Hematologia y Embarazo

Hematologia y Embarazo

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  Haematology of pregnancy Karyn Longmuir Sue Pavord PREGNANCY Abstract The physiological changes that occur during pregnancy, to meet the needs of the developing fetus, can lead to complications in vulnerable patients. Close proximity of fetal and maternal circulations enables effective transfer of nutrients and oxygen but passage of certain substances can also have disastrous consequences for mother or baby. For example, tera-togenicity may arise from maternal drugs, and fetal antigenic material passing into the maternal circulation may cause maternal alloimmune sensitization syndromes. Iron deficiency and lack of other haematinics may result from increased demand. The massive increase in uterine blood flow and vascular compliance, necessary to maintain the blood supply for the developing fetus, can lead to significant haemorrhage at the time of placental separation. Changes in coagulation factors help to combat this risk but increase the potential for systemic thromboembolic events. Women with pre-existing haematological disease may be at particular risk during pregnancy or the pregnancy may be compromised by the underlying state. Whilst the majority of pregnancies progress without complication, management of high-risk cases should be coordi-nated in joint obstetric haematology clinics. Keywords anaemia; haematology; haemolytic disease; neonatal alloimmune thrombocytopenia; pregnancy; sickle; thrombocytopenia; thrombophilia; venous thromboembolic disease Anaemia In pregnancy there is an increase in red cell mass of 25% but a fall in haemoglobin concentration due to a proportionally greater expansion (50%) of plasma volume. This gives rise to the phys-iological anaemia of pregnancy, which is maximal at 32 weeks. Iron deficiency The total iron requirements of pregnancy exceed 1000 mg;1 this exhausts most women’s iron stores. The consequences of iron deficiency include fatigue, reduced resistance to infection, cardiovascular stress, poor tolerance to blood loss at delivery, and an increased need for transfusion. Iron deficiency may also increase the risk of intrauterine growth restriction, premature membrane rupture and early delivery. Diagnosis is difficult as serum ferritin increases throughout pregnancy and the usual microcytosis can be masked by the physiological increase in mean cell volume (MCV) of 5e10 fl. A trial of oral iron supplementation is often helpful. Absorption is optimized by administration with vitamin C 1 hour before food. True iron malabsorption is unusual and the most common indications for parenteral iron are non-compliance and intoler-ance. Some studies have advocated universal iron supplemen-tation 2 in pregnancy, but others have questioned the value of this approach. Folate and vitamin B12 deficiency Folate requirements increase in pregnancy as nucleic acid formation escalates. Folic acid supplements (400 mg daily) must be given in the first trimester to reduce the risk of neural tube defects in the fetus. A co-existing iron deficiency can mask the increased MCV of folate deficiency, requiring evaluation of the blood film to aid diagnosis. Although vitamin B12 concentration falls in pregnancy, this usually represents a dilutional effect and an increase in binding globulin, rather than a true tissue defi-ciency; the concentration returns to normal post-partum without treatment. Haemoglobinopathies Screening for haemoglobinopathies must be carried out as early as possible, to allow genetic counselling and prenatal diagnosis if the offspring is at risk of major haemoglobinop-athy. Screening should be in accordance with the NHS Sickle Cell and Thalassaemia Screening Programme, using the family origin questionnaire, routine blood cell indices and tests for sickle cell and other haemoglobin (Hb) variants, depending on the risks identified and the prevalence of the local population. Affected mothers will need close multidisciplinary management to support their pregnancy. Sickle cell disease Women with sickle cell anaemia and other haemoglobin combinations giving rise to sickle cell disease (such as HbSC, HbSb-thalassaemia, HbSD, HbSE and HbSO-Arab) have a very high morbidity risk, with more than half experiencing acute painful crisis and a quarter requiring peripartum admission to intensive care.3 In addition to sickle cell crisis and chest syndrome, maternal complications include severe anaemia, infection e especially urinary and respiratory4,5 e hypertension and thromboembolic events. Fetal risks are also higher and include miscarriage, growth restriction, stillbirth and prematurity. Women should be counselled preconceptually about potential problems, screened for end-organ damage and offered an opportunity to discuss the plan for management. General crisis prevention measures include avoidance of cold, dehydration5,6 and over-exertion. Compliance with folate supplements (5 mg) and continuation of prophylactic antibiotics should be empha-sized along with the need for prompt treatment of infection. Aspirin is recommended from 12 weeks’ gestation to reduce the risk of pre-eclampsia.7 Non-steroidal anti-inflammatory drugs (NSAIDs) should only be used between 12 and 32 weeks’ gestation.8 Hydroxycarbamide, which increases fetal haemoglo-bin (HbF) and therefore reduces the HbS percentage, is terato-genic and should be stopped 3 months before conception.8 Karyn Longmuir MBChB MRCP FRCPath is a Consultant Haematologist at Kettering General Hospital, UK. Competing interests: none declared. Sue Pavord MBChB FRCP FRCPath is a Consultant Haematologist and Senior Lecturer in Medical Education at the University Hospitals of Leicester, UK. Competing interests: none declared. MEDICINE 41:4 248 2013 Published by Elsevier Ltd.
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  PREGNANCY Routine top-upor exchange transfusion may be useful in reducing painful crises but has not been shown to affect overall outcome. Transfused blood should be negative for HbS and cytomegalovirus (CMV) as well as fully Rh phenotyped8,9 to reduce the development of alloantibodies. Venous thromboembolic disease Pregnancy is a prothrombotic state with a 10-fold increased risk of venous thromboembolic disease (VTE) in the antenatal period,10,11 increasing to 25-fold in the post-partum period. In addition to venous stasis due to reduced vascular tone and the pressure from the gravid uterus, the haemostatic system undergoes several changes in preparation for delivery: increased coagulation factors, including VII, VIII, fibrin-ogen and vWF (von Willebrand factor) reduction in anticoagulation activity, including a decrease in free protein S concentration and an increased resistance to activated protein C increased concentration of inhibitors of fibrinolysis. Management of acute VTE in pregnancy Objective diagnosis is crucial but difficult, as there is a progres-sive elevation in D-dimer concentration with pregnancy and a need to avoid potentially harmful imaging techniques. Once VTE is suspected, unless there are major contraindications, treatment should be given until the diagnosis is excluded.10 Meta-analysis has shown low-molecular-weight heparin (LMWH) to be at least as effective as unfractionated heparin, with a reduced risk of bleeding.10 The Royal College of Obste-tricians and Gynaecologists (RCOG) guidelines advise a twice daily dosing regimen10 to minimize peak and trough concentra-tions. Anti-Xa activity should be measured if there is renal impairment or extreme body weight. Treatment should continue for at least 3 months and until at least 6 weeks post-partum.10 Warfarin should be avoided as it is a teratogen, affecting facial, skeletal and nervous system development. Prevention of VTE All women should be risk assessed at booking and throughout the pregnancy and post partum period. A personal history of unprovoked or oestrogen-related venous thrombosis is a signifi-cant risk factor.12 Other risks include a family history of unpro-voked thrombosis, thrombophilia, age greater than 35 years, multiparity, obesity and immobilization.11,13 The most common inherited thrombophilias are heterozy-gosity for either factor V Leiden (FVL) or prothrombin gene mutation (PTGM), which account for up to 44 and 17% of cases, respectively. However, the relative risk (RR) of VTE is most marked with anti-thrombin (AT) deficiency, which has a relative risk of 119 compared to 6.9 and 9.5 for heterozygosity for FVL and PTGM, respectively.14 There is no role for routine thrombophilia screening but this may be indicated if the result would justify a change in manage-ment (i.e. provision of pharmacological thromboprophylaxis). If required, testing should include: antithrombin concentration protein C concentration polymerase chain reaction (PCR) for FVL and PTGM. The genetic test for FVL is preferable to a phenotypic test for activated protein C resistance as the latter is affected by the physiological changes to the coagulation system in pregnancy anti-phospholipid syndrome (APS) screen (only if there is a personal history of VTE). Protein S concentration falls in pregnancy and should be tested after 3 months post-partum. Management of at-risk pregnancies includes advice on general deep vein thrombosis (DVT) prevention, including leg care, compression stockings, mobilization and hydration, along with prophylactic LMWH as indicated. The duration of LMWH depends on the cumulative inherited and acquired risk factors. Some women may require treatment only in the post partum period but if antenatal thromboprophy-laxis is indicated this should start as soon as the pregnancy is confirmed as studies have shown that thrombotic risk is elevated in all trimesters. Anti-phospholipid syndrome Anti-phospholipid syndrome (APS) is an autoimmune disorder and an acquired thrombophilic state. The clinical features vary significantly but include placental insufficiency, recurrent fetal loss, thrombocytopenia and thrombotic events, both arterial and venous. Definitions for pregnancy morbidity include: three or more unexplained consecutive spontaneous abortions at less than 10 weeks’ gestation one or more unexplained death of a fetus at 10 weeks’ gestation or longer.15 Laboratory testing includes detection of anti-cardiolipin anti-bodies, a lupus anticoagulant or antibodies to b2-glycoprotein, on two or more occasions distant from the clinical event and more than 12 weeks apart. The use of aspirin and prophylactic LMWH in pregnancy has improved the rates of live birth from 10 to 70%.16 Prosthetic heart valves and pregnancy Anticoagulation for prosthetic heart valves is one indication for continuing warfarin throughout pregnancy, but the potential for teratogenic effects, especially with doses greater than 5 mg a day during weeks 6e9, must be considered. An alternative option is to switch to therapeutic LMWH,17 either for the duration of pregnancy or for the period up to 14 weeks and after 36 weeks. Monitoring with anti-Xa concentration is required. Joint management between haematology, obstetrics and cardiology, is essential along with full pre-pregnancy counselling. Bleeding disorders Inherited Pregnant women with von Willebrand’s disease (vWD) or carriers of haemophilia have an increased risk of bleeding. Factor VIII18 and vWF increase from 6 to 8 weeks’ gestation, reaching levels of three- to fivefold baseline by term. Whilst this provides protection for delivery for women with haemophilia A carrier status and most cases of vWD, they remain vulnerable in early pregnancy and in the puerperium, when levels may fall abruptly. DDAVP (desmopressin) can be used to cover first-trimester procedures and the post-partum period. Oral tranexamic acid is useful to prevent excessive post partum bleeding. Factor IX level does not change in pregnancy and women with a low factor IX MEDICINE 41:4 249 2013 Published by Elsevier Ltd.
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  PREGNANCY level (carriersof haemophilia B) may require recombinant factor concentrate for invasive procedures and delivery. Factor levels of 50% are generally considered safe for vaginal delivery and regional anaesthesia, although levels of 80% are usually required for caesarean section. Acquired Maternal haemorrhage remains a significant cause of maternal mortality.19 Haemorrhage is commonly due to uterine atony, but other causes include placental abruption, placenta praevia or increta, and uterine rupture, all of which can lead to dilutional coagulation deficits, disseminated intravascular coagulation (DIC) and hypovolaemic shock. DIC may also be triggered by eclampsia, sepsis, retained products or amniotic fluid embolus. All units should have a transfusion protocol for the management of massive obstetric haemorrhage. Thrombocytopenia The causes of thrombocytopaenia in pregnancy are numerous. The majority of cases are due to gestational thrombocytopenia, which affects approximately 6% of pregnancies. The platelet count tends to fall by about 10%; this is most pronounced in the third trimester20 and resolves by 6 weeks post-partum. Immune thrombocytopenia complicates 0.01e0.05% of pregnancies.20 The maternal autoantibodies may cross the placenta and cause fetal thrombocytopenia. This is usually mild with only 10% of babies having a platelet count under 50 109/ litre. Treatment for the mother is indicated if there are haemor-rhagic manifestations, the count is under 20 109/litre or if delivery is imminent when a count of over 50 109/litre is required.20 First-line therapy is corticosteroids;20 alternatives include anti-D or intravenous immunoglobin. Azathioprine or splenectomy in the second trimester can also be considered. Rituximab has been trialled in severe refractory cases, but evidence for its use and safety profile in pregnancy is lacking. A labour plan should be constructed to facilitate safe delivery, including the avoidance of ventouse, fetal blood sampling, external cephalic version and rotational forceps. The maternal platelet count should be over 80 109/litre for an epidural.20 The differential diagnosis of maternal thrombocytopenia includes thrombotic thrombocytopenic purpura (TTP), which does not cause fetal thrombocytopenia but may cause intra-uterine growth restriction and fetal loss. Untreated TTP is asso-ciated with a 90% maternal mortality. Other causes include haemolysis, elevated liver enzymes and low platelets (HELLP) syndrome, pre-eclampsia, haemolytic uraemic syndrome and conditions resulting in DIC. Alloimmune disorders Haemolytic disease of the newborn Haemolytic disease of the newborn (HDN) is caused by the transplacental passage of maternal alloantibodies against fetal paternally-derived red cell antigens, the mother having been sensitized by previous transfusion or pregnancy. This can lead to haemolysis of fetal red cells, causing anaemia and in severe cases, hydrops and fetal death. In the UK all pregnant women are tested for alloantibodies at booking and at 28 weeks.21 If anti-D, c or K is detected, quantitative monitoring is required on a monthly and then fort-nightly basis.21 If antibodies are detected, the father can be tested for the corresponding antigen to determine the risk to the baby.21 If the father is heterozygous, fetal DNA can be extracted from maternal blood samples from 12 weeks to determine the status of the fetus; red cell antigens that can be detected include D, c and K. Fetal ultrasonography, incorporating middle cerebral artery Doppler to screen for fetal anaemia, has replaced invasive tech-niques such as amniocentesis and has revolutionized the management of affected pregnancies, guiding the need to undertake intrauterine transfusion. Prevention of sensitization In the 15% of women who are Rh D negative, sensitization can be prevented by giving intramuscular anti-D within 72 hours22 following events such as termination of pregnancy, threatened abortion, abdominal trauma, chorionic villus sampling, amnio-centesis and delivery. A dose of 250 IU is sufficient for gestations up to 20 weeks, but at least 500 IU are required in later preg-nancy. This dose covers 4 ml of feto-maternal haemorrhage, so a Kleihauer test or flow cytometry should routinely be requested after 20 weeks to exclude larger haemorrhages requiring bigger doses.22 NICE recommend that all Rh D negative women be routinely offered 500 IU of anti-D at 28 and 34 weeks of pregnancy.22 Some units give 1500 IU at 28 weeks, which is effective, more conve-nient and improves compliance.22 Whilst routine antenatal anti-D prophylaxis has substantially reduced the number of cases of HDN,22 there are still new cases of sensitization to Rh D each year, mostly due to non-compliance with the national guidelines or occult feto-maternal haemorrhage occurring before 28 weeks. In addition, anti-D prophylaxis has no effect on the development of other alloantibodies, for example anti-c, anti-A or -B, or anti-K, which together account for 5% of cases of clinically significant HDN. Neonatal alloimmune thrombocytopenia In neonatal alloimmune thrombocytopenia (NAIT) the mother produces antibodies against paternally derived antigens, which are expressed on fetal platelets, usually HPA-1a or 5b23 It is one of the most common causes of severe thrombocytopenia in the neonate, affecting 1/2000 births.23 Around 50% of cases occur in the first pregnancy as opposed to HDN, where the first baby is usually unaffected.23 The diagnosis is suspected if the neonate has bruising, purpura or an unexpectedly low platelet count post-delivery.23 Other complications include intracranial haemorrhage, fetal anaemia and recurrent late miscarriage. Fortunately, the vast majority of cases are uneventful but in 20%, long-term neuro-logical sequelae are seen and 10% of cases are fatal.24 If the neonatal platelet count is under 30 109/litre or there is significant neonatal bleeding, platelet transfusion is required. Ideally these should be HPA compatible, but if this is not possible, random platelets can be used, although these have lower efficacy and survival. The diagnosis is confirmed by laboratory testing of both parents and has implications for future pregnancies, requiring careful counselling. Maternal treatment with intravenous immunoglobulin with or without corticosteroids and fetal blood MEDICINE 41:4 250 2013 Published by Elsevier Ltd.
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  sampling with inutero platelet transfusion may be required in subsequent pregnancies.23 A REFERENCES 1 Woodward M, Hoffbrand AV. Iron metabolism, iron deficiency and disorders of haem synthesis. Postgraduate Haematology. 5th edn. Oxford: Blackwell Publishing, 2005. 2 Milman N, Bergholt T, Eriksen L, et al. Iron prophylaxis during preg-nancy e how much iron is needed? A randomized dose-response study of 20e80 mg ferrous iron daily in pregnant women. Acta Obstet Gynecol Scand 2005; 84: 238e47. 3 Knight M, McClymont C, Fitzpatrick K, et al on behalf of UKOSS. United Kingdom oObstetric Surveillance sSystem (UKOSS) Annual Report 2012. National Perinatal Epidemiology Unit. Oxford, 2012. 4 Pastore LM, Savitz DA, Thorp JM Jr, Koch GG, Hertz-Picciotto I, Irwin DE. Predictors of symptomatic urinary tract infection after 20 weeks gesta-tion. J Perinatol 1999; 19: 488e93. 5 Ladwig P, Murray H. Sickle cell disease in pregnancy. Aust NZ J Obstet Gynaecol 2000; 40: 97e100. 6 Embury SH. Sickle cell disease. In: Hoffman R, Benz Jr EJ, Shattil SJ, Furie B, Cohen HJ, eds. Haematology: basic principles and practice. 2nd edn. New York: Churchill Livingstone, 1995. 7 RCOG Green-top Guideline No. 61 Management of sickle cell disease in pregnancy. London: Royal college of Obstetricians and Gynaecol-ogists, 2011. 8 Standards for the clinical care of adults with sickle cell disease in the UK. Sickle Cell Society. Available at: http://www. sicklecellsociety.org/ Carebook.pdf; 2008 (accessed 24th December 2008). 9 BCSH. Guidelines for the management of the acute painful crisis in sickle cell disease. Br J Haematol 2003; 120: 744e52. 10 RC OG green-top guideline No. 28 Thromboembolic disease in pregnancy and the puerperium: acute management. London: Royal College of Obstetricians and Gynaecologists, 2007. 11 RCOG Green-top Guideline No. 37 Thromboprophylaxis during preg-nancy, labour and after vaginal delivery. London: Royal College of Obstetricians and Gynaecologists, 2004. 12 Zotz RB, Gerhardt A, Scharf RE. Inherited thrombophilia and gesta-tional venous thromboembolism. Best Pract Res Clin Haematol 2003; 16: 243e59. 13 Walker ID, Greaves M, Preston FE. Investigation and management of heritable thrombophilia. Br J Haematol 2001; 114: 512e28. 14 Clinical updates in women’s healthcare: thrombosis, thrombophilia and thromboembolism, vol. VI. No. 4. American College of Obstetri-cians and Gynaecologists, 2005. 15 Hunt B, Greaves M. Acquired venous thrombosis. In: Hoffbrand V, Tuddenham E, Catovsky D, eds. Postgraduate haematology. 5th edn. Oxford: Blackwell Publishing, 2005. 16 Rai R, Regan L. Antiphospholipid antibodies, infertility and recurrent miscarriage. Curr Opin Obstet Gynecol 1997; 9: 279e82. 17 Chan WS, Anand S, Ginsberg JS. Anti-coagulation of pregnant women with mechanical heart valves: systematic review of the literature. Arch Intern Med 2000; 160: 191e6. 18 Chi C, Lee CA, Shiltagh N, Khan A, Pollard D, Kadir RA. Pregnancy in carriers of haemophilia. Haemophilia 2008; 14: 56e64. 19 Centre for Maternal and Child Enquiries (CMACE). Saving mothers’ lives: reviewing maternal deaths to make motherhood safer: 2006e08. The Eighth Report on Confidential Enquiries into maternal deaths in the United Kingdom. Br J Obstet Gynaecol 2011;118(suppl 1):1e203. 20 Guidelines for the investigation and management of idiopathic thrombocytopenic purpura in adults, children and pregnancy. Br J Haematol 2003; 120: 574e96. 21 Gooch A, Parker J, Wray J, Qureshi H. BCSH guidelines for blood grouping and antibody testing in pregnancy. London: BCSH, 2006. Available at: http://www.bcshguidelines.com/pdf/pregnancy_ 070606. pdf. 22 Parker J, Wray J, Gooch A, Robson S, Qureshi H. Guidelines for the use of prophylactic anti-D immunoglobulin. London: BCSH, 2006. Available at: http://www.bcshguidelines.com/pdf/Anti-D_ 070606. pdf. 23 Letsky EA, Greaves M. Guidelines on the investigation and manage-ment of thrombocytopenia in pregnancy and neonatal alloimmune thrombocytopenia. Maternal and Neonatal Haemostasis Working Party of the Haemostasis and Thrombosis Task Force of the British Society for Haematology. Br J Haematol 1996; 95: 21e6. 24 Kaplan C, Morel-Kopp M-C, Clemenceau S, Daffos F, Forestier F, Tchernia G. Fetal and neonatal alloimmune thrombocytopenia: current trends in diagnosis and therapy. Transfus Med 1992; 2: 265e71. PREGNANCY MEDICINE 41:4 251 2013 Published by Elsevier Ltd.