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REPRODUCTIVE ISSUES AND RHEUMATIC DISEASES By Walaa F. El Bazz MD Prof of Internal Medicine, Rheumatology& Immunology Al Azhar University (Girls) Rheumatic diseases occur ↑ in F, childbearing yrs. This confirmed conviction sex hormone have important role in disease development and course. During pregnancy, hormonal changes↑ free steroid hormones; glucocorticoids, progesterone and estrogen, induces changes in functions of immuno-competent cells B cells, T cells and monocytes. Clinical symptoms of immune-mediated RDs are modified related to pathophysiological process; some improve, others unchanged or worsen. Cutolo M, Capellino S, Straub RH:Estrogens in rheumatic diseases: friend or . foe? Rheumatology 2008;47 Suppl. 3:iii2-5 Pregnancy outcome may be threatened by severe organ involvement and presence of autoantibodies. Rare diseases with anecdotal pregnancy experience, like vasculitides, pose problems in management. Fetal and neonatal effects of maternal autoantibodies are well known, but the long-term outcome of those children is still insufficiently studied. Likewise, causes of impairment of fertility in RDs patients need more investigation, specialy in males. Immunomodulatory effects of oestrogens (A) S. estrogens in physiological conc.are implicated in maturation of Th cells (Th0) into Th1-type. In pharmacological conc.( high), they mainly support the maturation of Th0 T cells into Th2 type and B-cell activation. (B) pregnancy, ↑ s. estrogen shift to a Th2 response , therefore classical Th1-driven diseases such as RA are improved in 50–75%, classical Th2-driven diseases as SLE may be negatively influenced (complications in 40–70%) Physiologic Adaptation In Pregnancy May Influence the Course Of Rheumatic Diseases I – Volume & BP changes: Patients with rheumatic disease are not able to tolerate ↑ intravascular volume. Vascular bed of patients may lack sufficient compliance to accommodate ↑ fluid volume. Subclinical myocarditis, valvulitis, pericarditis cong cardiomyopathy, valvular insufficiency, constrictive pericarditis. II – coagulation changes: Normal pregnancy * ↓ survival of platelets * ↑ plasma fibrinogen * ↑ factor VIII * ↑ platelet production no change in P platelets. Thrombocytopenia uncomplicated pregnancy. Rheumatic diseases with pregnancy: Activated coagulation system. thrombocytopenia Immunologic changes in pregnancy: ↓ Cell mediated immunity ↓ T cell / B cell ratios ↑Treg – helper T cell ratios ↓ lymphocyte – monocyte ratios ↓ cutaneous, humoral immune response due to ↓ leucocytes, chemotaxis, ↓ adhesion molecules ↑ Ig – secreting cells but ↓ inflammatory response. Pregnancy specific proteins: alpha feto protein, B1 glycoprotein, alpha 2 macroglobulin suppress in vitro lymphocyte function. ↑ Endogenous corticosteroids ↓ lymphocyte function. IL1, IL3, TNF alpha, IFN gamma, GM-CSF critical to sustain pregnancy. Pmncs show an increase in anti-dsDNA and IL-10 in response to estrogen. Cric IC (in rheumatic diseases) + local levels of cytokines may be constitutively or secondary abnormal. C3, C4, CD50 are falsely normalized or ↑ in pregnancy (pregnancy ↑ synthesis, Rh disease ↑ activation, ↓ synthesis) CD4+CD25+FOXP3+ Tregs suppress immune responses and supporting maternal tolerance towards the fetus. Hormonal changes: Estrogen up-regulate & androgens down-regulate T cell response, Ig synthesis. Sex hormones can regulate IL1, IL2, IL6, TNF alpha worsen rheumatic disease state. Also rheumatic diseases affect them deterimental to maintenance of pregnancy. Does Pregnancy Influence Coarse Of Rheumatic Disease? Pregnancy induce abnormalities similar to rheumatic diseases 1. Erythema. 2. Hair loss. 3. Arthralgia. 4. CV, pulmonary compromise. 5. Anaemia. 6. Thrombocytopenia. 7.HTN, proteinuria. So if ttt is directed to 1ry disease, not to complications of pregnancy harmful. Does Rheumatic Disease Affect Pregnancy? Rheumatic diseases ↓ fertility (Debate). RA high frequency in nullipara. Scleroderma subnormal fertility. NSAID ↓ fertility. Anaemia, fever ↓ fetal growth. TTT of renal, pulmonary, cardiac dysfunction affect fetal outcome. Continuous medications may be harmful to fetus. Maternal antibodies may cause fetal illness. Antiphospholipid Syndrome 10% of female with past history of recurrent fetal loss. 2 – 3 % of apparently normal pregnant females low titre of aPL, high titre 0.2% aPL may present in infections, HIV, HCV, lyme disease, enteric diseases. B2 glycoprotein, cofactor for pathogenic aPL. 1ry, 2ry APS ↑ mid pregnancy fetal loss. Presence of high titre of IgG, IgM, IgA (less)aCL, LA. antiB2 glycoprotein, thrombocytopenia ↑ fetal loss Effect of pregnancy on APS No evidence of ↑ or ↓ thrombotic events. May be due to anticoagulation for sake of fetus. Postpartum ↑ incidence of stroke, MI, ischemic myopathy. ↑ Thrombocytopenia remit after labour. Effect of APS on pregnancy Early pregnancy N., after 15 ws ↓ fetal growth, bradycardia, ↓ fetal motion, ↓ amniotic fluid ↓ placental size fetal death. Different aPL-mediated pathogenic mechanisms (i) placental thrombotic events; (ii) placental inflammatory events following local C activation; (iii) direct aPL effect on trophoblast cells inducing defective placentation. 2ryAPS ↑ pre-eclampsia triggered by placental dysfunction ↑ its severity HELLP syndrome plasmapharesis. Genetic polymorphisms, dysregulation of angiogenic factors maternal endothelial cell dysfunction (placental dysfunct) A recent study showed that cell-free, fetal nucleic acids (DNA and mRNA), released by the placental trophoblast, ↑ in cases with early-onset pre-eclampsia, correlated with disease severity but not in cases with normal pregnancy outcome. No specific histological pattern, C activation was detected for abortive placentas /at term. aPL compete with placental anticoagulant proteins annexin V coagulation in placenta. Fetal loss proportionate to titre of IgG aCL, previous fetal loss (20%SR) Tans-placental passage of APL Infants will not have APS Management If aCL IgG, M+ve no serial test, if –ve serial test once/trimester platelet count/month. High titre IgG, M aCL: - Primigravida,multipara with recent live born low dose aspirin or no ttt except thrombocytopenia. - multipara with preg failure > 15 ws aspirin to concieve then heparin 5000 bid during all pregnancy. LMWH more safe, effective. Low titre aCL IgG, M: - primigravida , multipara with no fetal loss no ttt. - Multipara with prior pre-eclampsia, IUGR, HTN, renal D l d aspirin after 1st trimester. SC heparin or LMWH in therapeutic dose female with prior thrombotic events Continue aspirin heparin or warfarin postpartum 3 ms or more (thrombotic event (No contraceptive pills.) Many live born infants premature or GR failure of breast feeding. Breast feeding allowed aCL Ig, LA, aspirin transmitted no complications, heparin not transmitted allowed. 20% of pregnancies still experience poor outcome despite conventional treatment. ↑ the dose of LMWH, or adding either steroids, HCQ or IVIG. SLE & pregnancy SLE is commoner in females child bearing period. Drug induced SLE is rare in pregnant females. Pregnancy can cause SLE flare mainly 2nd - 3rd trimester or at perperium. ↑ Renal flares in pregnant SLE patients . Recent study↓↓ in renal function similar to those in non-pregnant patients with LN In SLE. Identify flare of SLE during pregnancy is difficult as pregnancy induce thrombocytopenia, proteinuria. The presence of: New or increased rash Lympadenopathy Arthritis Fever Ant ds DNA titre increase Indicate SLE flare > pre-eclampsia. Thrombocytopenia in pregnant females: APS Active SLE Pre-eclampsia ITP (less common) remit after delivery. Anaemia of LE ↑dueto pregnancy dilutional anaemia Proteinuria SLE nephritis. Pre-eclampsia. Normal C3, C4 pre-eclampsia. Decrease C3, C4 nephritis. Joints non inflammatory effusion during pregnancy. Active arthritis active SLE. Neurologic manifestation induced or exacerbate in pregnancy. Some develop stroke postpartum usually APS. Lupus nephritis predispose pre-eclampsia. Patients with preserved renal function, minimal hypertension good pregnancy outcome. Thrombocytopenia is not independent predictor of fetal death. Neuro-psychiatirc disease little direct effect on outcome, ?? fetal injury from hypoxia during seizures, sedation or addiction from anticonvulsants. Prematurity, IUGR, fetal death common in SLE related to disease severity, APS. High clinical activity and abnormal serology (complement or anti-dsDNA) predictive of a poor obstetric outcome. Women with SLE have ↓levels of DHEA,further reduced by ttt with prednisone. In clinical trials, DHEA suppleme was helpful both for disease activity and for BMD. Estrogen substitution in post-menopausal women↑ mild/moderate, not significantly severe flares . Oral contraceptive (OCP) is an established risk factor for SLE particularly, recently use, suggesting an acute effect in a susceptible women. OCPs do not increase flares in women with established SLE that is inactive or only moderately active. Neonatal lupus Ant Ro, Ant La present in 30% SLE patient child with neonatal lupus. 1–2%. Maternal HLA DRW3 increase risk. The risk of recurrence is 15–20%; unfortunately high dose IVIGs are not effective in reducing this risk . A typical skin rash, transient photosensitivity that resolves spontaneously within 6 ms. Congenital heart block most common presentation(85%), thrombocytopenia, liver abnormalities, hemolytic anemia. All are reversible except heart block, neonatal lupus identified at 23 ws ttt. Dexamethazone or Betamethazone, plasmapharesis inverse incomplete heart block, myocarditis, heart failure. After delivery cardiac lesion no progression. Early delivery indicated, decrease cardiac function, congestive heart failure. CHB permanent pace maker Management Prednisolone 30 – 60 drug of choice. Hydroxychloroquine benign in pregnancy. Small dose of aspirin APS, prevent pre-eclampsia with lupus nephritis. NSAIDs spasm of ductus arteriosus, prolonged labour, peripartum bleeding. Neuropsychiatric lupus non pregnant. Cyclophosphamide not used due to teratogenicity. Rheumatoid Arthritis Common female: male (3: 1). All races (1%) population Unknown cause, HLA DR4, DR1, familial. Insidious onset, periods of remission & exacerbation with systemic manifestation, ↓ wt, fever, lymphadenopathy. Articular & extra-articular manifestation Articular: proliferative synovitis erosion of cartilage, bone permanent deformity variable prognosis. Management: a lot of medication Retrospective and prospective studies 48% RA improves (DAS-28), 41% flares after delivery. Improvement of disease activity, post-partum flare not associated with changes in ACPAs or RF levels. Women -ve for ACPA and RF more likely to improve during pregnancy . Higher disease activity during pregnancy was associated with lower birth weight Gestational age at delivery of patients using prednisone is shorter, and delivery more often premature . Affected joints that influence obstetric care, hips, knees Associated osteoporosis fracture with rough handling the patient ↑↑levels of fetal Mc were found in the circulation of women with RA who improved during pregnancy. Decades after birth fetal Mc persists in the mother and maternal Mc in offspring. RA Women have no RA-risk alleles were recently reported to harbour Mc with RA-risk alleles signif. more than healthy women. Thus, Mc could contribute to both health and disease RA patients, circulating Tregs ↑during pregnancy and ↓ post-partum as healthy women (unable to suppress effectively the pro-inflammatory cytokine response). Pregnancy restores Treg function creating an antiinflammatory cytokine milieu in 3rd trimester time of maximal improvement of disease activity. Pregnancy ameliorates disease due to ↑ endogenous corticosteroids, pregnancy specific proteins ptnA antiinflal Remission may be due to maternal fetal HLADQ DR disparity.. Postpartum is time of ↑ risk for new cases of RA. RA joints more unstable C1 – C2 sublaxation is common and need special concern during labour. A preponderance of 16α-hydroxylated estrogen metabolites observed in RA SF is unfavourable in synovial inflammation enhance cell proliferation including synoviocytes [2]. 17β-oestradiol taken during HRT rapidly increase estrone sulphate after conversion in adipose tissue by aromatases, pro-inflammatory effects to the inflamed RA synovial tissue [1]. Management To conceive stop some DMARDs due to potential fetal toxicities of DMARDs. Azathioprine, hydroxychloroquine used without ill effect. Some case reports of fetal harm. Cyclophosphamide, MTX contraindicated early in pregnancy, used in severe, late cases Moderate dose of aspirin – low dose corticosteroids safest Little is known about NSAIDs during pregnancy aCL IG ant SSA/Ro, anti. SSB/La rare in RA. Labour need team work, obstetrician & rheumatologist. Identify joint disabilities, range of motions, her permissible activities (hip, knee, neck). Potential risk of fracture, cord compression (forced motion) If no free motion of neck, hip, knees Cesarean section. TMJ affection prevent wide opening of mouth need special anesthesiologist familiar to these cases Special techniques & equipments for transporting patient to delivery suite No special risks to fetus other than those related to maternal ttt Counseling of parents can be optimistic If medication permit breast feeding is possible but arthritis of shoulders, elbows, hands, wrists discomfort to the mother Systemic Sclerosis Incidence 1: 10000. Female > male (3: 1) Age 20 – 40 years. Raynoud’s phenomenon present in 90%, edema of hands, face then tight thinning of skin of affected areas, hypopigmentation, hyperpigmentation. Oesophageal dismotility, GERD, pulmonary fibrosis, duodeno-jejunal dilatation, cardiac dysrythmia, PH, HTN, hyperreninaemic RF renal crisis needs ACE inhibitor reverse RF to normal. Prognosis is affected by systemic afection. Diagnosis is clinically, skin biopsy, +ve ANA, antiScl 70, ACL (uncommon). CREST syndrome anticentromer antibodies. No effective ttt vasodilator * Ca channel blockers, immuno-suppressors * corticosteroids for myositis, haemolytic anaemia. * ACE inhibitors life saving in renal crisis. * Diuretics is dangerous ↓ COP in patients with PH, renal crisis. EFFECT OF SScON PREGNANCY Pregnancy losses occurred in 4% of SSc women Prematurity (25%),IUGR the most prominent adverse outcome Pre-eclampsia and hypertension less common 1.5% . Pregnancy outcomes were similar in limited and diffuse SSc. Skin involvement stable in 69% of women, RP improved in 40%, GERD worsened in 24%, spirometry and echo remained stable in 72%, 98%. Renal crisis was less observed. Uncomplicated, successful pregnancies, provided the disease is stable and organ damage mild. Management during pregnancy Fertility before & after disease normal. High miscarriage rate in severe late scleroderma. Patient may tolerate pregnancy well or poorly vascular, visceral disease. (non distensible vascular bed, preexisting renal, cardiac, pulmonary insufficiency) GERD oesophageal dismotility ↑ disabling disease H2 blocker, prokinetic drug, Oesoph. stricture dilatation. Renal scleroderma bad prognosis, so gestation is contraindicated/ interrupted. ACE inhibitors contraindicated, except if renal hypertensive crisis occur. Patients with atonic small bowel N pregnancy with parentral nutrition. Pregnancy success rate is normal Wound healing normal. Anesthesia; intubation difficult small opening of the mouth. Emergency use of ACE inhibitor for HTN, oliguria, whatever its cause. Dermatomyositis & polymyositis Female predominate. Peak of onset 25y (25 – 50) Malignancy may be associated with older group. Chronic disease, remission, relapse with proximal Ms weakness, pulmonary fibrosis, weakness of respiratory muscles aspiration respiratory failure (danger in late pregnancy) ↑ creatinine kinase, aldolase, AST, EMG. Skin ms biopsy, +ve ANA, +ve antiJo-1 (antihistidyl tRNA synthase antibody) association with pulmonary disease + poor prognosis to ttt. Corticosteroids, immune suppressive MTX, azathioprine, IV Ig safe with pregnancy. During pregnancy: Uncommon 14% of patients get disease in chiild bearing peroid. Muscle fatigue +respiratory impairment greatest risk for pregnant. No antibodies cross placenta to fetus ms weakness. Pulmonary fibrosis compromise maternal respiratory reserve especially in late pregnancy. Ms strength, respiratory function monitored during pregnancy & delivery. Uterine ms contraction Normal in labor but m weakness for pushing in 3rd stage may be limited factor Risk for fetus is due to mother’s ttt and complication during pregnancy. DRUGs AND PREGNANCY During pregnancy, HCQ, low-dose glucocorticoids and AZA can be safely used. Pulse i.v. steroids can be given in cases of severe SLE or vasculitis flares. CYC, MTX and MMF are contraindicated during pregnancy and lactation Exposure to anti-TNF therapies, especially if this occurs at the time of conception or during the first trimester, is not associated with↑ risk of adverse pregnancy and foetal outcomes. INF, ADA are found in cord blood in the 2nd and 3rd trimester transport across the placenta at birth and for up to 6 months thereafter. • Due to the absence of the Fc fragment, certolizumab (CZP) has the lowest level of placental transfer There are increasing reports of pregnancies in women exposed to rituximab prior to or during pregnancy 60% live births (76% full-term deliveries) and 21% in first trimester miscarriages Exposure to rituximab during the 2nd and 3rd trimester results in transient B-cell lymphopenia in the child but the longterm effects on immune system development remain unknown. Safe to stope. Data on other biologic therapies, including anakinra, abatacept, tocilizumab and belimumab, are scarce. Breast-feeding Glucocorticoids, azathioprine, hydroxychroquine, and sulfasalazine are generally considered as safe. There is limited data on breastfeeding and the use of biologics HOME MESSAGE Pregnancy is a state of↑↑ concentration of sex hormones and cross-talk between mother and fetus. Throughout pregnancy, the hormonal, biochemical and immunological equilibrium in the mother changes tolerance to the semi-allogeneic fetus. Female gonadal hormones exert an important role in the aetiology and course of chronic inflammatory /autoimmune diseases. Epidemiological, immunological and clinical evidence shows that menstrual cycle, pregnancy, menopausal status and OCPs are significant influencing factors. Optimum disease control, remission or low disease activity before pregnancy is the requirement for good outcomes. Previous complicated pregnancies, renal disease, irreversible organ damage, anti-Ro/SSA and aPL and high doses of glucocorticoids increase the risk of complications. Pregnancy is contraindicated in women with symptomatic pulmonary hypertension, heart failure, severe restrictive pulmonary disease, severe chronic renal failure, recent high disease activity and recent arterial thrombosis. There is a need for a change “cautions against pregnancy” to “embraces pregnancy” through the individualised, pre- and post-conceptual, multidisciplinary care. REFRENCES MEKINIAN A, LACHASSINNE E, NICAISEROLAND P et al.: European registry of babies born to mothers with antiphospholipid syndrome. Ann Rheum Dis 2013; 72: 217- 22. ZHAO C, ZHAO J, HUANG Y et al.: Newonset systemic lupus erythematosus during pregnancy. Clin Rheumatol 2013; 32: 815- 22 CLOWSE MEB, JAMISON M, MYERS E, JAMES AH: A national study of the complications of lupus in pregnancy. Am J Obstet Gynecol 2008; 199: 127.e1--27.e6. NILI F, MCLEOD L, O’CONNELL C, SUTTON E, McMILLAN D: Maternal and neonatal outcomes in pregnancies complicated by systemic lupus erythematosus: a populationbased study. J Obstet Gynaecol Can 2013; 35: 323-28 CIMAZ R, SPENCE DL, HORNBERGER L, SILVERMAN ED: Incidence and spectrum of neonatal lupus erythematosus: a prospective study of infants born to mothers with antiRo autoantibodies. J Pediatr 2003; 142: 678-83 IZMIRLY PM, LLANOS C, LEE LA, ASKANASE A, KIM MY, BUYON JP: Cutaneous manifestations of neonatal lupus and risk of subsequent congenital heart block. Arthritis Rheum 2010; 62: 1153-57. IZMIRLY PM, COSTEDOAT-CHALUMEAU N, PISONI CN et al.: Maternal use of hydroxychloroquine is associated with a reduced risk of recurrent anti-SSA/Ro-antibodyassociated cardiac manifestations of neonatal lupus. Circulation 2012; 126: 76-82 MIYAKIS S, LOCKSHIN MD, ATSUMI T et al.: International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS). J Thromb Haemost 2006; 4: 295-306. WIJETILLEKA S, SCOBLE T, KHAMASHTA M: Novel insights into pathogenesis, diagnosis and treatment of antiphospholipid syndrome. Curr Opin Rheumatol 2012; 24: 473-81 RUFFATTI A, TONELLO M, VISENTIN MS et al.: Risk factors for pregnancy failure in patients with anti-phospholipid syndrome treated with conventional therapies: a multicentre, case-control study. Rheumatology (Oxford) 2011; 50: 1684-89. WALLENIUS M, SKOMSVOLL JF, IRGENS LM et al.: Pregnancy and delivery in women with chronic inflammatory arthritides with a specific focus on first birth. Arthritis Rheum 2011; 63: 153442. WALLENIUS M, SALVESEN KA, DALTVEIT AK, SKOMSVOLL JF: Rheumatoid arthritis and outcomes in first and subsequent births based on data from a national birth registry. Acta Obstet Gynecol Scand 2013 TARABORELLI M, RAMONI V, BRUCATO A et al.: Brief report: successful pregnancies but a higher risk of preterm births in patients with systemic sclerosis: an Italian multicenter study. Arthritis Rheum 2012; 64: 1970-77. CHAKRAVARTY EF: Vascular Complications of Systemic Sclerosis during Pregnancy. 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LATEEF A, PETRI M: Hormone replacement and contraceptive therapy in autoimmune diseases. J Autoimmun 2012; 38: J170-6 23. STEEGERS EA, von DADELSZEN P, DUVEKOT JJ, PIJNENBORG R: Pre-eclampsia. Lancet 2010; 376: 631-44. IMBASCIATI E, TINCANI A, GREGORINI G et al.: Pregnancy in women with pre-existing lupus nephritis: predictors of fetal and maternal outcome. Nephrol Dial Transplant 2009; 24: 519-25 IMBASCIATI E, TINCANI A, GREGORINI G et al.: Pregnancy in women with pre-existing lupus nephritis: predictors of fetal and maternal outcome. Nephrol Dial Transplant 2009; 24: 519-25 33. VINET E, LABRECQUE J, PINEAU CA et al.: A population-based assessment of live births in women with systemic lupus erythematosus. Ann Rheum Dis 2012; 71: 557-9 34. JAWAHEER D, ZHU JL, NOHR EA, OLSEN J: Time to pregnancy among women with rheumatoid arthritis. Arthritis Rheum 2011; 63: 1517-21. 38. 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