12 Sarah Davis1 and Sue Pavord2 1 Milton Keynes University Hospital, Milton Keynes, UK 2 Department of Haematology, Oxford University Hospitals NHS Foundation Trust, Oxford, UK Pregnancy is associated with physiological adaptation of the haematological system. An understanding of these changes is essential for distinguishing the normal from the pathological state. There is an increased likelihood of certain haematological complications, with thromboembolism and haemorrhage being leading causes of direct maternal deaths. This chapter covers the normal physiological changes, haematological complications of pregnancy and common haematological diseases which may impact on or be influenced by pregnancy. To accommodate the developing uteroplacental circulation, plasma volume increases by approximately 1250 mL (45%) and red cell mass by approximately 250 mL (10–20%) by the end of pregnancy. This produces a total blood volume increase of around 1500 mL but fall in haemoglobin concentration, as plasma volume is increased disproportionately to red cell mass (Table 12.1). Consequently, red cell count and haematocrit are lower in pregnancy. Other red cell indices remain largely stable except mean cell volume (MCV) which increases by about 4–6 fL, secondary to greater numbers of larger young red cells from the increase in red cell mass. Table 12.1 Changes in blood composition with gestation. Expansion of red cell mass requires 450–600 mg of iron and approximately 300 mg is transferred to the fetus and placenta, mainly in the last 4 weeks. Coupled with 0.8 mg daily basal loss (240 mg over duration of pregnancy) and 250 mg average loss at delivery, this suggests that most women require 1250 mg of iron during pregnancy. Serum folate levels fall by around half, due to a twofold increase in folate requirements but red cell folate levels are relatively spared. Functional vitamin B12 levels change very little and it is extremely unusual for a woman to have genuine B12 deficiency in pregnancy, even though serum levels often appear low. Typically, pregnancy causes a neutrophilia and therefore leucocytosis. There is usually an increase in circulating immature neutrophils (left shift) and evidence of toxic granulation. Levels may be markedly elevated after delivery but usually return to normal by 4 weeks post partum. Lymphocyte counts are often reduced, particularly in the first and second trimesters, and monocyte counts may be elevated, especially in the first trimester. A reduction in platelet count, mainly secondary to hyperdestruction and shortened lifespan, is common and around 10% of pregnancies have a platelet count below 150 × 109/L in the third trimester. It is usually mild, with 80% of counts remaining above 115 × 109/L, and does not seem to have an adverse effect on platelet function, possibly due to increased fibrinogen levels in pregnancy. Von Willebrand factor (vWF) and factors VII, VIII and X increase markedly with gestation and remain elevated in the early postpartum period. Factor IX remains unchanged. The natural anticoagulant protein S decreases with no change in protein C levels. This creates a prothrombotic state and activated partial thromboplastin time (APTT) is often shortened in pregnancy. Anaemia is defined as a haemoglobin (Hb) two standard deviations below the mean for a healthy age‐matched population. However, consensus on what is normal in pregnancy is lacking. The British Society of Haematology (BSH) and the US Centers for Disease Control and Prevention (CDC) use a value of less than 110 g/L in the first trimester but less than 105 g/L in the second and third trimesters as this takes into account the marked expansion in plasma volume at this stage. Postpartum anaemia is defined as Hb less than 100 g/L and African populations in general have lower Hb levels than Caucasians. Iron requirements for pregnancy, the fetus and delivery are substantial, with the average woman requiring at least 1250 mg. Western diets typically provide 15 mg/day, of which 10% is absorbed. During pregnancy, absorption increases to around 30% by 30 weeks but this is often insufficient to meet demand. Furthermore, many women start pregnancy already iron depleted, due to poor diet, increased need, menstruation and previous pregnancies within 2 years. Iron deficiency leads to anaemia and decreased tissue oxygen transport and affects iron‐dependent enzymes in every cell. Iron deficiency anaemia is a significant problem worldwide, affecting 50% of pregnant women (56% in developing and 18% in developed countries). The early stages of iron deficiency are often asymptomatic or show non‐specific symptoms. These include fatigue, poor concentration and irritability. As the anaemia develops tiredness is common but patients also complain of headaches, palpitations, dizziness and shortness of breath. Signs, if any, are pallor of mucous membranes and a hyperdynamic circulation. Specific signs, such as angular cheilitis, glossitis and koilonychia, can occur in severe cases. Iron deficiency may affect maternal morbidity. Cellular immunity and phagocytosis is impaired, rendering women more susceptible to infection, and its effect on iron‐dependent enzymes of the nervous system may lead to poor work performance and emotional instability, especially in the postpartum period. There may also be a link between iron deficiency, low birthweight and preterm delivery but this is, as yet, unproven. The fetus is relatively spared, as preferential delivery of iron is facilitated by upregulation of placental transferrin. However, infants born to iron‐deficient mothers are more likely to develop iron deficiency in the first 3 months of life. Initially, as iron stores are depleted, serum ferritin levels fall. A low serum ferritin is diagnostic of iron deficiency but as it is an acute‐phase reactant, it can be elevated in active inflammation or infection despite iron deficiency. Levels of transferrin, the iron transporter protein, increase as it attempts to deliver more iron to tissues. Anaemia develops as iron for erythropoiesis is reduced. MCV is an unreliable measure in pregnancy due to the physiological increase. Serum iron and total iron binding capacity (TIBC) are also unhelpful as they are affected by factors such as recent iron ingestion and infection. The British Committee for Standards in Haematology (BCSH) [1] suggest the following. The principles of treating iron deficiency are as follows: The recommended daily iron intake for pregnant women is 30 mg and all women should receive dietary advice on iron‐rich foods and factors that aid or inhibit absorption (Table 12.2). Table 12.2 Factors affecting iron absorption. Iron deficiency in pregnancy cannot be corrected through diet alone so iron supplementation is necessary. Oral, intramuscular and intravenous preparations are available. For most women oral replacement is the best option because it is effective, safe and inexpensive and can be started in primary care. The optimal dose has not yet been established but the current recommendation in the UK is 100–200 mg elemental iron daily with Hb level checked in 2 weeks. Hb should rise by around 20 g/L every 3–4 weeks and treatment should continue for at least 3 months after Hb has normalized and until at least 6 weeks post partum. Non‐anaemic women with low serum ferritin (<30 µg/L) should be started on 65 mg of elemental iron daily with a repeat Hb and ferritin in 8 weeks. Postpartum women with Hb below 100 g/L who are haemodynamically stable with minimal symptoms should be offered 100–200 mg elemental iron daily for 3 months to replenish iron stores. There are several different iron preparations available and choice should be based on dose of elemental iron and side‐effect profile (Table 12.3). Around 10–20% of patients experience gastrointestinal side effects, which are mostly dose related. Table 12.3 Elemental iron content in oral iron preparations. To maximize absorption, patients should take tablets with orange juice on an empty stomach, avoid tea and coffee for an hour either side of the tablet and not take with other medications, especially antacids. However, if side effects do occur and lowering the dose does not help, it may be appropriate to take tablets with meals despite the reduction in absorption. Intravenous iron is reserved for patients who fail to respond to oral iron or who are truly intolerant. Intravenous iron preparations have no licence for use in the first trimester due to concerns that oxidative free radicals could cause toxicity to placental membranes. They are relatively contraindicated in patients with chronic liver disease or active infection. The risk of anaphylaxis is exceedingly rare but other non‐allergic reactions occur in around 1 in 200 000. The older intravenous preparations do not raise Hb levels quicker than correctly taken oral iron. However, newer preparations such as iron carboxymaltose, which is given as a single dose over 15 min, produces a faster response (approximately 10 g/L improvement per week) so may be particularly beneficial for those women who present late in pregnancy. Intramuscular iron is rarely used as it is painful, has variable absorption and can cause permanent skin staining if not given correctly. With optimum care most women will no longer be anaemic at the point of delivery. However, women whose Hb is less than 100 g/L should deliver in hospital (<95 g/L in an obstetrician‐led unit), have intravenous access, a group and save available, and active management of the third stage of labour to minimize bleeding. Worldwide, megaloblastic anaemia during pregnancy secondary to folate deficiency is common due to poor diet and increased folate requirements. In the UK prevalence is less than 5% as many women take folate supplements to prevent neural tube defects. However, women with haemolytic disorders, malabsorption syndromes, myeloproliferative disorders and those on anticonvulsants are at high risk and should receive folate supplements. Folate deficiency is suggested by an elevated MCV, although the physiological increase in MCV and possible coexisting iron deficiency make this an unreliable parameter for diagnosis. The blood film may show hypersegmented neutrophils and oval macrocytes, and if iron deficiency coexists a dimorphic picture (two populations of red cells). Red cell folate levels are usually reduced and unaffected by recent folate intake but sensitivity and specificity during pregnancy are poor. The gold standard is a bone marrow biopsy demonstrating megaloblastic erythropoiesis but a trial of folate supplementation with assessment of Hb response is more practical. Patients at increased risk of folate deficiency should take 5 mg of folate daily as prophylaxis during pregnancy. Those with established folate deficiency should take 5 mg three times daily and all patients should be given dietary advice. Vitamin B12 deficiency in pregnancy is extremely rare as body stores last for several years. The commonest cause of B12 deficiency in the UK is pernicious anaemia, which typically affects older people. Furthermore, B12 deficiency is usually associated with infertility. A platelet count below 100 × 109/L occurs in less than 1% of pregnancies. Causes can be specific to or concurrent with pregnancy and can result in either isolated thrombocytopenia or thrombocytopenia in association with a systemic disorder. The majority of cases are secondary to the benign condition gestational thrombocytopenia (Fig. 12.1). However, causes may be life‐threatening and thrombocytopenia has implications for mode of delivery and the bleeding risk of mother and neonate. EDTA in full blood count tubes can induce platelet clumping leading to pseudo‐thrombocytopenia. Therefore, thrombocytopenia should always be confirmed with a repeat full blood count (FBC) and blood film and a citrate platelet count performed if clumping is present. Fig. 12.1 Causes of thrombocytopenia in pregnancy. AFLP, acute fatty liver of pregnancy; HELLP, haemolysis, elevated liver enzymes, low platelet count; HUS, haemolytic uraemic syndrome; SLE, systemic lupus erythematosus; TTP, thrombotic thrombocytopenic purpura. Gestational thrombocytopenia is a benign condition. Its pathogenesis is unclear but likely reflects platelet consumption within the placental circulation, haemodilution and hormonal inhibition of megakaryocytopoiesis. It usually causes a mild thrombocytopenia in the third trimester with no symptoms of bruising or bleeding and no history of thrombocytopenia outside pregnancy. It has no pathological significance for mother or fetus. There is no diagnostic test except the platelet count normalizes within 6 weeks post partum. It is therefore a diagnosis of exclusion and may cause diagnostic difficulty with autoimmune thrombocytopenia, especially if there are no pre‐pregnancy counts. It is extremely unusual for gestational thrombocytopenia to produce platelet counts below 70 × 109/L so levels below this should prompt consideration of alternative diagnoses. Immune thrombocytopenic purpura (ITP) is an autoimmune condition in which autoantibodies are directed against platelet surface glycoproteins (GPIIb/IIIa and/or GP1b/IX). This leads to premature clearance of platelets via Fc receptors in the reticuloendothelial system (mainly spleen). It is often chronic and presents a particular problem in pregnancy as the antibodies can cross the placenta rendering the fetus thrombocytopenic. It affects up to 5 in 10 000 pregnancies, two‐thirds of these being women who have a previous diagnosis of ITP and one‐third who have their diagnosis made during pregnancy. It is the most common cause of thrombocytopenia in the first trimester. Platelet counts in ITP are usually less than 70 × 109/L and it is a diagnosis of exclusion. For women with a pre‐pregnancy diagnosis of ITP, the accuracy of the diagnosis should be checked, response to treatments documented as well as the course and outcome of previous pregnancies, including neonatal platelet counts. The aim of ITP treatment in pregnancy is to maintain the platelet count at a level that avoids haemorrhagic problems for the mother during pregnancy and allows a safe delivery. Suggested platelet counts are detailed in Table 12.4. Table 12.4 Suggested platelet counts for immune thrombocytopenic purpura in pregnancy. This approach minimizes maternal and fetal exposure to therapeutic agents. Women do not usually require treatment before 36 weeks, providing they are asymptomatic and platelet levels are above 20 × 109/L. For those that need treatment, the first line is usually oral corticosteroids, starting with prednisolone 20 mg daily and titrated to response, and/or intravenous immunoglobulin if a more immediate response is required. If a woman with ITP goes into labour with an uncorrected platelet count, intravenous immunoglobulin 1 g/kg should be given immediately and platelet transfusion if birth is imminent or haemorrhage occurs. Mode of delivery should be led by obstetric indications. Rarely, transplacental transfer of maternal autoantibody can cause thrombocytopenia in the baby, increasing risk of intracranial haemorrhage at delivery. To minimize this risk, fetal scalp monitoring and blood sampling, ventouse and high/mid‐cavity forceps should be avoided. Active management of the third stage of labour reduces bleeding risk in the mother and non‐steroidal anti‐inflammatory drugs should be avoided. Because there is no correlation between maternal and fetal platelet counts, predicting which babies will have thrombocytopenia is difficult, unless the previous sibling was affected. Therefore all neonates born to mothers with ITP should have a cord blood count. If normal there is no need to repeat, but if abnormal a count should be repeated at 3–5 days of age, when the neonatal spleen has developed. Thrombotic thrombocytopenic purpura (TTP) is a life‐threatening condition characterized by thrombocytopenia and a microangiopathic haemolytic anaemia. Renal dysfunction, fever and neurological abnormalities also occur. Although rare, it is precipitated by pregnancy in 5–25% of cases. It can cause diagnostic confusion with other thrombotic microangiopathies such as HELLP (haemolysis, elevated liver enzymes, low platelets), pre‐eclampsia and disseminated intravascular coagulation. Prompt plasma exchange can be life‐saving. The sickle cell disorders (SCDs) are a group of conditions in which the sickle β gene is inherited with another abnormal haemoglobin. Sickle cell anaemia (HbSS) is the commonest and most severe, but the SCDs also includes HbSβthal and HbSC disease amongst others. HbS polymerizes at low oxygen tensions, which causes the red cells to sickle. Cells are inflexible in small blood vessels, contributing to vaso‐occlusion and have a shorter lifespan, leading to a chronic haemolytic anaemia. The clinical phenotype is varied, with some patients experiencing an almost ‘normal’ life and others suffering frequent crises. These crises may be haemolytic, vaso‐occlusive, visceral or aplastic and many patients develop chronic organ damage. Pregnancies are high risk for both mother and fetus. Crisis frequency may increase, anaemia usually worsens, infections, especially urinary, are common (secondary to hyposplenism and a more complex immune defect), and pre‐eclampsia occurs in around one‐third of patients. There is also an increased thrombotic risk with both pregnancy and SCD. Patients have an increased risk of miscarriage, premature delivery and intrauterine growth restriction. Therefore, patients should be managed within a multidisciplinary team including midwives, haematologists, anaesthetists and obstetricians. Ideally, pregnancy should be planned to allow women’s health to be optimized. Patients should undergo pre‐conception screening to assess end‐organ damage, their vaccination status should be up to date and any medications that are potentially teratogenic should be stopped. These include hydroxycarbamide (used to control frequent crises), angiotensin‐converting enzyme (ACE) inhibitors and iron chelators. Unless contraindicated, women should continue penicillin V for infection prophylaxis and take folic acid 5 mg daily. Antenatal care should particularly focus on continued education to avoid crisis triggers, such as dehydration from vomiting. Blood tests and monitoring for asymptomatic urinary infections, pregnancy‐induced hypertension and pre‐eclampsia should be carried out monthly, along with ultrasound scans to assess fetal growth and liquor volume [2]. Blood transfusions are not required routinely but regular transfusion programmes may be helpful in women with poor medical or obstetric histories in order to suppress HbS production. Examples include women previously on hydroxycarbamide, those with history of stroke or chest crisis and those with previous fetal loss or prematurity. Exchange transfusion may be preferred in these cases, depending on Hb. Acute chest crisis, pre‐eclampsia or other emergencies may benefit from exchange Hb to allow more aggressive reduction in HbS levels. All patients should have an extended red cell phenotype; many will have red cell alloantibodies making it difficult to provide blood quickly and the fetus may be at risk of haemolytic disease of the newborn. Severe crises in pregnancy are most frequent in the third trimester and may precipitate labour. The principles of treatment are the same as for a non‐pregnant patient and include keeping the woman warmth, well hydrated and oxygenated, with adequate analgesia and screening for and treatment of any infection. Indications for transfusion should be discussed with a haematologist and the possibility of chest crisis should always be considered and treated as a priority. Patients are at risk of thrombosis so unless otherwise contraindicated should be on low‐molecular‐weight heparin (LMWH) and fetuses should be monitored with regular cardiotocography (CTG). Mode of delivery should be led by obstetric indications and spontaneous vaginal delivery is usual. The mother should be kept warm, well hydrated and oxygenated and prolonged labour avoided. Continuous CTG monitoring is suggested and epidural anaesthesia is the pain relief of choice. There is an increased risk of postpartum haemorrhage, infection and thromboembolism so mothers should be closely monitored and attention paid to thromboprophylaxis. The thalassaemias are a group of inherited disorders characterized by reduced or absent production of the α or β haemoglobin chains. This causes a relative excess of the remaining chain, resulting in ineffective erythropoiesis and chronic haemolysis. There are four α‐globin genes and two β‐globin genes. A complete absence of α‐chains is incompatible with life but otherwise a wide variety of genetic abnormalities exist. For this reason thalassaemias are classified by their clinical phenotype into thalassaemia carriers, thalassaemia intermedia and thalassaemia major. The more severe intermedia patients and those with thalassaemia major are transfusion dependent and the main cause of morbidity and mortality is organ dysfunction caused by iron loading. Carriers or those who have mild thalassaemia intermedia syndromes can be treated as ‘normal’ pregnancies, except that pre‐conception counselling about a couple’s risk of having a baby with a haemoglobinopathy should occur and women should have ferritin checked before starting on iron. Pregnancies in women with β thalassaemia major and severe intermedia syndromes are high risk and should be managed in a multidisciplinary setting. Pre‐conception counselling should be offered, covering the risk of subfertility due to hypogonadotrophic hypogonadism, fetal haemoglobinopathy and the risks pregnancy poses to life if patients have cardiac or hepatic dysfunction. Screening for iron‐induced organ damage should be performed, including diabetic testing, thyroid function, cardiac and hepatic T2* MRI and echocardiography. Ideally, patients should have no myocardial and minimal liver iron before pregnancy, otherwise a pre‐conception period of intensive iron chelation should be considered. Teratogenic medications, including iron chelators, bisphosphonates and ACE inhibitors, should be stopped 3 months before conception. Folic acid 5 mg daily and calcium and vitamin D supplements, if bone density is reduced, should be taken. Extended red cell phenotyping and antibody screen should be performed. Antenatal care should be multidisciplinary and individualized. Particular focus should be given to transfusion, cardiac and liver status, diabetes, thrombotic risk and bone problems. Transfusion requirements often increase during pregnancy and patients who were not previously transfusion dependent may become so. Pre‐transfusion haemoglobin should remain above 100 g/L and any red cell antibodies (e.g. Kell, rhesus) should be monitored and the risk of haemolytic disease of the newborn considered. Between 6 and 8% of patients are diabetic due to iron overloading. They should be managed as per standard guidelines for diabetes in pregnancy. Transfusion‐dependent patients are often osteoporotic and osteopenic and may worsen during pregnancy. Vitamin D, calcium supplements and analgesia should be given as necessary. Caesarean section is frequent as many patients have small stature due to cephalopelvic disproportion. Thrombotic risk is significant, particularly in splenectomized transfusion‐independent thalassaemia intermedia patients. The Royal College of Obstetricians and Gynaecologists guidelines recommend aspirin 75 mg/day in splenectomized patients or patients with a platelet count above 600 × 109/L, and aspirin and LMWH prophylaxis if they have both. Because cardiac failure and arrhythmias are the commonest cause of death, women with thalassaemia should see a cardiologist before pregnancy. Monitoring with regular echocardiography and iron chelation with desferrioxamine during pregnancy may be appropriate in those with cardiac decompensation or high liver iron (associated with significant myocardial iron). An ultrasound scan at 7–9 weeks, for the high rate of fetal loss, and 4‐weekly growth scans from 24 weeks are recommended. Delivery should be as per obstetric indications and individualized. Peripartum iron chelation to minimize the risk of iron free radicals causing myocardial damage during labour is suggested in transfusion‐dependent patients. Regular iron chelation should restart post partum and breastfeeding is safe with this. Women with thalassaemia are high risk for venous thromboembolism.
Haematological Problems in Pregnancy
Physiological changes to the blood in pregnancy
Gestation (weeks)
Non‐pregnant
20
30
40
Plasma volume (mL)
2600
3150
3750
3850
Red cell mass (mL)
1400
1450
1550
1650
Total blood volume (mL)
4000
4600
5300
5500
Haematocrit
35
32
30
30
Anaemia in pregnancy
Iron deficiency anaemia
Diagnosis
Treatment
Factors increasing iron absorption
Haem iron (red meats, fish and poultry)
Acids, e.g vitamin C
Ferrous form (Fe2+)
Factors reducing iron absorption
Tannins in tea and coffee
Foods rich in calcium
Antacids
Iron preparation
Tablet size (mg)
Elemental iron per tablet (mg)
Ferrous sulfate
200
65
Ferrous fumarate
200
65
Ferrous gluconate
300
35
Megaloblastic anaemia
Thrombocytopenia in pregnancy
Gestational thrombocytopenia
Autoimmune thrombocytopenia
First and second trimesters of pregnancy: >20 × 109/L
Vaginal delivery: >40 × 109/L
Operative/instrumental delivery: >50 × 109/L
Epidural: >80 × 109/L
Thrombotic thrombocytopenic purpura
Sickle cell disorders
Thalassaemia
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