donors is an important measure for ensuring the safety, quality, availability and accessibility of blood transfusion. Family replacement donation should be discouraged in developing countries. Blood donated by spouses and relatives of women of child bearing age can put recipients potentially at risk of producing immune antibodies to clinically significant antigen that the husband and relatives have but which the wife or partner lacks. The developing foetus can also inherit an antigen to which the mother has developed alloantibodies. These alloantibodies can potentially cross the placenta barrier and destroy the foetal red cells resulting in HDN in subsequent pregnancies.

Red cell immunization during pregnancy remains a major challenge to obstetricians and transfusion practitioners in developing countries. It is best practice to screen all antenatal women for alloantibodies in early pregnancy. This is to enable remedial action to be taken if the women if found positive for a clinically significant antibody that has the potential to cause HDFN. The antibody titre will need to be monitored through the pregnancy in such patients. It may be worthwhile to determine if the woman’s spouse is positive for the antigen to which the alloantibody is specific. Foetal genotype may need to be carried out to determine if the developing foetus is indeed carrying the antigen to which the maternal antibody is specific. Amniocentesis may also be carried out particularly with a rising antibody titre in the mother to determine the potential risk to the developing foetus. In severe cases intrauterine transfusion may be indicated to manage the resulting anaemia and hyperbilirubinaemia in the developing foetus. All these evidenced- based practices will need to be urgently implemented in developing countries as a way of optimising the immuno-haematological services delivered to pregnant women in developing countries.

There is also the need for the availability of FMH measurements following potentially sensitizing events in Rh negative pregnant women. The low cost acid elution method, a modification of the KleihauerBetke (KB) test, can become a readily available, affordable and minimum alternative to flow cytometric measurement of FMH particularly in low income countries. Knowledge of anti-D prophylaxis among obstetricians, biomedical scientist, midwives, traditional birth attendants, pharmacists, and nurses in Africa needs to be improved. This will facilitate quality antenatal and postnatal care offered to Rh-negative pregnant population and improve perinatal outcomes.

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