autoimmune disease pregnany obstetrics and their management

Autoimmune disorders pregnancy

1. Autoimmune disorders in pregnancy Dr.Rajesweri pg3 Dr.Sakshi pg2 Consultant Dr.Archana Mishra Dr.Vijay Zutshi, Dr.Renu arora ,Dr.Upma saxena

2. introduction Chronic diseases caused by immune responses directed toward autologous(SELF) components of the body More common in females than males(10:1 ) especially child bearing age Reasons not well understood Estrogen/X chromosome/innate immune response in females/different environment exposure may be the reason for gender bias. Clinically progressive with relapse and remissions

3. Pregnancy and immunity

4. Types of Autoimmune Disorders in pregnancy Organ-Specific • Single tissue or organ • M ultiple organ-specific • E.g.- Type 1 DM, autoimmune hepatitis, thyroiditis System-specific (older name- collagen vascular disease) • Multiple organs of the same system Different systems are affected by the same autoantibodies • E.g.- SLE, Sjogren’s Syndrome, Scleroderma

5. Autoimmune disorders in pregnancy Antiphospholipid antibody syndrome Systemic lupus erythematosus Rheumatoid Arthritis Immune Thrombocytopenic Purpura Sjogren syndrome Systemic sclerosis/scleroderma Takayasu arteritis Inflammatory bowel disease/Crohn’s Disease Myasthenia Gravis/Ehlers danlos syndrome Autoimmune thyroiditis/autoimmune hepatitis/Vasculitis/dermatitis/psoriatic arthropathy Type 1 diabetes mellitus……

6. Antiphospholipid antibody syndrome(APS) Acquired systemic autoimmune disorder moderate to high levels of antiphospholipid antibodies specific clinical features (arterial or venous thrombosis or pregnancy morbidity) m/c acquired thrombophilia Also called Hughes syndrome

7. CLASSIFICATION OF APS CLINICAL CLASSIFICATION Thrombotic Obstetric Non-criteria Obstetric Seronegative CAPS Asymptomatic carriers (1-5%) Primary : 50% other features of connective tissue disease are absent Secondary : 50% secondary to connective tissue disease e.g. SLE Catastrophic antiphospholipid antibody syndrome(CAPS)/Ascherson syndrome: Rare/1% of patients/progressive/mortality 50%

8. Aetiology Although aPL antibodies are clinically linked to APS whether they are involved in pathogenesis is unclear Possible triggers Infections (via molecular mimicry),Syphilis, Hepatitis C infection, HIV , Malaria and Bacterial septicaemia Drugs - Procainamide, Quinidine, propranolol, hydralazine, phenytoin, chlorpromazine, quinine Genetic predisposition- HLA –DRW53,DR7—HISPANIC DR4 - white .

9. The family of APL ab are heterogenous and the targets vary. Lupus anticoagulant-LA-Misnomer Anti cardiolipin antibody- aCL Anti b2 glycoprotein 1-Anti B2GP1 Normally-- B2GPI helps in elimination of apoptotic cells and as natural anticoagulant. ACL---risk of stroke—arterial thrombosis LA---venous thrombosis TNF alpha and complement activation(C3) –pregnancy loss ANTIPHOSPHOLIPID ANTIBODIES

10. Pathogenesis Homeostatic regulation of blood coagulation is altered. Defect in cellular apoptosis---exposure of membrane phospholipids(negatively charged) to the binding of various plasma proteins---b2gp1 complex, neoepitope---target for autoantibodies. Oxidized b2GP1 ---activates dendritic cells –autoantibodies are produced. Apl’s inhibit production of placental prolactin and insulin growth factor binding protein-1--- trophoblast syncytium formation, placental apoptosis A ntibodies against prothrombin, proteinC , S annexins. Ab react against oxidized LDL— atherosclerosis and MI.

11. Abnormal placental function in aps Narrowing of spiral arteries Intimal thickening Acute atherosis Fibrinoid necrosis Infarction and thrombosis in placenta Endothelial cell activation-increased adhesion molecules, cytokines, arachidonic acid metabolites Reactive oxygen species C3 ACTIVATION AND TNF ALPHA-RPL

12. Complications Recurrent pregnancy loss : 15% of RPL Preeclampsia/eclampsia : 15-50%. 15% of severe PE before 34 w have APL Ab 3. FGR : 30%-60% 4. Preterm labor/prom 5. Maternal thrombosis: 5-12% vs 0.025-0.1%(gen obs population) 6. Catastrophic APS and postpartum syndrome

13. Catastrophic Antiphospholipid Syndrome(CAPS) A syndrome of multisystem involvement. <1% of patients. Multiple small vessel occlusions---multi organ failure. Acute onset 3 different organ systems involve in a week Acute microangiopathy is characteristic ARF,ARDS,CEREBRAL INJURY,MYOCARDIAL ischemia. Potentially lethal! Trigger factors involved--infections, trauma, neoplasia, pregnancy, lupus flares. SLE-higher mortality. T riple therapy : anticoagulation, corticosteroid(prednisolone 1 mg/kg/day or pulsed methyl pred plasmapheresis/immunoglobulin Rituximab can be used in refractory cases. Recent studies--anti-C5 monoclonal antibody ( eculizumab )

14. DIFFERENTIAL DIAGNOSIS FOR CAPS SYNDROME

15. Other system complications in APS

16. DIAGNOSIS obstetric APS (2006) At least 1 clinical and 1 laboratory criterion Sydney modification of Sapporo criteria 2006 Med-high titers > 12 weeks apart and <= 5 year interval

17. DIAGNOSIS CRITERIA

18. CLINICAL CRITERIA 1.VASCULAR THROMBOSIS One or more clinical episodes of arterial, venous, or small-vessel thrombosis in any tissue or organ Confirmed by imaging, Doppler studies, or histopathology, with the exception of superficial venous thrombosis. For HPE, thrombosis without significant evidence of inflammation of the vessel wall. Biopsy kidney - glomerular and small arterial microthrombi. ACR/EULAR 19

19. CLINICAL CRITERIA 2. Obstetric morbidity in APS 1. ≥1 unexplained fetal deaths ≥10 weeks of gestation with normal anatomy by prenatal ultrasound examination or direct postnatal examination. 2. ≥1 preterm deliveries of a morphologically normal infant before 34 weeks of gestation due to severe preeclampsia, eclampsia, or features consistent with placental insufficiency . 3. ≥3 unexplained, consecutive, spontaneous pregnancy losses <10 weeks of gestation , after exclusion of maternal anatomic and hormonal abnormalities and paternal and maternal chromosomal abnormalities. ACR EULAR 19

20. HOW TO SUSPECT placental insufficiency I nclude any of the following: Abnormal or non-reassuring fetal surveillance tests ( e.g , lack of fetal heart rate accelerations [nonreactive nonstress test], low score on a biophysical profile) Abnormal Doppler waveform ( eg , absent or reversed end-diastolic flow in the umbilical artery) Oligohydramnios ( i.e , low amniotic fluid volume) Birth weight <10 percentile for the gestational age (fetal growth restriction/small for gestational age infant) placental abruption is not a defining morbidity for APS UPTODATE

21. FACTORS ASSOCIATED WITH HIGHER RISK OF ADVERSE EVENTS LUPUS ANTICOAGULANT---- 39% adverse outcome vs 8% in IgG- aCL vs 13% in IgGB2 TRIPLE POSITIVITY DOUBLE POSITIVITY Persistent HIGH aPL titres ACR EULAR 19

22. Non criteria obstetric APS 50% of women with obstetric APS  had low positive aCL and/or a2GPI in the absence of LA. (Gardiner et al.2013) Live birth rate 79.4 % with O APS 93.7 % patients with non criteria O APS (European Registry on O APS (EURO APS), 2012) LDA+-LMWH  starting as soon as pregnancy is confirmed  continuing until 6 w post-partum. (The European Registry on Obstetric AntiphospholipidSyndrome (EUROAPS)2012; Gardiner et al, 2013)

23. algorithm strategy for APS diagnosis aPS /PT : antiphosphatidylserine prothrombin antibodies;

24. Lab diagnosis IgG and IgM Anticardiolipin and anti beta 2- GP1 antibodies by ELISA. LA testing (Elongates APTT, Kaolin clotting time, dilute russells viper venom time ( dRVVT ) Repeat the assays after 12 weeks to confirm the diagnosis. Recently—antibodies against annexin V, protein C Thrombocytopenia is modest(>50000/cu mm) Proteinuria and microscopic haematuria ESR, Hb, and TLC usually normal (except in acute thrombosis)

25. Tests for Lupus anti coagulant(LA) No test for LAC shows 100% specificity and sensitivity because aPLs are heterogeneous. More than 1 test system is needed APTT : - variability in reagents result in inconsistent sensitivity. - acute phase reaction and pregnancy may shorten APTT and mask a weak LAC ------A normal APTT does not exclude LAC KCT- Kaolin clotting time more sensitive DRVVT- Dilute Russell’s viper venom time more sensitive to presence of b2 GPI TTI - Tissue thromboplastin inhibition test

26. DRVVT Detection of LA In vitro test ---ability of venom of russells viper to induce thrombosis. In drvvt assay time is set to 23-27 sec A prolonged clotting time of 30 sec or greater that does not correct with addition of an equal volume of normal plasma suggests the presence of LA. Excess phospholipid is added- --Normalised Both the tests are determined to a ratio. >1.2---may have.1.6 ---confirm.

27. indications of Apl testing Unexplained stillbirth Recurrent pregnancy loss Unexplained 2 nd or 3 rd T fetal death FGR Severe pre-eclampsia at less than 34 weeks Autoimmune diseases: SLE, thrombocytopenia(25%-coexist) Unexplained thrombosis Haemolytic anaemia Stroke, especially between 25-50 yr Livedo reticularis False positive serologic test for syphilis Obstetric indications of testing Non obstetric indication of testing

28. Principles of management 1 . To maximize the chance of successful fetal outcome. 2. To prevent thrombosis and other clinical manifestations of APS in the mother. 3. To ensure good counseling and planning for future pregnancies.

29. Pre pregnancy counselling Clinical: Review medical and obstetric history Laboratory: document and confirm persistent antiphospholipid antibodies assess renal function assess full blood count for presence of thrombocytopenia and/or anemia antibody testing: lupus anticoagulant, aCL , anti-2GPI, anti-Ro and La antibodies (even if there is no evidence of SLE: these antibodies are associated with a 2% risk of complete heart block in the fetus and up to a 5% risk of neonatal lupus).

30. Treatment-Pre pregnancy (a) Optimize the woman's clinical state and pharmacological treatment (b) Postpone pregnancy if a thrombotic event has occurred within the last 6 months (c) Postpone if SLE has been active or hypertensive (d) Assess individual additional risk factors such as obesity and maternal age (e) Ensure that the plan is understood, e.g. substituting heparin for warfarin at the time of the first missed period

31. Antenatal care With no treatment - only 20-30% of patient with aPL antibody has successful delivery. Combination of heparin with low dose aspirin provide the highest success rate in terms of live birth . Both therapies were associated with relatively high live-birth rates, ranging from 71 to 84 percent for combined therapy and 42 to 80 percent for ASA alone. Prophylactic dose heparin with low dose aspirin reduces the pregnancy loss by 54%. Low dose aspirin 75-100mg(recent 100-150mg-optimum dose still unclear) should be initiated before conception and discontinued 4 weeks before EDD

32. Baseline platelet count, serum creatinine concentration, urine protein-to-creatinine ratio, ALT and AST for comparison in the event of active APS or other complications later in pregnancy . Antenatal visit: 4 weeks until 20W then /1-2 weekly Monitor for fetal death, PE, FGR USG: 4 weekly beginning at 20 weeks. Assess fetal growth Fetal surveillance: weekly from 30W. CTG and or bpp Uterine artery Doppler: at 20 weeks-22 weeks for prediction of PE If early diastolic notch seen: do 2 weekly growth scans due to high risk of FGR Continued…

33. Anticoagulant therapy Low dose aspirin (75-100mg) peri conceptional till 36 weeks Heparin should be initiated in first trimester as soon as intrauterine pregnancy is confirmed and continued until the onset of spontaneous labor or night before scheduled induction/operative delivery. If the patient is fully anticoagulated and delivery is emergent – 1mg per 100 units of heparin(max 50mg) Protamine sulphate , iv over 10 min . (<8hrs heparin last dose) do pt / aptt 15 min. minor or no bleeding-observe after stopping anticoagulant. The heparinised pregnant patient- increase her calcium. NEUTRAHEP

34. LMWH Heparin p revents obstetric complications caused by aPL , by blocking complement activation rather than through its antithrombotic properties. LMWH - have therapeutic effect with less side effect. Single daily dose/less osteopenia/less thrombocytopenia(HIT) . Inhibit factor 10 a and thrombin • Prophylactic LMWH- Enoxaparin( clexane ) - 40mg s/c once/day Dalteparin - 5000u s/c once/day • Therapeutic LMWH- Enoxaparin-1mg/kg/12 hr Dalteparin-200u/kg once daily.

35. lmwh Routine monitoring not required. Except severe obesity or renal failure. twice weekly cbc ( plt ) Doa-24-48hours/excreted urine 40%

36. UFH Prophylactic UFH - 5000 u s/c every 12 hr. Therapeutic UFH - 10,000 u s/c every 12 hr Monitoring required with APTT(60-90 seconds) daily monitoring twice weekly cbc Duration of action 4 hours –stop 4-6 hours before surgery. HIT, osteopenia, bleeding risk higher Reversal complete by protamine sulphate

37. Warfarin : oral vitamin k antagonist (2,7,9,10 factors) History of recurrent thrombosis or cerebral thrombosis. After 1 st trimester-warfarin embryopathy. until then continue with LDA +_heparin Doa-5-7days,half life-20-60 hours, excreted urine 92% Reversal-vitamin k 10mg iv slow-major bleed/ FFP 10-15ml/kg/PCC 25-50 units kg iv IV immunoglobulin: Expensive No extra benefit relative to heparin & low dose aspirin. Reserved for cases refractory to aspirin & heparin Corticosteroids (prednisone) : abandoned {do not improve the live birth/ significant maternal & fetal morbidity}

38. timing of delivery Elective termination of pregnancy at term to time the discontinuation of antithrombotic agents so that delivery can be planned. If on Therapeutic LMWH- shift to UFH (short half life) at 36-37 weeks stop 24hrs before labor or if c sec (epidural) If on prophylactic dose of LMWH- 12 hours interval needed. If no high risk- stop aspirin any time after 36 weeks. If history of stroke or MI on aspirin continue through labor and delivery.(minor incisional bleeding occurs-risk outweigh benefit) Caesarean delivery associated with higher rate of peripartum thrombosis. Vaginal delivery is preferred . Epidural anesthesia is not recommended in marked drop in the maternal platelet count.

39. Postpartum care Post vaginal delivery - Ambulation as soon as possible. Post cesarean delivery - Pneumatic compression stocking until ambulation. Aspirin low dose as soon as possible–reinitiated. Heparin should be restarted post partum at lowest pre delivery dosage – continue for 4-6 week . In pt. With thromboembolic events - full anticoagulant - 6 wk. Supplemental calcium to be continued as long as pt is on heparin. No evidence indicates adverse effects related to breastfeeding with low dose aspirin and heparin. Breastfeeding is not recommended if high doses of cytotoxic or immunosuppressive agents are required . (secondary APS)

40. Once the diagnosis - diagnosis for life long. ( inspite of resolution). Inform about potential maternal and obstetric problems. Consultation with specialists in Maternal-Fetal Medicine and Rheumatology . APS and 1 or more prior thrombotic events, lifelong anticoagulation with warfarin - to avoid recurrent thrombosis!

41. Summary of management of O-APS

42. Follow up LIFE STYLE MODIFICATION- •Maintain a normal weight. •DM,HTN,DYSLIPIDEMIA-morbidity •Avoid tobacco/smoking CONTRACEPTION - Estrogen containing oral contraceptives should be avoided in repeated positive aPL . • Progesterone only pills, barrier method, IUD can be used. APS in IVF- GnRH antagonist rather than agonist. Estrogen excess causes increased risk of thrombosis. Should not discontinue treatment. Evidence suggesting direct causation of infertility is not present.

43. Systemic Lupus Erythematosus in pregnancy • Occurs in approx. 1 per 500(1000) pregnancies Multisystem autoimmune disease Skin, kidneys, liver, CNS, immune system, hematologic Clinical features: variable---fever, arthritis, rash, pleuro-pericarditis, photosensitivity, anemia, cognitive dysfunction Loss of tolerance becomes clinically evident by the presence of antinuclear antibodies. The nucleic acid content of nuclear particles from netting or apoptotic neutrophils activates innate and adaptive immunity by TLR7 and TLR9, which triggers an IFN-α–mediated antiviral host defense program that accounts for many of the nonspecific SLE symptoms. As such, dendritic cells, T helper cells, B cells, and plasma cells all contribute to the aberrant polyclonal autoimmunity.

44. pathogenesis

45. Diagnosis Slicc and ACR/EULAR criteria Many patients have a lupus-like illness without fulfilling these. 1. CBC: Normochromic normocytic anaemia, Neutropenia,Thrombocytopenia . 2. ESR: raised {high immunoglobulin levels} 3. CRP: Normal 4. 3rd or 4th components of complement: low or falling: active disease.

46. SLICC 2012 criteria for the classification of SLE ACR : 86% sensitivity and 93% specificity for lupus SLICC : 94% sensitivity and 92% specificity Clinical criteria Immunologic criteria Acute cutaneous lupus Chronic cutaneous lupus Non scarring alopecia Oral ulcers Synovitis Serositis Renal disease Neurologic disorder( seizure,severe depression and stroke) Hemolytic anemia Leukopenia / lymphopenia Thrombocytopenia ANA Anti ds DNA Anti Sm APLA Low complement levels DCT 4 or more (at least 1 clinical & 1 immunological criteria) or biopsy proven lupus nephritis with + ve ANA or anti ds DNA

47. Auto antibodies in SLE Antibody Prevalence% Clinical associations ANA 90 Best screening test Anti ds DNA 70 SLE specific; correlate with disease activity, nephritis , vasculitis Anti Sm 32 SLE specific Anti RNP 35 Not SLE specific Anti - Ro (SS-A) 40 Not SLE specific; a/w neonatal lupus ith heart block Anti - La (SS-B) 25 a/w anti Ro Anti histone 70 Seen in drug induced lupus Anti phospholipid 35 Anti erythrocyte 60 DCT + ve Anti platelet 30 Thrombocytopenia in 15%; poor clinical test Williams obstetrics 25 th ed

48. effect of pregnancy on lupus Lupus flares - 10 to 60% - at any stage of pregnancy or puerperium - prediction not possible, more likely if conception occurs with in 6 mnths of active disease. Progression of renal disease Maternal thromboembolism

49. Risks in pregnancy Maternal Foetal Hypertension Pre eclampsia (30%) VTE Risk of major morbidity during pregnancy 7% Early Pregnancy loss 22% Still births PTB 15-50% FGR 12-40% NLS (neonatal lupus syndrome ) Drug induced : Diabetes 2. infection 3. Osteoporosis 4. teratogenicity

50. Congenital Heart Block • 1/3 patients with SLE have SSA or SSB antibodies • Approx. 1-3% risk for with no affected child • Increases to 25-30% risk of CHB with one affected child • Highest risk between 18-28 weeks gestation • Latest recommendation: weekly monitoring of fetal PR Interval with ultrasound if SSA or SSB positive-pulsed doppler mechanical PR interval-normal 120+-10 milliseconds • Suggested to monitor until 28 weeks • Reason: once in CHB- will not reverse in most cases • PR interval abnormally increased- suggest 1st deg. heart block • Dexamethasone is recommended to prevent progression to complete heart block?

51. Pregnancy outcome best if : 1. lupus activity quiescent 6 months before conception. 2. No lupus nephritis -no proteinuria , no renal dysfunction 3. Anti phospholipid Ab - ve 4. no superimposed pre eclampsia Outcome is poor if:

52. LUPUS FLARE Maternal Complications- usually involves flare Lupus flare- increased symptoms, decreased complement levels Developing active flare in pregnancy – Risk of pregnancy loss – 40% Symptoms: Arthralgia, pleuritic pain, skin rash A . Urine: Red blood cells or cellular casts B. Rising anti-DNA antibody titre C. Fall in complement levels >25% fall in C3 or C4 suggests active SLE. E levation of Ba & Bb, often accompanies flares, so high ratios of CH50: Ba may differentiate PE from active lupus.

53. Risk for SLE flare during pregnancy At the time of conception flare rate Active disease 60% Inactive disease 10% Flare risk depends on 1. Disease activity at the time of conception 2. H/O lupus nephritis 3. H/O > 3 severe flares prior to pregnancy 4. Discontinuation of HCQS maintenance therapy 5. Primigravida

54. Differentiating lupus flare from pre eclampsia pre eclampsia lupus flare common features LFT Uric acid level Onset<20 weeks Active urinary sediment/cellular casts/ Hematuria Anti ds DNA Complement levels Hypertension Proteinuria Edema Renal impairment Thrombocytopenia

55. Neonatal lupus syndrome Due to passively acquired fetal autoimmunity from maternal antibodies, anti-Ro and anti-La antibodies. Rash, hematologic and hepatic abnormalities ( transaminitis ) at 4-6 weeks. (transient) Cardiac complications : due to permanent damage to the foetal cardiac conduction system by maternal antibodies. Cardiac manifestations of NLS - conduction defects, structural abnormalities, cardiomyopathy and congestive cardiac failure . The most common issue is congenital heart block (CHB)

56. Management Pre conception Past and current disease activity Pre existing organ damage Serological profile Review medications Additional medical disorders Past obstetric history Baseline blood pressure CBC, KFT,LFT, Urinalysis, 24 hrs urinary proteins, uric acid

57. Current remission currently active disease Severe impairment of organ function and/or preexisting organ damage Review medications Safe to plan pregnancy Review medications Postpone pregnancy Use effective contraception discourage pregnancy

58. Right time to conceive No evidence of active disease for 6 mnths or more Prednisone < 10mg/d May take HCQS No teratogenic medications for at least 6mnths If placed on new regimen, no e/o active disease for 2-3 mnths

59. Relative contraindications to pregnancy Severe lupus flare (including renal flare) within the past 6 months. Stroke within the past 6 months. Pulmonary hypertension. Moderate-to-severe heart failure Severe valvulopathy Severe restrictive lung disease Chronic kidney disease stage 4–5 Uncontrolled hypertension Previous severe early-onset (<28 weeks) preeclampsia or HELLP syndrome despite therapy with aspirin plus heparin

60. Following conception Multidisciplinary care with rheumatologist ( at least 1 visit in each trimester) ANC visits 1 st and 2 nd trimester 2-4wkly, 3 rd trimester 1-2 wkly Factors affecting pregnancy outcomes in SLE 1. Disease activity 2. Lupus nephritis (both in terms of hypertension and renal impairment) 3. Anti-Ro/anti-La antibodies 4. Antiphospholipid syndrome 5. Cardiac/lung involvement

61. Monitor disease activity Consider low dose aspirin Treat for APS Lab evaluation in pregnant SLE pts First visit Subsequent visits Anti phospholipid Ab , anti Ro/La Ab , Anti dsDNA , C3 C4 levels CBC,urinalysis , 24 hrs urinary proteins KFT, LFT, uric acid Anti ds DNA, complement levels CBC, Urinalysis, 24 hrs urinary proteins KFT

62. Treatment of SLE exacerbations Immunosuppressive therapy(azathioprine) may be needed in severe disease and to decrease steroid dose Plasmapheresis and IVIg : severe life threatening or unresponsive cases

63. Hydroxychloroquine should be continued {stopping may precipitate flare}. For control of hypertension: Drug of choice: methyldopa ; 2nd -line agents: nifedipine or hydralazine Differentiation of active renal lupus from PE Difficult 1. The two conditions may be superimposed. 2. Hypertension, proteinuria, thrombocytopenia& even renal impairment are all features of PE 3. A doubling of baseline proteinuria may be expected in pregnancy but more than this would be indicative of either worsening lupus nephritis or PE Hyperuricaemia & abnormal LFT point more towards PE. Renal biopsy --- The only definitive investigation. Rarely undertaken in pregnancy. More likely to be appropriate prior to fetal viability TT of active lupus nephritis--- Increase oral prednisolone, Pulsed IV methyl predisolone . Azathioprine. Rarely cyclophosphamide Lupus nephritis

64. Prevention of flare : HCQS 400mg/d, initiated btw 6-10 wks of gestation if not already on the medication 1. previous affected child 2. anti Ro/La ab + ve Maternal cortiosteroid administration for t/t of CHB controversial and is currently not recommended Williams 25 th e

65. Medications in pregnancy Low risk No data High risk Aspirin Steroids HCQS Azathioprine Cyclosporin Tacrolimus Heparin IVIg Rituximab belilumab Mycophenolate Methotrexate Cyclophosphomide Leflunomide Warfarin

66. Medications in lactation Low risk No data High risk Aspirin Steroids HCQS Heparin IVIg Rituximab Belilumab Azathioprine Cyclosporin tacrolimus Mycophenolate Methotrexate Cyclophosphomide Leflunomide

67. Low dose aspirin + Hydroxy chloroquine With a lupus flare - prednisone +/- azathioprine Add cyclosporine or tacrolimus if unresponsive Consider plasma exchange or plasmapheresis with severe life threatening flares

68. Labour and delivery Deliver at term, avoid post dates Continuous FHR monitoring Stress dose glucocorticoid treatment IV hydrocortisone every 8 hrs for pts at risk for adrenal crisis (>10mg prednisone daily for 3 weeks or more)

69. Post partum Monitor for SLE exacerbation Resume pre-pregnancy maintenance therapy. Assess neonate for NLE manifestations Postpartum contraception : - tubectomy /tubal occlusion - IUD - Progestin only pills - inj MPA

70. Management Close colaboration between haematologist , obstetrician neonatologist and anaesthetist for goodpregnancy outcome. Platelet count may decrease with advancing pregnancy and is monitored closely as follows: 1 st to 2 nd trimester : monthly 3 rd trimester : 2 weekly At term : weekly MODALITIES OF TREATMENT First line : corticosteroids and IVIG ( safe and effective) Contraindicated in pregnancy : androgen analogs such as danazol and cytotoxic agents due to teratogenicity . ITP >/= 3months / unresponsive to corticosteroids , 2 nd line treatment includes: Thrombopoietin receptor agonist like eltrombopag , romiplostim - Rituximab and spleenectomy .

71. Spleenectomy only when above measures fail tomelevate platelet count and bleeding persists. Best deferred until 2 nd trimester to prevent miscarriage. When to treat : Platelet count < 30,000 Symptomatic bleeding at any trimester.

72. Management before 36weeks of gestation Asymptomatic pts with mild to moderate thrombocytopenia ( platelet > 30,000 ) - No treatment is required. symtomatic pts or those with moderate to severe thrombocytopenia (platelet < 30,000 )- coticosteroid prednisolone 0.5-2 mg/kg/day or dexa 40mg /day for 4days - Short course </= 6 weeks is preferred. And/or IVIG 1g/kg( pre pregnancy weight) every month . Severe thrombocytopenia( platelet count < 10,000): High dose corticosteroids ( methyl prednisolone / dexamethasone ) And Periodic high dose IVIG 1g/kg for 2 days

73. Management after 36 weeks of gestation : The mother should be assessed at 36 wks by both haematologist and obstetrician. Platelet count > 30,000- safe for normal vaginal delivery in pts with normal coagulation. Platelet count < 30,000- admit for pulsed IVIG and close monitoring. Mode of delivery is based on obstetric indications. C-section only for obstetric indication and pt will require: IV corticosteroids if platelet count between 30-50,000. IV corticosteroids and IVIG if platelet count <30,000. IV corticosteroids and IVIG plus platelet tranfusion if platelet count < 10,000.

74. Management during labour SAFE PLATELET THRESHOLDS FOR DELIVERY: -Vaginal delivery > 30,000 -c-section > 50,000 -epidural anaesthesia > 80,000 . Post partum thromboprophylaxis as increased risk of VTE.

75. INTERNATIONAL CONSENSUS REPORT GUIDELINES / AMERICAN SOCIETY OF HEMATOLOGY DIAGNOSIS OF ITP IN PREGNANCY : Pt with history suggestive of ITP or platelet count < 80,000 should be evaluated for ITP . It is the diagnosis of exclusion . Lab investigations same as in non – pregnant women detailed before . Bone marrow examination not recommended Antiplatelet antibody testing also not recommended as it does not predict the course of maternal and neonatal thrombocytopenia or distinguish ITP from gestational thrombocytopenia .

76. 2. TREATMENT OF ITP IN PREGNANCY: Platelet count of 20-30,000 in non bleeding women is safe for most pregnancies . Platelet count of >/=50,000 is preferred for delivery. Initial treatment is with oral steroids or IVIG. In Rh D positive non spleenectomized women ,IV anti-D appears to be well tolerated and effective ( may cause maternal or fetal hemolysis ). IVIG provides rapid but transient increase in platelet count , so used during blleding or delivery. Combining therapies ( steroid with IVIG or IV Anti –D can be used in pt refractory to single agent . Rituximab used in very severe cases ( neonatal and perinatal immuno suppression ) In rare cases, spleenectomy is required , usually done in 2 nd trimester .

77. 3. OBSTETRIC ANALGESIA AND ANAESTHESIA: Regional anaesthesia safe if platelet count >/= 70,000 in absence of other hemostatic abnormalities. NSAIDS should be avoided if counts are < 70,000. Safe for delivery - >/=50,000 Prophylaxis for VTE to all women , postpartum. 4. MANAGEMENT OF DELIVERY: mode of delivery as per obstetric indications. Procedures with increased risk of bleeding like ventouse , forceps should be avoided. Previous spleenectomy worsens maternal ITP in next pregnancy and also neonatal thrombpocytopenia .

78. Rheumatoid Arthritis in Pregnancy Systemic autoimmune disease with chronic inflammation of joints and other structures mainly mediated by TH1 helper cells . no tests are pathagnomic . suspect clinically if symmetric arthritis is present mainly hands and feet Lab- CRP/ESR/RHEUMATOID FACTOR-NON SPECIFIC/ANTI CCP/ANA IN 40%

79. Pregnancy morbidity Antepartum- usual improvement of arthritic symptoms- approx. 75% of patients( ostrogen decreases th1 and progesterone increases th2) Postpartum- higher risk for flare( prolactin /shift to th1/proinflammatory stage) Glucocorticoids can be used either antepartum or postpartum for flares Small increased risk for IUGR Consider monitoring fetal growth Weekly testing based on growth pattern

80. Pathogenesis and diagnosis Acr / eular 2015

81. Counselling and management in pregnancy Fertility affected-risk factors include age,nulli,nsaids and prednisone >7.5mg/day Antepartum concerns-mild increase in miscarriage. Routine oral calcium and vitamin d needed. C section only if hip joint is affected. Medications: nsaids -Avoid preconception-interfere with blastocyst implantation…c/I 3 rd trimester-non selective/short acting nsaids can be used in 1 st and 2 nd t(EULAR) brufen /diclofenac HYDROCORTISONE/CORTISONE/PREDNISONE PREFERRED -converted to cortisone inactive form in fetus(10% of maternal levels)-lowest possible dose.<10mg/day-minimal side effects seen. All trimesters.

82. Sjogren’s Syndrome (SS) in Pregnancy Lymphocytic infiltration of epithelial cells of various tissues leading to immune complex deposition or B-cell hyperactivity Primary SS- immune complexes in salivary and tear glands- leads to oral/ocular dryness Secondary SS- systemic or found with other autoimmune diseases (e.g.- SLE) -Can lead to immune complex deposition within tissues-- Nephritis, obstructive bronchiolitis, cholangitis B-cell hyperactivity--- Glomerulonephritis, neuropathy, B-cell lymphoma Associated with anti-SSA ( anti Ro) and anti SSB ( anti La) antibodies. Anti SSA antibodies are associated with congenital heart block. May lead to FGR and oligohydromnios .

83. Sjogren outcome Sjogren syndrome worsens during pregnancy and post partum. Maternal morbidity- usually uncomplicated Depends on underlying disease state- primary vs. secondary Fetal/neonatal morbidity Mainly secondary to presence of SSA and SSB antibodies SSA- 60-80% of pts, SSB- 30-40% of pts. SSB is never present unless SSA is present in Sjogren’s Synd. SSA and SSB antibodies have affinity for specific fetal myocardial antigens and epitopes .

84. MANAGEMENT: -disease should be well controlled 3-6 months prior to conception. -most dreaded complication is CHB Associated with anti SSA ab. Serial echos and obs USG between 16-20 wks and thereafter is required. - dexamethasone is indicated in cases of CHB as it reduces inflammatory damage to cardiac nodal tissues. - plasmapheresis and IVIG in rare cases.

85. Scleroderma (Systemic Sclerosis) in pregnancy Uncommon disease of unknown cause and variable presentation. Male : female ratio = 1:3 , usually in reproductive age group. 3 types LOCALISED CUTANEOUS FORM ( Morphoea )- waxy thickened skin . SYSTEMIC SCLEROSIS : Associated with raynaud’s phenomenon , may cause progressive fibrosis MC of oesophagus ( 80%) followed by lungs , heart and kidneys . - CREST SYNDROME. Hallmarks : autoimmunity, inflammation, pathologic alteration of small blood vessels, interstitial and vascular fibrosis in the skin and internal organs

86. EFFECT OF SCLERODERMA ON PREGNANCY: -More favourable outcome in those without systemic disease. -increased risk of preterm delivery , miscarriage , pre- eclampsia , FGR. -general anaesthesia is difficult due to difficult intubation and regional anaesthesia may also be difficult if there is involvement of back. EFFECT OF PREGNANCY ON SCLERODERMA: -prognosis of localised cutaneous scleroderma is good. -early diffuse disease ( < 4 yrs ) or renal disease may worsen - raynaud’s disease tends to improve due to vasodilation and increased blood flow .

87. Systemic Sclerosis MANAGEMENT Symptomatic treatment To delay pregnancy till disease is stabilised . Pre pregnancy assessment with lung function test and echocardiography . In Multiple/severe organ involvement like renal crisis, pulmonary fibrosis , pulmonary hypertension , women are adviced against pregnancy. Proton pump inhibitors and prokinetics in case of esophageal symptoms. Scleroderma renal crisis 2-3% of Scleroderma pregnancies Can be indistinguishable from severe pre-eclampsia/HELLP Delivery sometimes indicated due to acute renal failure ACE inhibitors indicated postpartum but has fetal effects antepartum Increased risk for IUGR/placental insufficiency antenatal monitoring of growth and weekly antenatal testing in the third trimester

88. Takayasu Arteritis in Pregnancy Immune arteritis causing inflammation of the aorta, major branches and pulmonary arteries Early age onset (< 30y/o ), more common Asian women. Organ involvement- cardiac, lungs, aorta, kidneys Cardiac- 6-16% with coronary artery disease , heart failure; Aorta- increased risk for aneurysms Lungs- pulmonary hypertension Pregnancy morbidity- based on maternal disease C/F – fatigue , arthralgia , myalgia , low grade fever , intermittent claudication , visual defects, fainting attacks , pulselessness ( BP variability in upper and lower limb .

89. Increased risk of Pre- eclampsia , preterm delivery and FGR. Treatment – steroids 1mg/kg for 4 weeks and then taper . SUSPECT WHEN PATIENTS PRESENT WITH PULSELESS PERIPHERAL PULSES.

90. MyasTHenia gravis Prevalence is 1-4/10,000 . Female : male preponderance – 2:1 Onset usually in 2 nd and 3 rd trimesters. Clinical features : Exacerbations and remissions of fatigable , painless muscle weakness. Diplopia and ptosis Dysphagia Respiratory muscle weakness ( in severe cases) 10-15% associated with thymoma which is usually benign About 10% have associated thyroid disease.

91. PATHOGENESIS

92. Effect of pregnancy on MG: - Exacerbation of disease- 40%, no change In 30% , remissions in 30%. -postpartum exacerbations in 30% cases. -physiology of pregnancy indirectly influences the disease . Like nausea and vomitting in early pregnancy , delayed gastric emptying and increased volume of distribution and renal clearance may all lead to sub-therapeutic levels of medication .

93. Effect of MG on pregnancy : -since uterus has smooth muscle , first stage of labor Is unaffected . But materbal voluntary efforts using striated muscles in 2 nd stage is affected. -transplacental passage of antibodies in severe cases may lead to fetal arthrogryposis where fetus develops contractures due to lack of movement. -impaired swallowing in fetus may lead to polyhydromnios . -Transient neonatal myasthenia gravis may develop in neonates in 10-20% cases.

94. MANAGEMENT in PREGNANCY - Measure Thyroid function in those who haven’t checked in past 1 year. -long acting anticholinestrases like pyridostigmine should be continued. -increased dosage maybe required as pregnancy advances. - Immunosuppression with corticosteroids , azathioprine , tacrolimus should be maintained . Methotrexate and mycophenolate moefitil should be discontinued pre pregnancy . -periodic fetal scans to monitor polyhydromnios and fetal movements are advised/ -c-section only for obstetric indication. -in women with well controlled MG, Vaginal delivery with spontaneous labor onset is the aim . - plasmapheresis and IVIG are reserved for severe cases.

95. Caution with drugs in women with MG Drugs that impair neuromuscular transmission may increase weakness like gentamicin . Drugs which block neuromuscular transmission – beta blockers particularly propranol . Drugs which exacerbate muscle fatigue like beta adrenergics ( ritodrine , salbutamol ), narcotics. Magnesium sulphate should be avoided as it may precipitate crises . Epidural anaesthesia is preferred over general anaesthesia .

96. MANAGEMENT: Prepregnancy referral to geneticist for categorization of disorder , if not previously confirmed. Preterm termination of pregnancy( at 34 wks ) in vascular type ,to prevent aortic / uterine rupture towards the end of third trimester. Avoidance or termination of pregnancy in type 4. Obstetrics anesthetist referral for management of pain relief during labor as there is increases resistance to local anesthesia.

97. INFLAMMATORY BOWEL DISEASE Ulcerative colitis(UC) and Crohns disease (CD) IBD usually affects young adulthood and 25% of females conceive after diagnosis. PATHOGENESIS Cause is not known. May involve infections, autoimmunity, genetics, environmental factors.

98. ULCERATIVE COLITIS Affects more women than men. Clinical features: Diarrhoea Lower abdominalpain Passage of blood and mucus per rectum Urgency of defecation. Complications: Toxic megacolon Malignancy.

99. CROHNS DISEASE Both sexes are equally affected. Affects terminal ileum alone in 30%, only colon in 20%,and both in 50%. May affect entire GIT from mouth to anus. Clinical features: Any of the features seen in UC , although bleeding is more common in UC. Cases with ileitis may present with cramping mid abdominal pain , diarrhea, weight loss. Complications: Perforation Stricture formation Perianal problems/Fistulae Abscess formation/Malabsorption.

100. EFFECT OF PREGNANCY ON IBD: In pregnancy , risk of exacerbation of UC is doubled. Also UC flares 6 times more in postpartum and 35% of those who conceive in remission will flare during pregnancy. CD is no more likely to flare in pregnancy or postpartum. Highest risk in those with active disease at conception, and who develop IBD for the first time in pregnancy . It usually occurs in 1 st and 2 nd trimesters.

101. EFFECT OF IBD ON PREGNANCY: Decreased fertility and increased risk of miscarriage and preterm delivery in active disease Majority (80-90%)have full term normal pregnancy. In women with quiescent disease, risk of stillbirths , miscarriage , fetal abnormalities is not increased. Successful pregnancies and vaginal deliveries are possible following ileostomy , pouch surgery, proctocolectomy and ileoanal anastomosis. Ileostomy dysfunction may occur in 2 nd trimester. The most serious complication is intermittent intestinal obstruction. peristomal cracking and bleeding may occur due to stretching of abdominal wall.

102. MANAGEMENT: Women encouraged to conceive during phase of remission. Oral and topical 5-Aminosalicylates ( sulphasalazine , mesalazine ) used for maintaining remissions in UC and colonic CD can be safely used throughout pregnancy and breastfeeding. Oral and rectal preparation of corticosteroids is safe in pregnancy which is usually used in active phase of disease’. Supplemental folic acid 5mg is usually started pre- conception as sulphasalazine is a dihydrofolte retuctase inhibitor that converts folate to its active metabolite. Metronidazole is used in pouchitis in pregnancy. Biologics ( anti TNF alpha agents ) . It is not secreted in breast milk. Rarely surgery for perforation , hemarrhage , toxic megaolon obstruction may be required and must no be delayed due to pregnancy. C-section is required for obstetric indication only except for severe perianal CD ( inelastic perineum due to deformed or scarred rectum) and rectovaginal fistulas.

103. Summary Autoimmune Disorders in Pregnancy Multidisciplinary approach with maternal fetal medicine and rheumatologist Important to be aware of the various autoimmune D isorders due to the predominance in women SLE in pregnancy should be monitored closely as any flare can impact the pregnancy in terms of placental function and delivery timing SSA and SSB should be checked with certain disorders (SLE, Sjogren’s, Scleroderma) due to risk of CHB Antenatal monitoring important to optimize fetal outcome. Caution-drugs used in rheumatology and the modifications used in pregnancy-teratogenic effects Suspect-diagnose-treat-control-counsel