Management Rheumatic Disease Around Pregnancy Carlos Zevallos Jr, DO Crystal Arthritis Center Akron, Ohio Pregnancy in Rheumatic Disease • Pregnancy causes shift from Th1 to Th2 lymphocyte dominance. • Th1 disease like RA - remission • Th2 diseases like SLE - flare • High Risk: woman’s previous obstetric history, organ damage, disease activity, serologic profile, additional medical history Fertility • Fertility not generally affected except CKD 3-5, eGFR<50ml/min, amenorrhea – due to cyclophosphamide, active disease • RA and scleroderma - lower birth rates compared with the general population • NSAIDs – stop when trying to conceive • Assisted reproductive techniques – increase risk of flare and thrombotic events – particularly SLE Systemic Lupus Erythematosis • Plan pregnancy after remission for 6 months – active lupus = inc risk of flare – Active lupus nephritis and LN in remission = inc risk flare – The higher Cr, the greater risk of deterioration • Lupus flares generally non-severe = arthralgias, rash, mild hematologic issues – Severe flare with organ damage can occur • Unless contraindicated, continue hydroxychloroquine – Protects against organ damage, flares, thrombosis, bone mass loss, long-term survival Systemic Lupus Erythematosis • Risk of multiple medical and obstetrical complications during pregnancy, especially those with active disease or nonreversible organ damage (CVA, CKD, PHTN, Mod/Sev CM, Sev Rest Lung Dz • Increased ESR due to high fibrinogen production in liver • C3 and C4 rise in pregnancy – increased liver production (can be normal in active SLE) • Pts with protein loss due to LN may have increased proteinuria due to increased renal blood flow without indicating active LN (expect double proteinuria levels) Effect of SLE on Pregnancy • 20 fold increased risk of maternal mortality, inc rate of HTN, diabetes, renal impairment, PHTN, major infections, thrombotic events, hematologic complications than general population • 2-4 fold higher risk of preeclampsia, c-section, preterm labor, IUGR (particularly in pts with chronic HTN, renal impairment, high dose steroids) – Those with SLE in remission without major organ issues likely have normal pregnancy • 25% of SLE pregnancies end in preterm delivery • 6-35% incidence of small for gestational age babies • Miscarriage in 20% (risk inc with HTN, proteinuria >500mg/d, low plt, APS) • 3-4 fold increased chance of preeclampsia Rheumatoid Arthritis and Other Arthritis • 50-66% women with RA and the majority of women with psoriatic arthritis and JIA improve in pregnancy. (When both RF and CCP+ = less likely to improve) • Women with ankylosing spondylitis stay unaltered during pregnancy. • Postpartum flares can occur within the first 4 months (new onset RA 3-5 fold more likely to occur here) • Women with active disease have a higher risk of preterm delivery and small for gestational age babies. • RA has a higher risk of hypertensive disorders during pregnancy. • Children more likely small for gestational age, preterm, lower birth weight Scleroderma • Pregnancy does not seem to affect disease activity in the majority of patients (63-72%). – 1/3 will improve or worsen during pregnancy • Associated with higher risk of hypertensive disorders and higher rates of adverse pregnancy outcomes. (preeclampsia)(Monitor for renal crisis) • Raynauds improves, GERD worsens, Skin stays stable or improves (may worsen postpartum) • Recent onset dz, diffuse cutaneous dz, SCL70, RNA polymerase 3 = increased risk of more active disease. Scleroderma • Pts with marked malabsorption, CKD (Cr>2.5-2.8), PHTN, mod/sev CM (EF<30-40%), or severe RLD are at highest risk of medical and obstetric complications and should be counseled against conception • Renal crisis rate is same, but may need to treat with ACE inh if it occurs • Previous renal crisis does not contraindicate further pregnancy, but should delay for several years after stabilized. • Corticosteroid for lung maturation should not be given, may precipitate renal crisis. • SSC associated with increased risk of preterm delivery (14-29%) – Inc risk of IUGR, miscarriage Vasculitis • If in remission prior to pregnancy, low rate of complications and good pregnancy outcomes are reported. • Hypertensive disorders, including preeclampsia, are associated with poorer outcomes. • ESR not reliable, but CRP is reliable • RX – Low dose steroids (<7.5-10mg) and azathioprine. CYC if life threatening disease (contraindicated in 1st and early 2nd trimesters – may need IVIG during this time period) • Behcet’s – mild ulcers to severe CNS involvement or thrombosis(V/A). Antiphospholipid Syndrome • Antiphospholipid antibodies represent one of the major risk factors for poor obstetric outcome. – incr risk of preeclampsia, IUGR, prematurity, miscarriage – Recheck aPL shortly prior to pregnancy in SLE • Double or triple positive antibodies, and/or those with thrombotic antiphospholipid syndrome have the worst obstetric outcomes. • Rx – LDA, LMWH – for recurrent early miscarriage, or previous fetal death >10 weeks gestation and/or preterm <34 weeks Undifferentiated Connective Tissue Disease, Polymyositis,/Dermatomyositis, Mixed Connective Tissue Disease • Outcomes for UCTD and MCTD resemble those of SLE. (increased risk of preeclampsia, IUGR, preterm delivery) • Active PM and DM is associated with preterm delivery and pregnancy loss. – 50% will flare Neonatal Lupus • In Anti-Ro and/or anti-La can cause neonatal lupus syndrome affecting skin, heart, liver, cytopenias • Cutaneous neonatal lupus is seen in approximately 5% of offspring (resolve 3-6 months after birth), whereas congenital heart block is seen in about 2% (risk is 18% if prior child with CHB, 50% if 2 prior children with CHB) – risk of perinatal death is 20% - will need permanent pacemaker if survives. – Abs cross placenta between 16th-30th week gestation • Repeated fetal echocardiograms from the 16th week of gestation recommended • Rx – Fluorinated steroids – betamethasone and dexamethasone (less metabolized by the placenta) Pregnancy Management Plan • Pre-pregnancy assessment is vital. • Emphasis on previous obstetric and medical history, serology profile, disease activity, and extent of organ damage. • Monitor UA for proteinura, assess HTN, labs – DNA, C3/4, CRP, CBC, Cr, LFTs • Higher risk of preeclampsia – may use LDA to decrease risk • Calcium 1 gm daily showed >50% reduction in risk of preeclampsia and 25% reduction in risk of preterm delivery • Antenatal and postnatal plan and multidisciplinary team input are essential to achieve good maternal and fetal outcomes. Postpartum • Close surveillance for 2-3 months after delivery is important owing to high risk of flare and thrombosis. • All women with aPL should receive prophylactic LMWH for at least 7 days after delivery • Counseling on contraception. Hydroxycholroquine • Crosses the placenta • Category C • Found in human breast mild. Infant may be exposed to 2% of maternal dose • Rec – Continue HCQ during pregnancy and lactation with SLE to help prevent flares Sulfasalizine • Crosses the placenta • Category B/D • Lactation – drug concentrations is 40% that of the maternal level. Use with caution. • Rec- Does not appear to increase the adverse fetal outcome or have adverse affects during lactation – Concomitant folate supplementation is recommended and the dose of SSZ should not exceed 2 gm per day. NSAID and LDA • Minimal fetal/maternal risk when use is limited to 1st to end of 2nd TM • Category C for 1st two TM • Lactation – Excreted in breast milk in small amounts. May be compatible with breast feeding, but use with caution – See drug information guide for each drug • Recs – avoid NSAIDs during planned conception cycle until pregnant. NSAIDs may be associated with an increased risk of spontaneous abortion before 20 weeks of gestation. Avoid after week 30. Glucocorticoids • Prednisone and prednisolone cross the placenta but appear in only small amounts in cord blood • Dexamethasone and betamethasone reach higher concentrations in the fetus • Prednisone is cat B. Other GC are cat C. • May increase risk of cleft palate, adrenal hypoplasia • May increase risk of premature rupture of membranes, intrauterine growth restriction • In MOM – pregnancy induced HTN, gest DM, OP, infection • Lactation – excreted in breast milk. Discard breast mild for first 4 hours after pred dose >20mg. • Recs – use lowest dose. Try to avoid during first TM when hard palate is forming. May need stress dose during labor, delivery, and immediately postpartum. Azathioprine • Cat D • 64-93% of AZA mother dose in fetal blood as inactive metabolite – Placenta metabolizes AZA to thiouric acid – which is inactive – Fetal liver lacks enzyme inosinate pyrophosphorylase which is necessary to convert AZA and 6-MP to active metabolites • Study of 101 pregnancies revealed no association with poor pregnancy outcomes at doses of 100mg/d • Recs – Manufacturer insert state excreted in breast milk. More recent data suggests -Very low excretion in breast milk. TNF inh • Pregnancy outcome, preterm birth rates, spontaneous abortions, congenital abnormalities similar to women with RA • A case report suggested a possible association with VACTERL (Vertebral anomaly, Anal atresia, Cardiac defects, Tracheoesophageal fistula, Esophageal atresia, Renal anomalies, Limb dysplasia) • Category B • Lactation – insuf data • Recs – Discontinue TNF inh prior to conception IVIG • Crosses the placenta after 30-32 weeks of gestation • Category C • Lactation – Not known • Recs – Reasonable to use during some preg Cyclosporine • Little or no transplacental transfer in some reports – other yes • Risk of teratogenicity is low • Assoc with lower birth weights, inc maternal DM, HTN, renal allograft rejection • A report on 6 infants born to mother on cyclosporine found that T, B, NK cell development and maturation were impaired with effects still seen at 1 year – without development of predominant health problems at reproductive age • Category C • Lactation – is excreted in milk – not rec to breast feed • Recs – When needed, use lowest dose. Tacrolimus • Cat C • Lactation - not rec • Long-term immunomodulatory effect on offspring not known. Use smallest dose. Monitor BP and renal fxn. Cyclophosphamide • Risk of infertility and amenorrhea associated with med • Risk of ovarian failure depends on age - >31yo = highest risk; also accumulative dose • Animals – exopthalmos, cleft palate, skeletal abn, fetal resorption, growth retardation, • Risk of teratogenicity is high ~20% • Used only when disease poses grave health threat to mother • Normal children have been born to offspring exposed to CYC • Risk of terat highest during 1st TM • Cat D • Lactation – avoid • Recs – avoid except in life threatening disease without other alternatives available Chlorambucil • Rodents – bone formation defects, renal hypoplasia • Case reports of healthy infants • Cat D • Lactation – not rec • Recs – Strongly rec avoiding Methotrexate • Folate antagonist – inhibits dihydrofolate reductase and thus interferes with folic acid metabolism and purine synthesis • Embryotoxic in early preg • Skeletal abnormalities and cleft palate later in preg • Hydrocephalus, anecephaly, menigomyelopathy, congenital stenosis of tubular bones, abn facial features, delayed ossification • Rate of cong abn 9-17% • Widely distributed in maternal tissues • Persists in liver up to 4 months after exposure • Discontinue med 3-4 months prior to conception • Continue folic acid through preg • Cat X • Lactation- contraindicated • Recs – Strongly rec against use during preg or lactation Mycophenolate Mofetil • Cleft lip/palate, microtia and external auditory canals, anomalies – distal limbs, heart, esophagus, kidneys • Inc in 1st TM miscarriages • Cat D • Should discontinue at least 6 weeks before conception is attempted • Lactation – avoid • Recs – don’t use Leflunomide • T1/2 15 days • Teiflunomide (=major metabolite) undergoes extensive enterohepatic circulation and remains detectable in serum for up to 2 years • Eliminate with use of cholestyramine 8g TID for 11d and confirm level <0.02mg/L on 2 tests 2 weeks apart • Embryotoxic and marked teratogenicity in animal studies • Cat X • Lactation – avoid • Recs - Avoid Lef up to 2 years before preg. Do not use during preg or lactation. Wait at least 3 menstrual cycles after cholestyramine before attempting conception Anakinra • Recombinant human interleukin 1 receptor antagonist • Cat B • Lactation – Insuf data –avoid • Recs – avoid preg and lact Rituximab • Chimeric monoclonal ab • Peripheral B cell depletion by targeting CD20 antigen on B lymphocytes • Detected in high concentrations in umbilical blood • Cat C • Lactation – Insuf data – avoid • Recs – avoid preg and lact Abatacept • • • • • CTLA4-Ig is an inhibitor of T-cell co-stimulation Not teratogenic in animals Cat C Lactation – insuf data Recs – Avoid in preg and lact Tocilizumab • • • • • Interleukin 6 receptor inhibitor Animals – may cause fetal harm Cat C Lact – insuf data Recs – avoid in preg and lact Summary - Medications • Azathioprine, plaquenil, sulfasalizine, ciclosporin, and tacrolimus, IVIG are safe in pregnancy and lactation. • Steroids are safe but can have increased side effects and complications if used for prolonged periods and at doses >7.5mg daily. Limited boluses are safe. – Nonfluorinated steroids (prednisone, methylprednisolone, hydrocortisone) are largely metabolized by placenta and thus minimal amounts reach fetal circulation – Cat B – Dexamethasone and betamethasone cross the placenta with similar maternal and fetal concentrations – Cat C – At high doses of prednisone >20mg daily, wait until 4 hours after the dose to breastfeed. Summary - Medications • Biologics – TNF inhibitors may be safe in the 1st and 2nd trimesters and lactation. • Avoid – MTX, Arava, Rituxan, Cellcept, Cyclophosphamide, Endothelin receptor antagonisits, bisphosphonates • Unknown – abatacept, tocilizumab, belimumab • NSAIDs are class B for intermittent use, but D if >30 weeks gestation Summary - Medications • Mild disease – Low dose prednisone 5-15 mg per day, Plaquenil, SSZ • Moderate to Severe disease – Plaquenil, GC, Azathioprine, Cyclosporine, IVIG • Life-threatening disease – High dose GC, Cyclosporine, Azathioprine, 6mercaptopurine, – Cyclophosphamide if no other alternative available • Avoid Leflunomide, Methotrexate, chlorambucil , mycophenylate mofetil References • Ateka-Barrutia O, et al. Management of Rheumatologic Diseases in Pregnancy. Int J Clin Rheumatol. 2012;7(5):541-558. • Temprano K, et al. Anti-rheumatic Drugs in Pregnancy and Lactation. Semin Arthritis Rheum 2005;35:112-121. • Bermas B. Use of Anti-inflammatory and Immunosuppressive Drugs in Rheumatic Diseases During Pregnancy and Lactation. UpToDate 2013.