Fertility? 2. Recurrent Spontaneous Abortions in RD. Causes/Investigations/management strategies

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1 1. Does RD affect Fecundity & Fertility? 2. Recurrent Spontaneous Abortions in RD. Causes/Investigations/management strategies Dr Sarath Chandra Mouli Veeravalli MD;MRCP(UK) Clinical Director, Dept of Rheumatology and Clinical Immunology Krishna Institute of Medical Sciences Hyderabad

2 Rheumatic diseases touch all aspects of life, includes sexuality and reproduction Autoimmune rheumatic diseases (ARD) affect mainly young women during their reproductive years Fertility may not be diminished but the time it takes to conceive is usually longer.

3 In ARD more often, fecundity (time to achieve pregnancy) is affected. In a population-based study women with rheumatic disease had a lower number of births and fewer women achieved subsequent pregnancy compared to healthy controls.

4 Infertility affects 10 15% of all couples, and is higher in male and femalee patients with rheumatic disease.* Decreased libido, erectile dysfunction and failure to ejaculate has been reported in 19-35% of men with SLE.** *Crazzolara S, Wunder D, Nageli E, Bodmer C, Graf S, Birkhauser MH. Semen parameters in a fertile Swiss population. Swiss Med Wkly 2007;137: ** Silva CA, Bonfá E, Borba EF et al. Reproductive health in male systemic lupus erythematosus.

5 Infertility is a heterogeneous condition that can be related to. -immunological mechanisms, -pregnancy loss, -disease burden -therapy -choices in regard to family size. Progress in reproductive medicine has made it possible for more patients with rheumatic disease to have children.

6 Periods of impotence occur in patients with rheumatic disease. Hypoandrogenicity with low levels of testosterone has been found in men with RA, especially in the presence of high disease activity.* Gonadal and sexual dysfunction has been found at an increased rate in men with SLE.** Rheumatic diseases can impair also male fertility by direct involvement of the gonads, by disturbances of the hypophyseal- gonadal hormonal balance and by autoantibodies to testicular cells. A Brazilian study revealed impaired testicular and sexual function in 35 male SLE patients. SLE patients had lower median testicular volume in both testes (P = and P = 0.004), total sperm count (P = 0.002) and total motile sperm count (P = 0.004) compared with 35 healthy controls. ** *Packham JC, Hall MA. Longterm follow-up of 246 adults with juvenile idiopathic arthritis: social function, relationships and sexual activity. Rheumatol 2000; 41:440-3.

7 *Silva CA, Moraes AJ, Leal MM et al. Reproductive health aspectss in men with idiopathic in ammatory myopathy. A multicenter study. Rev Bras Comparing reproductive health of 25 men with IIM to 25 healthy men studied by the same methods showed significantly impaired sexual activity and fertility in patients. * Of concern was the significant increase of testicular atrophy in men with IIM and of abnormal semen morphology. Damage to gonadal tissue didd impair fertility in these patients. Long disease duration and older age was associated with erectile dysfunction in patients with IIM whereas disease activity and treatment or hypogonadism did not influence it.

8 In women with primary Sjögren s syndrome, vaginal dryness and other disease-related symptoms increase distress and sexual dysfunction [3]. In fact, patients with systemic lupus erythemathosous (SLE), systemic sclerosis (SS) or rheumatoid arthritis(ra) also show a predisposition to vaginal dryness and dyspareunia [3,4] 3. Maddali Bongi S, Del Rosso A, Orlandi M, Matucci-Cerinic M. Gynaecological symptoms and sexual disability in women with primary Sjogren s syndrome and sicca syndrome. Clin Exp Rheumatol 2013; 31 (5): Maddali Bongi S, Del Rosso A, Mikhaylova S, Baccini M, Matucci Cerinicc M. Sexual function in Italian women with systemic sclerosis is a ected by

9 Systemic sclerosis-related facial and body changes, impaired touch due to finger sclerosis and vaginal tightness can have a deleterious effect on foreplay and intercourse [4] Raynaud s phenomena, 4. Maddali Bongi S, Del Rosso A, Mikhaylova S, Baccini M, Matucci Cerinic M. Sexual function in Italian women with systemic sclerosis is a ected by disease- related and psychological concerns. J Rheumatol 2013; 40 (10):

10 Amenorrhea due to severe flares, hypofertility related to renal insufficiency, and gonadotoxicity associated with cyclophosphamide or high dose glucocorticoids may be the origin of this condition[5]. Other conditions like luteinized unruptured follicle syndrome after high dose non-steroidal antiinflammatory drugs(nsaids) have been described.

11 Psychosocial factors and their negative impact on childbearing decisions also affect fecundity. Among women with chronic disease the fear of genetic transmission or parenting disability is still common. In summary, immunological mechanisms, pregnancy loss, disease disability, treatment, or the decision to limit family size contribute to impaired fertility/fecundity in women with ARD [7]. 7. Ostensen M, Andreoli L, Brucato A, et al. State of the art: reproduction and pregnancy in rheumatic diseases. Autoimmun Rev 2015; 14 (5):

12 Recurrent Pregnancy Loss: SLE/APS

13 The rate of early and late pregnancy losses is significantly increased in the APS, particularly when combined with SLE. Danowski et al analyzed 122 women with primary APS or APS associated with SLE [12]. In the first group 10% had a history of miscarriages and in the second group 39%.

14 In 1000 patients with APS : miscarriage rate of 35% was found for miscarriages < 10 weeks of pregnancy 17% for losses > 10 weeks of pregnancy [13]. [13]. Cervera R., Serrano R., Pons-Estel G.J., Ceberio-Hualde, Shoenfeld Y., de Ramón E., et al:

15 It has been demonstrated that a combination of apl, ASCA, and apt has the most predictive value for RPL compared with controls [18]. A significant association between the presence of IgG apt and pregnancy loss, particularly early pregnancy loss, has been found [19]. [18]. Shoenfeld Y., Carp H.J., Molina V., Blank M., Cervera, Balasch J., et al: Autoantibodies and prediction of reproductive failure. Am J Reprod Immunol 2006; 56: pp [19]. von Landenberg P., Matthias T., Zaech J., Schultz M., Lorber M., Blank M., et al: Antiprothrombin antibodies are associated with pregnancy loss in patients with the antiphospholipid syndrome. Am J Reprod Immunol 2003; 49: pp

16 Recurrent Pregnancy loss Lupus anticoagulant Anti-cardiolipin (acl) Anti-β2 glycoprotein I (aβ2gp1) Antibodies to thyroid antigens (ATA), such as thyroglobulin (atg) and thyroid peroxidase (atpo) Antibodies to nuclear antigens (ANA) Anti-laminin Anti-prothrombin antibodies (apt) Anti-saccharomyces cerevisiae antibodies (ASCA)

17 Treatment Treatment with low dose aspirin (LDA) and heparin (H) or low molecular weight heparin (LMWH) proved to be effective in the majority of patients [86] [86]. Mak A., Cheung M.W., Cheak A.A., and Ho R.C.: Combination of heparin and aspirin is superior to aspirin alone in enhancing live births in patients with recurrent pregnancy loss and positive antiphospholipid antibodies: a meta-analysis of randomized controlled trials and meta-regression. Rheumatology (Oxford) 2010; 49: pp

18 Low dose aspirin before conception and heparin after positive pregnancy test increase the probability of good outcome, particularly in casess of APS pregnancies. Adequate calcium and vitamin D supplementation especially in women receiving glucocorticoids and heparin is recommended [7]. 7. Ostensen M, Andreoli L, Brucato A, et al. State of the art: reproduction and pregnancy in rheumatic diseases. Autoimmun Rev 2015; 14 (5):

19 Therapeutic options for the high risk patients are not yet clear. The addition of first-trimester low-dose prednisolone has resulted in a higher live-birth rate than conventional therapy alone [90]. Intravenous immunoglobulins, or weekly apheresis procedures have been applied with some success in high risk patients [91]. [90]. Bramham K., Thomas M., Nelson-Piercy C., et al: First-trimester low-dose prednisolone in refractory antiphospholipid antibody-related pregnancy loss. Blood 2011; 117: pp [91]. Ruffatti A., Salvan E., Del Ross T., et al: Treatment strategies and pregnancy outcomes in antiphospholipid syndrome patients with thrombosis and triple antiphospholipid positivity. A European multicenter retrospective study. Thromb Haemost 2014; 112: pp

20 ART Since women in affluent western societies have postponed their first pregnancy, a proportion of patients with rheumatic disease do experience fertility problems and opt for ART. SLE or APS undergoing risk of a lupus flare hyperstimulation [23] infertility treatment - after ovarian The risk for a flare is low in well controlled disease and when coadjuvant therapy is given, but higher in active disease [23].

21 The most threatening adverse event in women undergoing ovarian stimulation is thrombosis. Ovarian stimulation can result in high concentrations of estradiol, exceeding physiological levels, with a risk for ovarian hyperstimulation syndrome (OHSS) resulting in a capillary leak-syndrome and raised hematocrit which increases the risk of thrombosis [24]. The risk can be reduced by using stimulation protocols with gonadotropin-releasing hormone (GnRH) antagonists and ovulation induction with GnRH agonists which almost completely avoids ovarian hyperstimulation syndrome [25]. [24]. Henriksson P., Westerlund E., Wallén H., Brandt, Hovatta O., Ekbom A., et al: Incidence of pulmonary and venous thromboembolism in pregnancies after in vitro fertilisation: cross sectional study.

22 [26]. Bellver J., and Pellicer A.: Ovarian stimulation in SLE and antiphospholipid syndrome. Fertil This protocol requires a cryopreservation of all fertilized oocytes and an interval of at least one month before embryo transfer. Friendly ovarian stimulation, single embryo transfer, avoidance of OHSS, administration of coadjuvant therapy, and use of natural estrogen or progesterone through a non-oral route may constitute the safest approach [26]

23 E. All of the above Quiz Which of the following factors influence fertility in autoimmune rheumatic diseases A. Hormones B. Therapy C. Antibodies D. Active disease