Optimizing the care of the care of the reproductively active rheumatic patient

1. Optimizing the care of the care of the reproductively active rheumatic patient Salahuddin Kazi

2. The Epidemiology of Fertility, Pregnancy and Outcomes in Rheumatic Patients

3. Pregnancy and lupus • ~4500 pregnancies in women with SLE each year in the United States • one third will result in a cesarean section • 33% will have preterm birth • more than 20% will be complicated by preeclampsia • Pregnancy in scleroderma • the overall success rate ( live birth) was: • 84% in women who had limited scleroderma • 77% in women who had diffuse scleroderma • 84% in the historical controls. Clowse M.E.B., Jamison M.G., Myers E., et al:  National study of medical complications in SLE pregnancies.  Arthritis Rheum 54. (9 Suppl): S263-S264.2006 Steen V.D.:  Pregnancy in women with systemic sclerosis.  Obstet Gynecol 94. (1): 15-20.1999

4. The spectrum of reproduction • The patient preventing/postponing reproduction • The patient preserving fertility • The patient actively planning pregnancy • The pregnant patient • The postpartum patient • The lactating/nursing patient

5. The patient preventing/postponing pregnancy • Oral Contraceptives – likely safe • SELENA trail – 1 year placebo controlled study in SLE • Patients with inactive or stable active lupus • Women with moderate anticardiolipin or the lupus anticoagulant were excluded • No increase in lupus flares • Depo-Progesterone – effective and safe for short term use • FDA advised that the use be limited to 2 years because of an increased risk of osteoporosis with long-term use • IUD - a woman with SLE who has a single partner and who is not on immunosuppressive drugs other than low-dose prednisone is considered an appropriate candidate

6. The patient preserving fertility • Less important issue with decreasing use of cyclophosphamide and shorter durtaion of therapy • The PREGO study – ongoing – will compare monthly injection of gonadotropin-releasing hormone analogue (GnRH-a) to placebo in young SLE patients during cyclophosphamide therapy • The only established method for preservation of child-bearing potential in women at risk of gonadal failure is embryo cryopreservation

7. Immunosuppressive Drugs in Pregnancy

8. The patient actively planning pregnancy • When to discontinue medications • Methotrexate – 3 months • Leflunomide – 2 years! + washout if < 2 years • CellCept – 3 months • NSAIDS – 2 weeks • Anti-TNF – after pregnancy confirmed

9. The pregnant patient • The patient with well controlled disease • The patient with active disease • The special case of the SSA/Ro positive patient • The patient with antiphospholipid antibodies

10. Patient with well controlled RA on an anti-TNF agent • JW is a 32 year old woman with RF+ve, CCP + RA • She avoided methotrexate and has been on Humira monotherapy – with well controlled disease for 18 months • She is now keen to start a family • Should she stop/continue anti-TNF therapy?

11. Table 1 Pregnancy risk categories (adapted from FDA Consumer60) associated with antirheumatic drugs Skomsvoll JFet al. (2007) Drug Insight: anti-tumor necrosis factor therapy for inflammatory arthropathies during reproduction, pregnancy and lactation Nat Clin Pract Rheumatol3:156–164 doi:10.1038/ncprheum0426

12. Skomsvoll JFet al. (2007) Drug Insight: anti-tumor necrosis factor therapy for inflammatory arthropathies during reproduction, pregnancy and lactation Nat Clin Pract Rheumatol3:156–164 doi:10.1038/ncprheum0426

13. Key Points • No increased risk of adverse pregnancy outcome has been demonstrated in patients treated with anti-tumor necrosis factor (anti-TNF) drugs • In general, anti-TNF therapy should be stopped before pregnancy, as there are limited data concerning the risk to the fetus • Anti-TNF therapy might, however, be used in selected patients with inflammatory arthropathies where there is high disease activity, according to an individual risk–benefit analysis, until early pregnancy is detected (although this might result in possible exposure in early pregnancy)

14. VACTERL and anti-TNF therapy • The authors examined reports of congenital abnormalities submitted to the US FDA over a 5–10 year period, and identified 41 children with birth defects born to mothers who received infliximab or etanercept at some point during their pregnancy • Of these children, 24 had a set of anomalies that, in the view of the authors, constituted part of the so-called VACTERL association, a nonrandom association of birth defects comprising vertebral, anal, cardiac, tracheal, esophageal and renal malformations or problems Carter, J. D. et al. A safety assessment of tumor necrosis factor antagonists during pregnancy: a review of the FDA database. J. Rheumatol. doi:10.3899/jrheum.080545 (2008)

15. VACTERL and anti-TNF therapy • The VACTERL association occurs spontaneously in 0.3–2.1 per 10,000 live births, and its multiple malformations originate during the early weeks of pregnancy • The design of the Carter study makes it impossible to judge whether or not TNF inhibitors taken during pregnancy increase the risk for birth defects • The main limitation is the unknown number of total pregnancy exposures to TNF inhibitors, which precludes a meaningful assessment of the magnitude of risk (if any) Carter, J. D. et al. A safety assessment of tumor necrosis factor antagonists during pregnancy: a review of the FDA database. J. Rheumatol. doi:10.3899/jrheum.080545 (2008)

16. The Patient with active disease/flare in pregnancy • Prednisone is largely metabolized by the placenta - fetal exposure is small • Doses greater ≥20 mg increase the risk of both preeclampsia and of gestational diabetes in SLE pregnancy • Intravenous methylprednisolone, 1000 mg daily for 3 days, given over 90 minutes, can help achieve quick control of an SLE flare • Fetal exposure to corticosteroids may not be completely benign • Cognitive impairment has been found in premature infants exposed to corticosteroids • This must be balanced against the severe risks experienced by very preterm babies

17. The Patient with active disease/flare in pregnancy • It is well know that nonsteroidal anti-inflammatory drugs (NSAIDs) should be avoided during the second and third trimesters because of their effect on the ductus arteriosus • NSAIDs must be avoided even in the first trimester • NSAIDs rarely have a deleterious effect on fertility Ofori B., Oraichi D., Blais L., et al:  Risk of congenital anomalies in pregnant users of non-steroidal anti-inflammatory drugs: a nested case-control study.  Birth Defects Res B Dev Reprod Toxicol 77. (4): 268-279.2006

18. The Patient with active disease/flare in pregnancy • Antimalarials: Initially, there was concern because of case reports of congenital malformations in pregnancies with chloroquine exposure • Both chloroquine and hydroxychloroquine cross the placenta, and both are also present in breast milk • Hydroxychloroquine should be continued during pregnancy because cessation of hydroxychloroquine leads to increased disease activity, lupus flares, and preterm birth

19. The Patient with active disease/flare in pregnancy • Azathioprine has a long track record of use in pregnancy with an acceptable safety profile – rare reports of neonatal immunosuppression. • Mycophenolate mofetil has been associated with rare fetal malformations of the corpus callosum and digit - advisable to switch to azathioprine before conception • Cyclophosphamide must be avoided during the first and early second trimesters – use in the third trimester in several patients who had severe lupus nephritis not responding to high-dose corticosteroids and other immunosuppressive drugs was followed by intrauterine fetal demise • Cyclosporine has been associated with growth restriction - may reflect the underlying maternal diseases for which it was prescribed

20. The patient with SSA/Ro antibodies • ML is a 22 year old nursing student with SLE (+ANA, +dsDNA, + SSA/Ro, pericarditis) – on HCQ alone • She is now 12 weeks pregnant • What is the risk for neonatal lupus syndromes? • How should she be managed?

21. SLE 35% SS 70% SCLE 80% Neonatal Lupus Syndromes 95% Asymptomatic Women 0.44% Frequency of Anti-Ro Antibodies

22. The patient with SSA/Ro antibodies • Neonatal lupus is a passively transferred autoimmune disease that occurs in about 1 to 2 percent of babies born to mothers with SSA/Ro antibodies • The incidence of congenital complete heart block appears to be more common in women with high titers of anti-Ro/SSA and anti-La/SSB • The incidence of heart block rises to about 18 percent in women with anti-Ro/SSA and/or anti-La/SSB antibodies who have had a previous child with congenital heart block

23. The patient with SSA/Ro antibodies • Antibodies with a specificity for the 52 kD component of the Ro/SSA protein are more frequently found and are present at higher concentrations in the serum of children with congenital heart block and their mothers • The combination of anti-Ro/SSA and anti-La/SSB antibodies may increase the likelihood of cutaneous manifestations of neonatal lupus

25. The patient with SSA/Ro antibodies • Complete heart block generally persists despite steroid therapy • incomplete heart block often is reversible, but may progress to complete heart block despite therapy • Glucocorticoids may suppress the associated pleuropericardial effusion or hydrops, and may improve outcomes

26. The patient with SSA/Ro antibodies • Complete heart block generally persists despite steroid therapy • incomplete heart block often is reversible, but may progress to complete heart block despite therapy • Glucocorticoids may suppress the associated pleuropericardial effusion or hydrops, and may improve outcomes • There are no formal guidelines for the type or the frequency of testing to detect fetal heart block • Dr. Jill Buyon recommends performing weekly pulsed Doppler fetal echocardiography from the 16th through the 25th week of pregnancy and then every other week until 32 weeks

27. Dr. Buyon is a great resource if you have questions Dear Dr. Buyon, I'm following a very interesting 33 year old patient with Sjogren's syndrome who is positive for ANA, anti-SSA and anti-SSB. She is especially interesting because she presented with hypokalemia and was found to have a renal tubular acidosis approximately 11 years ago. She subsequently developed sicca symptoms and in 2006 successfully delivered a baby without any complications. She has a Masters in Library Sciences and read about the differences between 52 kD and 60 kD Ro and the varying risk for congenital heart block. She is interested in determining what kind of anti-SSA/Ro antibody she may be carrying. I recognize that this is a research assay and not commercially available. All the same, both she and I are curious if your lab or any other lab that you are aware off is able to perform this determination. She would also be interested in participating in any research study that would enroll her. Thanks! Dino Kazi

28. Dr. Buyon is a great resource if you have questions Dear Dino, Thank you for your email. The long and short of it is that I am not in agreement that your patient really needs any testing beyond anti-Ro and La. Here is why. Her risk of a child with CHB is 2% if she has high titer anti-Ro (almost all anti-Ro is high titer). If she also has anti-La it may be 4-5%, no more. The presence of antibodies to Ro52 is common in mothers of children with CHB but in FACT it does not jack the risk up any higher than 5%. Almost every mother in our PRIDE study (Circulation) had anti-52Ro and as you will see the incidence was as expected, no higher. She should have weekly PR intervals done on her fetus from 16-26 weeks if possible. Thereafter the risk is decreased. If PR greater than 150msec she should have her Peds Cards call me urgently. There is no reliable prophylactic med and we are currently studying HCQ and IVIG. The recurrence rate is about 19%. Hope this all helps. Jill

29. The patient with SSA/Ro antibodies • If the fetus develops incomplete heart block, prenatal treatment should be considered with the administration of fluorinated glucocorticoids that are not inactivated by placental 11-beta hydroxysteroid dehydrogenase (eg, oral dexamethasone 4 mg daily or betamethasone 2 or 3 mg per day), beginning as soon after detection as feasible, and continuing through the end of pregnancy. • If heart block does not improve despite several weeks of glucocorticoid therapy, and if there is no other indication for their use, they may be discontinued. • Careful observation of infants whose atrioventricular block has been reversed in utero is necessary in the postnatal period, as there is still a risk of progression to a higher degree heart block, even with clearance of maternal autoantibodies

30. The patient with positive antiphospholipid antibodies • Antibodies alone • Antibodies + pregnancy-related event (early severe preclampsia, IUGR) • Antibodies + recurrent embryonic loss • Antobodies + late fetal loss • Antibodies + prior VTE

31. Antiphospholipid antibodies alone • Therapeutic options for these women include no therapy, low dose ASA alone, or low dose ASA and prophylactic heparin • Advisory Board of the 10th International Congress on aPL favored using low dose ASA alone in these patients • The American College of Chest Physicians Evidence-Based Clinical Practice Guidelines concluded these women are probably at increased risk of developing pregnancy-related venous thrombosis and suggested they be managed antepartum with either close clinical surveillance, prophylactic unfractionated heparin, or prophylactic low molecular weight heparin, and that they receive postpartum anticoagulation

32. APL + history of severe pre-eclampsia or IUGR • Low dose aspirin (50-100 mg) in 2nd and 3rd trimester • Consider prophylactic LMWH or UFH in cases of ASA failure or when placental examination shows extensive thrombosis

33. APL + late fetal loss • For women with laboratory criteria for aPL and one or more fetal losses after 10 weeks of gestation • Combined therapy with low dose ASA (81 mg per day begun as soon as conception is attempted) and prophylactic LMWH • Low dose ASA and prophylactic or intermediate dose unfractionated heparin is a reasonable alternative

34. APL + recurrent embryonic losses • Management of women with laboratory criteria for aPL and multiple embryonic losses (less than 10 weeks of gestation) is controversial, as there are many causes of early recurrent pregnancy loss • If the woman has had three or more such losses and a structurally normal uterus and documentation of euploid losses • low dose ASA and prophylactic or intermediate-dose heparin therapy or low dose ASA and prophylactic LMWH heparin during pregnancy can be offered

35. APL + prior VTE • Women with laboratory criteria for aPL and a prior history of arterial or venous thrombosis are at high risk of recurrence and are generally on lifelong anticoagulation with warfarin • These women should receive thromboprophylaxis during pregnancy and postpartum

36. Dosing Heparin with prior VTE • For most pregnant women a low molecular weight heparin (LMWH)-based regimen, rather than an unfractionated heparin (UFH)-based regimen is recommended • Continue therapy postpartum for 6 weeks

37. The postpartum patient • Watch for disease flares • Screen for thyroid disease • Continue anticoagulation (if applicable) for 6 weeks • Discuss resumption of medications • Discuss resumption of contraception

38. Lactation/Nursing • Prednisone is excreted into the breast milk, but use during lactation is deemed compatible by the American Academy of Pediatrics (AAP) if justified by the potential benefit to the health of the mother • Azathioprine is likely safe – very low levels in infants • Sulfasalazine is safe – folate supplementation recommended • HCQ - HCQ is found in human breast milk. Breastfed infants may be exposed to 2 percent of the maternal dose The AAP considers use of HCQ compatible with breastfeeding • CSA is excreted in breast milk, and therapeutic levels have been reported in breastfed infants - the use of CSA by lactating mothers is not recommended • Methotrexate, leflunomide, CellCept and Cytoxan are all contraindicated

39. The lactating/nursing patient