- Email: [email protected]
Haematology of pregnancy
AUTOIMMUNE CYTOPENIAS
Prednisolone – a short course of prednisolone, 1 mg/kg/day, is the first-choice treatment. IVIg is an alternative to prednisolone, but carries a risk of viral transmission. Platelet transfusions have no place unless there is lifethreatening haemorrhage. Chronic ITP usually requires corticosteroids, IVIg and possibly splenectomy.
Haematology of pregnancy Elizabeth A Letsky
FURTHER READING Gordon-Smith E C, Hows J M, Luzzatto L. Acquired haemolytic anaemias. In: Hoffbrand A V, Lewis S M, Tuddenham E G D. Postgraduate haematology. 4th ed. Oxford: Butterworth-Heinemann, 1999: 144–63. Huhn R D, Fogarty P F, Nakamura R et al. High dose cyclophosphamide with autologous lymphocyte-depleted peripheral blood stem cell (PBSC) support for treatment of refractory chronic autoimmune thrombocytopenia. Blood 2003; 101: 71–7. (Reports durable remission in some patients with refractory ITP.) Provan D, Newland A. Fifty years of idiopathic thrombocytopenic purpura (ITP): management of refractory ITP in adults. Br J Haematol 2002; 118: 933–44. Smith M A, Smith J G. Clinical experience with the use of rhG-CSF in secondary autoimmune neutropenia. Clin Lab Haematol 2002; 24: 93–8. (Illustrates the efficacy and tolerability of granulocyte colonystimulating factor in the treatment of autoimmune neutropenia.) Stasi R, Pagano A, Stipa E et al. Rituximab chimeric anti-CD20 monoclonal antibody treatment for adults with chronic idiopathic thrombocytopenic purpura. Blood 2001; 98: 952–7. Stasi R, Stipa E, Forte V et al. Variable pattern of response to rituximab treatment in adults with chronic idiopathic thrombocytopenic purpura. Blood 2002; 99: 3872–3. (These two papers discuss preliminary results and possible mechanisms of action of rituximab therapy in ITP.) Willis F, Marsh J C W, Bevan D H et al. The effect of treatment with Campath-1H in patients with autoimmune cytopenias. Br J Haematol 2001; 114: 891–8.
The physiological changes that occur in the blood during pregnancy are largely beneficial to mother and baby, but can sometimes cause problems. • Expansion of RBC mass and tissue proliferation results in increased demand for haematinics, and often nutritional anaemia. • Increase in total blood volume and haemostatic changes help to combat the hazard of haemorrhage at delivery, but pregnancy is thereby a hypercoagulable state and carries risks of various haemostatic disorders (Figure 1), from thromboembolism to disseminated intravascular coagulation (DIC). • Paternal antigens carried by the fetus but not present in the mother may provoke maternal immune responses, and alloimmune anaemia and thrombocytopenia.
Anaemia The dramatic increase in plasma volume (50%) and RBC mass (18–25%, depending on iron status) results in a dilutional decrease in haemoglobin concentration termed ‘physiological anaemia of pregnancy’. This is maximal at 32 weeks’ gestation. In iron-replete women, haemoglobin returns to normal by the second week postpartum, provided blood loss at delivery is not excessive.1 The WHO recommends that haemoglobin concentration should ideally be maintained at or above 11.0 g/dl and should not decline below 10.5 g/dl in the second trimester.2 Iron: more than 90% of cases of pathological anaemia are caused by iron deficiency associated with depleted iron stores and defi-
Practice points
What’s new ?
• Most patients with autoimmune cytopenia who need treatment respond to standard doses of immunosuppressive drugs (or G-CSF in autoimmune neutropenia) and can be managed as out-patients • In a small porportion, the disease is refractory and may be life-threatening; management of these patients is more problematic • The aim of management is to minimize treatment with as little toxicity as possible, to treat for the shortest period of time, and to achieve a safe blood count; the aim is not to cure the patient or achieve a normal blood count – over-treatment may result in significant morbidity and mortality • New, experimental monoclonal antibody therapies for refractory autoimmune cytopenias can induce remission and are undergoing clinical trials
MEDICINE
• Strategies to harvest fetal material from maternal blood to facilitate prenatal diagnosis of haematological disorders during pregnancy have been developed, thus avoiding hazardous invasive procedures
Elizabeth A Letsky is Honorary Consultant Perinatal Haematologist at Queen Charlotte’s and Chelsea Hospital, London, UK. She qualified from the University of Durham, and trained in haematology at the Royal Postgraduate Medical School and Great Ormond Street Hospital for Children, London. Her research interests include optimum management of thromboembolism in pregnancy, and investigation and management of alloimmune disorders of the fetus and newborn.
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cient intake. In addition, iron deficiency is associated with preterm labour, anaemia and impaired cognitive development in the infant, and possibly hypertension in middle age.3 There is confusion about iron requirements in pregnancy and whether routine supplements are indicated. It is safer, more practical and, in the long term, less expensive (in terms of investigations, hospital admission and treatment) to give all women once-daily iron supplements from 16 weeks’ gestation, particularly because this prophylaxis appears to do no harm.
this drug because of the theoretical risk of teratogenicity. However, healthy live-born infants are being reported in increasing numbers of women who inadvertently took hydroxyurea during pregnancy.5 Sickle cell trait is not normally associated with spontaneous clinical manifestations, but an increased incidence of pre-eclampsia has been demonstrated in women who are heterozygous for the sickle gene.6 Prenatal diagnosis – all women should be screened for the carrier state at their first antenatal visit; if they are positive, their partner should also be tested. Couples should be counselled if there is a possibility of severe haemoglobinopathy in their offspring, and offered prenatal diagnosis if appropriate.7
Folic acid: demands for folic acid exceed supply during pregnancy, resulting in a relative deficiency. Megaloblastic anaemia is more common in pregnancies supporting a greater tissue mass (e.g. multiple pregnancy). Diagnosis may be complicated by iron deficiency, masking megaloblastic macrocytic changes, and folate deficiency should therefore be suspected in any woman who responds only partially to iron alone. Megaloblastic anaemia arising de novo in pregnancy is always caused by folate deficiency. Folate supplements and neural tube defects – in 1991, a UK Medical Research Council trial showed that periconceptional folate supplements significantly reduced recurrence of neural tube defects, and a Hungarian study showed that supplements also appeared to prevent their first occurrence. The mechanism remains unclear, however, and though women are encouraged to take supplements of folate, 400 µg daily, when planning to conceive, a recent study has shown no reduction in the incidence of neural tube defects in the UK. It has been suggested that folate should be added to basic foodstuffs such as bread, as iron is added.4
Disorders of haemostasis Thromboembolism: risk factors for thromboembolism include greater age, multiparity, obesity, operative delivery and previous thromboembolism. It is important to make a definitive diagnosis, to ensure correct treatment and because of the implications for subsequent pregnancies. Diagnosis usually requires Doppler ultrasonography for deep vein thrombosis and a lung scan for pulmonary embolus. All patients should be screened for thrombophilic factors, including: • antithrombin deficiency • protein C deficiency • protein S deficiency • activated protein C resistance (usually caused by factor V Leiden) • prothrombin gene mutation • antiphospholipid syndrome. It is debatable whether screening for deficiency of methylenetetrahydrofolate reductase (a thrombophilic factor of uncertain but low risk in pregnancy) is necessary.8 Use of warfarin for treatment of venous thromboembolism is avoided because of the risk of maternal and fetal haemorrhage and fetal embryopathy in early pregnancy.9 High-dose intravenous unfractionated heparin should be used for initial therapy,
Vitamin B12: maternal serum B12 levels decrease in pregnancy, but the total transfer of B12 to the fetus is proportionately small. Serum B12 can decline to as low as 100 pg/ml, but this is not associated with megaloblastic changes in the marrow, nor with B12 deficiency, and does not cause anaemia of pregnancy. Haemoglobinopathies: in the management of haemoglobinopathy, it is important to identify: • women who require special management or prophylaxis to overcome the extra haematological stress of pregnancy • couples whose offspring are at risk of serious haemoglobinopathy. All women with chronic haemolysis during pregnancy need extra folic acid supplements. Thalassaemia – iron-deficient indices may be confused with thalassaemic indices; serum ferritin levels indicate whether true iron deficiency is present. It is a myth that oral iron should not be given to thalassaemic patients (though parenteral iron should never be given). Women with the thalassaemia trait may become iron deficient, as might any woman, and should be offered oral iron supplements in pregnancy. Parenteral folic acid may help absorption in those who become folate deficient. Sickle cell syndromes – the consensus is that there is no advantage to routine prophylactic transfusions in sickle cell disease, which may result in the development of atypical RBC antibodies that severely limit provision of compatible blood to cover surgery or haemorrhage. Transfusion should therefore be reserved for the management of medical emergencies. Hydroxyurea is not recommended in pregnancy. Men and women who wish to conceive are advised to stop treatment with
MEDICINE
Haematological complications during pregnancy Anaemia • Deficiency Iron Folic acid (Vitamin B12) • Haemoglobinopathies Thalassaemias Sickle cell syndromes Disorders of haemostasis • Thromboembolism • Haemorrhage ± disseminated intravascular coagulation • Thrombocytopenia Immune responses provoked by and affecting the fetus • Haemolytic disease of the newborn • Alloimmune thrombocytopenia 1
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followed by subcutaneous low molecular weight heparin (LMWH) until 6 weeks post-partum. It is safe for a mother on warfarin to breast-feed her infant; therefore, heparin (which is associated with osteoporosis) may be substituted by warfarin in the puerperium. LMWH is increasingly used for initial treatment of thromboembolism. In the author’s opinion, this should be reserved for isolated calf thromboses, because of the difficulties of rapid reversal in the event of an obstetric emergency. Prophylaxis in women with previous thromboembolism – it is common practice to give prophylactic low-dose aspirin, 75 mg daily, antenatally in women who have had a single previous thromboembolic episode. Women with a history of recurrent thromboembolism or additional risk factors are given antenatal LMWH, one injection daily. All those with an isolated previous thromboembolism receive intrapartum heparin prophylaxis, then heparin or warfarin for 6 weeks post-partum. Use of perinatal prophylactic anticoagulants, particularly when an epidural is needed, requires close collaboration between haematologist, anaesthetist and obstetrician. Prophylaxis in women with an artificial heart valve – anticoagulant therapy during pregnancy in women who have undergone heart valve replacement remains controversial. The combination leads to a high-risk pregnancy that is difficult to manage. Warfarin should be avoided at 6–12 weeks’ gestation and stopped 2 weeks before planned delivery. Use of warfarin should be strictly controlled; INR should be monitored to maintain a prothrombin ratio of about 2.0–2.5, using low-to-medium doses. Long-term therapeutic heparin is not ideal and should be used only when interruption of warfarin therapy is necessary. Bioprostheses, which do not require anticoagulant cover, tend to deteriorate rapidly in young women under the stress of pregnancy.10 Thrombophilia and fetal loss – since the observation that the prevalence of genetic thrombophilic factors was greater in women with complications of pregnancy,11 many studies worldwide have refuted the original findings.12 A recent meta-analysis showed that the association between thrombophilia and fetal loss varied according to the type of thrombophilia and the type of fetal loss.13 The indications for thrombophilia screening in pregnancy continue to increase, but in the interests of economy should be limited by mutual agreement to clinically relevant situations.14
Haemorrhage remains a significant direct cause of maternal mortality,15 usually because of delay in appropriate replacement therapy and development of DIC. It is easy to underestimate the amount of blood lost, particularly when it is partially concealed. All obstetric units should have a written protocol for dealing with this hazard and should undertake regular rehearsals. Thrombocytopenia: maternal thrombocytopenia often occurs in the third trimester of healthy pregnancy and is usually benign in both mother and child, even when associated with idiopathic thrombocytopenic purpura.16 Invasive procedures (e.g. intrauterine fetal blood or scalp sampling) should be performed only if absolutely necessary; they carry risks and may give misleading results. However, thrombocytopenia may be a valuable marker of disease severity and fetal outcome in pre-eclampsia and associated syndromes. Identification of reduced von Willebrand factor-cleaving protease in association with thrombotic thrombocytopenic purpura (TTP) has clarified the pathogenesis of this disorder.17,18 Differential diagnosis of TTP, haemolytic uraemic syndrome, pre-eclampsia and associated syndromes will be facilitated by this finding, enabling prompt and appropriate management of these conditions.
Alloimmune disorders19 Fetal alloimmune anaemia and haemolytic disease of the newborn Prophylaxis – in the UK, introduction of routine anti-D prophylaxis post-natally (1969), following termination of pregnancy (1976) and to cover events that may cause sensitization during the antenatal period (1989) has dramatically reduced the incidence of haemolytic disease of the newborn. In the last decade, however, the number of deaths resulting from anti-D was four times that caused by all other antibodies combined. In 1997, a consensus conference recommended routine antenatal prophylaxis in all atrisk pregnancies.20 The routine prophylactic dose varies between centres. In post-natal prophylaxis, an attempt should be made to assess the mother’s exposure to Rh D-positive cells. Use of anti-D immunoglobulin prophylaxis has resulted in an increase in the proportion of fetal alloimmune anaemia caused by other antibodies (e.g. anti-c, anti-Kell), but an overall reduction in severe cases, most of which are caused by anti-D. Investigations in at-risk pregnancies are initiated when immune RBC blood group antibodies are found on screening of maternal serum during the antenatal period. Depending on the clinical history, the concentration of antibodies and the rate of the increase, further procedures such as amniocentesis and/or fetal blood sampling may be indicated. Detection of fetal DNA in maternal plasma and serum21 has led to fetal blood grouping in the first trimester,22 avoiding hazardous invasive procedures when the partner is heterozygous for the offending antigen. Ultrasonography has revolutionized both the investigation and the management of fetuses at risk of severe disease. Changes in blood flow and cardiac function caused by compensated anaemia can be visualized and measured objectively before hydrops develops in utero. The only clinically significant antibodies, other than anti-D, that cause fetal anaemia requiring antenatal intervention (with rare exceptions, e.g. Fγa) are anti-Kell and anti-c, alone or in combination with other antibodies. Intrauterine transfusion can be performed from as early as 18 weeks’ gestation, but is best
DIC is associated with various complications in pregnancy. It may be compensated, with little change in tests of haemostatic function and no bleeding (as seen in patients with pre-eclampsia), or may be associated with intractable haemorrhage, gross consumption of coagulation factors and platelets, and increased fibrin degradation products (as classically seen in abruptio placentae). DIC is usually triggered by prolonged shock following inadequately treated massive haemorrhage from any cause.3 Haemorrhage: all women haemorrhage at delivery. Singleton vaginal delivery leads to blood loss of 500 ml and caesarean section 1000 ml, but physiological changes and blood volume expansion help women tolerate this, provided they are not anaemic (< 11 g/dl) at term and are not suffering pre-eclampsia with reduced plasma volume expansion. Contraction of the myometrium on the placental site is the principal mechanism of haemostasis at delivery. Prolonged haemorrhage may result from extended episiotomy or concealed cervical or upper vaginal vault tears.
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delayed to 22 weeks when the overall fetal loss rate is reduced to 1–2%. Management aims to prevent hydrops in utero, and to time delivery to maximize the likelihood of infant survival with no long-term handicap. This is achieved by a series of intrauterine transfusions at 2–4-week intervals, usually prompted by clinical history, rapidly increasing antibody, ultrasonography, and amniotic fluid bilirubin in some cases.23
7 Modell B, Harris R, Lane B et al. Informed choice in genetic screening for thalassaemia during pregnancy: audit from a national confidential inquiry. BMJ 2000; 320: 337–41. 8 de Swiet M. Thromboembolism. In: de Swiet M, ed. Medical disorders in obstetric practice. Oxford: Blackwell Science; 2002: 103–4. 9 Greer I A. Thrombosis in pregnancy: maternal and fetal issues. Lancet 1999; 353: 1258–65. 10 de Swiet M. Heart disease in pregnancy. In: de Swiet M, ed. Medical disorders in obstetric practice. Oxford: Blackwell Science; 2002: 135–43. 11 Kupferminc M J, Eldor A, Steinman N et al. Increased frequency of genetic thrombophilia in women with complications of pregnancy. N Engl J Med 1999; 340: 9–13. 12 Morrison E R, Miedzybrodzka Z H, Campbell D M et al. Prothrombotic genotypes are not associated with pre-eclampsia and gestational hypertension; results from a large population based study and systematic review. Thromb Haemost 2002; 87: 779–85. 13 Rey E, Kahn S R, David M et al. Thrombophilic disorders and fetal loss: a meta-analysis. Lancet 2003; 361: 901–8. 14 Baglin T, Greaves M. Rebuttal: is a nihilistic approach to thrombophilia screening justified? Thromb Haemost 2002; 88: 700–1. 15 Lewis G, ed. Why mothers die 1997–1999. The confidential enquiries into maternal deaths in the United Kingdom. London: RCOG Press, 2001. 16 British Committee for Standards in Haematology General Haematology Task Force. Guidelines for the investigation and management of idiopathic thrombocytopenic purpura in adults, children and in pregnancy. Br J Haematol 2003; 120: 574–96. 17 Furlan M, Robles R, Galbusera M et al. Von Willebrand factor-cleaving protease in thrombotic thrombocytopenic purpura and the hemolyticuremic syndrome. N Engl J Med 1998; 339: 1578–84. 18 Tsai H, Lian E-Y. Antibodies to von Willebrand factor-cleaving protease in acute thrombotic thrombocytopenic purpura. N Engl J Med 1998; 339: 1585–94. 19 Hadley A G, Soothill P. Alloimmune disorders of pregnancy. Cambridge: Cambridge University Press, 2002. 20 Robson S C, Lee D, Urbaniak S. Anti-D immunoglobulin in Rh D prophylaxis. Br J Obstet Gynaecol 1998; 105: 129–34. 21 Lo Y M D, Corbetta N, Chamberlain P F et al. Presence of fetal DNA in maternal plasma and serum. Lancet 1997; 350: 485–7. 22 Costa J M, Giovangrandi Y, Emault P et al. Fetal RHD genotyping in maternal serum during the first trimester of pregnancy. Br J Haematol 2002; 119: 255–60. 23 Moise K J Jr. Management of rhesus alloimmunization in pregnancy. Obstet Gynecol 2002; 100: 600–11. 24 Williamson L M, Hackett G, Rennie J et al. The natural history of fetomaternal alloimmunization to the platelet-specific antigen HPA-1a (PLA1, Zwa) as determined by antenatal screening. Blood 1998; 92: 2280–7. 25 Overton T G, Duncan K R, Jolly M et al. Serial aggressive platelet transfusion for fetal alloimmune thrombocytopenia: platelet dynamics and perinatal outcome. Am J Obstet Gynecol 2002; 186: 826–31. 26 Kaplan C, Murphy M F, Kroll H et al. Feto-maternal alloimmune thrombocytopenia: antenatal therapy with IvIgG and steroids – more questions than answers. Br J Haematol 1998; 100: 62–5. 27 Jolly M C, Letsky E A, Fisk N M. The management of fetal alloimmune thrombocytopenia. Prenat Diagn 2002; 22: 96–8.
Fetomaternal alloimmune thrombocytopenia (FMAIT): severe alloimmune thrombocytopenia is a rare but important cause of fetal death and long-term neurological morbidity. Most clinically significant cases arise from fetomaternal incompatibility for the human platelet antigen HPA-1a.24 Diagnosis and screening – it is important to identify FMAIT as a cause of fetal or neonatal thrombocytopenia, because of the high risk of recurrence and of intracranial haemorrhage in subsequent pregnancies. Currently, diagnosis of the maternal condition is usually made after the birth of a thrombocytopenic infant or identification of a fetus (or neonate) with unexplained intracranial haemorrhage. Serological testing of both parents is sufficient to establish the diagnosis. Female relatives of the mother should be tested for HPA-1a status, to identify potential cases before the birth of a first affected infant. Antenatal management – the primary aim of antenatal management is to prevent in utero or perinatal intracranial haemorrhage. First pregnancies may be severely affected, and the maternal alloimmune platelet antibody has not been useful in identifying or monitoring the severity of the condition in the fetus. Fetal blood sampling and platelet count is the only certain means of identifying an affected fetus. Suitable platelet concentrates should be available to cover the procedure. The risk of exsanguination at fetal blood sampling appears to be higher than in other conditions when cordocentesis is performed.25 It has been suggested that function is disturbed by binding of the antibody to a platelet membrane site involved in fibrinogen binding and aggregation, and to HPA-1a sites on the vascular endothelium. Optimal management remains undetermined and the appropriate therapy in individuals is uncertain; all approaches have disadvantages.26 The assessed risk of the disease in the fetus must be weighed against the risk of invasive procedures.27 REFERENCES 1 Letsky E A. The haematological system. In: Broughton Pipkin F, Chamberlain G V P, eds. Clinical physiology in obstetrics. Oxford: Blackwell Science, 1998: 71–110. 2 Stoltzfus R J, Dreyfuss M L. Guidelines for the use of iron supplements to prevent and treat iron deficiency anemia on behalf of the International Nutritional Anemia Consultative Group (INACG). Washington: International Life Sciences Institute Press, 1998. 3 Letsky E A. Maternal anaemia in pregnancy. Iron and pregnancy – a haematologist’s view. Fetal Matern Med Rev 2001; 12: 159–75. 4 Kadir R A, Sabin C, Whitlow B et al. Neural tube defects and periconceptional folic acid in England and Wales: retrospective study. BMJ 1999; 319: 92–3. 5 Halsey C, Roberts I A. The role of hydroxyurea in sickle cell disease. Br J Haematol 2003; 120: 177–86. 6 Larrabee K D, Monga M. Women with sickle cell trait are at increased risk for preeclampsia. Am J Obstet Gynecol 1997; 177: 425–8.
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Prednisolone – a short course of prednisolone, 1 mg/kg/day, is the first-choice treatment. IVIg is an alternative to prednisolone, but carries a risk of viral transmission. Platelet transfusions have no place unless there is lifethreatening haemorrhage. Chronic ITP usually requires corticosteroids, IVIg and possibly splenectomy.
Haematology of pregnancy Elizabeth A Letsky
FURTHER READING Gordon-Smith E C, Hows J M, Luzzatto L. Acquired haemolytic anaemias. In: Hoffbrand A V, Lewis S M, Tuddenham E G D. Postgraduate haematology. 4th ed. Oxford: Butterworth-Heinemann, 1999: 144–63. Huhn R D, Fogarty P F, Nakamura R et al. High dose cyclophosphamide with autologous lymphocyte-depleted peripheral blood stem cell (PBSC) support for treatment of refractory chronic autoimmune thrombocytopenia. Blood 2003; 101: 71–7. (Reports durable remission in some patients with refractory ITP.) Provan D, Newland A. Fifty years of idiopathic thrombocytopenic purpura (ITP): management of refractory ITP in adults. Br J Haematol 2002; 118: 933–44. Smith M A, Smith J G. Clinical experience with the use of rhG-CSF in secondary autoimmune neutropenia. Clin Lab Haematol 2002; 24: 93–8. (Illustrates the efficacy and tolerability of granulocyte colonystimulating factor in the treatment of autoimmune neutropenia.) Stasi R, Pagano A, Stipa E et al. Rituximab chimeric anti-CD20 monoclonal antibody treatment for adults with chronic idiopathic thrombocytopenic purpura. Blood 2001; 98: 952–7. Stasi R, Stipa E, Forte V et al. Variable pattern of response to rituximab treatment in adults with chronic idiopathic thrombocytopenic purpura. Blood 2002; 99: 3872–3. (These two papers discuss preliminary results and possible mechanisms of action of rituximab therapy in ITP.) Willis F, Marsh J C W, Bevan D H et al. The effect of treatment with Campath-1H in patients with autoimmune cytopenias. Br J Haematol 2001; 114: 891–8.
The physiological changes that occur in the blood during pregnancy are largely beneficial to mother and baby, but can sometimes cause problems. • Expansion of RBC mass and tissue proliferation results in increased demand for haematinics, and often nutritional anaemia. • Increase in total blood volume and haemostatic changes help to combat the hazard of haemorrhage at delivery, but pregnancy is thereby a hypercoagulable state and carries risks of various haemostatic disorders (Figure 1), from thromboembolism to disseminated intravascular coagulation (DIC). • Paternal antigens carried by the fetus but not present in the mother may provoke maternal immune responses, and alloimmune anaemia and thrombocytopenia.
Anaemia The dramatic increase in plasma volume (50%) and RBC mass (18–25%, depending on iron status) results in a dilutional decrease in haemoglobin concentration termed ‘physiological anaemia of pregnancy’. This is maximal at 32 weeks’ gestation. In iron-replete women, haemoglobin returns to normal by the second week postpartum, provided blood loss at delivery is not excessive.1 The WHO recommends that haemoglobin concentration should ideally be maintained at or above 11.0 g/dl and should not decline below 10.5 g/dl in the second trimester.2 Iron: more than 90% of cases of pathological anaemia are caused by iron deficiency associated with depleted iron stores and defi-
Practice points
What’s new ?
• Most patients with autoimmune cytopenia who need treatment respond to standard doses of immunosuppressive drugs (or G-CSF in autoimmune neutropenia) and can be managed as out-patients • In a small porportion, the disease is refractory and may be life-threatening; management of these patients is more problematic • The aim of management is to minimize treatment with as little toxicity as possible, to treat for the shortest period of time, and to achieve a safe blood count; the aim is not to cure the patient or achieve a normal blood count – over-treatment may result in significant morbidity and mortality • New, experimental monoclonal antibody therapies for refractory autoimmune cytopenias can induce remission and are undergoing clinical trials
MEDICINE
• Strategies to harvest fetal material from maternal blood to facilitate prenatal diagnosis of haematological disorders during pregnancy have been developed, thus avoiding hazardous invasive procedures
Elizabeth A Letsky is Honorary Consultant Perinatal Haematologist at Queen Charlotte’s and Chelsea Hospital, London, UK. She qualified from the University of Durham, and trained in haematology at the Royal Postgraduate Medical School and Great Ormond Street Hospital for Children, London. Her research interests include optimum management of thromboembolism in pregnancy, and investigation and management of alloimmune disorders of the fetus and newborn.
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cient intake. In addition, iron deficiency is associated with preterm labour, anaemia and impaired cognitive development in the infant, and possibly hypertension in middle age.3 There is confusion about iron requirements in pregnancy and whether routine supplements are indicated. It is safer, more practical and, in the long term, less expensive (in terms of investigations, hospital admission and treatment) to give all women once-daily iron supplements from 16 weeks’ gestation, particularly because this prophylaxis appears to do no harm.
this drug because of the theoretical risk of teratogenicity. However, healthy live-born infants are being reported in increasing numbers of women who inadvertently took hydroxyurea during pregnancy.5 Sickle cell trait is not normally associated with spontaneous clinical manifestations, but an increased incidence of pre-eclampsia has been demonstrated in women who are heterozygous for the sickle gene.6 Prenatal diagnosis – all women should be screened for the carrier state at their first antenatal visit; if they are positive, their partner should also be tested. Couples should be counselled if there is a possibility of severe haemoglobinopathy in their offspring, and offered prenatal diagnosis if appropriate.7
Folic acid: demands for folic acid exceed supply during pregnancy, resulting in a relative deficiency. Megaloblastic anaemia is more common in pregnancies supporting a greater tissue mass (e.g. multiple pregnancy). Diagnosis may be complicated by iron deficiency, masking megaloblastic macrocytic changes, and folate deficiency should therefore be suspected in any woman who responds only partially to iron alone. Megaloblastic anaemia arising de novo in pregnancy is always caused by folate deficiency. Folate supplements and neural tube defects – in 1991, a UK Medical Research Council trial showed that periconceptional folate supplements significantly reduced recurrence of neural tube defects, and a Hungarian study showed that supplements also appeared to prevent their first occurrence. The mechanism remains unclear, however, and though women are encouraged to take supplements of folate, 400 µg daily, when planning to conceive, a recent study has shown no reduction in the incidence of neural tube defects in the UK. It has been suggested that folate should be added to basic foodstuffs such as bread, as iron is added.4
Disorders of haemostasis Thromboembolism: risk factors for thromboembolism include greater age, multiparity, obesity, operative delivery and previous thromboembolism. It is important to make a definitive diagnosis, to ensure correct treatment and because of the implications for subsequent pregnancies. Diagnosis usually requires Doppler ultrasonography for deep vein thrombosis and a lung scan for pulmonary embolus. All patients should be screened for thrombophilic factors, including: • antithrombin deficiency • protein C deficiency • protein S deficiency • activated protein C resistance (usually caused by factor V Leiden) • prothrombin gene mutation • antiphospholipid syndrome. It is debatable whether screening for deficiency of methylenetetrahydrofolate reductase (a thrombophilic factor of uncertain but low risk in pregnancy) is necessary.8 Use of warfarin for treatment of venous thromboembolism is avoided because of the risk of maternal and fetal haemorrhage and fetal embryopathy in early pregnancy.9 High-dose intravenous unfractionated heparin should be used for initial therapy,
Vitamin B12: maternal serum B12 levels decrease in pregnancy, but the total transfer of B12 to the fetus is proportionately small. Serum B12 can decline to as low as 100 pg/ml, but this is not associated with megaloblastic changes in the marrow, nor with B12 deficiency, and does not cause anaemia of pregnancy. Haemoglobinopathies: in the management of haemoglobinopathy, it is important to identify: • women who require special management or prophylaxis to overcome the extra haematological stress of pregnancy • couples whose offspring are at risk of serious haemoglobinopathy. All women with chronic haemolysis during pregnancy need extra folic acid supplements. Thalassaemia – iron-deficient indices may be confused with thalassaemic indices; serum ferritin levels indicate whether true iron deficiency is present. It is a myth that oral iron should not be given to thalassaemic patients (though parenteral iron should never be given). Women with the thalassaemia trait may become iron deficient, as might any woman, and should be offered oral iron supplements in pregnancy. Parenteral folic acid may help absorption in those who become folate deficient. Sickle cell syndromes – the consensus is that there is no advantage to routine prophylactic transfusions in sickle cell disease, which may result in the development of atypical RBC antibodies that severely limit provision of compatible blood to cover surgery or haemorrhage. Transfusion should therefore be reserved for the management of medical emergencies. Hydroxyurea is not recommended in pregnancy. Men and women who wish to conceive are advised to stop treatment with
MEDICINE
Haematological complications during pregnancy Anaemia • Deficiency Iron Folic acid (Vitamin B12) • Haemoglobinopathies Thalassaemias Sickle cell syndromes Disorders of haemostasis • Thromboembolism • Haemorrhage ± disseminated intravascular coagulation • Thrombocytopenia Immune responses provoked by and affecting the fetus • Haemolytic disease of the newborn • Alloimmune thrombocytopenia 1
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followed by subcutaneous low molecular weight heparin (LMWH) until 6 weeks post-partum. It is safe for a mother on warfarin to breast-feed her infant; therefore, heparin (which is associated with osteoporosis) may be substituted by warfarin in the puerperium. LMWH is increasingly used for initial treatment of thromboembolism. In the author’s opinion, this should be reserved for isolated calf thromboses, because of the difficulties of rapid reversal in the event of an obstetric emergency. Prophylaxis in women with previous thromboembolism – it is common practice to give prophylactic low-dose aspirin, 75 mg daily, antenatally in women who have had a single previous thromboembolic episode. Women with a history of recurrent thromboembolism or additional risk factors are given antenatal LMWH, one injection daily. All those with an isolated previous thromboembolism receive intrapartum heparin prophylaxis, then heparin or warfarin for 6 weeks post-partum. Use of perinatal prophylactic anticoagulants, particularly when an epidural is needed, requires close collaboration between haematologist, anaesthetist and obstetrician. Prophylaxis in women with an artificial heart valve – anticoagulant therapy during pregnancy in women who have undergone heart valve replacement remains controversial. The combination leads to a high-risk pregnancy that is difficult to manage. Warfarin should be avoided at 6–12 weeks’ gestation and stopped 2 weeks before planned delivery. Use of warfarin should be strictly controlled; INR should be monitored to maintain a prothrombin ratio of about 2.0–2.5, using low-to-medium doses. Long-term therapeutic heparin is not ideal and should be used only when interruption of warfarin therapy is necessary. Bioprostheses, which do not require anticoagulant cover, tend to deteriorate rapidly in young women under the stress of pregnancy.10 Thrombophilia and fetal loss – since the observation that the prevalence of genetic thrombophilic factors was greater in women with complications of pregnancy,11 many studies worldwide have refuted the original findings.12 A recent meta-analysis showed that the association between thrombophilia and fetal loss varied according to the type of thrombophilia and the type of fetal loss.13 The indications for thrombophilia screening in pregnancy continue to increase, but in the interests of economy should be limited by mutual agreement to clinically relevant situations.14
Haemorrhage remains a significant direct cause of maternal mortality,15 usually because of delay in appropriate replacement therapy and development of DIC. It is easy to underestimate the amount of blood lost, particularly when it is partially concealed. All obstetric units should have a written protocol for dealing with this hazard and should undertake regular rehearsals. Thrombocytopenia: maternal thrombocytopenia often occurs in the third trimester of healthy pregnancy and is usually benign in both mother and child, even when associated with idiopathic thrombocytopenic purpura.16 Invasive procedures (e.g. intrauterine fetal blood or scalp sampling) should be performed only if absolutely necessary; they carry risks and may give misleading results. However, thrombocytopenia may be a valuable marker of disease severity and fetal outcome in pre-eclampsia and associated syndromes. Identification of reduced von Willebrand factor-cleaving protease in association with thrombotic thrombocytopenic purpura (TTP) has clarified the pathogenesis of this disorder.17,18 Differential diagnosis of TTP, haemolytic uraemic syndrome, pre-eclampsia and associated syndromes will be facilitated by this finding, enabling prompt and appropriate management of these conditions.
Alloimmune disorders19 Fetal alloimmune anaemia and haemolytic disease of the newborn Prophylaxis – in the UK, introduction of routine anti-D prophylaxis post-natally (1969), following termination of pregnancy (1976) and to cover events that may cause sensitization during the antenatal period (1989) has dramatically reduced the incidence of haemolytic disease of the newborn. In the last decade, however, the number of deaths resulting from anti-D was four times that caused by all other antibodies combined. In 1997, a consensus conference recommended routine antenatal prophylaxis in all atrisk pregnancies.20 The routine prophylactic dose varies between centres. In post-natal prophylaxis, an attempt should be made to assess the mother’s exposure to Rh D-positive cells. Use of anti-D immunoglobulin prophylaxis has resulted in an increase in the proportion of fetal alloimmune anaemia caused by other antibodies (e.g. anti-c, anti-Kell), but an overall reduction in severe cases, most of which are caused by anti-D. Investigations in at-risk pregnancies are initiated when immune RBC blood group antibodies are found on screening of maternal serum during the antenatal period. Depending on the clinical history, the concentration of antibodies and the rate of the increase, further procedures such as amniocentesis and/or fetal blood sampling may be indicated. Detection of fetal DNA in maternal plasma and serum21 has led to fetal blood grouping in the first trimester,22 avoiding hazardous invasive procedures when the partner is heterozygous for the offending antigen. Ultrasonography has revolutionized both the investigation and the management of fetuses at risk of severe disease. Changes in blood flow and cardiac function caused by compensated anaemia can be visualized and measured objectively before hydrops develops in utero. The only clinically significant antibodies, other than anti-D, that cause fetal anaemia requiring antenatal intervention (with rare exceptions, e.g. Fγa) are anti-Kell and anti-c, alone or in combination with other antibodies. Intrauterine transfusion can be performed from as early as 18 weeks’ gestation, but is best
DIC is associated with various complications in pregnancy. It may be compensated, with little change in tests of haemostatic function and no bleeding (as seen in patients with pre-eclampsia), or may be associated with intractable haemorrhage, gross consumption of coagulation factors and platelets, and increased fibrin degradation products (as classically seen in abruptio placentae). DIC is usually triggered by prolonged shock following inadequately treated massive haemorrhage from any cause.3 Haemorrhage: all women haemorrhage at delivery. Singleton vaginal delivery leads to blood loss of 500 ml and caesarean section 1000 ml, but physiological changes and blood volume expansion help women tolerate this, provided they are not anaemic (< 11 g/dl) at term and are not suffering pre-eclampsia with reduced plasma volume expansion. Contraction of the myometrium on the placental site is the principal mechanism of haemostasis at delivery. Prolonged haemorrhage may result from extended episiotomy or concealed cervical or upper vaginal vault tears.
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delayed to 22 weeks when the overall fetal loss rate is reduced to 1–2%. Management aims to prevent hydrops in utero, and to time delivery to maximize the likelihood of infant survival with no long-term handicap. This is achieved by a series of intrauterine transfusions at 2–4-week intervals, usually prompted by clinical history, rapidly increasing antibody, ultrasonography, and amniotic fluid bilirubin in some cases.23
7 Modell B, Harris R, Lane B et al. Informed choice in genetic screening for thalassaemia during pregnancy: audit from a national confidential inquiry. BMJ 2000; 320: 337–41. 8 de Swiet M. Thromboembolism. In: de Swiet M, ed. Medical disorders in obstetric practice. Oxford: Blackwell Science; 2002: 103–4. 9 Greer I A. Thrombosis in pregnancy: maternal and fetal issues. Lancet 1999; 353: 1258–65. 10 de Swiet M. Heart disease in pregnancy. In: de Swiet M, ed. Medical disorders in obstetric practice. Oxford: Blackwell Science; 2002: 135–43. 11 Kupferminc M J, Eldor A, Steinman N et al. Increased frequency of genetic thrombophilia in women with complications of pregnancy. N Engl J Med 1999; 340: 9–13. 12 Morrison E R, Miedzybrodzka Z H, Campbell D M et al. Prothrombotic genotypes are not associated with pre-eclampsia and gestational hypertension; results from a large population based study and systematic review. Thromb Haemost 2002; 87: 779–85. 13 Rey E, Kahn S R, David M et al. Thrombophilic disorders and fetal loss: a meta-analysis. Lancet 2003; 361: 901–8. 14 Baglin T, Greaves M. Rebuttal: is a nihilistic approach to thrombophilia screening justified? Thromb Haemost 2002; 88: 700–1. 15 Lewis G, ed. Why mothers die 1997–1999. The confidential enquiries into maternal deaths in the United Kingdom. London: RCOG Press, 2001. 16 British Committee for Standards in Haematology General Haematology Task Force. Guidelines for the investigation and management of idiopathic thrombocytopenic purpura in adults, children and in pregnancy. Br J Haematol 2003; 120: 574–96. 17 Furlan M, Robles R, Galbusera M et al. Von Willebrand factor-cleaving protease in thrombotic thrombocytopenic purpura and the hemolyticuremic syndrome. N Engl J Med 1998; 339: 1578–84. 18 Tsai H, Lian E-Y. Antibodies to von Willebrand factor-cleaving protease in acute thrombotic thrombocytopenic purpura. N Engl J Med 1998; 339: 1585–94. 19 Hadley A G, Soothill P. Alloimmune disorders of pregnancy. Cambridge: Cambridge University Press, 2002. 20 Robson S C, Lee D, Urbaniak S. Anti-D immunoglobulin in Rh D prophylaxis. Br J Obstet Gynaecol 1998; 105: 129–34. 21 Lo Y M D, Corbetta N, Chamberlain P F et al. Presence of fetal DNA in maternal plasma and serum. Lancet 1997; 350: 485–7. 22 Costa J M, Giovangrandi Y, Emault P et al. Fetal RHD genotyping in maternal serum during the first trimester of pregnancy. Br J Haematol 2002; 119: 255–60. 23 Moise K J Jr. Management of rhesus alloimmunization in pregnancy. Obstet Gynecol 2002; 100: 600–11. 24 Williamson L M, Hackett G, Rennie J et al. The natural history of fetomaternal alloimmunization to the platelet-specific antigen HPA-1a (PLA1, Zwa) as determined by antenatal screening. Blood 1998; 92: 2280–7. 25 Overton T G, Duncan K R, Jolly M et al. Serial aggressive platelet transfusion for fetal alloimmune thrombocytopenia: platelet dynamics and perinatal outcome. Am J Obstet Gynecol 2002; 186: 826–31. 26 Kaplan C, Murphy M F, Kroll H et al. Feto-maternal alloimmune thrombocytopenia: antenatal therapy with IvIgG and steroids – more questions than answers. Br J Haematol 1998; 100: 62–5. 27 Jolly M C, Letsky E A, Fisk N M. The management of fetal alloimmune thrombocytopenia. Prenat Diagn 2002; 22: 96–8.
Fetomaternal alloimmune thrombocytopenia (FMAIT): severe alloimmune thrombocytopenia is a rare but important cause of fetal death and long-term neurological morbidity. Most clinically significant cases arise from fetomaternal incompatibility for the human platelet antigen HPA-1a.24 Diagnosis and screening – it is important to identify FMAIT as a cause of fetal or neonatal thrombocytopenia, because of the high risk of recurrence and of intracranial haemorrhage in subsequent pregnancies. Currently, diagnosis of the maternal condition is usually made after the birth of a thrombocytopenic infant or identification of a fetus (or neonate) with unexplained intracranial haemorrhage. Serological testing of both parents is sufficient to establish the diagnosis. Female relatives of the mother should be tested for HPA-1a status, to identify potential cases before the birth of a first affected infant. Antenatal management – the primary aim of antenatal management is to prevent in utero or perinatal intracranial haemorrhage. First pregnancies may be severely affected, and the maternal alloimmune platelet antibody has not been useful in identifying or monitoring the severity of the condition in the fetus. Fetal blood sampling and platelet count is the only certain means of identifying an affected fetus. Suitable platelet concentrates should be available to cover the procedure. The risk of exsanguination at fetal blood sampling appears to be higher than in other conditions when cordocentesis is performed.25 It has been suggested that function is disturbed by binding of the antibody to a platelet membrane site involved in fibrinogen binding and aggregation, and to HPA-1a sites on the vascular endothelium. Optimal management remains undetermined and the appropriate therapy in individuals is uncertain; all approaches have disadvantages.26 The assessed risk of the disease in the fetus must be weighed against the risk of invasive procedures.27 REFERENCES 1 Letsky E A. The haematological system. In: Broughton Pipkin F, Chamberlain G V P, eds. Clinical physiology in obstetrics. Oxford: Blackwell Science, 1998: 71–110. 2 Stoltzfus R J, Dreyfuss M L. Guidelines for the use of iron supplements to prevent and treat iron deficiency anemia on behalf of the International Nutritional Anemia Consultative Group (INACG). Washington: International Life Sciences Institute Press, 1998. 3 Letsky E A. Maternal anaemia in pregnancy. Iron and pregnancy – a haematologist’s view. Fetal Matern Med Rev 2001; 12: 159–75. 4 Kadir R A, Sabin C, Whitlow B et al. Neural tube defects and periconceptional folic acid in England and Wales: retrospective study. BMJ 1999; 319: 92–3. 5 Halsey C, Roberts I A. The role of hydroxyurea in sickle cell disease. Br J Haematol 2003; 120: 177–86. 6 Larrabee K D, Monga M. Women with sickle cell trait are at increased risk for preeclampsia. Am J Obstet Gynecol 1997; 177: 425–8.
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