Abstract
Incidence Obstetric blood transfusion represents a small proportion of overall blood use. However, the use of blood products in obstetrics is rising as postpartum haemorrhage rates continue to increase.
There is evidence of increasing rates of maternal red blood cell transfusion during childbirth worldwide, mainly in the context of postpartum haemorrhage [1–4]. In the United States, there was a steep increase in peripartum transfusion (from 0.3% to 1.0%) between 1998 and 2009 [5].
Outside the context of major haemorrhage, there is little evidence for the benefit of blood transfusion in fit, healthy, asymptomatic patients. The decision to transfuse must be based on careful clinical assessment in conjunction with the haemoglobin level [6].
Blood Transfusion
Key Facts
Incidence Obstetric blood transfusion represents a small proportion of overall blood use. However, the use of blood products in obstetrics is rising as postpartum haemorrhage rates continue to increase.
There is evidence of increasing rates of maternal red blood cell transfusion during childbirth worldwide, mainly in the context of postpartum haemorrhage [1–4]. In the United States, there was a steep increase in peripartum transfusion (from 0.3% to 1.0%) between 1998 and 2009 [5].
Outside the context of major haemorrhage, there is little evidence for the benefit of blood transfusion in fit, healthy, asymptomatic patients. The decision to transfuse must be based on careful clinical assessment in conjunction with the haemoglobin level [6].
Risk Factors for Peripartum Haemorrhage
Complications
Since 2005, it has been a legal requirement to report all serious adverse reactions related to the safety or quality of blood (Serious Hazards of Transfusion Annual Report) [8].
Complications of blood transfusion during pregnancy and labour are generally the same as in the non-pregnant population. However, the immune response in pregnancy is different and this may possibly affect the severity of complications. Red cell allo-antibodies are formed as in pregnancy [9].
Transfusion Reactions
Early
Haemolytic Reactions
Haemolysis may be intravascular or extravascular. Extravascular haemolysis is more common and occurs when donor red blood cells coated with immunoglobulin G (IgG) or complement are attacked in the liver or spleen [10]. Intravascular haemolysis can be caused by ABO antibodies following the administration of group-incompatible blood. Symptoms include fever; rigours; nausea; vomiting; dyspnea; hypotension; diffuse bleeding; haemoglobinuria; oliguria; anuria; pain at the infusion site; and chest, back and abdominal pain. Associated complications are acute or exacerbated renal failure, disseminated intravascular coagulation, need for dialysis and death secondary to complications [11].
Non-haemolytic Febrile Reactions
A rise in body temperature of at least 1°C above 37°C within 24 hours of transfusion. Febrile reactions result from the release of antibody-mediated endogenous pyrogens or the release of systemic cytokines [12].
Allergic Reactions to Proteins, IgA
A range of allergic reactions can occur from mild (urticarial reaction) to life threatening anaphylaxis.
Transfusion-Related Acute Lung Injury (TRALI)
TRALI is defined as new, acute lung injury during or within 6 hours of blood product administration in the absence of temporally associated risk factors for acute lung injury.
Activation of the recipient’s immune system by antineutrophil cytoplasmic antibodies or anti-HLA antibodies results in massive pulmonary oedema.
TRALI is clinically characterized by a rapid onset of dyspnoea, tachypnoea, fever, cyanosis and hypotension. Clinical examination reveals hypoxic respiratory distress with evidence of bilateral pulmonary oedema on chest radiograph which is not associated with heart failure (non-cardiogenic pulmonary oedema) [13].
Circulatory Overload
Rapid infusion of large volumes of blood products can result in symptoms of circulatory overload. Signs and symptoms include tachycardia, dyspnoea, hypertension, elevated central venous pressure and elevated pulmonary wedge pressure. Cardiomegaly and pulmonary oedema can sometimes be seen on chest radiography [12].
Hyperkalaemia
The potassium concentration of blood increases during storage, by as much as 5–10 mmol per unit [14]. Large-volume transfusion can result in elevated levels of serum potassium concentration in the transfusion recipient and may require treatment.
Citrate Toxicity
Stored blood is mixed with sodium citrate to prevent it from clotting. During a massive transfusion, the recipient may be administered large amounts of citrate. Citrate is usually metabolised rapidly into bicarbonate unless there is liver dysfunction. However, during a massive transfusion, this metabolic pathway may become overwhelmed and metabolic alkalosis may occur [15].
Hypothermia
Red blood cells are refrigerated at 4°C during storage. Hypothermia may be caused by the rapid transfusion of blood stored. A drop in body temperature can be minimised by administering blood through a warming device.
Clotting Abnormalities (After Massive Transfusion)
A massive transfusion of plasma-reduced red blood cells that contain neither coagulation factors nor platelets may lead to a dilutional coagulopathy and increased risk of bleeding. In addition, haemorrhage can result in disseminated intravascular coagulation, which causes consumption of platelets and coagulation factors [16].
Late
Transmission of Infection
Although UK donor blood is routinely screened for transmissible diseases, transmission is still possible, although incredibly rare. Transmitted infections can be viral (hepatitis A, B, C, HIV, CMV), bacterial (Treponema pallidum, Salmonella), or parasitic (malaria, toxoplasma) [14, 17].
Graft-vs.-Host Disease
This complication is very rare because of the implementation of the universal leucodepletion of blood products before transfusion. Donor-derived immune cells, particularly T lymphocytes, can cause an immune response against host tissue. Clinical features include maculopapular rash (typically affecting the face, palms and soles), abdominal pain, diarrhoea and abnormal liver function tests. Pancytopenia occurs because of the destruction of bone marrow stem cells by donor T lymphocytes [14].
Iron Overload
Some patients may require repeated blood transfusions, such as patients with haemoglobinopathies. Chronic transfusion of blood may result in elevated levels of total body iron and the patient may develop a clinical syndrome such as haemochromatosis.
Immune Sensitization
Red blood cells carry a number of surface antigens including the Rhesus D antigen. Patients who carry the antigen are referred to as Rhesus positive and those without the antigen are referred to as Rhesus negative. Rhesus carrier status is inherited and therefore the Rhesus status of the fetus may differ from that of the mother. If a Rhesus negative mother is carrying a Rhesus positive baby, maternal sensitisation (the formation maternal of anti-Rhesus antibodies) can occur if fetal blood cells enter the maternal circulation. This presents a particular risk for subsequent pregnancies when the maternal immune system mounts an immunological attack on Rhesus antigen positive blood cells that may cross from the fetal circulation into the maternal circulation, but also within the fetal circulation. This can cause severe, in utero fetal anaemia and in severe cases may result in pregnancy loss.
The 2017 Serious Hazards of Transfusion (SHOT) report described pulmonary complications as the leading cause of transfusion-related death in the period of 2010–2017. Two deaths were reported from ABO group incompatible transfusion [8].
Anaphylaxis
Key Facts
Different definitions of anaphylaxis have been proposed by European and North American academic authorities; however, an attempt has been made to streamline these definitions. The American Academy of Allergy, Asthma, and Immunology defines anaphylaxis as often life threatening and almost always an unanticipated reaction. The European Academy of Allergology and Clinical Immunology defines it as a severe, life-threatening, systemic immediate hypersensitivity reaction [18].
The American Academy use the word anaphylactoid for non-IgE-mediated reactions that produce a clinical response similar to anaphylaxis. However, this term has been discouraged by the European Academy [18].
Immediate clinical reactions can be divided into two types. Non-allergic immediate hypersensitivity refers to reactions without an immunologic mechanism (events resulting in sudden mast cell and basophil degranulation in the absence of immunoglobulin); allergic immediate hypersensitivity refers to those reactions in which an immunological mechanism can be proven (usually immunoglobulin [Ig]E-mediated) [18, 19].
Pathophysiology
Immunopathological mechanisms of anaphylaxis can be divided into immunological (IgE-mediated and non–IgE-mediated [e.g., IgG and immune complex complement–mediated]) and non-immunological anaphylaxis (events resulting in sudden mast cell and basophil degranulation in the absence of immunoglobulins) [19]. Immunological mediated reactions require prior exposure to the antigen and the production of antibodies. Non-immunological reactions can occur without prior antigen exposure. T and B cells also play important roles in the development of antibodies. Increasing attention has also focused on the internal compensatory mechanisms activated in response to anaphylaxis [20].
The physiological responses to the release of anaphylaxis mediators include smooth muscle spasm in the respiratory and gastrointestinal (GI) tracts, decreased vascular tone, increased vascular permeability and stimulation of sensory nerve endings [21].
Clinical Presentation
There are different grading systems of severity of anaphylaxis, the most quoted one in the literature was developed by Ring and Messmer in 1977 [22]. It features a scale from 1 to 4, with grade 1 being cutaneous features, a mild fever reaction, or both, through to grade 4 when cardiopulmonary resuscitation is required. Subsequently, most other grading systems have used similar classifications. A Scandinavian guideline added a fifth severity category, which is death (Table 34.1).
| Grade | Severity | Clinical features |
|---|---|---|
| Grade 1 | Not life threatening | Rash erythema and/or swelling |
| Grade 2 | Not life threatening | Unexpected hypotension not severe, not requiring treatment |
| Grade 3 | Life threatening | Unexpected severe hypotension and/or severe bronchospasm and/or swelling with actual or potential airway compromise +/− Grade 1 features |
| Grade 4 | Life threatening | Fulfilling indications for CPR |
| Grade 5 | Fatal |
According to NAP6, minor or moderate reactions (grade 1 and grade 2) are correctly termed ‘hypersensitivity’, and should not be called ‘anaphylaxis’ and only grade 3, 4 and 5 hypersensitivity can correctly be termed anaphylaxis [23].
Anaphylaxis in Pregnancy
Anaphylaxis in pregnancy is potentially a rapidly fatal systemic hypersensitivity reaction, especially when it occurs during the third trimester of pregnancy, because of the additive effects of aortocaval compression on the profound and often refractory hypotension associated with anaphylaxis [19].
It is characterised by life-threatening airway, breathing or circulatory problems, often with skin or mucosal change [24].
The immune status is altered in pregnancy, and it has been suggested that increased progesterone levels during pregnancy may predispose pregnant patients to anaphylaxis [23].
Incidence
There is very little information regarding the incidence of anaphylaxis in pregnancy in the UK.
Eight cases of obstetric anaphylaxis were identified in the 6th National Audit Project of the Royal College of Anaesthetists [23], all of which were grade 3. The NAP6 Activity Survey reported an estimated incidence of severe obstetric perioperative anaphylaxis of 3.4 per 100 000.
The UK Obstetric Surveillance System (UKOSS) conducted a population-based prospective study of anaphylaxis in pregnancy from all obstetrician-led maternity units in the UK over a 3-year period (2012–2015) [24]. The estimated incidence of anaphylaxis was 1.6 per 100 000. Of the 37 cases reported, 19 occurred in association with perioperative care, caesarean section or surgical management of postpartum haemorrhage after vaginal delivery [24].
A further study in the USA suggested an incidence of 2.7 cases per 100 000 deliveries after retrospectively reviewing hospital discharge records over a 2-year period [25]. The Scottish Confidential Audit of Severe Maternal Morbidity identified 18 cases of anaphylactic shock, over the period 2003–2012, giving an incidence of 3 per 100 000 births [26].
Aetiology
Before the immediate peripartum period, the aetiology of anaphylaxis in pregnancy is similar to that of anaphylaxis in the general population. It typically occurs as a result of mast cell activation through an IgE-mediated mechanism. Causative agents include allergens such as foods (shellfish, peanut, tree nuts and others), stinging insect venoms, medications and natural rubber latex [27].
In addition, the aetiology of anaphylaxis in pregnancy includes exposure to allergens such as antibiotics mainly given for surgical or group B Streptococcus (GBS) prophylaxis to prevent neonatal transmission [20, 28, 29], although routine screening for GBS carriage is not recommended in the UK [24]. Another commonly reported allergen is latex [20, 28–30].
However, in NAP6 there were no obstetric cases of perioperative obstetric anaphylaxis caused by antibiotics and no cases related to latex reported in the 1-year data collection period. The main causative agents in obstetric perioperative anaphylaxis were anaesthetic drugs including suxamethonium, atracurium and probably ondansetron [23]. Interestingly, chlorhexidine used in surgical skin preparations was also identified as a causative agent.
Differential Diagnosis
Altered immune responses in pregnancy can modify the classical clinical features of anaphylaxis, such that hypotension may be the predominant or only sign [31].
In NAP6, delays in diagnosing anaphylaxis and in starting anaphylaxis-specific treatment were greater in obstetric cases than in others. This may have been due to the overlapping clinical features of anaphylaxis, especially hypotension, with other acute obstetric morbidities, particularly in the presence of neuraxial blockade.
During the first three trimesters, before labour and delivery, the differential diagnosis of anaphylaxis in pregnancy is similar to that in non-pregnant patients. Common differentials include acute asthma, acute generalised urticaria, acute angioedema, syncope (fainting) and acute panic or anxiety attack [16, 27].
During labour and delivery, the differential diagnosis of anaphylaxis includes all other causes of maternal respiratory distress or cardiovascular compromise, such as pulmonary embolism, pulmonary oedema, cardiomyopathy, acute coronary syndrome, mitral stenosis, hypotension, cerebrovascular accident and amniotic fluid embolism [32, 33].
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