Usage of blood components in obstetric practice

INTRODUCTION

Transfusion of red cells and various components of blood has substantially reduced the maternal mortality and morbidity across the globe. Hemorrhage is now responsible for substantial proportion of maternal mortality and morbidity across the world being responsible for 27% of 78,000 deaths during childbirth across the world annually.^[1] In fact, there is a trend of increase in blood product transfusion in obstetric care even in developed countries.^[2] Present review focuses on main indications of transfusion in obstetric practice and challenges to meet them in developing countries.

MATERIAL AND METHODS

The present review was built on PubMed search between 2000 and 2018 with key words like “pregnancy,” “anemia in pregnancy,” “obstetric practice,” “obstetric complications,” “hemoglobinopathies in pregnancy,” “blood transfusion,” “red cell transfusion,” “component therapy,” complications of transfusion in pregnancy,” “disseminated intravascular coagulation (DIC),” “amniotic fluid embolism,” antepartum hemorrhage,” and “postpartum hemorrhage,” transfusion medicine. We mainly focused and reviewed these topics and also relevant guidelines published by learned obstetric societies across the globe. Case reports were excluded, though few case series were considered that studied the complications of transfusion in obstetric practice. A total of 3573 published articles were available in the PubMed; 3375 were excluded on the basis of title of the paper. Out of the remaining 198 papers, 157 were excluded due to duplication of data and similar findings compared to more recent papers (all read by both the authors). Thus, 44 papers were finally selected and used in this review. In addition, a national database, that is, IndMed (National Databases of Indian Medical Journals) and recent review articles were also evaluated for the review. Reviews were classified into groups of papers such as – (I) Anemia in obstetrics, (II) Hemoglobinopathies in obstetrics practice, (III) Hemorrhage in obstetrics, (IV) Situation requiring massive transfusion (Massive Transfusion Protocol), and (V) Other hematological and non-hematological disorders not necessarily related to obstetrics but required transfusion therapy as demanded by the patient condition. [Tables 1- 9] summarize the various indications, available blood products, classification, guidelines, scores, etc., for transfusion therapy in obstetric practice.

ANEMIA IN OBSTETRIC PRACTICE

Anemia is not uncommon in pregnancy. According to National Family Health Survey–IV (2015–16), the prevalence of anemia among women in the reproductive age was 53.1%; being 5^th highest globally; 63–70% of pregnant ladies are anemic,^[3,4] The prevalence in India is much higher than the global scenario as per the World Health Organization fact sheet (37% of pregnant women and 30% of women 15– 49 years of age are affected by anemia)^[5,6] Good antenatal care starting with the diagnosis of pregnancy is the best way to control anemia in pregnancy. In normal pregnancy, though red cell production increases by 30%, still there is hemodilution due to the fact that in addition plasma volume also increases by 50%, leading to hemodilution in the face of increased red cell mass.^[7] Hence, the cutoff value of hemoglobin under which a pregnant lady in considered to have anemia is 110 g/L and severe anemia, that is, <70– 80 g/L of hemoglobin. Severe anemia affects a small number of normal pregnancies in developed countries, but, in developing countries, this number is substantial. A patient with severe anemia and pregnancy is predisposed to many pregnancy related complications including peripartum hemorrhage. Hence, whatever may be the cause (from iron/Vitamin B12/folate deficiency, traits/carriers of some common hemoglobinopathy such as – sickle cell, hemoglobin E (HbE) or beta-thal trait, symptomatic hemoglobinopathies, antepartum blood loss, and other hematological disorders) of severe to moderate anemia in pregnancy, it needs correction as soon as possible and definitely before the patient goes to labor. During labor, even a small amount of blood loss (which is unavoidable) may precipitate cardiac failure, hypoxia, and various other complications leading to shock and death if the patient has severe anemia from the antenatal period itself.

HEMOGLOBINOPATHIES

There is a large increase in maternal mortality in sickle cell anemia (SCA) varying from 0.07% to 9.2%.^[8] Asymptomatic carrier status of beta thalassemia and carrier state of sickle cell disease is very common in many parts of the world. Although majority of these carriers have normal or slightly lower hemoglobin with progress of pregnancy, their hemoglobin level may drop, significantly more so with thalassemia-intermedia (NTDT), HbE thalassemia, SCA, and various combinations of sickle cell gene along with other hemoglobinopathies. Usually, these conditions (except severe iron loaded transfusion-dependent thalassemias) do not interfere with fertility and pregnancy (Except severe iron loaded transfusion dependent states) and these patients very quickly drop in Hb with progress of pregnancy. They will need red cell transfusion as and when required to keep their hemoglobin >100 g/L. Patient who has sickle cell disease or double heterozygous state of sickle cell gene may need close follow-up during pregnancy. Their red cell transfusion should be carefully calibrated to use Hb level between 80 and 100 g/L; as Hb >100 g/L may precipitate sickling events. Some of these patients may need red cell exchange.^[9] Detailed accounts of transfusion management in SCA^[8,10-12] and in other hemoglobinopathies^[9,13] during pregnancy are available elsewhere and beyond the scope of discussion here. Patients of sickle cell disease who due to previous complications (e.g., stroke) require regular exchange transfusion need to continue the same during pregnancy. Normally, if cesarean section is required in these patients, a regional anesthesia is preferred as general anesthesia can predispose to additional complications of sickling crisis if hemoglobin S (HbS) levels are very high.

Conventionally, during delivery or surgery, HbS level in SCA patients was lowered to ≤40% by exchange transfusion, as this is the level usually found in carriers of sickle cell gene (sickle cell trait) who normally has uneventful pregnancy, delivery, and postpartum recovery. However, this contention is now debatable and with improvement of antenatal care and care at various stages of delivery, red cell exchange program may not be needed. One of the major challenges of red cell transfusion in multi-transfused beta thalassemia or SCA during pregnancy is prior alloantibody formation due to isoimmunization against one or multiple red cell antigens. In countries where alpha-thalassemia in cis mutation (both alpha 1 and alpha 2 genes in cis are involved in carriers) is common in the general population, hydrops fetalis is not uncommon. These cases of non-immune hydrops will need close monitoring like isoimmune hydrops and needs to be differentiated from the immune form of hydrops by serological and other tests. These patients may develop the problem very early in pregnancy and will need intrauterine exchange transfusion^[14] which needs to be irradiated for prevention of transfusion-associated graft versus host disease. Although most of the non-immune hydrops have very bad prognosis, survival is possible with Hb Barts hydrops if early diagnosis and regular intrauterine transfusion therapy with irradiated packed red cells is initiated.

Although prevalence of pregnancy in even well-chelated multitransfused beta-thalassemia major patients is rare, alloantibodies in these patients could be a challenge in providing properly cross matched blood for such patients. The situation in cases of pregnancy with SCA is very different as the prevalence of significant alloantibodies in such patients could be very high, even it may go up to 12–50% of such transfused patients.^[15,16] Hence, these patients needs to be screened and red cells should be fully phenotyped so that matched red cell concentrates can be made available when they are needed in an emergency.

HEMORRHAGE

Hemorrhage in obstetrics is an important cause of maternal mortality across the world.^[17-19] It is the major cause of maternal mortality in developing countries. To reduce this cause of maternal mortality, Government of India has developed a concept of blood storage centers in remote areas of the country where blood is made readily available for transfusion in small hospitals where quick saline spin ABO and Rh grouping is done and blood is given.^[20] The definition of postpartum hemorrhage (PPH) and the important causes of it are shown in [Tables 3 and 4], respectively. PPH requiring red cell transfusion is defined differently by different national and international bodies [Table 5], but any blood loss above 700 mL or continuous blood loss or symptomatic blood loss requires attention. Hb of <8 g/dL has been agreed on by most of the expert bodies as the transfusion threshold for these complications. Hemorrhagic shock has been classified in trauma or other situations into four categories for quick clinical identification and management [Table 6]. Of the four categories, Class III and Cass IV definitely need transfusion support so also a large proposition of patients in Class II.

As hemorrhage in antepartum or peripartum state may have several causes, commoner among them being antepartum hemorrhage (namely, placenta previa Grades III and IV), accidental hemorrhage, amniotic fluid embolism and uterine atony, trauma, retained placenta, DIC, etc. Management of all these conditions requires a specific approach to address the cause along with transfusion support to maintain adequate tissue oxygenation, blood coagulation, and to some extent volume replacement along with crystalloids. Various specialist bodies have addressed their therapeutic approach for bleeding in obstetric practice [Table 5].^[21]

In any obstetric hemorrhage, transfusion of specific/required blood products should be initiated early rather than initiate red cell transfusion when it is too late. Specific challenges of getting proper blood products in adequate amount require screening for ABO and Rh blood groups and atypical antibody screening in the antenatal stage. Quick ABO and RhD matching in emergency in the absence of alloantibodies and in dire emergency with unknown ABO status of the mother, RhD negative “O” blood could be released without any delay. Patients having alloantibodies should be specially cared for with proper blood units and stand by donors for possible emergencies.

When blood loss is substantial, that is, loss of more than 200 mL/kg/h or loss of 50% of the blood volume in 4 h and/or patient need replacement of whole blood volume in 24 h, massive transfusion protocol needs to be implemented either with 3: 2: 1 (RBC: FFP: Platelet) or 2: 1: 1 or 1: 1: 1 or similar such protocol keeping an eye on fluid overload.^[21,22] In obstetric hemorrhage, there is uncertainty of it as regards the amount and speed with which blood may be lost in a given condition so the management team should be ready with massive transfusion protocol [Table 2] if the situation on ground so demands.^[22-24] Hemorrhagic shock has been classified [Table 6] depending on amount of blood loss and symptoms that it produces; obviously prior anemia compounds this problem.^[25]

If the patient is undergoing cesarean section, then the obstetrician has the additional advantage of tackling the problems, that is, uterine stitches, artery ligation, hysterectomy, etc., can be easily undertaken where applicable. In addition in a well set up facility and under certain circumstances, intraoperative red cell salvage technique may be applied when the blood from the operative field may be collected, washed, and transfused through manual macroaggregate blood filter in a transfusion set, etc. There are various indications where autologous blood through red cell salvage can be used in the operation room [Table 7].

However, having a point of care instrument to assess the global coagulation parameter such as thromboelastography^[26] or similar such machine is helpful and can rationally direct blood product management [Table 8] and also can suggest at what point rationally tranexamic acid or similar fibrinolytic inhibitor therapy may be given. Blood substitute, that is, artificial O₂ carrier or bioengineered Hb molecules is still some distance away from routine use and is unlikely to be used in obstetric practice unless its safety and efficacy has been unequivocally demonstrated in trauma and other cases. However, when available they can be used along with intraoperative blood salvage to prevent exposure of allergenic/immunogenic blood products with their associated side effects.

Hypofibrinogenemia is an important cause of PPH.^[27] This has to be attended early during the course using fibrinogen concentrate or cryoprecipitate. During pregnancy, normal fibrinogen levels are very high (4–6 g/L). Hence, fibrinogen levels of 2 g/L or less should be considered as hypofibrinogenemia threshold in need of replacement therapy.^[27] Management of coagulopathy associated with PPH has been well described in International Society of Thrombosis and Hemostasis guidelines.^[23]

DIC

Some of the severe causes of peripartum hemorrhage (i.e., accidental hemorrhage) can develop into DIC as also patients with intrauterine fetal death, sepsis, malaria, amniotic fluid embolism, etc. The management of DIC involves management of the primary cause and then replacement of critically altered blood products.^[21-24] to correct hemoglobin and deranged coagulation system. Platelets are to be infused cautiously in this situation only if platelet count is below 30 × 10⁹/L and the patient is bleeding. Prothrombin time should be kept at <1.5 times of mean reference range and fibrinogen level should be replaced when below 2 g/L by cryoprecipitate or fibrinogen concentrate. International Society of Thrombosis and Hemostasis (ISTH) developed a DIC score for diagnosis and follow-up of DIC cases.^[28,29] ISTH-DIC score and its parameters need some modification for pregnancy as fibrinogen level in normal pregnancy is very high and a fall below 2 g/L is indicative of low fibrinogen level, similarly, D-dimer level lose most of it diagnostic value in pregnancy unless serial measurements are available to compare and gestational thrombocytopenia being common, the impact of platelet count is also minimized. Considering all these factors a modified DIC score applicable during pregnancy has been proposed.^[29] Both the ISTH-DIC score^[28] and pregnancy modified score^[29] are presented here as a composite chart in [Table 9]. Good assessment of peripheral smear for fragmented RBC along with thrombocytopenia will help in diagnosis of microangiopathic hemolysis in this condition.

CONGENITAL BLEEDING DISORDERS

In the event of congenital bleeding disorders of the mother associated with pregnancy, concentrates for deficient coagulation factor should be used whenever they are available in adequate quantity and frequency under the care of a trained hematologist.^[30,31] For hereditary platelet defects, platelet concentrates needs to be transfused even if the platelet counts are high and the patient is bleeding. Not infrequently these patients have antiplatelet antibodies making platelet transfusion relatively ineffective; hence, in those cases, larger amounts of cross-matched platelets in continuous infusion or recombinant activated factor VII (rFVIIa) needs to be used. rFVIIa has increasingly been used to treat hemorrhages due to congenital platelet defected or when PPH has not slopped in spite of replacing the coagulation factors and platelets in adequate amount.^[31]

THROMBOTIC THROMBOCYTOPENIC PURPURA (TTP) AND OTHER MICROANGIOPATHIES

Although rare, TTP in pregnancy is a serious complication and often comes in differential diagnosis of hemolysis, elevated liver enzymes, and low platelets (HELLP) syndrome, severe pre-eclampsia, atypical hemolytic uremic syndrome, or other rare causes associated with microangiopathic hemolytic anemia. The condition in acquired state is caused by development of autoantibody to ADAMTS-13 metalloproteinase that is involved in cleaving ultra-high molecular weight von Willebrand factor.^[32] Treatment for this complication is regular plasmapheresis and replacement with cryo deficient plasma. More often the thrombotic microangiopathy is due to HELLP syndrome where delivery of the baby is curative; supportive measures including blood transfusion may be required in all of them.

Similarly, severe Plasmodium falciparum infected patients with pregnancy may need erythrocytapheresis with replacement of packed red cell coupled with antimalarial therapy when high levels of parasitemia affects the patient (>10% parasitemia). Erythrocytapheresis could be life-saving in this condition.^[33]

OTHER COMPLICATIONS AND CHALLENGES OF TRANSFUSION IN OBSTETRIC PRACTICE

Usually, common non-hemolytic transfusion reactions are also common in obstetrics and gynecological practice too. However, reactions have substantially reduced after universal prestorage leucodepletion has become the norm of blood collection. The presence of alloantibody to red cell antigen is more frequent in obstetric practice and most of the time, they are directed against RhD antigen, but other important red cell antigens may also be involved.^[15,34-36] Transfusion management of this condition broadly follows that of RhD isoimmunization.^[35] Sometimes mother may have alloantibodies due to past transfusion, past pregnancies or may have developed autoimmune hemolysis. In that case providing compatible, red cell concentrates may be challenging to the transfusion service. Delayed hemolytic transfusion reaction due to evanescent antibodies (e.g., anti-Jk) could be missed during pretransfusion screening and may cause delayed hemolytic transfusion reaction.

Two other more serious reaction to transfusion which is more likely to occur is transfusion-associated cardiac overload (TACO)^[37] and transfusion-related acute lung injury (TRALI).^[38,39] TACO is most likely to happen during implementation of massive transfusion protocol or during third stage of labor when uterus is contracting and sending a large part of the blood sequestered within to systemic circulation. This could be avoided by judicious control of rate of transfusion and use of diuretics along with careful patient monitoring. TRALI more often happens in obstetric practice because transfusion of blood products particularly whole blood, platelet concentrates, and plasma products containing anti-human leukocyte antigen antibodies or anti-neutrophil antibodies may react with recipient neutrophils or in those places where leucodepletion is not routinely used a reverse mechanism involving residential leukocytes in blood products (neutrophils) may interact with alloantibodies circulating in the blood of pregnant ladies may cause infiltration of these cells in the lung interstitium. TRALI can also occur in the absence of antibodies where lipid peroxides in donor blood components may activate recipient neutrophils. TRALI is a serious complication of blood transfusion and has high mortality.^[38] Incidence of antibody mediated TRALI has been drastically reduced after avoiding plasma/cryo/buffy coat platelets from multiparous donors.^[40]

CHALLENGES FOR THE DEVELOPING COUNTRIES

Major challenges in preventing obstetric hemorrhage, anemia, and its dire consequences on fetal morbidity and mortality in developing countries stems from a combination of factors such as – availability and access of adequate antenatal care, endemic malaria and hemoglobinopathies along with presence of anemia in large number of pregnant women, lack of timely availability of red cells, and other blood products and lack of communication and expertise. In India, these challenges have recently been partly solved by improved road connectivity and ambulance access and ensuring availability of blood at blood storage centers^[20] and antenatal care for the remote areas are being administered through multipurpose health workers.

Several studies have shown two doses of tranexamic acid can reduce maternal deaths due to hemorrhage and may reduce requirement of blood.^[41-44] while there are debates about magnitude of this effect and some complications related to this therapy.^[42,45] However, generally, it was recognized safe, inexpensive, and at least moderately effective in reducing blood loss and should be given.^[41,43] Autologous collection of blood for future transfusion in complicated cases and erythrocyte salvage using simple devices has also been suggested to improve blood availability.^[46,47] Other challenges for transfusion service for obstetric care in developing countries have been described elsewhere.^[47,48] Obstetric practice requires almost all types of blood components in different scenarios and judicious use of these components in adequate amounts^[40] taking cognizance of the complications can save lives and improve maternal mortality rate in a country.