AUTOIMMUNE DISEASES IN PREGNANCY SEMINAR

PRESENTATION

1. AUTOIMMUNE DISEASES IN PREGNANCY DR. Medha Premnath Moderator: DR. Sailaja

2. Systemic lupus erythematosus in pregnancy Idiopathic, chronic inflammatory disease that affects skin, joints, kidneys, lungs, serous membranes, liver, CNS and other systems of the body. Phases of remission and relapse. 10x more common in women than men. Familial predisposition Alterations in HLA system Clinical features- multisystemic -fatigue, fever, arthralgia, myalgia, weight loss, skin rashes, lymphadenopathy, nephropathy, effusions (pleural and pericardial), seizures and psychosis.

3. Pathophysiology Increased SLE disease activity-increased levels of estrogen, prolactin, and T–helper 2 cell cytokines . Possible causes of flares during the postpartum period include the following: -Decreased levels of anti-inflammatory steroid -Elevated levels of prolactin -Changes in the neuroendocrine axis -Changes in estrogen and progesterone levels

4. Risk factors of SLE General risk factors: • Family history(10%) • Genetic factors (25to 40% concordance rate in monozygotic twins). • The genes involved in SLE are HLADR3, STAT4, APOL1, FCGR3A . • The strongest genetic risk factor for developing SLE is compliment defciency , most common is Cl9> C2> C4. • The relative risk of SLE rises if the autoimmunity gene on chromosome 16 is inherited.

5. Environmental factors: Have an important role only in females who are genetically susceptible for SLE 1.OCP/HRT (most important). 2 UVB rays. 3. Vitamin D deficiency. 4. Epstein barr virus. 5. Smoking

6. Pathogenesis - type 3 hypersensitivity reaction . -immune complex mediated disease. Antibodies in SLE: Appear three years before the onset of clinical features. A number of auto antibodies are produced in patients with SLE. Antinuclear antibodies • Seen in 98% cases of SLE.

7. Best screening test for connective tissue disorders. • ANA is absent when tested twice - SLE, connective tissue disorders unlikely. • Significant method : Indirect immunofluorescence test using hep 2 cell line. • Titre : >/=1: 80 (Significant). Anti ds DNA antibody : • Seen in 75% patients. • Specific antibody (Anti smith › Anti ds DNA). • Titre directly proportional to disease activity. • Associated with increased risk of nephritis and vasculitis.

8. Anti smith antibody : • most specific antibody. • Seen in 25% to 35% patients. Anti RO (Anti SSA) and Anti LA (Anti SSB) antibody: • Predisposes to cutaneous lupus. Associated with neonatal lupus with heart block. Good prognosis- decreased risk of vasculitis and nephritis.

9. Anti phospholipid antibody : Associated with thrombosis and thrombocytopenia and fetal loss. Other Anti RNP antibody: Anti histone antibody : Seen in drug induced lupus . Anti erythrocyte antibody • may develop hemolysis. • Associated with anemia. • Direct Coombs test is positive. Anti platelet antibody

10. Drug induced lupus Drugs inducing a lupus like syndrome: Proton pump inhibitors. 2. Thiazide diuretics. 3. Anti fungal 4. Antihypertensive. 5. Statins. 6. Anti epileptics. Anti histone antibody is positive. Rarely associated with glomerulonephritis. It usually regresses when the medication is stopped

11. Diagnosis Suspected by clinical features and confirmed by serological markers indicating the presence of autoantibodies. Revised American College of Rheumatology Classification Criteria for Systemic Lupus Erythematosus - SLE ; patients must have at least 4 of 11 clinical and laboratory criteria at one time or serially. -less than four features of SLE, (do not meet the criteria); lupus-like disease.

12. Lupus and pregnancy Epidemology : • Incidence I in 900 pregnancies. • During pregnancy, lupus improves in one third of women, remains unchanged in one third and worsens in the remaining third • maternal mortality rate with SLE is 325 per 100000. • maternal deaths occur in those with active disease. Pregnancy outcome : • It is best in the following conditions: i Well controlled disease 6 months before conception ii. Lupus nephritis manifested by proteinuria or renal dysfunction is absent iii. No coexisting APLA or lupus anticoagulant iv Superimposed pre-eclampsia does not develop. • women who have confined cutaneous lupus, do not have adverse outcomes. • Newly diagnosed SLE during pregnancy tends to be severe.

13. Pre-conceptional counselling Controlled prior to pregnancy by adjusting the dose of the maintenance medications. Counsel patients about the teratogenicity and adverse effects of the medications used to treat SLE before therapy is initiated Informed about the risk of flares, preeclampsia and fetal compromise. Pregnancy avoided in active lupus nephropathy, nephrotic syndrome and severe hypertension . Renal failure is an absolute contraindication to pregnancy.

14. Multidisciplinary team Antenatal care should begin early. Frequent antenatal visits every fortnight in the first and second trimesters and weekly in the third trimester. Early dating ultrasonography (USG) should be performed. Strict monitoring; SLE flares, preeclampsia and IUGR For lupus nephritis patients, baseline 24-hour urine creatinine clearance and total proteins should be assessed and repeated as required. Delivered at term. Postdatism should be avoided.

15. Pregnancy complications : • Pregnant females with SLE are at greater risk for thrombotic complications, including preeclampsia and eclampsia Preterm delivery. • infections. • Fetal loss. • Still birth • Cesarean delivery. PPH • LBW infants. • NICU admission.

16. Management during pregnancy First antenatal visit investigations : In all patients with SLE at the first antenatal visit obtain baseline values of • СВС • 24 hour urine collection/urine analysis : • Serum complement levels : C3 and C4 ( CH 50). • ds DNA titres • Anti RO and anti LA antibodies should be checked, as it is associated with congential heart blocks in the fetus . • Lupus anticoagulant and Anticardiolipin antibody

17. Investigations to be done in each trimester/monthly if disease severity increases: •CBC GFR • Anti ds DNA • Protein: creatinine ratio. • compliment study Other investigations done : • Obstetric ultrasound for fetal growth restriction and oligohydramnios - every three weeks- at 24 weeks of gestation. • Antepartum testing fetal surveillance weekly or twice weekly-initiated at 32 weeks . Serial fetal echocardiography

18. Pharmacological treatment According to ACR guideline Hydroxychloroquine (HCQ) during pregnancy, if possible. low‐dose aspirin (81 or 100 mg daily), beginning in the first trimester. EULAR guidelines HCQ before conception and throughout pregnancy to control disease activity. HCQ, oral glucocorticoids(prednisolone and methylprednisolone), azathioprine, cyclosporine, and tacrolimus can be used to prevent or manage SLE flares during pregnancy. Moderate-to-severe flares can be managed with additional strategies, including glucocorticoid intravenous pulse therapy, intravenous immunoglobulin, and plasmapheresis.

19. Drugs which are contraindicated in pregnancy: • mycophenolate( category D) • methotrexate(category X) • Cyclophosphamide ( category D) Leflunamide (category X)

20. Drugs while breastfeeding Short-acting NSAIDs ( eg , ibuprofen), antimalarials, low-dose prednisone, warfarin, and heparin seem to be safe Prednisone (< 15-20 mg/d) can be used safely during breastfeeding because only small amounts (5% of the dose) are secreted in breast milk. HCQ is also secreted in breast milk; therefore, this drug should be used with caution. HCQ may displace bilirubin, resulting in kernicterus. Azathioprine, methotrexate, cyclophosphamide, or mycophenolate are contraindicated.

21. Intrapartum management Throughout labour , fetal monitoring should be continuous. Intravenous (IV) glucocorticoids should be given in patients receiving maintenance therapy during pregnancy. Hydrocortisone 100mg IV every eight hourly for 48 hours at the time of delivery Postpartum management Postpartum SLE flares looked for. Maintenance therapy restarted as before. Neonatal lupus looked for.

22. Lupus nephritis in pregnancy Lupus nephropathy may worsen during pregnancy. Increased proteinuria in patients with chronic renal failure. • high incidence of gestational hypertension and preeclampsia. • maternal mortality rate -13%. • Nephritis during pregnancy → immunosuppressive therapy should be continued with hydroxychloroquine, cyclosporin, azathioprine and tacrolimus. • New onset nephritis or severe renal flare → Treated with tacrolimus and intravenous corticosteroids or intravenous immunoglobulin may be added

23. SLE and pregnancy SLE exacerbation (SLE flare) SLE flares is controversial- pre-eclampsia may mimic SLE flares . Rate of flares during pregnancy or postpartum varies between 15%-60% Increased risk of flare; active pre-pregnancy disease, discontinue medication during pregnancy.

24. Lupus vs preeclampsia/ eclampsia Features:• Preeclampsia and SLE share common features of hypertension, proteinuria, edema , and renal function deterioration. • Central nervous system involvement with SLE can result in convulsions similar to those of eclampsia management: • Treatment of Lupus nephritis –immunosuppression • Treatment of severe preeclampsia or eclampsia → immediate delivery

25. Differentiating Pre-eclampsia and Systemic Lupus Erythematosus (SLE)/Lupus Nephropathy Flare

26. Management of SLE flare in pregnancy Starting glucocorticoids or increasing their dosage treats mild-to moderate SLE flares without renal or CNS involvement. Prednisolone (15–30 mg/day) results in improvement. Severe exacerbations without renal or CNS involvement , prednisolone 1–1.5 mg/kg/day in divided doses for 10 days and tapered. Severe exacerbations involving CNS or kidneys- Initially a daily IV dose of methylprednisolone 10–30 mg/kg for 5 days and tapered gradually. Plasmapheresis and IVIG reserved to treat severe cases of SLE flare refractory to the standard therapy.

27. Neonatal lupus syndrome : • Characterised by skin lesions that is lupus dermatitis/skin rash (seen in 30 to 40% of infants). • Skin lesions appear at 4 to 6 weeks of age. thrombocytopenia and hemolysis in 5 to 10% cases. • Cutaneous lupus, thrombocytopenia and autoimmune haemolytic anemia is transient and clears within few months There may be hepatic involvement also • occasionally congenital heart block , which is permanent can be seen • Recurrence -25% The only proven maternal treatment which lowers the risk of neonatal lupus is hydroxychloroquine. Steroids decrease the risk as per some studies.

28. Congenital heart block : • Fetal and neonatal heart block results from diffuse myocarditis and fibrosis in the region between atrioventricular node and bundle of his. Heart block is permanent and a pacemaker is generally necessary. • Congenital heart block develops exclusively in fetuses of women with antibodies to SSA and SSB antigens .(2-3%) 20% with a prior affected child. • 20% of them die after birth and one third are stillborn. • Congenital heart block is also associated with a risk for cardiomyopathy .

29. PR interval and dexamethasone (PRIDE) study → antiSSA and anti SSB when present -maternal oral dexamethasone 4 mg daily and weekly fetal echocardiography → To check for the development of heart block → The study concluded that maternal dexamethasone did not prevent progression from 2nd to 3rd block and 3rd Av block was irreversible →Dexamethasone did not decrease the disease progression nor the need for pacemaker in the neonatal period or overall survival rates → Dexamethasone not recommended for this indication. • more recent studies have shown that in patients with SLE with prior affected children → Early treatment with hydroxychloroquine was associated with a significant decrease in recurrence of congenital heart block • Another study showed treatment with hydroxychloroquine was associated with greater than 50% reduction in the rate of fetal heart block.

30. Contraception • Contraception of choice : Progesterone containing injections, implants Importance of using contraception while they are taking methotrexate, leflunomide, cyclophosphamide, and mycophenolate. • OCPs are contraindicated if APLA antibodies are present, or if there is history of thrombosis or vasculitis • IUCDs are not contraindicated even if patient is on immunosuppressive therapy. • Tubal sterilisation is best done in the postpartum period or whenever SLE is quiescent.

31. Thromboprophylaxis in pregnancy MBRRACE-UK DEC 2015 DIRECT CAUSES OF DEATH RATE PER 100000 MATERNITIES THROMBOSIS AND THROMBOEMBOLISM 1.01 APH AND PPH 0.55 AMNIOTIC FLUID EMBOLISM 0.42 SEPSIS 0.29 ECTOPIC PREGNANCY 0.25 PREECLAMPSIA AND ECLAMPSIA 0.25 ANAESTHESIA 0.13

32. Hemorrhage is the leading direct cause of death [30.23%] followed by thromboembolism [25.58%]. Indirect cause for maternal mortality is anemia (67.44%)(Maternal mortality in India:IEG Working Paper, 2015)

33. Thromboprophylaxis in pregnancy The current 2015 RCOG guidelines look at the number of risk factors for DVT Risk Factors to be Considered in Pregnancy/Puerperium for Evaluating Thromboembolism

34. New onset/transient risk factors Hyperemesis gravidarum, dehydration Ovarian hyperstimulation syndrome (OHSS) in first trimester especially after in vitro fertilisation Bone fracture Any surgical procedure in pregnancy or puerperium, current systemic infection Immobility > 3 days or prolonged travel > 4 hours

35. RISK ASSESMENT

36. Initiation of Thromboprophylaxis 4 OR > RISK FACTORS Through out pregnancy and 6 weeks postpartum 3 RISK FACTORS 28 WEEKS OF GESTATION AND 6 WEEKS POSTPARTUM 2 RISK FACTORS 10 DAYS POSTPARTUM Any previous VTE except a single event related to surgery: As early as possible usually after pregnancy is confirmed

37. Recurrent VTE who are on oral anticoagulants such as warfarin should be converted to LMWH prior to 6 weeks or within 15 days of the missed period . Undergoing caesarean section should be considered for thromboprophylaxis. Risk of VTE is higher after an emergency lower segment caesarean section (LSCS) than an elective LSCS. Those on LMWH must take their dose one day prior to LSCS and omit it on the day of the caesarean section.

38. Methods of thromboprophylaxis Noninvasive and mechanical method Early mobilisation , adequate hydration, calf exercises, graduated stockings Graduated compression stockings have been recommended for the following group of patients: - Hospitalised patients with contraindication to LMWH. Postcaesarean section while in the hospital (along with LMWH) in those with high risk for VTE. Patients with the previous VTE managed on outpatient basis. Prolonged travel (>4 hours)

39. Drugs for thromboprophylaxis recommended drug of choice is LMWH. unfractionated heparin may be used. Newer drugs include heparinoids, direct thrombin inhibitors, factor Xa inhibitors Aspirin is not recommended for thromboprophylaxis in pregnancy.

40. UFH vs LMWH • UFH is cheaper, shorter half life, S/C or I/V and can be reversed rapidly • UFH causes HIT, bone loss, needs monitoring baseline platelet count, after 2-3 days, weekly x 2 weeks then monthly • UFH preferred in patients with severe renal insufficiency. • LMWH is effective, easy to administer S/C, has more predictable response and do not require routine monitoring.

41. Heparin anticoagulation dosing • Prophylactic dose anticoagulation Reduce risk of thromboembolism Minimize risk of bleeding • Intermediate dose anticoagulation Adjustment of prophylactic dose with weight gain in pregnancy • Therapeutic dose anticoagulation Doses reserved for treatment of thromboembolic disease

42. Low-molecular-weight heparin LMWH-drug of choice safe in pregnancy and do not cross the placenta. administered subcutaneously. enoxaparin, dalteparin and tinzaparin. Effectiveness assessed by measuring anti-Xa levels. Monitoring anti-Xa level is not recommended. baseline platelet count and another one after starting the therapy must be done as thrombocytopenia may occur. subsequent monitoring is not required.

43. Dose of LMWH for antepartum and postpartum prohylaxis

44. dose needs to be modified in cases of obesity and renal failure. In the high-risk group, therapeutic dose of enoxaparin which is 1 mL/kg twice daily needs to be given. disadvantages: Action of LMWH is not completely reversible with protamine sulphate. Other disadvantages are higher cost and longer half-life making management in labor little difficult. risk of osteopenia. Enoxaparin or dalteparin reversal is based on the following

45. Contraindications to LMWH

46. Unfractionated heparin safe in pregnancy, not cross the placenta; lacks fetal toxicity. heparin is administered subcutaneously( prophylaxis) dose is dependent on the weight and aPTT value. In case of high and very high risk group, therapeutic dose needs to be given to achieve target aPTT value which is 2–2.5 times INR

47. Dose of UFH Inj Heparin 5000 IU subcutaneously 12 hrly throughout pregnancy Inj Heparin subcutaneously 12 hrly with increasing doses as pregnancy progresses 5000 IU - 7500 IU 1st trimester 7500 IU - 10000 IU 2nd trimester 10,000 3rd trimester No monitoring usually but aPTT done if any concern about bleeding or thrombosis

48. Unfractionated heparin is used intravenously in case of an acute episode of DVT. The loading dose of 80 units/kg given bolus followed by 18 units/kg IV so as to achieve the required aPTT of 1.5–2.5 times the control. The aPTT must be checked 4–6 hours after loading dose, 6 hours after changing the dose and then daily once target level is achieved. Intravenous heparin is continued for 5–7 days and then converted to subcutaneous. Therapeutic anticoagulation must be continued for at least 6 weeks postpartum or for a total duration of 6 months after the episode.

49. Complications; bleeding, skin necrosis, thrombocytopenia and osteoporosis. HIT -early or late onset. Early onset or benign or reversible thrombocytopenia occurs generally in the first 48 hours of the initiation of therapy; selflimited late-onset HIT is immune mediated (IgG antibodies). Platelet count falls to less than 50% of the baseline. due to formation of antibodies against the heparin-platelet factor 4 complex; . Heparin needs to be stopped. Platelet transfusion is not indicated as it increases the risk of thrombosis. manifests 5 and 14 days of heparin therapy . platelet count should be done prior to initiation, after 3 days and 1 week.

50. Osteoporosis; Calcium intake should be increased, sometimes heparin therapy requires to be stopped. Effect of heparin is reversed with protamine sulphate . One milligram of protamine sulphate neutralises 100 units of unfractionated heparin

51. Warfarin • Avoided as it crosses placenta • Teratogen cause fetal embryopathy (6-12 weeks) • Fetal anticoagulation resulting in intracranial haemorrhage 14%–50% risk of causing miscarriages, 30% chance of congenital fetal anomalies, bleeding disorder and stillbirth. • Considered only for women with high risk of thrombosis like mechanical valves • Safe in breast feeding

52. Antepartum conversion to UFH Women receiving therapeutic or prophylactic LMWH may be converted to unfractionated heparin in the last month of pregnancy or sooner if delivery appears imminent or planned delivery with withholding of anticoagulants for 24 h.

53. Thromboprophylaxis discontinued • Woman has any vaginal bleeding or in labor Anticoagulation to be stopped before elective delivery and in labour . Before induction of labour or elective caesarean, UFH needs to be stopped at least 12 hours prior, 24 hours for LMWH • If elective CS is planned: Regional technique avoided for at least 12 hrs after prophylactic dose of LMWH and 24 hrs of therapeutic dose; 6 hrs and 12 hrs with UFH • If epidural catheter is to be removed: Epidural catheter not to be removed within 12 hrs of recent injection.

54. When to initiate thromboprophylaxis postnatally LMWH/ UFH • Vaginal delivery:after 6-12 hrs if no PPH and no epidural After Caesarean section: after 12-24 • Resumption in patients receiving antenatal thromboprophylaxis can be earlier 4-6 hrs after vaginal delivery and 6-12 hrs after CS in the absence of significant bleeding.

55. Thromboprophylaxis continued postpartum

56. If thromboprophylaxis is not discontinued Warned regarding per vaginal bleeding. Anticoagulation must be stopped in any such episode. Labour , the time of the last dose of heparin noted. Baseline platelet count and aPTT should be done. Protamine sulphate should be kept available. Fresh frozen plasma should also be kept ready if required. Care should be taken to prevent postpartum haemorrhage

57. Danaparoid is a heparinoid with anti-II and anti-Xa activity. can be given subcutaneously or intravenously No adverse fetal outcome. Direct thrombin inhibitors such as lepirudin , hirudin, bivalirudin and argatroban . category B drugs and not sufficient data are available regarding the safety of these drugs in human pregnancy. Fondaparinux is an anti-Xa inhibitor. Placental transfer of this drug is minimal and it appears to be the safest newer anticoagulant as an alternative to heparin in the absence of danaparoid. Newer oral anticoagulants, dabigatran and rivaroxaban. These act by direct inhibition of thrombin and factor Xa, However, not approved for use in pregnancy.

58. Thank you!