Immunological diseases in pregnancy

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  • Thus, the woman may experience both early and late fetal loss. Vascular thrombosis can occur in any organ or tissue(2). Deep vein thrombosis in the legs is most frequent, but the renal vein, the pulmonary vein, the inferior vena cava and the hepatic and portal vein may also be affected. The most common site of arterial thrombosis is the cerebral circulation, but occlusion of coronary and retinal arteries has also been reported(3;11;12). APA, particularly LA, is an independent risk factor for first and possibly recurrent ischemic stroke in young adults(13). Cerebral ischemic events can occur in any vascular territory(14). Cerebral angiography typically demonstrates intracranial branch or trunk occlusion or is normal in about one third of patients so studied(15). In addition, leg ulcer, chorea, and migraine have been associated with APAs(3). A wide range of abdominal manifestations have been reported in APApositive patients. Hepatic involvement is most numerous, thereafter thrombotic events in branches of the intestinal vasculature(16).
  • There is a variety of mechanisms by which APA antibodies may cause pregnancy loss. APAantibodies may interfere with the normal in vivo function of phospholipids or phospholipidbindingproteins that are crucial to regulation of coagulation(2). Tissue factor (TF), the majorcellular initiator of the coagulation protease cascade, plays important roles in boththrombosis and inflammation(64). In-vitro studies have shown that certain APAs, specificallythose directed against β2GP1, induce expression of TF(37;65). APAs also dysregulate thefibrinolytic system by cross-linking with annexin II (profibrinolytic endothelial cell surfacereceptor) on the endothelial cell surface inducing increased expression of TF(64).Autoantibodies have a causative role in monocyte TF expression. Growing evidencesuggests that APA-dependent induction of TF activity on circulating blood monocytes is animportant mechanism of hypercoagulability in APS(64). TF acting as an pro-inflammatorymolecule enhances neutrophil activity which may cause trophoblast injury, placentaldysfunction and damage to the embryo(64). Activated neutrophiles release reactive oxygenspecies and proteolytic enzymes leading to decidual damage(64). Complement C3 and C5play a role in APA-induced thrombosis(64). In vitro and animal studies have shown thatAPAs can bind directly to trophoblasts cells and cause cellular injury, defective extravillouscytotrophoblast (EVT) invasion (in the decidua and spiral arteries), and induce a localinflammatory response as a result of activation of complement(8). Activation of complementand recruitment of inflammatory
  • The most common known trigger for CAPS is infection. Other less common causes areanticoagulation withdrawal or low international normalised ratio (INR),medications (e.g., oral contraceptive), obstetric complications, neoplasia, systemic lupus erythematosus(SLE) flares, trauma and surgery. Nevertheless, in almost half of the cases, no obviousprecipitating factors have been identified and CAPS can often occur in patients without any previousthrombotic history
  • Although the initial presentation of CAPS may involve a single organ, in a very short period of time,typically days to weeks, patients develop clinical evidence of multiple organ thrombosis anddysfunction leading to organ failure that requires intensive care unit (ICU) admission. In the samecohort of CAPS patients [2] during the catastrophic episode, intra-abdominal involvement wasidentified in the majority of patients, mainly consisting of renal (71%), hepatic (33%), gastrointestinal(25%), splenic (19%), adrenal (13%) and pancreatic (8%) manifestations. Intrathoracic involvementwas also common and included pulmonary complications (64%), mainly acute respiratory distresssyndrome (ARDS) and pulmonary embolism, but occasionally intra-alveolar haemorrhage, as well ascardiac manifestations (51%), mainly cardiac failure and myocardial infarction or valve lesions.Cerebrovascular complications were also frequently present (62%), mainly consisting of encephalopathyand cerebrovascular accidents, but occasionally seizures, headache or silent brain infarcts.Skin manifestations were also frequent (50%) with livedoreticularis, leg ulcers, necrotic lesions,digital gangrene, purpura, splinter haemorrhages and multiple ecchymosis. Deep venous thrombosis(23%) and peripheral arterial occlusive disease (11%) were less frequently detected. Otherlesions occasionally encountered were retinal involvement (7%), mononeuritis multiplex (5%) andbone marrow necrosis (4%) [2].
  • I.v. heparin is usually administrated during the critical period. When the patient is stable, oralanticoagulation with an INR target around 3.0 can be initiated. Heparin is discontinued when thetarget INR is achieved with warfarin. The beneficial effects of Heparin are mediated by its capacityto inhibit thrombin, factor Xa and other activated clotting factors [11]. Heparin alsoinhibits complement activation [12]. Nevertheless, this mechanism has not been proven in humans,but in the setting of CAPS where there is an important inflammatory component, might be relevant.Corticosteroids are recommended in a situation with SIRS and excessive cytokine release, as they areable to inhibit the proinflammatory status mediated by both the nuclear factor-kappa B (NF-kB) andmitogen-activated protein kinase pathway [13].When initiated promptly, plasma exchange (PE) can be considered an effective and safetreatment for CAPS. It is useful by removing pathological aPL, cytokines and complement and alsoincorporating natural anticoagulants like antithrombin and protein C. The treatment of CAPS withPE is not well standardised. The best replacement fluid for PE is still a controversial issue [14].However, the efficacy of PE has been shown in other thrombotic microangiopathy and since CAPSis a critical situation with a high rate of mortality, it is recommended as part of the CAPS treatment[15].The rationale to use IVIG in the treatment of CAPS is based on its capacity to block pathologicalantibodies, increases its clearance, acts on the complement system and supresses cytokines [16]. Theiruse in refractory cases of APS resistant to standard therapy has also been recently reported [17]. IVIGshould be specially indicated in situations where there is concomitant infection because of its role asimmunomodulator rather than immunosuppressor.
  • Thrombotic thrombocytopenic purpura (TTP)
  • Immunological diseases in pregnancy

    1. 1. IMMUNOLOGICAL DISEASES IN PREGNANCY Presented by: Nandinii Ramasenderan & Mohd Amir Ghani
    2. 2. Overview: • Introduction • Antiphospholipid syndrome • Systemic Lupus Erythematosus • Idiopathic thrombocytopenic purpura
    3. 3. Introduction: Maintain pregnancy Maternal host bypass/ compensate for usual immunological process To ensure recognition & elimination of non-self molecules Bidirectional interaction btwn maternal & feto- placental unit Redirection of maternal immunology away from cell med. towards humoral responsiveness Conceptus protect: secreting TH2 cytokine & down regulates TH1 (IL2, INF γ, TNF) -harmful to the maintenance of pregnancy- Course of autoimmune disease is attended Imm adaptation facilitate intrauterine implantation of the blastocyst & maintenance of the fetal semi-allograft Normal preg: Not associated with increase in autoantibody production A preexisting autoimmune disease in the mother may influence the outcome of pregnancy Source: Buyon, JP., The effects of pregnancy on autoimmune diseases, 1998. Journal of Leucocyte Biology, 63, 281-283.
    4. 4. 1. ANTIPHOSPHOLIPID SYNDROME (APS)
    5. 5. A multisystemic disease, characterized by venous or arterial thromboses, or certain obstetric complications, & the presence of antiphospholipid antibodies (APAs) APAs are a heterogeneous group of autoantibodies that bind to negatively charged phospholipids, phospholipid-binding protein, or a combination of the two. Lupus anticoagulant (LA), anticardiolipin antibodies (aCL) & anti-beta 2 glycoprotein 1 (anti-β2GP1) antibodies are the main types. occurs in isolation as a primary APS in > 50% of the cases, or associated with other autoimmune diseases, most often with systemic lupus erythemathosus (SLE). occurs > in young women of fertile age (rarely in children, and only 12% of all APS occur after 50 years of age) Source: Haram, K., Jacobsen, EM., Sandset, PM., Antiphospholipid Syndrome : Chapter 10: APS in Pregnancy. 2012. inTech, Norway, 161-173.
    6. 6. Antiphospholipid Antibodies in Pregnancy IUGR Recurrent miscarriage Preeclampsia Placental abruption In addition: Arterial / Venous thrombosis Premature delivery or fetal death Source: Haram, K., Jacobsen, EM., Sandset, PM., Antiphospholipid Syndrome : Chapter 10: APS in Pregnancy. 2012. inTech, Norway, 161-173.
    7. 7. Pathogenesis of APS Source: Haram, K., Jacobsen, EM., Sandset, PM., Antiphospholipid Syndrome : Chapter 10: APS in Pregnancy. 2012. inTech, Norway, 161-173. Antiphospholipid antibodies Pregnancy loss Impair both trophoblast invasion in the decidua &the spiral arteries &the placental hormone production  uteroplacental insufficiency and fetal loss
    8. 8. Mechanism: Interfere with the normal in vivo fx of phospholipids or phospholipid binding proteins that are crucial to regulation of coagulation β2GP1, induce expression of TF (major cellular initiator of the coagulation protease cascade, plays important roles in both thrombosis and inflammation) APAs: Dysregulate the fibrinolytic system by cross-linking with annexin II (profibrinolytic endothelial cell surface receptor) on the endothelial cell surface inducing TF APAs bind directly to trophoblasts cells and cause cellular injury, defective extravillous cytotrophoblast (EVT) invasion (in the decidua and spiral arteries), and induce a local inflammatory response as a result of activation of complement TF acting as an pro inflammatory molecule enhances neutrophil activity which may cause trophoblast injury, placental dysfunction and damage to the embryo Source: Haram, K., Jacobsen, EM., Sandset, PM., Antiphospholipid Syndrome : Chapter 10: APS in Pregnancy. 2012. inTech, Norway, 161-173.
    9. 9. Diagnosis of APS -Both on clinical criteria and persistent positivity for APA. Laboratory testing for APA (ELISA) is used to confirm or refute the diagnosis -Essential that a positive test for APA is repeated after at least 12 weeks to confirm diagnostic criteria. • Clinically based on: 1) one or more unexplained deaths of normal fetuses at or beyond the 10th week of gestation, or 2) one or more premature births before the 34th week of gestation because of eclampsia, severe preeclampsia, or placental insufficiency, or 3) three or more unexplained consecutive spontaneous abortions before the 10th gestational week. Pregnant women with such complications should have laboratory testing. (Source: Miyakis, S., Lockshin, MD,. Atsumi, T., Branch, DW., Brey, RL., Cervera, R., et al. International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS), 2006. J Thromb Haemost, 4(2):295-306.) Source: Haram, K., Jacobsen, EM., Sandset, PM., Antiphospholipid Syndrome : Chapter 10: APS in Pregnancy. 2012. inTech, Norway, 161-173.
    10. 10. Outcome of pregnancy in APS • There is increasing evidence that the outcome of pregnancy in APS is influenced by the underlying phenotype. • Women with obstetric APS have better pregnancy outcomes than women with thrombotic APS. Source: Soh, MC., Pregnancy: Antiphospholipid Syndrome : Five-year View, 2010. MedScape MultiSpeciality Article, http://www.medscape.org/ viewarticle/732034_11 [Accessed on: 23-08-2013]
    11. 11. Current management of APS Heparin combined with aspirin. LMWHs are at least as effective as unfractioned heparin and are safer. MOA: Aspirin  inhibit APA med. hypercoagulopathy in the intervillous space of the placenta Heparin  prevent APA from interfering with cytotrophoblast migration & promote blastocyst implantation in addition to prevention of venous thrombosis  Prolonged heparin treatment may induce osteoporosis. (Better to use LMWH)  The pregnancy- associated prothrombotic changes in the coagulation system are maximal immediately after delivery. It is well accepted that persistent APA-positive women require post-partum anticoagulation. Therefore, it is desirable to continue LMWH during labor or delivery in women receiving antenatal thromboprophylaxis. The duration of recommendations range from 3-5 days(RCOG), to 6-8 weeks(Derksen, et al.) and up to 12 weeks(Erkan, D.,). Source: Haram, K., Jacobsen, EM., Sandset, PM., Antiphospholipid Syndrome : Chapter 10: APS in Pregnancy. 2012. inTech, Norway, 161-173.
    12. 12. Use of anticoagulant during pregnancy • Warfarin crosses the placenta and is teratogenic in the first trimester. • Women, who are on long- term warfarin treatment because of previous thrombosis, should switch to heparin when trying to conceive or when pregnancy is confirmed. • In high risk groups, such as women with mechanical heart valves, warfarin may be used in pregnancy, but only after organogenesis (6th-12th week) because of high risk of fetal malformations. • Warfarin treatment is however, also associated with spontaneous abortions, prematurity and CNS abnormalities. • As warfarin cross the placenta and subsequently affect fetal coagulation, there is a risk for bleeding complications in the fetus and during birth. Source: Haram, K., Jacobsen, EM., Sandset, PM., Antiphospholipid Syndrome : Chapter 10: APS in Pregnancy. 2012. inTech, Norway, 161-173.
    13. 13. Use of anti-coagulants in lactating women • Heparin and LMWHs are not secreted into breast milk and can be safely given to nursing mothers. • Warfarin is safe after delivery & for breast feeding, but requires close monitoring, frequent visits to an anticoagulant clinic & carries an increased risk of postpartum hemorrhage and perineal hematoma compared with LMWH. • In women with APA antibodies, and a history of severe preeclampsia, at least low dose aspirin (75-80 mg once a day) is recommended. • Glucocorticoids, cytotoxic agents, and intravenous immunoglobulin have no confirmed benefit and should not be used to treat pregnant women with APS. Source: Haram, K., Jacobsen, EM., Sandset, PM., Antiphospholipid Syndrome : Chapter 10: APS in Pregnancy. 2012. inTech, Norway, 161-173.
    14. 14. Contraception after birth • Oral estrogen coating contraceptives increase the maternal thrombotic risk of women with APAs and SLE. • Intrauterine devices are more appropriate. • However, progesterone-only contraceptives do not increase the risk of thrombosis. • If a woman with APS wants to be pregnant again, pre-conceptional treatment deserves consideration. • Some women with APS may need life-long warfarin treatment. Source: Haram, K., Jacobsen, EM., Sandset, PM., Antiphospholipid Syndrome : Chapter 10: APS in Pregnancy. 2012. inTech, Norway, 161-173.
    15. 15. CATASTROPHIC ANTIPHOSPHOLIPID SYNDROME (CAPS)
    16. 16. CAPS A very severe variant of the classic APS. Life threatening condition CH: clinical evidence of multiple organ involvement developing over a very short period of time, histopathological evid. of multiple small vessel occlusions and laboratory confirmation of the presence of aPL usually in high titre Common trigger: Infection Others: anticoagulation withdrawal or low INR, medications (e.g., oral contraceptive), obstetric complications, neoplasia, SLE flares, trauma and surgery
    17. 17. Source: Sciascia, S., Pedrera, CL., Roccatello, D. & Cuadrada, MJ., Catastrophic Antiphospholipid Syndrome (CAPS), 2012. Best Practice & Research Rheumatology, 26, 535-537.
    18. 18. Source: Sciascia, S., Pedrera, CL., Roccatello, D. & Cuadrada, MJ., Catastrophic Antiphospholipid Syndrome (CAPS), 2012. Best Practice & Research Rheumatology, 26, 535-537.
    19. 19. Management: • Current treatment guidelines suggest, in addition to early diagnosis, aggressive therapies to avoid the potentially fatal outcome. • The combination of: - high doses of intravenous (i.v.) heparin, - i.v. steroids, - i.v. immunoglobulins and/or - Repeated plasma exchanges are the basic treatment of choice for all patients with this severe condition (Evidence Level II) Source: Sciascia, S., Pedrera, CL., Roccatello, D. & Cuadrada, MJ., Catastrophic Antiphospholipid Syndrome (CAPS), 2012. Best Practice & Research Rheumatology, 26, 535-537.
    20. 20. 2. IDIOPATHIC THROMBOCYTOPENIC PURPURA (ITP)
    21. 21. IDIOPATHIC TROMBOCYTOPENIc PURPURA (ITP) Thrombocytopenia in pregnancy is relatively common, occurring in 7 to 10% of unselected pregnancies. ITP only accounts for approximately 3% of these cases as compared to gestational or incidental thrombocytopaenia of pregnancy (74%) and hypertensive disorders of pregnancy (21%) Source: Ministry of Health Malaysia, Management of immune thrombocytopenic purpura (ITP), 2006. Clinical Practice Guidelines, 24-29.
    22. 22. PATHOPHYSIOLOGY Platelet destruction secondary to a circulating immunoglobulin (IgG) antiplatelet antibody that crosses the placenta and may affect fetal platelets
    23. 23. Clinical Manifestation: • Abnormally heavy menstruation • Bleeding into the skin causes a characteristic skin rash that looks like pinpoint red spots (petechial rash) • Easy bruising • Nosebleed or bleeding in the mouth
    24. 24. Diagnosis: • a. Clinical • The diagnosis of ITP in pregnancy remains one of exclusion as there is no confirmatory laboratory test. • Important to obtain a detailed history and physical examination to exclude other secondary causes and to assess the clinical severity of haemostatic defects. • b. Laboratory • The aim of investigation is to confirm thrombocytopenia and to exclude secondary causes. If gestational thrombocytopenia is suspected, only regular monitoring of platelet counts is required without further investigations Source: Ministry of Health Malaysia, Management of immune thrombocytopenic purpura (ITP), 2006. Clinical Practice Guidelines, 24-29.
    25. 25. Differential Diagnosis HELLP syndrome TTP DIC APS Folate deficiency Viral: Dengue, HIV, HCV Spurious due to platelet clumping or macrothromb -ocytes Drug- related Gestational or incidental thrombocytopeni a of pregnancy Pre- eclampsia Modified from British Committee for Standards in Haematology General Haematology Task Force (2003) Source: Ministry of Health Malaysia, Management of immune thrombocytopenic purpura (ITP), 2006. Clinical Practice Guidelines, 24-29.
    26. 26. Investigations: 1) Full blood count 2) Peripheral blood film: to exclude platelet clumping and red cell fragmentation (in TTP, pre-eclampsia, HELLP or DIC) 3) Coagulation screen (PT, APTT, BT, fibrinogen, D-dimer) 4) Liver function tests 5) HIV screening 6) ANA 7) Lupus anticoagulant/ anticardiolipin antibody ~for patients with past history of unexplained pregnancy losses/ thrombosis (Grade C) ~Bone marrow examination is unnecessary unless there is suspicionof myelodysplastic syndrome, leukaemia or lymphoma(Grade C) Source: Ministry of Health Malaysia, Management of immune thrombocytopenic purpura (ITP), 2006. Clinical Practice Guidelines, 24-29.
    27. 27. Management: • Close collaboration between haematologist, obstetrician, neonatologist and anaesthetist is needed to ensure a good pregnancy outcome. • Platelet counts in women with ITP may decrease as pregnancy progresses and need to be monitored closely as follows: -1st to 2nd trimester : monthly -3rd trimester : 2 weekly -at term : weekly • The principal of management in ITP during pregnancy is to do least harm to both the mother and the foetus. The decision to treat is based on assessment of the risk of significant haemorrhage. Source: Ministry of Health Malaysia, Management of immune thrombocytopenic purpura (ITP), 2006. Clinical Practice Guidelines, 24-29.
    28. 28. Modalities of treatment of ITP in pregnancy • Corticosteroids and IVIG are effective and safe in pregnancy and are used as first line therapy. (Grade B) • Androgen analogs such as danazol and cytotoxic agents are contraindicated in the treatment of ITP in pregnancy due to its teratogenecity. (Grade C) • Splenectomy is considered only if above measures fail to elevate the platelet counts and patient has serious bleeding. This is best deferred until the second trimester to prevent miscarriage. Source: Ministry of Health Malaysia, Management of immune thrombocytopenic purpura (ITP), 2006. Clinical Practice Guidelines, 24-29. Recommendations : When to treat? • Platelet count < 20 x 109/L before 36 weeks • Symptomatic bleeding at any trimester • Platelet count < 30 x 109/L after 36 weeks
    29. 29. Management before 36 weeks: • Management can be divided into 3 groups based on clinical presentation & platelet count. 1) Asymptomatic patients with mild to moderate thrombocytopenia (platelet count >20 x 109/L) a. No treatment is required b. To expect further drop of platelet during 3rd trimester 2) Symptomatic patients or those with moderate to severe thrombocytopenia (platelet count <20 x 109/L) a. Corticosteroid prednisolone 1mg/kg/day with rapid taper to keep <30mg/day (safe from adverse foetal effects) AND/ OR b. IVIG 1g/kg (according to pre-pregnant weight) every month Source: Ministry of Health Malaysia, Management of immune thrombocytopenic purpura (ITP), 2006. Clinical Practice Guidelines, 24-29.
    30. 30. 3) Severe thrombocytopaenia (platelet count <10 x 109/L) • The approach in managing these groups of patients is to deliver the minimum amount of therapy necessary. a. high dose corticosteroid (methylprednisolone/dexamethasone) AND b. periodic high dose IVIG 1g/kg x 2 days ~Splenectomy during 2nd trimester is considered if above measures fail to elevate the platelet count.~
    31. 31. Management after 36 weeks: • The mother should be assessed at 36 weeks by both the haematologistand the obstetrician. • platelet count >30 x 109/L - safe for normal vaginal delivery in patients with otherwise normal coagulation • platelet count <30 x 109/L - admit for pulsed IVIG and close monitoring • The mode of delivery in a mother with ITP is based on obstetric indications. • Caesarian section is only for obstetric indications and the patient will require: i. iv corticosteroids if platelet count between 30-50 x 109/L ii. IVIG and iv corticosteroids if platelet count <30 x 109/L iii. IVIG and iv corticosteroids plus platelet transfusion if platelet count<10 x 109/L Source: Ministry of Health Malaysia, Management of immune thrombocytopenic purpura (ITP), 2006. Clinical Practice Guidelines, 24-29.
    32. 32. Management during labor: • Platelet count above 50 x 109/L is safe for caesarian section under general anaesthesia but not epidural anaesthesia. • Epidural anaesthesia is best avoided because of the risk of epidural haematoma and cord compression. • However, patients who prefer epidural analgesia need to be admitted earlier for IVIG infusion in order to raise the platelet counts to a safe level >80 x 109/L. • If platelet counts are less than 50 x 109/L and patient requires immediate caesarian delivery, administer IVIG and methylprednisolone. • Give platelet transfusion just prior to surgery. Source: Ministry of Health Malaysia, Management of immune thrombocytopenic purpura (ITP), 2006. Clinical Practice Guidelines, 24-29. ‘Safe’ Platelet Thresholds for delivery • vaginal delivery: > 30 x 109/L • caesarean section: > 50 x 109/L • epidural anaesthesia: > 80 x 109/L (Grade C)

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