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State of the art: Reproduction and pregnancy in rheumatic diseases
State of the Art: Reproduction and Pregnancy in Rheumatic Diseases Monika Østensen, Laura Andreoli, Antonio Brucato, Irene Cetin, Christina Chambers, Megan Clowse, Nathalie Costedoat-Chalumeau, Maurizio Cutolo, Radboud Dolhain, M. Fenstad, Frauke F¨orger, Marie Wahren-Herlenius, Guillermo Ruiz-Irastorza, Hege Koksvik, Catherine Nelson-Piercy, Yehuda Shoenfeld, Angela Tincani, Peter M. Villiger, Marianne Wallenius, Michael von Wolff PII: DOI: Reference:
S1568-9972(14)00311-5 doi: 10.1016/j.autrev.2014.12.011 AUTREV 1664
To appear in:
Autoimmunity Reviews
Received date: Accepted date:
12 December 2014 23 December 2014
Please cite this article as: Østensen Monika, Andreoli Laura, Brucato Antonio, Cetin Irene, Chambers Christina, Clowse Megan, Costedoat-Chalumeau Nathalie, Cutolo Maurizio, Dolhain Radboud, Fenstad M, F¨ orger Frauke, Wahren-Herlenius Marie, RuizIrastorza Guillermo, Koksvik Hege, Nelson-Piercy Catherine, Shoenfeld Yehuda, Tincani Angela, Villiger Peter M., Wallenius Marianne, von Wolff Michael, State of the Art: Reproduction and Pregnancy in Rheumatic Diseases, Autoimmunity Reviews (2014), doi: 10.1016/j.autrev.2014.12.011
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ACCEPTED MANUSCRIPT State of the Art: Reproduction and Pregnancy in Rheumatic Diseases Monika Østensen, Laura Andreoli, Antonio Brucato, Irene Cetin, Christina Chambers, Megan Clowse, Nathalie Costedoat-Chalumeau, Maurizio Cutolo, Radboud Dolhain, M Fenstad, Frauke Förger, Marie Wahren-Herlenius, Guillermo Ruiz-Irastorza, Hege Koksvik, Catherine Nelson-Piercy , Yehuda
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Shoenfeld, Angela Tincani, Peter M. Villiger, Marianne Wallenius, Michael von Wolff
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Affiliation:
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Monika Østensen MD, National Advisory Unit on Pregnancy and Rheumatic diseases, Department of Rheumatology, St. Olavs Hospital, University Hospital of Trondheim, Norway, E-mail: [email protected]
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Laura Andreoli MD, Rheumatology and Clinical Immunology, Spedali Civili of Brescia and Department of Clinical and Experimental Sciences, University of Brescia, Italy
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Antonio Brucato MD, Department of Internal Medicine, Ospedale Riuniti, 24128 Bergamo, Italy Irene Cetin MD, Department of Mother and Child, Hospital Luigi Sacco, University of Milano, Italy Christina Chambers MD, Department of Pediatrics, University of California San Diego, La Jolla, CA
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92093-0828, USA
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Center, Durham, NC, USA
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Megan Clowse MD, Division of Rheumatology, Department of Medicine, Duke University Medical
Nathalie Costedoat-Chalumeau MD, Université Paris-Descartes, Paris, France ; AP-HP, Hôpital Cochin, Centre de référence maladies auto-immunes et systémiques rares, Service de médecine
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interne, Paris, France
Maurizio Cutolo, MD, Research Laboratories and Academic Division of Clinical Rheumatology, Department of Internal Medicine,University of Genova, Genova, Italy Radboud J.E.M. Dolhain MD, Department of Rheumatology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands. Mona H. Fenstad, Department of immunology and transfusion medicine, St.Olavs hospital, Trondheim, Norway. Frauke Förger MD, Department of Rheumatology and Clinical Immunology/Allergology, University Hospital of Bern, CH-3010 Bern, Switzerland Marie Wahren-Herlenius MD, Department of Medicine, Centre for Molecular Medicine, Karolinska Universitetssjukhuset, Stockholm, Sweden
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ACCEPTED MANUSCRIPT Guillermo Ruiz-Irastorza MD, Autoimmune Diseases Research Unit, Department of Internal Medicine, Biocruces Health Research Institute, Hospital Universitario Cruces, University of the Basque Country, Bizkaia, Spain Hege Svean Koksvik R.N. National Advisory Unit on Pregnancy and Rheumatic diseases, Department
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of Rheumatology, St. Olavs Hospital, University Hospital of Trondheim, Norway
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Catherine Nelson-Piercy, MD, Women’s Health Academic Centre, St Thomas’ Hospital, London, UK Yehuda Shoenfeld MD. Zabludowicz Center for Autoimmune Diseases, Sheba Medical Center, TelAviv University, Tel-Hashomer, Israel
Angela Tincani MD, Department of Rheumatology and Clinical Immunology, Ospedale Civile and
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University of Brescia, Brescia, Italy
Peter Villiger MD, Department of Rheumatology and Clinical Immunology/Allergology, University
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Hospital of Bern, Bern, Switzerland
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Marianne Wallenius MD, National Service for Pregnancy and Rheumatic Diseases, Department of Rheumatology, Trondheim University Hospital, Trondheim, Norway and Dept of Neuroscience, Norwegian University of Science and Technology (NTNU), Trondheim, Norway
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Michael von Wolff M.D. University Women’s Hospital, Division of Gynaecological Endocrinology and Reproductive Medicine, University of Berne, Berne, Switzerland
Corresponding author:
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Monika Østensen, MD. National Advisory Unit on Pregnancy and Rheumatic diseases, Department of Rheumatology, St. Olavs Hospital, University Hospital of Trondheim, Norway, E-mail: [email protected]
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ACCEPTED MANUSCRIPT Abstract Throughout the last decade, increasing awareness has been raised on issues related to reproduction in rheumatic diseases including basic research to clarify the important role of estrogens in the aetiology and pathophysiology of immune/inflammatory diseases. Sub- or infertility is a heterogeneous
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condition that can be related to immunological mechanisms, to pregnancy loss, to disease burden, to
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therapy, and to choices in regard to family size. Progress in reproductive medicine has made it possible for more patients with rheumatic disease to have children. Active disease in women with
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rheumatoid arthritis (RA) affects their children’s birth weight and may have long-term effects on their future health status. Pregnancy complications as preeclampsia and intrauterine growth restriction are still increased in patients with systemic lupus erythematosus (SLE) and antiphospholipid syndrome
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(APS), however, biomarkers can monitor adverse events, and several new therapies may improve outcomes. Pregnancies in women with APS remain a challenge, and better therapies for the obstetric APS are needed. New prospective studies indicate improved outcomes for pregnancies in women with
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rare diseases like systemic sclerosis and vasculitis. TNF inhibitors hold promise for maintaining remission in rheumatological patients and may be continued at least in the first half of pregnancy. Preconceptional counselling and interdisciplinary management of pregnancies are essential for ensuring
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optimal pregnancy outcomes.
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211 Words
Key words: Estrogen - fertility - rheumatoid arthritis – systemic lupus erythematosus antiphospholipid syndrome – systemic sclerosis – vasculitis – pregnancy complications - placenta -
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TNF inhibitors
Running title: Reproduction in rheumatic disease
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ACCEPTED MANUSCRIPT Introduction Throughout the last decade, increasing awareness has been raised on issues related to reproduction in chronic diseases. Rheumatic diseases can affect quality of life and reproduction in both genders. Hormones, fertility, pregnancy, and management of high- risk pregnancy are important topics for
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patients and their doctors alike. This article gives a concise overview of current basic and clinical
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research presented at the VIII International Conference on Reproduction and Pregnancy and the
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rheumatic diseases 25. – 27. 2014 September in Trondheim, Norway.
Sex hormones and autoimmune diseases
The preponderance of women affected by chronic immune/inflammatory diseases clearly indicates that female sex hormones play an important role in the aetiology and pathophysiology of autoimmunity
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(1). In human subjects estrogens are generally considered as at least enhancing the humoral immune response. They act on cells by their peripheral metabolites rather than through their serum levels that
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may exert opposite dose-related effects (2).
Estrogen receptors (ERα and ERβ) are necessary for the action of estrogens. Recently, anti-ERα antibodies were detected in 45% of patients with systemic lupus erythematosus (SLE), whereas anti-
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ERβ antibodies were undetectable (3). In healthy donors, anti-ERα antibodies induced cell activation and consequent apoptotic cell death in resting lymphocytes. At the same time, they induced
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proliferation of anti-CD3-stimulated T lymphocytes, a mechanism that might contribute to autoreactive T cell expansion. A significant association between anti-ERα antibody levels and clinical parameters,
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like the SLE Disease Activity Index (SLEDAI) and arthritis, was found (3). Several investigations support an accelerated aromatase-mediated peripheral metabolic conversion of upstream androgen precursors to estrogen metabolites in peripheral tissues affected by
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immune/inflammatory reactions, both in male and female patients (4). In synovial tissue from rheumatoid arthritis (RA) patients, altered peripheral sex hormone synthesis (intracrine, e.g., at the level of macrophages and fibroblasts) mainly results in stimulation of cell proliferation and cytokine production (i.e. TNF) by these metabolites. It was shown that RA synovial cells mainly produce the cell proliferation promoting 16alpha-hydroxyestrone which, in addition to 16alpha-hydroxy-17betaestradiol, is the downstream estrogen metabolite that interferes with monocyte proliferation (5). Therefore, a preponderance of 16alpha-hydroxylated estrogens is an unfavorable sign, at least, in synovial inflammation and possibly related synovial tissue hyperplasia. Interestingly, urinary concentration and total urinary loss of 2-hydroxyestrogens was found 10 times higher in healthy subjects compared to RA or SLE patients irrespective of prior prednisolone treatment or sex (2). The intracrine synthesis of active estrogen metabolites at the level of cells involved in the immune response represents a common pathway that characterizes a similar final immune reactivity in both male and female patients (4).
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ACCEPTED MANUSCRIPT Contraception Traditionally, exogenous estrogens were considered to have the potential of worsening autoimmune processes. Typical oral contraceptive pills contain both estrogen and progesterone (combined oral contraceptives). Two randomized trials of these pills in women with mild-moderate stable SLE found
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no increase in SLE activity (6). However, women with very active SLE or active lupus nephritis were
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not included in these trials (6). The risk of thrombosis remains a significant concern, and estrogens
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should be avoided in women with antiphospolipid syndrome (APS), high levels of antiphospholipid antibodies (aPL), nephrotic-range proteinuria, or other conditions that increase thrombotic risk. The relative risk of venous thrombosis for combined oral contraceptives with 30-35 μg ethinylestradiol and rd
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gestodene, desogestrel, cyproterone acetate or drospirenone (3 or 4 generation progestogens) is nd
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similar and about 50-80% higher than for combined oral contraceptives with levonorgestrel (2 generation progestogen) (7).
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Fertility
Fertility problems in women with rheumatic disease occur not only in diseases with extensive systemic inflammation and autoantibody production, but also in the predominantly inflammatory joint diseases
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(IJD) (8). Women with IJD have a prolonged time to pregnancy compared to women in the general
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population, and seem also to require assisted reproduction more often (9). Whether they also have a reduced ovarian reserve has not been clarified. In a prospective study of 245 women with rheumatoid arthritis desiring children, 42 % experienced a greater than 12 months interval until conception (10).
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Disease activity and therapy were found associated with a prolonged interval to achieve pregnancy .
Women with rheumatic disease have fewer children than age matched controls from the general population (11). A reduced family size can be caused by increased pregnancy losses as well as
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disease related choices. Age at time of diagnosis is of importance for parity / nulliparity and for the final number of children. Women diagnosed with IJD before 25 years of age are more often childless or have fewer children than women diagnosed after 25 years of age (8). Studies have also shown that women with IJD are older than age matched controls at their first delivery and thus have a shorter reproductive period. The rate of early and late pregnancy losses is significantly increased in the APS, particularly when combined with SLE. Danowski et al. 2009 analysed 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%. The high risk for pregnancy loss in women with SLE and increased aPL, especially lupus anticoagulant (LA), was also confirmed by other studies. In 1`000 patients with APS including 820 women, a miscarriage rate of 35% was found for miscarriages <10 weeks of pregnancy and 17% for losses >10 weeks of pregnancy (13).
Reproductive failure is a heterogeneous condition that can be related in several autoimmune diseases to immunological pathomechanism (14). Beside the great role played by innate immunity, several
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ACCEPTED MANUSCRIPT autoantibodies have been associated with impaired fertility. Above all, the aPL including LA, anticardiolipin (aCL) and anti-β2 glycoprotein I (aβ2GP1) have all been reported to be associated with recurrent pregnancy loss (RPL) or as possible factors involved in infertility (15). In the context of RPL, complement-mediated placental inflammation has also been described to play a key role in
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experimental models of fetal loss induced by passive injection of aPL after implantation (16).
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Antibodies to thyroid antigens (ATA), such as thyroglobulin (aTG) and thyroid peroxidase (aTPO),
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antibodies to nuclear antigens (ANA), anti-laminin, anti-prothrombin antibodies (aPT) and antisacchromyces cerevisiae antibodies (ASCA), have also been implicated in pregnancy complications (16;17). 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
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and pregnancy loss, particularly early pregnancy loss, has been found (19). ATA have been suggested to be independent markers of pregnancies at risk for pregnancy loss (17). The association between pregnancy loss and thyroid antibodies may be a result of a direct effect of ATA on fetal tissue
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and the thyroid antibodies representing an underlying more generalized defect in autoimmunity (17). At present, the prognostic value of ATA remains uncertain. Cohort studies are necessary to determine the true incidence of pregnancy loss in the presence of each autoantibody or combination of
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autoantibodies.
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Understanding the pathogenesis of reproductive failure may help in developing specific therapies. Treatment with intravenous immunoglobulins (IVIg) has been the main option in patients with immunologic pregnancy loss (20), and is based on the concept that pregnancy loss may be caused by
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an aberrant immunological or inflammatory response involving cytokines or an autoimmune response as in APS. IVIg have been used to improve the live birth rate in women with unexplained RPL and APS though the results have been contradictory (21).
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Assisted reproduction (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. Initially, a negative influence of aPL on the success rate of in vitro fertilization (IVF) was suggested, however, a metaanalysis showed that this is not the case (22). Concerns in women with SLE or APS undergoing infertility treatment, are induction of a flare or thrombosis (23). Several retrospective studies have investigated the risk of a lupus flare after ovarian hyperstimulation (24). The conclusions of the studies are limited by lumping together different protocols of ovarian stimulation (clomiphen or gonadotropins). It appears that the risk for a flare is low in well controlled disease and when coadjuvant therapy is given, but higher in active disease (24). 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 increase the risk of thrombosis (25). The risk can be reduced by using stimulation protocols with Gonadotrophin-releasing hormone (GnRH) and ovulation induction with GnRH agonists
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ACCEPTED MANUSCRIPT which almost completely avoids ovarian hyperstimulation syndrome (25). This protocol requires 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
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safest approach (26). Active SLE, badly controlled arterial hypertension, pulmonary hypertension,
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advanced renal disease, severe valvulopathy or heart disease, and major previous thrombotic events
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are situations on which to discourage ART (24).
Progress in reproductive medicine has made it possible that women who undergo therapy with cyclophosphamide for lupus nephritis, systemic sclerosis or vasculitis can preserve their fertility (27).
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Pregnancy and rheumatic diseases
The response of rheumatic diseases to pregnancy varies in regard to disease activity. Likewise pregnancy outcome is different depending on disease extent and severity, presence of autoantibodies,
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comorbidities, therapy as well as non-disease related factors.
Rheumatoid arthritis
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Since the observation on predominant improvement made by Hench (28), the percentage of RA patients reported to improve during pregnancy declined from 90% to 48% in the most recent
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prospective cohort study on RA and pregnancy, the PARA study (29). Despite improvement during
trimester (29).
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pregnancy more than half of RA-patients still had active disease (DAS28 > 3.2) during the third
The very high percentage of patients that improved in the study of Hench should clearly be seen in the light of the very limited treatment options for RA in that era and the influence of self- reporting. Disease
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activity is more likely to decline during pregnancy when measured by self- report compared to objectively measured disease activity, as determined by DAS28. Other factors, which might explain a lower percentage of improvement in pregnant RA patients are disease activity and autoantibody status. Women with active disease and those negative for ACPA and rheumatoid factor were more likely to ameliorate during pregnancy (29;30). Therefore, also differences in patient selection might contribute to the observed differences. Another intriguing finding of the PARA-study is that women treated with prednisone show hardly any spontaneous improvement of disease activity during pregnancy, in contrast to women not using glucocorticoids (31) indicating a spontaneous, positive influence of the physiological rise in glucocorticoids during pregnancy. Throughout the decades after Hench`s description, the spontaneous improvement of RA during pregnancy has been felt intriguing. Among the different factors suggested to be involved are regulatory T cells (Treg). Treg originate in the thymus as naturally occurring Treg and can also be induced in the periphery. Recently it has been shown in animal models, that peripheral induced Treg, not thymic derived Treg, are critically involved in feto-maternal tolerance (32). Animal studies have shown that Treg expansion during pregnancy is mainly driven by fetal antigens which give rise to fetal
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ACCEPTED MANUSCRIPT antigen-specific peripheral Treg.(32) In RA patients, the ameliorating effect of pregnancy has been associated with an expansion of Treg that induce a pronounced anti-inflammatory cytokine milieu (33). By contrast, Treg of ankylosing spondylitis (AS) patients who experience active disease during pregnancy fail to support an anti-inflammatory milieu (34). Thus, active disease might provide an
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environment that promotes the differentiation from Treg to proinflammatory Th17 cells (35), yet this
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has not been shown in pregnant patients with rheumatic diseases.
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Other factors suggested to be involved are changes in the glycosylation of IgG during pregnancy. Glycosylation influences the tertiary structure of a protein and hence its function. Glycosylation is the addition of a glycan to a protein and influences the binding of immunoglobulins to the Fc-receptor with a major impact on the ability to cause antibody-dependent cell-mediated cytotoxicity. In the 1990ies
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an association between the glycosylation of IgG and improvement of RA during pregnancy was described (36). New studies using mass spectrometry showed that galactosylation of IgG, but not sialylation, was associated with improvement of RA during pregnancy (37). In addition, it was shown
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that also the glycosylation of proteins other than immunoglobulins changed during pregnancy indicating that improvement of RA during pregnancy may not only result from changes in the glycosylation of IgG, but may also depend upon pregnancy induced changes in the glycosylation of
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several other key effector molecules involved in the pathogenesis of RA.
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In the Dutch PARA-study disease activity in pregnant RA-patients, was directly associated with lower birth weight, whereas the use of prednisone indirectly influenced birth weight by lowering gestational age (38). Lower birth weight, even within the normal range, is a risk factor for metabolic syndrome and
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cardiovascular disease in adulthood (39). To get more insight into possible long term consequences of the RA associated lower birth weight, the growth of 167 children from mothers with RA was analysed with a focus on rapid catch-up growth in weight during first year of life (40). Almost one third of children born to women with RA demonstrated rapid catch-up growth in weight, which was clearly
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associated with (higher) maternal DAS28 during the third trimester of pregnancy (40). In other studies rapid catch-up growth in weight has been shown to be associated with an unfavourable cardiovascular risk profile in early adulthood (41). Body composition, one of the indicators for future cardiovascular disease, was studied in 108 children age 5-10 years born to mothers with RA (42). However, no association between body composition at age 5-10 years and maternal disease activity during pregnancy could be found (42).
Systemic lupus erythematosus Pregnancy in women with SLE, particularly in those with lupus nephritis is associated with increased risks of pre-eclampsia, fetal growth restriction, fetal loss and preterm delivery. These increased risks are present even if the lupus nephritis is quiescent but are higher in the presence of hypertension or proteinuria (43). For women with renal impairment, the risk of deterioration in renal function is higher with higher serum creatinine and the chance of successful pregnancy outcome is lower. For women with a pre-pregnancy serum creatinine between 125 and 180 umol/L the risk of delivering preterm
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ACCEPTED MANUSCRIPT (less than 37 completed gestational weeks) is 60%, the risk of pre-eclampsia is 40 %, the risk of fetal growth restriction is 40 % and the risk of perinatal death is 5 %. The patient runs these risks in pregnancy while at the same time there is a 20 % risk of a permanent decline in renal function post
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partum and a 2% of reaching end stage renal failure within a year of delivery (44).
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Specific data for lupus nephritis are available and a meta-analysis of 362 pregnancies showed an
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incidence of renal flare in 11-43%, reversible acute renal failure in 3-27% and irreversible loss of renal function in 0-11% (45). A single centre study of 113 pregnancies in 81 women with pre-existing biopsyproven lupus nephritis included 6 women with class II, 8 with class III, 48 with class IV and 19 with class V disease. At conception, 49% were in complete and 27% partial remission. Pregnancy outcome
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included 9 miscarriages, 1 stillbirth, 5 neonatal deaths. There were 31 (30%) preterm deliveries, 34 (33%) babies with birth weight <2500 g. Pregnancy outcome was predicted by hypocomplementaemia at conception (RR 19.02; 90% CI 4.58-78.96) and use of aspirin during pregnancy (RR 0.11; 90% CI
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0.03-0.38) (46). Renal outcomes included 34 (33%) renal flares (pregnancy & postpartum) of which 20 were reversible and 3 with progressive decline of GFR (1 on dialysis). Renal flare was predicted by renal status at conception, so for those in partial remission relative risk (RR) of flare was 3.0; 90% CI 1.23-7.34, and for those in non remission RR was 9.0; 90% CI 3.59-22.57 (47). A more recent
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systematic review of outcomes in lupus nephritis which included 37 studies of 1842 patients and 2751
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pregnancies concluded that the chance of unsuccessful outcome was 23%, of preterm birth was 39%, of stillbirth or neonatal death was 6%,of fetal growth restriction was 13% and the risk of maternal
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complications including renal flare, hypertension and pre-eclampsia was 30-40% (48). Lupus activity is a key predictor of pregnancy outcome. High levels of lupus activity several months prior to conception increased the risk of pregnancy loss by 4-fold (49). High lupus activity during pregnancy doubles the risk of pregnancy loss and the risk for preterm delivery. Elevated dsDNA and
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low complement are each modestly associated with preterm birth. They are most predictive, however, when they are coupled with increased lupus activity (50). Several other readily available laboratory tests have been shown to be associated with preterm birth, but not confirmed in large studies. Elevated ferritin as a marker of inflammation and low estradiol as a marker of poor placentation, have both been associated with preterm birth in women with lupus (51). Drug therapy in the pregnant lupus patient includes prednisolone, azathioprine and hydroxychloroquine which are all safe in pregnancy and breast feeding, and can be continued (52). Many women with lupus nephritis are receiving mychophenolate mofetil (MMF) which is an established teratogen causing microtia, external auditory canal atresia, orofacial clefts, cardiovascular malformations and digital hypoplasia. (53). MMF should be stopped at least 6 week prior to conception, as it has a long half life with enterohepatic recirculation, and be switched to azathioprine. A recent study has demonstrated that in 23 women with lupus nephritis with a SLEDAI ≤ 4 switched to azathioprine prior to conception, there were 3 renal flares prior to pregnancy but none in 18 pregnancies and one post partum after 17 live births (54). This study also found that adverse pregnancy outcomes increased as prednisolone dose increased or as SLEDAI increased.
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ACCEPTED MANUSCRIPT Diagnosing pre-eclampsia in women with lupus nephritis may be challenging particularly if there is preexisting hypertension and / or proteinuria. Features which point to a diagnosis of lupus nephritis include hypocomplementaemia and other features of active SLE. It has been shown that reduced angiogenic (vascular endothelial growth factor, placental growth factor) and increased antiangiogenic
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factors (soluble fms-like tyrosine kinase 1, soluble endoglin) are useful predictors and diagnostic tools
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in SLE in the same way as they are in general (55).
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In the event of a lupus nephritis flare current consensus is to use glucocorticoids . However problems with this strategy are that steroids alone may be unable to control disease activity and their use is associated with higher rates of preterm delivery (secondary to preterm rupture of membranes), infection / sepsis and gestational diabetes. Webster et al.(56) have recently reported a case series of 9
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women treated with tacrolimus to maintain or achieve lupus nephritis remission in pregnancy. The rationale for use of tacrolimus is that calcineurin may cause damage to podocytes by dephosphorylation of the actin-organizing synaptopodin. Calcineurin inhibitors may inhibit the action of
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calcineurin on the actin cytoskeleton of podocytes, restoring normal structure and thus controlling proteinuria. Eight cases had stable/quiescent disease for > 1 year prior to pregnancy and one had no prior history of lupus nephritis. In three cases tacrolimus was commenced before conception, and disease remained stable throughout their pregnancies. Six women experienced disease flare, 5/6 in
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the first trimester. All were normotensive, with nephrotic range proteinuria at the time of flare. Induction
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of remission occurred despite reducing steroids by adding tacrolimus or by replacing azathioprine by tacrolimus. Tacrolimus dose was titrated to a trough level of 5–8 ng/ml and increases in doses were
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frequently required (56). This study supports the inclusion of tacrolimus as an adjuvant or alternative therapy to steroids with another potential safe therapy for the treatment of lupus nephrtis and controlling proteinuria during pregnancy. It has been previously demonstrated that although babies of mothers taking tacrolimus are born with therapeutic levels, these decline to become undetectable
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within a few weeks and the rate of decline is the same whether the baby is breast or bottle fed (57).
Neonatal Lupus syndromes Transplacental transfer of SS-A/Ro antibodies can induce neonatal lupus syndromes, either as a typical skin rash that does resolve spontaneously within 6 months after birth or a congenital heart block (CHB) in the child. CHB occurs in 1 to 2 % of pregnancies exposed to anti-SSA antibodies (58). The most common presentation is an unexpected advanced atrioventricular (AV) block in the fetus of a “healthy” “asymptomatic” mother (85% of cases) (58). Few data are available regarding the risk of the mothers of fetuses/children with CHB to develop an autoimmune disease. A retrospective study of the French registry of neonatal lupus evaluated the development of autoimmune disease in anti-SSA and/or anti-SSB antibody positive mothers who had a fetus or a child with CHB (59). At the time of diagnosis of CHB in 206 mothers, 153 mothers (74%) were asymptomatic and 53 mothers (26%) had an autoimmune disease with SLE, Sjögren syndrome, and undifferentiated connective tissue disease (UCTD) as the most frequent. After a median follow up period of 8.5 years, 89 of the 206 mothers
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ACCEPTED MANUSCRIPT (43%) remained symptom free whereas 117 mothers (57%) developed an autoimmune disease with SLE (n=41, Sjogren syndrome (n=35), UCTD (n=27), and RA (n=5) as the most common (59).
High doses of fluorinated glucocorticoids are frequently administered when an AV block is detected in
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an anti-Ro/SSA-positive mother. However, their efficacy is controversial (60). New clinical trials are in
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progress for the prevention of CHB by hydroxychloroquine and/or IVIG (61).
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Follow-up studies have investigated the neurodevelopment of children exposed to fluorinated corticosteroids with conflicting results (62). A recent Canadian study evaluated intelligence, visual skills, auditory and visual attention, verbal learning and memory, executive function, and behaviour in children aged 6-16 years with or without CHB, exposed prenatally versus not exposed to
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dexamethasone . All cohorts scored within the normal range and showed no significant difference between groups (63).
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Systemic sclerosis (SSc)
Systemic sclerosis (SSc) has not been as frequently studied than SLE and APS in regard to pregnancy, one reason truly being the higher age of onset and the rarity of the disease. The Italian
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IMPRESS study recorded pregnancy outcome of 109 SSc pregnancies (64). Compared with the
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general obstetrical population preterm deliveries (25% vs. 12%), severe preterm deliveries (<34 weeks) (10% vs. 5%), fetal growth restriction (6% vs. 1%) and very-low-birth-weight babies (5% vs. 1%) were significantly more frequent in SSc. Multivariable analysis found that glucocorticoids were
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associated with preterm deliveries (OR 3.63), while folic acid was protective (OR 0.30), as were antitopoisomerase antibodies (OR 0.26). The disease remained stable in most patients (64).
The management of SSc pregnancies is challenging and requires specialists familiar with the disease
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and high risk pregnancy (65). Predictors for a more aggressive disease course are < 4 years disease duration, diffuse cutaneous scleroderma, presence of anti-topoisomerase or RNA polymerase III antibodies.
Some important unanswered questions remain which a new prospective study, the International Multicentric PRospective Study on PREgnancy in Systemic Sclerosis ( IMPRESS 2) will investigate in pregnant SSc patients, non-pregnant SSc patients of fertile age, and a healthy pregnant comparison group: 1. disease activity of SSc during and after pregnancy, 2. pregnancy complications and outcome in patients with SSc, 3. children outcome at 1 and possibly 3 years, 4. the modern incidence of renal crisis, severe cardiac involvement and pulmonary hypertension both in pregnant and non-pregnant women with SSc. The study is endorsed by EUSTAR and partially funded by the Italian Society of Rheumatology and Italian patients associations (GILS; Gruppo LES, ALOMAR). Up to date, 28 pregnancies have been enrolled. Additional recruitment is urgently needed. The findings of the study
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ACCEPTED MANUSCRIPT will be relevant for many SSc women planning a pregnancy, and wishing for an experience natural to healthy women: to have a child. Vasculitis Vasculitis pregnancies are rare and therefore hard to study. A retrospective study comparing 496
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pregnancies before vasculitis to 74 pregnancies in women with vasculitis found an increase in
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pregnancy loss (22.4% pre-vasculitis vs 33.8% post-vasculitis, p=0.04) and an increased risk for preterm birth (11.4% pre-vasculitis vs 23.3% post-vasculitis, p=0.03) (66). Remarkably few women
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reported a flare of vasculitis during pregnancy – just 18% - but those pregnancies had a higher rate of preterm delivery (44.4%).
A review of the literature identified 48 pregnancies in women with granulomatous polyangiitis (GPA).
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Interestingly, GPA was diagnosed during pregnancy in almost 1/3 of the cases. A 40% flare rate and a 35% preterm birth rate were found (67). With the use of rituximab to treat ANCA-associated vasculitis, more women may be able to conceive after vasculitis diagnosis. A report of 8 pregnancies
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that occurred within 1 week to 16 months following Rituximab included 1 miscarriage with BeckwithWidemann Syndrome and 7 live births. At delivery, 6 women still had undetectable B cell levels, but 3 out of 3 tested infants had normal B cell levels at birth (68). Additional data on the use of Rituximab in
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pregnancy include 153 pregnancies with known outcomes (69). Among 90 live births 24% were
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preterm and 11 reported of neonatal cytopenias. Similar to data from other biologics, the effect on the cord blood levels and the neonate is greatest when the last dose is administered within 12 weeks of
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birth.
More data is available for pregnancy in Takayasu’s Arteritis, likely due to the young age of onset of this disease. A review of the literature uncovered 214 pregnancies and a very high rate of severe hypertension and/or preeclampsia (43%). Increased Takayasu’s Arteritis activity was rare in
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pregnancy, but complications from prior damage, including aortic dissection, congestive heart failure, aneurysms, and 2 maternal deaths were reported (67). Monitoring blood pressure is essential and can be challenging if there is subclavian disease (70). Some authors recommend a scheduled cesarean section to avoid the exertion and hypertension associated with a vaginal delivery, but this is controversial. A retrospective study of 76 pregnancies in Behçet’s disease (BD) patients found worsening of oral ulcerations, genital ulcerations and ocular complications in 35.5% (71). The mean ± SD annual rates of BD flares were 0.49 ± 0.72 during pregnancy and 1.46 ± 2.42 during the nonobstetrical period (P = 0.018 concordant with the rate of flare of 29.7% found in the literature. There was a trend toward fewer BD flares in patients treated with colchicine (27.9% versus 45.4% of patients not treated with colchicine (p = 0.11). The overall rate of complications during pregnancy was 15.8%, in keeping with previous reports, and not higher than in the general population.
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ACCEPTED MANUSCRIPT The Obstetric Antiphospholipid Syndrome The pathogenesis of Obstetric Antiphospholipid Syndrome (OAPS) is rather heterogeneous, complex and not fully understood yet. Differently from the model of aPL-mediated thrombosis, no need for a second hit is required for the induction of placental damage and pregnancy loss (72;73). As shown ex
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vivo on human term placentae and, more recently, in vivo in a mouse model, β2GPI is abundant on
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the trophoblast surface and is available for binding to aPL, particularly anti- β2GPI (74).
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Intraplacental thrombosis does not account for the full picture of OAPS. Non-thrombotic mechanisms can be identified on both the maternal and fetal side (73), causing the functional impairment of decidual and throphoblast cells respectively. Defective placentation is mediated by the inhibition of endometrial angiogenesis and by the reduction of trophoblast differentiation/invasiveness (75).
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Inflammation has been also described as a prominent feature in aPL-mediated placental damage. Particularly, complement activation and deposition has been claimed to be a major player, although there are some discordant reports on human placentas from APS patients (76). Conversely, a better
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defined association has been described between complement activation and/or alterations and the onset of preeclampsia (reviewed in 77). A novel mechanism has been proposed for preeclampsia: aPL can be internalized by human syncytiotrophoblast cells, leading to aberrant cell death and release of
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necrotic trophoblast debris and activation of maternal endothelial cells (78).
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Novel therapeutic targets have been proposed on the basis of a deeper understanding of the pathogenic mechanisms in OAPS. Antibodies directed against the domain 1 of β2GPI (anti-D1) were
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detected at high frequency in patients with OAPS (79). Their pathogenic role in pregnancy complications is supported by experimental data. In one study, a recombinant antibody recognizing the D1 of β2GP was able to induce fetal loss and clot formation in animal models, while the noncomplement fixing version of the antibody was able to prevent the procoagulant and proabortive
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effects of patient antibodies (80). Another study showed that tolerogenic dendritic cells specific for β2GPI D1 were able to attenuate APS in mice by lowering titers of anti-β2GPI and by reducing the percentage of fetal loss (81). Alternatively, the synthetic peptide TIFI mimicking the phospholipid binding site of β2GPI (domain 5) restored the aPL-mediated inhibition of human endometrial angiogenesis in an ex vivo model (82). Toll like receptor 4 (TLR 4) was found to mediate the pathogenic effects of aPL in reducing trophoblast fusion and differentiation. Hydroxychloroquine was able to reduce TLR4 mRNA and protein expression and to finally restore trophoblast function, suggesting the use of this drug in OAPS (83). According to a recent literature review, aPL are detected in more than 10% of unexplained pregnancy losses (84) and in fact the clinical recognition of this association goes back to the 80s. The formal clinical classification criteria of OAPS have been defined in 1998 and revised in 2004(85), basically including recurrent miscarriages, fetal loss, preeclampsia and placental insufficiency. However the real prevalence of aPL in patients with each of these clinical features is still far to be precisely defined because of the inconsistent results of different studies. The recent report of the International Task Force on OAPS (77) has recognized many differences in the published studies making it difficult to
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ACCEPTED MANUSCRIPT compare their results. The differences are related both to the lack of an uniform laboratory characterization of patients (lack of standardized tests to detect aPL and difficulties to include patients tested for all three “criteria” assays) and the lack of uniform definition of obstetrical clinical criteria. In addition it is today recognized that OAPS is probably not completely included in the formal
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classification criteria. In fact, apparently obstetrical pathology can occur also in patients with low
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antibody titers (by definition not included in the serological criteria) in contrast with thrombosis which is
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mainly recorded in patients with high aPL titers (86).
The treatment of OAPS was originally designed to counteract the prothrombotic effect of aPL. Treatment with low dose aspirin (LDA) and heparin (H) or low molecular weight heparin(LMWH) proved to be effective in the majority of patients (87) probably also because heparin was demonstrated active well beyond anticoagulation (76). However, a small percentage of women do not benefit of this
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“conventional” treatment. Therefore it is important to identify high risk patients in order to modify their management. According to recent reports, the high risk obstetrical profile is probably related to specific
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serology (positive LA, or positivity in all the three aPL assays) or to the clinical condition of the patient such as the presence of systemic autoimmune disease or the history of thrombotic episodes (88;89). In addition to the high risk, women with clinically or serologically incomplete OAPS and with antibodies in the absence of clinical manifestations (aPL carriers) should be carefully considered. In fact a recent
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revision of a single-center experience over the last 30 years shows that, in the absence of a combined
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treatment (LDA and H), a significant number of fetal/neonatal losses (6 out of 33 pregnancies), pregnancy complications (early severe preeclampsia: 2/33pregnancies) and even maternal
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thrombosis (DVT:2/33 pregnancies) are recorded in these patients (90). Finally the new therapeutic options for the high risk patients are not yet clear. The addition of firsttrimester low-dose prednisolone has resulted in a higher live-birth rate than conventional therapy alone (91).Intravenous immunoglobulins, or weekly apheresis procedures have been applied with some
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success in high risk patients (92). While the true relevance of these treatments has still to be confirmed, other suggestions relate to experimental models. Among these, hydroxychloroquine might be the first drug to be largely administered because of its well documented safety in pregnant patients (93). A rare but severe complication in the APS is the catastrophic antiphospholipid syndrome (CAPS) characterised by multiorgan failure caused by multiple small vessel thrombosis associated with thrombotic microangiopathy. It can be triggered by preceding events, one of them is pregnancy (94). Pregnancy-related CAPS is not exceptional and represents 6% of the cases included in the international CAPS registry (95). In a French, retrospective series of 13 patients CAPS in pregnant women was preceded by HELLP syndrome that occurred at a mean gestational age of 26.6 weeks (96). The most frequent manifestations of CAPS were cutaneous, hepatic, renal, cardiac and neurological . No maternal death was observed. The perinatal mortality was 54% and was mainly due to prematurity. In a follow-up for a mean of 4.8 years, seven patients had a subsequent pregnancy. No relapse of CAPS was observed, but HELLP occurred in two cases (96). An optimal management is
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ACCEPTED MANUSCRIPT associated with a reduction in maternal mortality, but foetal and neonatal prognosis will depend mostly on the gestational age at the onset of CAPS.
Complications of high risk pregnancies
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In spite of the overall improved outcomes of pregnancy in women with rheumatic disease several
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serious complications are still increased. Abnormal placentation may result in miscarriage, preterm
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birth, preeclampsia and intra-uterine growth restriction (IUGR) depending on severity and maternal constitutional factors (97;98). They are therefore most correctly perceived as part of a continuum of pregnancy complications (Figure 1). Immune dysregulation has over the last decade been accepted as the primary placental dysfunction in preeclampsia (98). The placental tissue is partly foreign to the
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mother, and a number of immune mechanisms are in place to protect the fetus from maternal immunological attack. This includes immunological priming by local Treg prior to conception, when the mother is exposed to cytokines and antigens from paternal seminal fluid (99). Treg play a decisive role
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in the immunologic adaption to pregnancy. Recently, it has been shown that memory T-reg specific for paternal antigens persist after pregnancy, providing increased protection in the next pregnancy with the same father (100).
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Overt preeclampsia is a state of increased systemic inflammation, oxidative stress and endothelial
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dysfunction, leading to organ failure, seizures and death in rare cases. A key biomarker of preeclampsia in pregnancy is the ratio of anti-angiogenic to angiogenic factors. In non-lupus
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pregnancy, preeclampsia can be predicted by elevated levels of soluble fms-like tyrosine-kinase-1 (sFlt-1, which inhibits blood vessel growth in the placenta) and lower levels of placental growth factor (PlGF, which promotes placental blood vessel growth (101). An elevated sFlt-1/PlGF ratio is associated with preeclampsia in SLE as well. In 52 SLE pregnancies, sFlt-1 was eleva ted in the 18
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pregnancies with preeclampsia when measured between weeks 22-32 of gestation (102). Similarly, in a prospective study of pregnancies sFlt-1 and the sFlt-1/PlGF ratio were both elevated between week 10 - 15 of gestation among pregnancies that developed preeclampsia (103). Limited research in women with severe forms of preeclampsia, shows that removal of anti-angiogenic factors either by column apheresis (104) or pharmacological intervention (105) may cause the syndrome to recede and give the mother a chance of delivering at term. An excessive maternal pro-inflammatory status, characterized by a type 1 immune bias, is a typical feature of preeclampsia (97). Therefore, it seems reasonable to investigate whether the inflammatory environment of rheumatic disease may favor preeclampsia development. In particular, IL-33, a recently discovered member of the IL-1 superfamily, has been related to rheumatic disease through activation of its soluble ST2 receptor (sST2L)(108), which has been found to be significantly increased in preeclampsia (109;110). sST2L seems to be a second anti-inflammatory factor (besides sFLT-1) produced by the placenta in excess amounts in preeclampsia.
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ACCEPTED MANUSCRIPT The only effective treatment of preeclampsia is delivery, therefore preeclampsia is a major cause of premature birth worldwide. Prophylactic treatment with aspirin and Low molecular weight heparin in high risk women has shown some, but limited effect (111). Recently statins have been suggested as a possible way of targeting the anti-angiogenic factors s-FLt1 and sEng through the heme oxygenase
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pathway (112). Randomised controlled trials for the use of statins in pregnancy are enrolling in both
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the UK and US. The complement system is another promising target for treatment (91). It remains to
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be seen if statins or complement inhibitors prove to be effective treatments in larger cohorts. IUGR is a pathology of pregnancy that affects between 5-10% of pregnancies. IUGR may be defined as the “failure of the fetus to reach its growth potential”, according to the known intrauterine growth curves. In recent years, a placental phenotype of IUGR has been described by numerous studies
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(113), so that a number of maternal, placental or fetal abnormalities with the potential to alter growth, permeability, perfusion, transport capacity and metabolic/endocrine function of the placenta may lead to changes in fetal growth trajectory then followed by mechanisms of adaption and eventually failure
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(reviewed in 114).
Normal implantation is a dynamic process regulated by a complex series of interactions between trophoblast itself and decidual tissues. A significant number of studies have investigated the
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involvement of the feto-maternal interface in APS, providing evidence that thrombotic events do not
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account for all of the histopathologic findings found in these placentas. Moreover, although very little is known about the possible reactivity of aPL with decidual/endometrial cell, recently in vitro culture studies show that aPL affect human endometrial angiogenesis (115). In cohort studies, the presence
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of anti- β2GPI has been associated with a 20 times increased significant risk of developing IUGR. At present, clinicians must be aware that rheumatic diseases, and in particular APS, significantly increase the risk of pregnancy pathologies associated with placental insufficiency, like IUGR and
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preeclampsia (116). Therefore, they must follow protocols for the early evaluation of placental function with uterine artery Doppler velocimetry and other biochemical placental markers such as sFLT-1 and PlGF.
Therapy before conception and during pregnancy Questions regarding therapy before and during pregnancy and lactation are of great concern for patients and their treating physicians. Special interest has focused on on inhibitors of tumor necrosis factor-alpha (TNF-alpha) because of their frequent use both in female and male patients with rheumatic disease (117).
Measurements of transplacental passage of four TNF inhibitors in an ex vivo human placental perfusion model, and in patients showed differences among adalimumab (ADA), etanercept (ETA), infliximab (IFX) and certolizumab (CZP). IFX, ADA and ETA demonstrated binding to the fetal Fc receptor (FcRn) and were actively transported across a cell layer by FcRn. ETA had a lower affinity of binding and transcytosis than the other TNF inhibitors (118). The ex vivo perfusion model showed
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ACCEPTED MANUSCRIPT no measurable transfer of CZP from the maternal to the fetal circulation in 5 out of 6 placentas that demonstrated positive-control IgG transport. In patients treated with ADA or IFX, active placental transfer of the anti-TNFs was observed. Neonatal levels of IFX and ADA on the day of birth were always higher than the level in the mother by up to 4.9 -fold. In contrast, the level of
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CZP in neonates was always much lower than the maternal level (the highest was only 24.4% of
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the maternal level), and often below the limit of quantification (<0.41μg/ml) (119). The study confirmed that the different molecular structure of CZP that does not contain an Fc region results in
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low placental transfer.
The safety of ADA during pregnancy was examined by a prospective cohort study between 2004 and 2013 by the OTIS Collaborative Research Group (120). Seventy-four women with RA in the ADA exposed group had at least one dose of the medication in the first trimester; approximately 43% of
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those women used the medication in all three trimesters. The rate of major defects in the exposed, disease-matched (80 RA pregnancies), and non-diseased comparison (218 women without any
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autoimmune disease) groups was not significantly different (Table 1). A total of 234 infants (70% of live born infants) received the study-related physical examination. The proportion of children with 3 or more minor malformations in the three groups did not differ, and there was no specific pattern of minor malformations identified (120). The rate of preterm delivery did not differ significantly among groups,
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nor did the proportion of infants who were small for gestational age. In spite of the small sample size,
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these results provide reassuring data to women with RA who require treatment with ADA. A follow-up questionnaire study examined outcomes of children exposed to TNF inhibitors in utero
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during the first 24 months after birth. Eleven children exposed were compared to nine children not exposed in utero to TNF inhibitors. The preliminary analysis of this ongoing study showed that children exposed in utero to anti-TNFα had a good birth outcome, normal growth and a normal response to vaccinations with no significant differences between exposed and non-exposed children born by
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mothers with chronic arthritis (121). Some infectious disorders were reported in the first year of life in several children, but with a benign course.
In men, cytotoxic and immunosuppressive drugs can impair spermatogenesis resulting in infertility or chromosomal defects in spermatozoa. At present, there are limited data to confirm or refute the risk of congenital malformations induced by antirheumatic drugs given to men.The majority of male patients with spondyloarthropathies (SpA) are affected during their peak reproductive years. Treatment with TNFα inhibitors has proved highly effective in patients with SpA. TNF-alpha plays a role in spermatogenesis – moderate levels in the testes appear to promote spermatogenesis whereas high levels inhibit it. In a prospective study of 23 men with AS and a comparison group of 46 healthy men, the influence of TNF-inhibitors on spermatogenesis was investigated (122). Sperm samples were analyzed prior to starting a TNF-inhibitor, and three and 12 months after therapy. Normal sperm quality was present in AS patients at baseline, and did not change significantly during three and 12 months of anti-TNF treatment. Together with two additional studies, this study suggests that TNFinhibitors do not impair sperm quality (123).
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ACCEPTED MANUSCRIPT Counselling and pregnancy planning Planning is essential to increase the probability of success of pregnancies. Planned pregnancies have demonstrated reduced flare rates and better obstetric outcomes in women with SLE (124). Thus, preconceptional risk assessment and counselling should be ideally performed in every woman with
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systemic autoimmune diseases before attempting pregnancy.
In the preconceptional visit, several issues should be assessed in order to estimate the risk for
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complications: the age of the patient; the outcome of previous pregnancies; the extent of organ involvement and the presence of irreversible damage; the degree of disease activity and the occurrence of recent flares; the presence of antiphospholipid antibodies / syndrome and of anti-Ro / anti-La antibodies; the current treatment, with special attention to any drugs forbidden during
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pregnancy. Highly active disease or a high degree of irreversible damage, especially in vital organs such as the kidneys, the lungs or the heart, should discourage conception. Drugs contraindicated during pregnancy must be stopped at the preconceptional visit and replaced by safe ones. However,
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any change in treatment before pregnancy should be given for at least two or three months to assure that disease keeps in remission with the new therapeutic combination (125). It is essential to bear in mind that hydroxychloroquine must not be stopped because of pregnancy or pregnancy planning,
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given its safety and the high risk for severe lupus flares after withdrawal (126).
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Active disease in the preconceptional visit must be treated. Pregnancy-compatible drugs like pulsemethyl prednisolone, medium-low dose prednisone, hydroxychloroquine and azathioprine can be used
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if needed. Once activity is controlled for at least three months, women can try to conceive. However, severe activity (for instance, lupus nephritis, neuropsychiatric lupus, vasculitis affecting vital organs, scleroderma lung disease), should be aggressively treated with drugs such as cyclophosphamide or mycophenolate, and pregnancy should be delayed for at least one year after remission. In patients
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with nephritis, the goal is achieving normal renal function with no significant proteinuria, or at least lower than 1 gr in 24 h (46). Progressive changes in therapy should then be started to assure a good control with drugs allowed during pregnancy. On the other hand, if a woman with a systemic autoimmune disease is in sustained remission taking hydroxychloroquine, low-dose prednisone -or no prednisone at all- or any other drug allowed during pregnancy, treatment should not be modified in the preconceptional visit given the risk of triggering a disease flare with not much to gain. All women with previous renal disease should be given low-dose aspirin within the first trimester of pregnancy up to delivery in order to decrease the risk of preeclampsia (127). Likewise, adequate prophylaxis for preeclampsia and thrombosis must be given to women with antiphospholipid antibodies taking into acount their immunological and clinical profile as well as the current guidelines (77). Placental Doppler studies are important predictors of preeclampsia and placental insufficiency, and should be planned in advance (128). It is important that rheumatologists raise the need for contraceptives with their female patients, particularly when potentially teratogenic medications like methotrexate, leflunomide, mycophenolate mofetil, and cyclophosphamide are prescribed to fertile women. There are many effective
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ACCEPTED MANUSCRIPT contraceptive options for women with rheumatic disease – no woman should be left with the impression that she cannot use birth control due to her rheumatologic diagnosis. Long-active contraceptives, like intrauterine devices ( IUD) and implantable progesterone, provide effective pregnancy prevention and will allow patients and physicians to plan pregnancies during periods of
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disease quiescence and when only safe medications are in use (6).
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Female patients with systemic inflammatory diseases have important family planning and pregnancy
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(FPP) concerns that need to be addressed by their treating physicians. Two online surveys performed in rheumatologists and gastroenterologists in Europe and the US showed that 49%-65% of physicians spontaneously reported having discussed FPP with their female patients of child-bearing age (129). Across specialties less than half of physicians who discussed FPP with their patients reported
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discussing FPP with the general practitioner treating the patient. More than 60% of patients reported their concerns relating to FPP are not adequately settled during their medical appointments. Many patients experienced a lack of consistency in communication on FPP across healthcare professionals
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revealing that there is low interaction between different caregivers. These data show that comprehensive pre-pregnancy counselling is the first step to managing pregnancy in women with chronic disease.
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Conclusion
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Reproduction issues including fertility and pregnancy are of great importance for women and men with rheumatic disease. Due to an increasing recognition of risk factors and an interdisciplinary approach
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women with rheumatic diseases can undergo successful infertility treatment and can have successful pregnancies. New therapeutic options are available both for the management of lupus complications and the APS during pregnancy. Increasing experience with the effect of TNF inhibitors on pregnancy will allow their use, when indicated, in women and men who desire children. Pre- pregnancy
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counselling and risk assessment remains a critical first step to achieve good pregnancy outcomes.
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Disclosure statement
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The authors declare no conflict of interest.
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34. Forger F, Villiger PM, Ostensen M. Pregnancy in patients with ankylosing spondylitis: do regulatory T cells play a role? Arthritis Rheum 2009;61(2):279-83. 35. Koenen HJ, Smeets RL, Vink PM, et al. Human CD25highFoxp3pos regulatory T cells differentiate into IL-17-producing cells. Blood. 2008;112(6):2340-52.
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42. De Steenwinkel FD et al. Arthritis Rheum 2013;65(supplement10):S172 43. Bramham K, Soh MC, Nelson-Piercy C. Pregnancy and renal outcomes in lupus nephritis: an update and guide to management. Lupus. 2012; 21(12):1271-83. 44. Williams, D. Davison J. Chronic kidney disease in pregnancy. BMJ 2008;336:211-215
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ACCEPTED MANUSCRIPT 84. Andreoli L, Chighizola CB, Banzato A, Pons-Estel GJ, de Jesus GR, Erkan D The estimated frequency of antiphospholipid antibodies in patients with pregnancy morbidity, stroke, myocardial infarction, and deep vein thrombosis. Arthritis Care Res 2013; 65: 1869–1873.
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87. Mak A, Cheung MW, Cheak AA, Ho RC. 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 metaregression. Rheumatology (Oxford) 2010; 49:281–288.
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ACCEPTED MANUSCRIPT 100. Rowe JH, Ertelt JM, Xin L, Way SS. Pregnancy imprints regulatory memory that sustains anergy to fetal antigen. Nature. 2012;490(7418):102-6. 101. Foidart JM, Schaaps JP, Chantraine F, Munaut C, Lorquet S. Dysregulation of anti-angiogenic agents (sFlt-1, PLGF, and sEndoglin) in preeclampsia--a step forward but not the definitive answer.J Reprod Immunol 2009;8:106-11.
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fragments and angiogenesis-related factors in early pregnancy and their association with preeclampsia.BJOG. 2010 Mar;117(4):456-62.
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105. Lefkou E, Mamopoulos A, Fragakis N, et al. Clinical improvement and successful pregnancy in a preeclamptic patient with antiphospholipid syndrome treated with pravastatin. Hypertension. 2014;63(5):e118-9.
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106. Berzan E, Doyle R, Brown CM. Treatment of preeclampsia: current approach and future perspectives. Curr hypertension Rep 2014;16(9):473.
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108. Liew FY, Pitman NI, McInnes IB. Disease-associated functions of IL-33: the new kid in the Il-1 family. Nature Reviews 2010; 10: 103-110.
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109. Granne I, Southcombe JH, Snider JV, Tannetta DS, Child T, Redman CW, Sargent IL. ST2 and IL-33 in pregnancy and preeclampsia. Plos One 2011; 6: 1-9. 110. Stampalija T, Chaiworapongsa T, Romero R, et al. Maternal plasma concentrations of sST2 and angiogenic/anti-angiogenic factors in preeclampsia. J Matern Fetal Neonatal Med 2013: 26:1359-1370. 111. Berzan E, Doyle R, Brown CM. Treatment of preeclampsia: current approach and future perspectives. Current hypertension reports. 2014;16(9):473. 112. Costantine MM, Cleary K. Pravastatin for the prevention of preeclampsia in high-risk pregnant women. Obst Gynecol. 2013;121(2 Pt 1):349-53.
113. Sibley CP, Turner MA, Cetin I, et al. Placental Phenotypes of Intrauterine Growth. Pediatr Research 2005; 58: 827-832 114. Cetin I, Alvino G. Intrauterine growth restriction: implications for placental metabolism and transport. A review. Placenta 2009; 30: 77-82. 115. Di Simone N, Di Nicuolo F, D’Ippolito S, et al. Antiphospholipid antibodies affect human endometrial angiogenesis. Biol Reproduction 2010; 83: 212-219.
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ACCEPTED MANUSCRIPT 116. Abou-Nassar K, Carrier M, Ramsay T, Rodger MA. The association between antiphospholipid antibodies and placenta mediated complications: a systematic review and meta-analysis. Thrombosis research 2011; 128: 77-85.
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117. Østensen M: Safety issues of biologics in pregnant patients with rheumatic diseases. Ann N Y Acad Sci. 2014 May;1317(1):32-8.
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118. Hassid B, Mahadevan U. The use of biologic therapy in pregnancy: a gastroenterologist's perspective. Curr Opin Rheumatol. 2014 May;26(3):347-53
Angela Tincani & Laura Andreoli, “personal communication 2014
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119. Mahadevan U, Wolf DC, Dubinsky M, et al. Placental transfer of anti-tumor necrosis factor agents in pregnant patients with inflammatory bowel disease. Clin Gastroenterol Hepatol. 2013 Mar;11(3):286-92 120. Chambers C, Johnson DL, Luo Y et al. Pregnancy Outcome in Women Treated with Adalimumab for the Treatment of Rheumatoid ArtTreatment of Rheumatoid Arthritis. Arthritis Rheumatol 2014;, 66:10 (Supplement), S 361 (abstract)
122. Micu M, Micu R, Surd S, Gîrlovanu M, Bolboacă SD, Ostensen M. TNF-alpha inhibitors do not impair sperm quality in males with ankylosing spondylitis after short term or long-term treatment. Rheumatology (Oxford). 2014;53(7):1250-5.
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125. Ruiz-Irastorza G, Khamashta MA. Lupus and pregnancy: ten questions and some answers. Lupus 2008; 17: 416-20.
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127. Askie LM, Duley L, Henderson-Smart DJ, Stewart LA, PARIS Collaborative Group. Antiplatelet agents for prevention of pre-eclampsia: a meta-analysis of individual patient data. Lancet 2007;369:1791–8. 128. Peart E, Clowse MEB. Systemic lupus erythematosus and pregnancy outcomes: an update and review of the literature. Curr Op Rheumatol 2014;26:118–23. 129. Chakravarty E, Clowse ME, Pushparajah DS, et al. Family planning and pregnancy issues for women with systemic inflammatory diseases: patient and physician perspectives. BMJ open 2014;4(2):e004081.
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5/74 (6.8)
0.91 (0.24,3.03)
4/72 (5.6)
6/77 (7.8)
0.71 (0.16,2.27)
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4/65 (6.2)
1.14 (0.26,4.93)
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Crude RR (95% CI)
Adjusted OR (95% CI)
Crude RR (95% CI)
Adjusted OR (95% CI)
---10/197 (5.1)
1.21 (0.40,3.54)
11/201 (5.5)
1.02 (0.34,2.94)
1.10 (0.32,3.82)
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1.26 (0.29,5.54)
NonDiseased Comparison n/N (%)
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Major Birth Defects in All Pregnancies Excluding Lost-ToFollow-Up
RA Comparison n/N (%)
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Major Birth Defects in Live Born Infants
ADA Exposed n/N (%)
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Birth Defects
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Table 1. Major Birth Defects in 1st Trimester-Adalimumab-Exposed Pregnancies Among Women with Rheumatoid Arthritis (RA) Compared to Disease-Matched and Non-Diseased Pregnancies Not Exposed to Adalimumab
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ACCEPTED MANUSCRIPT Text figure 1:
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Figure 1 is a modified version of the model for preeclampsia pathogenesis presented in Redman and Sargent (98). A stage of pre-conceptual immunological priming is followed by a stage 1 of immunological acceptance. Poor immunoregulation may lead to poor placentation and later to systemic inflammation. Preeclampsia is understood as part of a continuum. For the early stages this continuum ranges from miscarriage to normal pregnancy, whereas in the later stages, dominated by inflammation, maternal clinical complications range from hypertension and mild preeclampsia to severe preeclamptic manifestations in pregnancy. Maternal constitutional factors contribute to the development and outcome of all stages of placental pathology, and may also account for the increased risk of cardiovascular diseases later in life seen in women with preeclampsia.
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Abbreviations: Treg cells: T-regulatory cells, IDO: idoleamine 2,3 dioxygenase, FGR: fetal growth restriction, ER-stress: Endoplasmatic reticulum stress
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Figure 1. Pathogenesis of miscarriage, Intrauterine growth restriction, and preeclampsia (modified after Redman and Sargent 2010)
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S1568-9972(14)00311-5 doi: 10.1016/j.autrev.2014.12.011 AUTREV 1664
To appear in:
Autoimmunity Reviews
Received date: Accepted date:
12 December 2014 23 December 2014
Please cite this article as: Østensen Monika, Andreoli Laura, Brucato Antonio, Cetin Irene, Chambers Christina, Clowse Megan, Costedoat-Chalumeau Nathalie, Cutolo Maurizio, Dolhain Radboud, Fenstad M, F¨ orger Frauke, Wahren-Herlenius Marie, RuizIrastorza Guillermo, Koksvik Hege, Nelson-Piercy Catherine, Shoenfeld Yehuda, Tincani Angela, Villiger Peter M., Wallenius Marianne, von Wolff Michael, State of the Art: Reproduction and Pregnancy in Rheumatic Diseases, Autoimmunity Reviews (2014), doi: 10.1016/j.autrev.2014.12.011
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ACCEPTED MANUSCRIPT State of the Art: Reproduction and Pregnancy in Rheumatic Diseases Monika Østensen, Laura Andreoli, Antonio Brucato, Irene Cetin, Christina Chambers, Megan Clowse, Nathalie Costedoat-Chalumeau, Maurizio Cutolo, Radboud Dolhain, M Fenstad, Frauke Förger, Marie Wahren-Herlenius, Guillermo Ruiz-Irastorza, Hege Koksvik, Catherine Nelson-Piercy , Yehuda
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Shoenfeld, Angela Tincani, Peter M. Villiger, Marianne Wallenius, Michael von Wolff
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Affiliation:
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Monika Østensen MD, National Advisory Unit on Pregnancy and Rheumatic diseases, Department of Rheumatology, St. Olavs Hospital, University Hospital of Trondheim, Norway, E-mail: [email protected]
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Laura Andreoli MD, Rheumatology and Clinical Immunology, Spedali Civili of Brescia and Department of Clinical and Experimental Sciences, University of Brescia, Italy
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Antonio Brucato MD, Department of Internal Medicine, Ospedale Riuniti, 24128 Bergamo, Italy Irene Cetin MD, Department of Mother and Child, Hospital Luigi Sacco, University of Milano, Italy Christina Chambers MD, Department of Pediatrics, University of California San Diego, La Jolla, CA
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92093-0828, USA
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Center, Durham, NC, USA
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Megan Clowse MD, Division of Rheumatology, Department of Medicine, Duke University Medical
Nathalie Costedoat-Chalumeau MD, Université Paris-Descartes, Paris, France ; AP-HP, Hôpital Cochin, Centre de référence maladies auto-immunes et systémiques rares, Service de médecine
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interne, Paris, France
Maurizio Cutolo, MD, Research Laboratories and Academic Division of Clinical Rheumatology, Department of Internal Medicine,University of Genova, Genova, Italy Radboud J.E.M. Dolhain MD, Department of Rheumatology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands. Mona H. Fenstad, Department of immunology and transfusion medicine, St.Olavs hospital, Trondheim, Norway. Frauke Förger MD, Department of Rheumatology and Clinical Immunology/Allergology, University Hospital of Bern, CH-3010 Bern, Switzerland Marie Wahren-Herlenius MD, Department of Medicine, Centre for Molecular Medicine, Karolinska Universitetssjukhuset, Stockholm, Sweden
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ACCEPTED MANUSCRIPT Guillermo Ruiz-Irastorza MD, Autoimmune Diseases Research Unit, Department of Internal Medicine, Biocruces Health Research Institute, Hospital Universitario Cruces, University of the Basque Country, Bizkaia, Spain Hege Svean Koksvik R.N. National Advisory Unit on Pregnancy and Rheumatic diseases, Department
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of Rheumatology, St. Olavs Hospital, University Hospital of Trondheim, Norway
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Catherine Nelson-Piercy, MD, Women’s Health Academic Centre, St Thomas’ Hospital, London, UK Yehuda Shoenfeld MD. Zabludowicz Center for Autoimmune Diseases, Sheba Medical Center, TelAviv University, Tel-Hashomer, Israel
Angela Tincani MD, Department of Rheumatology and Clinical Immunology, Ospedale Civile and
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University of Brescia, Brescia, Italy
Peter Villiger MD, Department of Rheumatology and Clinical Immunology/Allergology, University
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Hospital of Bern, Bern, Switzerland
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Marianne Wallenius MD, National Service for Pregnancy and Rheumatic Diseases, Department of Rheumatology, Trondheim University Hospital, Trondheim, Norway and Dept of Neuroscience, Norwegian University of Science and Technology (NTNU), Trondheim, Norway
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Michael von Wolff M.D. University Women’s Hospital, Division of Gynaecological Endocrinology and Reproductive Medicine, University of Berne, Berne, Switzerland
Corresponding author:
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Monika Østensen, MD. National Advisory Unit on Pregnancy and Rheumatic diseases, Department of Rheumatology, St. Olavs Hospital, University Hospital of Trondheim, Norway, E-mail: [email protected]
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ACCEPTED MANUSCRIPT Abstract Throughout the last decade, increasing awareness has been raised on issues related to reproduction in rheumatic diseases including basic research to clarify the important role of estrogens in the aetiology and pathophysiology of immune/inflammatory diseases. Sub- or infertility is a heterogeneous
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condition that can be related to immunological mechanisms, to pregnancy loss, to disease burden, to
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therapy, and to choices in regard to family size. Progress in reproductive medicine has made it possible for more patients with rheumatic disease to have children. Active disease in women with
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rheumatoid arthritis (RA) affects their children’s birth weight and may have long-term effects on their future health status. Pregnancy complications as preeclampsia and intrauterine growth restriction are still increased in patients with systemic lupus erythematosus (SLE) and antiphospholipid syndrome
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(APS), however, biomarkers can monitor adverse events, and several new therapies may improve outcomes. Pregnancies in women with APS remain a challenge, and better therapies for the obstetric APS are needed. New prospective studies indicate improved outcomes for pregnancies in women with
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rare diseases like systemic sclerosis and vasculitis. TNF inhibitors hold promise for maintaining remission in rheumatological patients and may be continued at least in the first half of pregnancy. Preconceptional counselling and interdisciplinary management of pregnancies are essential for ensuring
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optimal pregnancy outcomes.
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211 Words
Key words: Estrogen - fertility - rheumatoid arthritis – systemic lupus erythematosus antiphospholipid syndrome – systemic sclerosis – vasculitis – pregnancy complications - placenta -
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TNF inhibitors
Running title: Reproduction in rheumatic disease
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ACCEPTED MANUSCRIPT Introduction Throughout the last decade, increasing awareness has been raised on issues related to reproduction in chronic diseases. Rheumatic diseases can affect quality of life and reproduction in both genders. Hormones, fertility, pregnancy, and management of high- risk pregnancy are important topics for
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patients and their doctors alike. This article gives a concise overview of current basic and clinical
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research presented at the VIII International Conference on Reproduction and Pregnancy and the
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rheumatic diseases 25. – 27. 2014 September in Trondheim, Norway.
Sex hormones and autoimmune diseases
The preponderance of women affected by chronic immune/inflammatory diseases clearly indicates that female sex hormones play an important role in the aetiology and pathophysiology of autoimmunity
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(1). In human subjects estrogens are generally considered as at least enhancing the humoral immune response. They act on cells by their peripheral metabolites rather than through their serum levels that
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may exert opposite dose-related effects (2).
Estrogen receptors (ERα and ERβ) are necessary for the action of estrogens. Recently, anti-ERα antibodies were detected in 45% of patients with systemic lupus erythematosus (SLE), whereas anti-
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ERβ antibodies were undetectable (3). In healthy donors, anti-ERα antibodies induced cell activation and consequent apoptotic cell death in resting lymphocytes. At the same time, they induced
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proliferation of anti-CD3-stimulated T lymphocytes, a mechanism that might contribute to autoreactive T cell expansion. A significant association between anti-ERα antibody levels and clinical parameters,
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like the SLE Disease Activity Index (SLEDAI) and arthritis, was found (3). Several investigations support an accelerated aromatase-mediated peripheral metabolic conversion of upstream androgen precursors to estrogen metabolites in peripheral tissues affected by
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immune/inflammatory reactions, both in male and female patients (4). In synovial tissue from rheumatoid arthritis (RA) patients, altered peripheral sex hormone synthesis (intracrine, e.g., at the level of macrophages and fibroblasts) mainly results in stimulation of cell proliferation and cytokine production (i.e. TNF) by these metabolites. It was shown that RA synovial cells mainly produce the cell proliferation promoting 16alpha-hydroxyestrone which, in addition to 16alpha-hydroxy-17betaestradiol, is the downstream estrogen metabolite that interferes with monocyte proliferation (5). Therefore, a preponderance of 16alpha-hydroxylated estrogens is an unfavorable sign, at least, in synovial inflammation and possibly related synovial tissue hyperplasia. Interestingly, urinary concentration and total urinary loss of 2-hydroxyestrogens was found 10 times higher in healthy subjects compared to RA or SLE patients irrespective of prior prednisolone treatment or sex (2). The intracrine synthesis of active estrogen metabolites at the level of cells involved in the immune response represents a common pathway that characterizes a similar final immune reactivity in both male and female patients (4).
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ACCEPTED MANUSCRIPT Contraception Traditionally, exogenous estrogens were considered to have the potential of worsening autoimmune processes. Typical oral contraceptive pills contain both estrogen and progesterone (combined oral contraceptives). Two randomized trials of these pills in women with mild-moderate stable SLE found
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no increase in SLE activity (6). However, women with very active SLE or active lupus nephritis were
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not included in these trials (6). The risk of thrombosis remains a significant concern, and estrogens
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should be avoided in women with antiphospolipid syndrome (APS), high levels of antiphospholipid antibodies (aPL), nephrotic-range proteinuria, or other conditions that increase thrombotic risk. The relative risk of venous thrombosis for combined oral contraceptives with 30-35 μg ethinylestradiol and rd
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gestodene, desogestrel, cyproterone acetate or drospirenone (3 or 4 generation progestogens) is nd
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similar and about 50-80% higher than for combined oral contraceptives with levonorgestrel (2 generation progestogen) (7).
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Fertility
Fertility problems in women with rheumatic disease occur not only in diseases with extensive systemic inflammation and autoantibody production, but also in the predominantly inflammatory joint diseases
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(IJD) (8). Women with IJD have a prolonged time to pregnancy compared to women in the general
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population, and seem also to require assisted reproduction more often (9). Whether they also have a reduced ovarian reserve has not been clarified. In a prospective study of 245 women with rheumatoid arthritis desiring children, 42 % experienced a greater than 12 months interval until conception (10).
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Disease activity and therapy were found associated with a prolonged interval to achieve pregnancy .
Women with rheumatic disease have fewer children than age matched controls from the general population (11). A reduced family size can be caused by increased pregnancy losses as well as
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disease related choices. Age at time of diagnosis is of importance for parity / nulliparity and for the final number of children. Women diagnosed with IJD before 25 years of age are more often childless or have fewer children than women diagnosed after 25 years of age (8). Studies have also shown that women with IJD are older than age matched controls at their first delivery and thus have a shorter reproductive period. The rate of early and late pregnancy losses is significantly increased in the APS, particularly when combined with SLE. Danowski et al. 2009 analysed 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%. The high risk for pregnancy loss in women with SLE and increased aPL, especially lupus anticoagulant (LA), was also confirmed by other studies. In 1`000 patients with APS including 820 women, a miscarriage rate of 35% was found for miscarriages <10 weeks of pregnancy and 17% for losses >10 weeks of pregnancy (13).
Reproductive failure is a heterogeneous condition that can be related in several autoimmune diseases to immunological pathomechanism (14). Beside the great role played by innate immunity, several
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ACCEPTED MANUSCRIPT autoantibodies have been associated with impaired fertility. Above all, the aPL including LA, anticardiolipin (aCL) and anti-β2 glycoprotein I (aβ2GP1) have all been reported to be associated with recurrent pregnancy loss (RPL) or as possible factors involved in infertility (15). In the context of RPL, complement-mediated placental inflammation has also been described to play a key role in
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experimental models of fetal loss induced by passive injection of aPL after implantation (16).
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Antibodies to thyroid antigens (ATA), such as thyroglobulin (aTG) and thyroid peroxidase (aTPO),
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antibodies to nuclear antigens (ANA), anti-laminin, anti-prothrombin antibodies (aPT) and antisacchromyces cerevisiae antibodies (ASCA), have also been implicated in pregnancy complications (16;17). 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
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and pregnancy loss, particularly early pregnancy loss, has been found (19). ATA have been suggested to be independent markers of pregnancies at risk for pregnancy loss (17). The association between pregnancy loss and thyroid antibodies may be a result of a direct effect of ATA on fetal tissue
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and the thyroid antibodies representing an underlying more generalized defect in autoimmunity (17). At present, the prognostic value of ATA remains uncertain. Cohort studies are necessary to determine the true incidence of pregnancy loss in the presence of each autoantibody or combination of
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autoantibodies.
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Understanding the pathogenesis of reproductive failure may help in developing specific therapies. Treatment with intravenous immunoglobulins (IVIg) has been the main option in patients with immunologic pregnancy loss (20), and is based on the concept that pregnancy loss may be caused by
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an aberrant immunological or inflammatory response involving cytokines or an autoimmune response as in APS. IVIg have been used to improve the live birth rate in women with unexplained RPL and APS though the results have been contradictory (21).
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Assisted reproduction (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. Initially, a negative influence of aPL on the success rate of in vitro fertilization (IVF) was suggested, however, a metaanalysis showed that this is not the case (22). Concerns in women with SLE or APS undergoing infertility treatment, are induction of a flare or thrombosis (23). Several retrospective studies have investigated the risk of a lupus flare after ovarian hyperstimulation (24). The conclusions of the studies are limited by lumping together different protocols of ovarian stimulation (clomiphen or gonadotropins). It appears that the risk for a flare is low in well controlled disease and when coadjuvant therapy is given, but higher in active disease (24). 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 increase the risk of thrombosis (25). The risk can be reduced by using stimulation protocols with Gonadotrophin-releasing hormone (GnRH) and ovulation induction with GnRH agonists
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ACCEPTED MANUSCRIPT which almost completely avoids ovarian hyperstimulation syndrome (25). This protocol requires 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
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safest approach (26). Active SLE, badly controlled arterial hypertension, pulmonary hypertension,
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advanced renal disease, severe valvulopathy or heart disease, and major previous thrombotic events
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are situations on which to discourage ART (24).
Progress in reproductive medicine has made it possible that women who undergo therapy with cyclophosphamide for lupus nephritis, systemic sclerosis or vasculitis can preserve their fertility (27).
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Pregnancy and rheumatic diseases
The response of rheumatic diseases to pregnancy varies in regard to disease activity. Likewise pregnancy outcome is different depending on disease extent and severity, presence of autoantibodies,
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comorbidities, therapy as well as non-disease related factors.
Rheumatoid arthritis
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Since the observation on predominant improvement made by Hench (28), the percentage of RA patients reported to improve during pregnancy declined from 90% to 48% in the most recent
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prospective cohort study on RA and pregnancy, the PARA study (29). Despite improvement during
trimester (29).
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pregnancy more than half of RA-patients still had active disease (DAS28 > 3.2) during the third
The very high percentage of patients that improved in the study of Hench should clearly be seen in the light of the very limited treatment options for RA in that era and the influence of self- reporting. Disease
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activity is more likely to decline during pregnancy when measured by self- report compared to objectively measured disease activity, as determined by DAS28. Other factors, which might explain a lower percentage of improvement in pregnant RA patients are disease activity and autoantibody status. Women with active disease and those negative for ACPA and rheumatoid factor were more likely to ameliorate during pregnancy (29;30). Therefore, also differences in patient selection might contribute to the observed differences. Another intriguing finding of the PARA-study is that women treated with prednisone show hardly any spontaneous improvement of disease activity during pregnancy, in contrast to women not using glucocorticoids (31) indicating a spontaneous, positive influence of the physiological rise in glucocorticoids during pregnancy. Throughout the decades after Hench`s description, the spontaneous improvement of RA during pregnancy has been felt intriguing. Among the different factors suggested to be involved are regulatory T cells (Treg). Treg originate in the thymus as naturally occurring Treg and can also be induced in the periphery. Recently it has been shown in animal models, that peripheral induced Treg, not thymic derived Treg, are critically involved in feto-maternal tolerance (32). Animal studies have shown that Treg expansion during pregnancy is mainly driven by fetal antigens which give rise to fetal
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ACCEPTED MANUSCRIPT antigen-specific peripheral Treg.(32) In RA patients, the ameliorating effect of pregnancy has been associated with an expansion of Treg that induce a pronounced anti-inflammatory cytokine milieu (33). By contrast, Treg of ankylosing spondylitis (AS) patients who experience active disease during pregnancy fail to support an anti-inflammatory milieu (34). Thus, active disease might provide an
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environment that promotes the differentiation from Treg to proinflammatory Th17 cells (35), yet this
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has not been shown in pregnant patients with rheumatic diseases.
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Other factors suggested to be involved are changes in the glycosylation of IgG during pregnancy. Glycosylation influences the tertiary structure of a protein and hence its function. Glycosylation is the addition of a glycan to a protein and influences the binding of immunoglobulins to the Fc-receptor with a major impact on the ability to cause antibody-dependent cell-mediated cytotoxicity. In the 1990ies
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an association between the glycosylation of IgG and improvement of RA during pregnancy was described (36). New studies using mass spectrometry showed that galactosylation of IgG, but not sialylation, was associated with improvement of RA during pregnancy (37). In addition, it was shown
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that also the glycosylation of proteins other than immunoglobulins changed during pregnancy indicating that improvement of RA during pregnancy may not only result from changes in the glycosylation of IgG, but may also depend upon pregnancy induced changes in the glycosylation of
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several other key effector molecules involved in the pathogenesis of RA.
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In the Dutch PARA-study disease activity in pregnant RA-patients, was directly associated with lower birth weight, whereas the use of prednisone indirectly influenced birth weight by lowering gestational age (38). Lower birth weight, even within the normal range, is a risk factor for metabolic syndrome and
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cardiovascular disease in adulthood (39). To get more insight into possible long term consequences of the RA associated lower birth weight, the growth of 167 children from mothers with RA was analysed with a focus on rapid catch-up growth in weight during first year of life (40). Almost one third of children born to women with RA demonstrated rapid catch-up growth in weight, which was clearly
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associated with (higher) maternal DAS28 during the third trimester of pregnancy (40). In other studies rapid catch-up growth in weight has been shown to be associated with an unfavourable cardiovascular risk profile in early adulthood (41). Body composition, one of the indicators for future cardiovascular disease, was studied in 108 children age 5-10 years born to mothers with RA (42). However, no association between body composition at age 5-10 years and maternal disease activity during pregnancy could be found (42).
Systemic lupus erythematosus Pregnancy in women with SLE, particularly in those with lupus nephritis is associated with increased risks of pre-eclampsia, fetal growth restriction, fetal loss and preterm delivery. These increased risks are present even if the lupus nephritis is quiescent but are higher in the presence of hypertension or proteinuria (43). For women with renal impairment, the risk of deterioration in renal function is higher with higher serum creatinine and the chance of successful pregnancy outcome is lower. For women with a pre-pregnancy serum creatinine between 125 and 180 umol/L the risk of delivering preterm
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ACCEPTED MANUSCRIPT (less than 37 completed gestational weeks) is 60%, the risk of pre-eclampsia is 40 %, the risk of fetal growth restriction is 40 % and the risk of perinatal death is 5 %. The patient runs these risks in pregnancy while at the same time there is a 20 % risk of a permanent decline in renal function post
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partum and a 2% of reaching end stage renal failure within a year of delivery (44).
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Specific data for lupus nephritis are available and a meta-analysis of 362 pregnancies showed an
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incidence of renal flare in 11-43%, reversible acute renal failure in 3-27% and irreversible loss of renal function in 0-11% (45). A single centre study of 113 pregnancies in 81 women with pre-existing biopsyproven lupus nephritis included 6 women with class II, 8 with class III, 48 with class IV and 19 with class V disease. At conception, 49% were in complete and 27% partial remission. Pregnancy outcome
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included 9 miscarriages, 1 stillbirth, 5 neonatal deaths. There were 31 (30%) preterm deliveries, 34 (33%) babies with birth weight <2500 g. Pregnancy outcome was predicted by hypocomplementaemia at conception (RR 19.02; 90% CI 4.58-78.96) and use of aspirin during pregnancy (RR 0.11; 90% CI
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0.03-0.38) (46). Renal outcomes included 34 (33%) renal flares (pregnancy & postpartum) of which 20 were reversible and 3 with progressive decline of GFR (1 on dialysis). Renal flare was predicted by renal status at conception, so for those in partial remission relative risk (RR) of flare was 3.0; 90% CI 1.23-7.34, and for those in non remission RR was 9.0; 90% CI 3.59-22.57 (47). A more recent
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systematic review of outcomes in lupus nephritis which included 37 studies of 1842 patients and 2751
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pregnancies concluded that the chance of unsuccessful outcome was 23%, of preterm birth was 39%, of stillbirth or neonatal death was 6%,of fetal growth restriction was 13% and the risk of maternal
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complications including renal flare, hypertension and pre-eclampsia was 30-40% (48). Lupus activity is a key predictor of pregnancy outcome. High levels of lupus activity several months prior to conception increased the risk of pregnancy loss by 4-fold (49). High lupus activity during pregnancy doubles the risk of pregnancy loss and the risk for preterm delivery. Elevated dsDNA and
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low complement are each modestly associated with preterm birth. They are most predictive, however, when they are coupled with increased lupus activity (50). Several other readily available laboratory tests have been shown to be associated with preterm birth, but not confirmed in large studies. Elevated ferritin as a marker of inflammation and low estradiol as a marker of poor placentation, have both been associated with preterm birth in women with lupus (51). Drug therapy in the pregnant lupus patient includes prednisolone, azathioprine and hydroxychloroquine which are all safe in pregnancy and breast feeding, and can be continued (52). Many women with lupus nephritis are receiving mychophenolate mofetil (MMF) which is an established teratogen causing microtia, external auditory canal atresia, orofacial clefts, cardiovascular malformations and digital hypoplasia. (53). MMF should be stopped at least 6 week prior to conception, as it has a long half life with enterohepatic recirculation, and be switched to azathioprine. A recent study has demonstrated that in 23 women with lupus nephritis with a SLEDAI ≤ 4 switched to azathioprine prior to conception, there were 3 renal flares prior to pregnancy but none in 18 pregnancies and one post partum after 17 live births (54). This study also found that adverse pregnancy outcomes increased as prednisolone dose increased or as SLEDAI increased.
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ACCEPTED MANUSCRIPT Diagnosing pre-eclampsia in women with lupus nephritis may be challenging particularly if there is preexisting hypertension and / or proteinuria. Features which point to a diagnosis of lupus nephritis include hypocomplementaemia and other features of active SLE. It has been shown that reduced angiogenic (vascular endothelial growth factor, placental growth factor) and increased antiangiogenic
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factors (soluble fms-like tyrosine kinase 1, soluble endoglin) are useful predictors and diagnostic tools
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in SLE in the same way as they are in general (55).
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In the event of a lupus nephritis flare current consensus is to use glucocorticoids . However problems with this strategy are that steroids alone may be unable to control disease activity and their use is associated with higher rates of preterm delivery (secondary to preterm rupture of membranes), infection / sepsis and gestational diabetes. Webster et al.(56) have recently reported a case series of 9
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women treated with tacrolimus to maintain or achieve lupus nephritis remission in pregnancy. The rationale for use of tacrolimus is that calcineurin may cause damage to podocytes by dephosphorylation of the actin-organizing synaptopodin. Calcineurin inhibitors may inhibit the action of
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calcineurin on the actin cytoskeleton of podocytes, restoring normal structure and thus controlling proteinuria. Eight cases had stable/quiescent disease for > 1 year prior to pregnancy and one had no prior history of lupus nephritis. In three cases tacrolimus was commenced before conception, and disease remained stable throughout their pregnancies. Six women experienced disease flare, 5/6 in
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the first trimester. All were normotensive, with nephrotic range proteinuria at the time of flare. Induction
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of remission occurred despite reducing steroids by adding tacrolimus or by replacing azathioprine by tacrolimus. Tacrolimus dose was titrated to a trough level of 5–8 ng/ml and increases in doses were
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frequently required (56). This study supports the inclusion of tacrolimus as an adjuvant or alternative therapy to steroids with another potential safe therapy for the treatment of lupus nephrtis and controlling proteinuria during pregnancy. It has been previously demonstrated that although babies of mothers taking tacrolimus are born with therapeutic levels, these decline to become undetectable
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within a few weeks and the rate of decline is the same whether the baby is breast or bottle fed (57).
Neonatal Lupus syndromes Transplacental transfer of SS-A/Ro antibodies can induce neonatal lupus syndromes, either as a typical skin rash that does resolve spontaneously within 6 months after birth or a congenital heart block (CHB) in the child. CHB occurs in 1 to 2 % of pregnancies exposed to anti-SSA antibodies (58). The most common presentation is an unexpected advanced atrioventricular (AV) block in the fetus of a “healthy” “asymptomatic” mother (85% of cases) (58). Few data are available regarding the risk of the mothers of fetuses/children with CHB to develop an autoimmune disease. A retrospective study of the French registry of neonatal lupus evaluated the development of autoimmune disease in anti-SSA and/or anti-SSB antibody positive mothers who had a fetus or a child with CHB (59). At the time of diagnosis of CHB in 206 mothers, 153 mothers (74%) were asymptomatic and 53 mothers (26%) had an autoimmune disease with SLE, Sjögren syndrome, and undifferentiated connective tissue disease (UCTD) as the most frequent. After a median follow up period of 8.5 years, 89 of the 206 mothers
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ACCEPTED MANUSCRIPT (43%) remained symptom free whereas 117 mothers (57%) developed an autoimmune disease with SLE (n=41, Sjogren syndrome (n=35), UCTD (n=27), and RA (n=5) as the most common (59).
High doses of fluorinated glucocorticoids are frequently administered when an AV block is detected in
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an anti-Ro/SSA-positive mother. However, their efficacy is controversial (60). New clinical trials are in
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progress for the prevention of CHB by hydroxychloroquine and/or IVIG (61).
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Follow-up studies have investigated the neurodevelopment of children exposed to fluorinated corticosteroids with conflicting results (62). A recent Canadian study evaluated intelligence, visual skills, auditory and visual attention, verbal learning and memory, executive function, and behaviour in children aged 6-16 years with or without CHB, exposed prenatally versus not exposed to
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dexamethasone . All cohorts scored within the normal range and showed no significant difference between groups (63).
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Systemic sclerosis (SSc)
Systemic sclerosis (SSc) has not been as frequently studied than SLE and APS in regard to pregnancy, one reason truly being the higher age of onset and the rarity of the disease. The Italian
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IMPRESS study recorded pregnancy outcome of 109 SSc pregnancies (64). Compared with the
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general obstetrical population preterm deliveries (25% vs. 12%), severe preterm deliveries (<34 weeks) (10% vs. 5%), fetal growth restriction (6% vs. 1%) and very-low-birth-weight babies (5% vs. 1%) were significantly more frequent in SSc. Multivariable analysis found that glucocorticoids were
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associated with preterm deliveries (OR 3.63), while folic acid was protective (OR 0.30), as were antitopoisomerase antibodies (OR 0.26). The disease remained stable in most patients (64).
The management of SSc pregnancies is challenging and requires specialists familiar with the disease
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and high risk pregnancy (65). Predictors for a more aggressive disease course are < 4 years disease duration, diffuse cutaneous scleroderma, presence of anti-topoisomerase or RNA polymerase III antibodies.
Some important unanswered questions remain which a new prospective study, the International Multicentric PRospective Study on PREgnancy in Systemic Sclerosis ( IMPRESS 2) will investigate in pregnant SSc patients, non-pregnant SSc patients of fertile age, and a healthy pregnant comparison group: 1. disease activity of SSc during and after pregnancy, 2. pregnancy complications and outcome in patients with SSc, 3. children outcome at 1 and possibly 3 years, 4. the modern incidence of renal crisis, severe cardiac involvement and pulmonary hypertension both in pregnant and non-pregnant women with SSc. The study is endorsed by EUSTAR and partially funded by the Italian Society of Rheumatology and Italian patients associations (GILS; Gruppo LES, ALOMAR). Up to date, 28 pregnancies have been enrolled. Additional recruitment is urgently needed. The findings of the study
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ACCEPTED MANUSCRIPT will be relevant for many SSc women planning a pregnancy, and wishing for an experience natural to healthy women: to have a child. Vasculitis Vasculitis pregnancies are rare and therefore hard to study. A retrospective study comparing 496
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pregnancies before vasculitis to 74 pregnancies in women with vasculitis found an increase in
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pregnancy loss (22.4% pre-vasculitis vs 33.8% post-vasculitis, p=0.04) and an increased risk for preterm birth (11.4% pre-vasculitis vs 23.3% post-vasculitis, p=0.03) (66). Remarkably few women
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reported a flare of vasculitis during pregnancy – just 18% - but those pregnancies had a higher rate of preterm delivery (44.4%).
A review of the literature identified 48 pregnancies in women with granulomatous polyangiitis (GPA).
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Interestingly, GPA was diagnosed during pregnancy in almost 1/3 of the cases. A 40% flare rate and a 35% preterm birth rate were found (67). With the use of rituximab to treat ANCA-associated vasculitis, more women may be able to conceive after vasculitis diagnosis. A report of 8 pregnancies
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that occurred within 1 week to 16 months following Rituximab included 1 miscarriage with BeckwithWidemann Syndrome and 7 live births. At delivery, 6 women still had undetectable B cell levels, but 3 out of 3 tested infants had normal B cell levels at birth (68). Additional data on the use of Rituximab in
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pregnancy include 153 pregnancies with known outcomes (69). Among 90 live births 24% were
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preterm and 11 reported of neonatal cytopenias. Similar to data from other biologics, the effect on the cord blood levels and the neonate is greatest when the last dose is administered within 12 weeks of
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birth.
More data is available for pregnancy in Takayasu’s Arteritis, likely due to the young age of onset of this disease. A review of the literature uncovered 214 pregnancies and a very high rate of severe hypertension and/or preeclampsia (43%). Increased Takayasu’s Arteritis activity was rare in
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pregnancy, but complications from prior damage, including aortic dissection, congestive heart failure, aneurysms, and 2 maternal deaths were reported (67). Monitoring blood pressure is essential and can be challenging if there is subclavian disease (70). Some authors recommend a scheduled cesarean section to avoid the exertion and hypertension associated with a vaginal delivery, but this is controversial. A retrospective study of 76 pregnancies in Behçet’s disease (BD) patients found worsening of oral ulcerations, genital ulcerations and ocular complications in 35.5% (71). The mean ± SD annual rates of BD flares were 0.49 ± 0.72 during pregnancy and 1.46 ± 2.42 during the nonobstetrical period (P = 0.018 concordant with the rate of flare of 29.7% found in the literature. There was a trend toward fewer BD flares in patients treated with colchicine (27.9% versus 45.4% of patients not treated with colchicine (p = 0.11). The overall rate of complications during pregnancy was 15.8%, in keeping with previous reports, and not higher than in the general population.
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ACCEPTED MANUSCRIPT The Obstetric Antiphospholipid Syndrome The pathogenesis of Obstetric Antiphospholipid Syndrome (OAPS) is rather heterogeneous, complex and not fully understood yet. Differently from the model of aPL-mediated thrombosis, no need for a second hit is required for the induction of placental damage and pregnancy loss (72;73). As shown ex
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vivo on human term placentae and, more recently, in vivo in a mouse model, β2GPI is abundant on
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the trophoblast surface and is available for binding to aPL, particularly anti- β2GPI (74).
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Intraplacental thrombosis does not account for the full picture of OAPS. Non-thrombotic mechanisms can be identified on both the maternal and fetal side (73), causing the functional impairment of decidual and throphoblast cells respectively. Defective placentation is mediated by the inhibition of endometrial angiogenesis and by the reduction of trophoblast differentiation/invasiveness (75).
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Inflammation has been also described as a prominent feature in aPL-mediated placental damage. Particularly, complement activation and deposition has been claimed to be a major player, although there are some discordant reports on human placentas from APS patients (76). Conversely, a better
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defined association has been described between complement activation and/or alterations and the onset of preeclampsia (reviewed in 77). A novel mechanism has been proposed for preeclampsia: aPL can be internalized by human syncytiotrophoblast cells, leading to aberrant cell death and release of
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necrotic trophoblast debris and activation of maternal endothelial cells (78).
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Novel therapeutic targets have been proposed on the basis of a deeper understanding of the pathogenic mechanisms in OAPS. Antibodies directed against the domain 1 of β2GPI (anti-D1) were
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detected at high frequency in patients with OAPS (79). Their pathogenic role in pregnancy complications is supported by experimental data. In one study, a recombinant antibody recognizing the D1 of β2GP was able to induce fetal loss and clot formation in animal models, while the noncomplement fixing version of the antibody was able to prevent the procoagulant and proabortive
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effects of patient antibodies (80). Another study showed that tolerogenic dendritic cells specific for β2GPI D1 were able to attenuate APS in mice by lowering titers of anti-β2GPI and by reducing the percentage of fetal loss (81). Alternatively, the synthetic peptide TIFI mimicking the phospholipid binding site of β2GPI (domain 5) restored the aPL-mediated inhibition of human endometrial angiogenesis in an ex vivo model (82). Toll like receptor 4 (TLR 4) was found to mediate the pathogenic effects of aPL in reducing trophoblast fusion and differentiation. Hydroxychloroquine was able to reduce TLR4 mRNA and protein expression and to finally restore trophoblast function, suggesting the use of this drug in OAPS (83). According to a recent literature review, aPL are detected in more than 10% of unexplained pregnancy losses (84) and in fact the clinical recognition of this association goes back to the 80s. The formal clinical classification criteria of OAPS have been defined in 1998 and revised in 2004(85), basically including recurrent miscarriages, fetal loss, preeclampsia and placental insufficiency. However the real prevalence of aPL in patients with each of these clinical features is still far to be precisely defined because of the inconsistent results of different studies. The recent report of the International Task Force on OAPS (77) has recognized many differences in the published studies making it difficult to
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ACCEPTED MANUSCRIPT compare their results. The differences are related both to the lack of an uniform laboratory characterization of patients (lack of standardized tests to detect aPL and difficulties to include patients tested for all three “criteria” assays) and the lack of uniform definition of obstetrical clinical criteria. In addition it is today recognized that OAPS is probably not completely included in the formal
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classification criteria. In fact, apparently obstetrical pathology can occur also in patients with low
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antibody titers (by definition not included in the serological criteria) in contrast with thrombosis which is
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mainly recorded in patients with high aPL titers (86).
The treatment of OAPS was originally designed to counteract the prothrombotic effect of aPL. Treatment with low dose aspirin (LDA) and heparin (H) or low molecular weight heparin(LMWH) proved to be effective in the majority of patients (87) probably also because heparin was demonstrated active well beyond anticoagulation (76). However, a small percentage of women do not benefit of this
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“conventional” treatment. Therefore it is important to identify high risk patients in order to modify their management. According to recent reports, the high risk obstetrical profile is probably related to specific
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serology (positive LA, or positivity in all the three aPL assays) or to the clinical condition of the patient such as the presence of systemic autoimmune disease or the history of thrombotic episodes (88;89). In addition to the high risk, women with clinically or serologically incomplete OAPS and with antibodies in the absence of clinical manifestations (aPL carriers) should be carefully considered. In fact a recent
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revision of a single-center experience over the last 30 years shows that, in the absence of a combined
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treatment (LDA and H), a significant number of fetal/neonatal losses (6 out of 33 pregnancies), pregnancy complications (early severe preeclampsia: 2/33pregnancies) and even maternal
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thrombosis (DVT:2/33 pregnancies) are recorded in these patients (90). Finally the new therapeutic options for the high risk patients are not yet clear. The addition of firsttrimester low-dose prednisolone has resulted in a higher live-birth rate than conventional therapy alone (91).Intravenous immunoglobulins, or weekly apheresis procedures have been applied with some
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success in high risk patients (92). While the true relevance of these treatments has still to be confirmed, other suggestions relate to experimental models. Among these, hydroxychloroquine might be the first drug to be largely administered because of its well documented safety in pregnant patients (93). A rare but severe complication in the APS is the catastrophic antiphospholipid syndrome (CAPS) characterised by multiorgan failure caused by multiple small vessel thrombosis associated with thrombotic microangiopathy. It can be triggered by preceding events, one of them is pregnancy (94). Pregnancy-related CAPS is not exceptional and represents 6% of the cases included in the international CAPS registry (95). In a French, retrospective series of 13 patients CAPS in pregnant women was preceded by HELLP syndrome that occurred at a mean gestational age of 26.6 weeks (96). The most frequent manifestations of CAPS were cutaneous, hepatic, renal, cardiac and neurological . No maternal death was observed. The perinatal mortality was 54% and was mainly due to prematurity. In a follow-up for a mean of 4.8 years, seven patients had a subsequent pregnancy. No relapse of CAPS was observed, but HELLP occurred in two cases (96). An optimal management is
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ACCEPTED MANUSCRIPT associated with a reduction in maternal mortality, but foetal and neonatal prognosis will depend mostly on the gestational age at the onset of CAPS.
Complications of high risk pregnancies
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In spite of the overall improved outcomes of pregnancy in women with rheumatic disease several
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serious complications are still increased. Abnormal placentation may result in miscarriage, preterm
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birth, preeclampsia and intra-uterine growth restriction (IUGR) depending on severity and maternal constitutional factors (97;98). They are therefore most correctly perceived as part of a continuum of pregnancy complications (Figure 1). Immune dysregulation has over the last decade been accepted as the primary placental dysfunction in preeclampsia (98). The placental tissue is partly foreign to the
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mother, and a number of immune mechanisms are in place to protect the fetus from maternal immunological attack. This includes immunological priming by local Treg prior to conception, when the mother is exposed to cytokines and antigens from paternal seminal fluid (99). Treg play a decisive role
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in the immunologic adaption to pregnancy. Recently, it has been shown that memory T-reg specific for paternal antigens persist after pregnancy, providing increased protection in the next pregnancy with the same father (100).
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Overt preeclampsia is a state of increased systemic inflammation, oxidative stress and endothelial
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dysfunction, leading to organ failure, seizures and death in rare cases. A key biomarker of preeclampsia in pregnancy is the ratio of anti-angiogenic to angiogenic factors. In non-lupus
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pregnancy, preeclampsia can be predicted by elevated levels of soluble fms-like tyrosine-kinase-1 (sFlt-1, which inhibits blood vessel growth in the placenta) and lower levels of placental growth factor (PlGF, which promotes placental blood vessel growth (101). An elevated sFlt-1/PlGF ratio is associated with preeclampsia in SLE as well. In 52 SLE pregnancies, sFlt-1 was eleva ted in the 18
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pregnancies with preeclampsia when measured between weeks 22-32 of gestation (102). Similarly, in a prospective study of pregnancies sFlt-1 and the sFlt-1/PlGF ratio were both elevated between week 10 - 15 of gestation among pregnancies that developed preeclampsia (103). Limited research in women with severe forms of preeclampsia, shows that removal of anti-angiogenic factors either by column apheresis (104) or pharmacological intervention (105) may cause the syndrome to recede and give the mother a chance of delivering at term. An excessive maternal pro-inflammatory status, characterized by a type 1 immune bias, is a typical feature of preeclampsia (97). Therefore, it seems reasonable to investigate whether the inflammatory environment of rheumatic disease may favor preeclampsia development. In particular, IL-33, a recently discovered member of the IL-1 superfamily, has been related to rheumatic disease through activation of its soluble ST2 receptor (sST2L)(108), which has been found to be significantly increased in preeclampsia (109;110). sST2L seems to be a second anti-inflammatory factor (besides sFLT-1) produced by the placenta in excess amounts in preeclampsia.
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ACCEPTED MANUSCRIPT The only effective treatment of preeclampsia is delivery, therefore preeclampsia is a major cause of premature birth worldwide. Prophylactic treatment with aspirin and Low molecular weight heparin in high risk women has shown some, but limited effect (111). Recently statins have been suggested as a possible way of targeting the anti-angiogenic factors s-FLt1 and sEng through the heme oxygenase
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pathway (112). Randomised controlled trials for the use of statins in pregnancy are enrolling in both
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the UK and US. The complement system is another promising target for treatment (91). It remains to
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be seen if statins or complement inhibitors prove to be effective treatments in larger cohorts. IUGR is a pathology of pregnancy that affects between 5-10% of pregnancies. IUGR may be defined as the “failure of the fetus to reach its growth potential”, according to the known intrauterine growth curves. In recent years, a placental phenotype of IUGR has been described by numerous studies
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(113), so that a number of maternal, placental or fetal abnormalities with the potential to alter growth, permeability, perfusion, transport capacity and metabolic/endocrine function of the placenta may lead to changes in fetal growth trajectory then followed by mechanisms of adaption and eventually failure
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(reviewed in 114).
Normal implantation is a dynamic process regulated by a complex series of interactions between trophoblast itself and decidual tissues. A significant number of studies have investigated the
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involvement of the feto-maternal interface in APS, providing evidence that thrombotic events do not
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account for all of the histopathologic findings found in these placentas. Moreover, although very little is known about the possible reactivity of aPL with decidual/endometrial cell, recently in vitro culture studies show that aPL affect human endometrial angiogenesis (115). In cohort studies, the presence
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of anti- β2GPI has been associated with a 20 times increased significant risk of developing IUGR. At present, clinicians must be aware that rheumatic diseases, and in particular APS, significantly increase the risk of pregnancy pathologies associated with placental insufficiency, like IUGR and
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preeclampsia (116). Therefore, they must follow protocols for the early evaluation of placental function with uterine artery Doppler velocimetry and other biochemical placental markers such as sFLT-1 and PlGF.
Therapy before conception and during pregnancy Questions regarding therapy before and during pregnancy and lactation are of great concern for patients and their treating physicians. Special interest has focused on on inhibitors of tumor necrosis factor-alpha (TNF-alpha) because of their frequent use both in female and male patients with rheumatic disease (117).
Measurements of transplacental passage of four TNF inhibitors in an ex vivo human placental perfusion model, and in patients showed differences among adalimumab (ADA), etanercept (ETA), infliximab (IFX) and certolizumab (CZP). IFX, ADA and ETA demonstrated binding to the fetal Fc receptor (FcRn) and were actively transported across a cell layer by FcRn. ETA had a lower affinity of binding and transcytosis than the other TNF inhibitors (118). The ex vivo perfusion model showed
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ACCEPTED MANUSCRIPT no measurable transfer of CZP from the maternal to the fetal circulation in 5 out of 6 placentas that demonstrated positive-control IgG transport. In patients treated with ADA or IFX, active placental transfer of the anti-TNFs was observed. Neonatal levels of IFX and ADA on the day of birth were always higher than the level in the mother by up to 4.9 -fold. In contrast, the level of
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CZP in neonates was always much lower than the maternal level (the highest was only 24.4% of
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the maternal level), and often below the limit of quantification (<0.41μg/ml) (119). The study confirmed that the different molecular structure of CZP that does not contain an Fc region results in
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low placental transfer.
The safety of ADA during pregnancy was examined by a prospective cohort study between 2004 and 2013 by the OTIS Collaborative Research Group (120). Seventy-four women with RA in the ADA exposed group had at least one dose of the medication in the first trimester; approximately 43% of
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those women used the medication in all three trimesters. The rate of major defects in the exposed, disease-matched (80 RA pregnancies), and non-diseased comparison (218 women without any
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autoimmune disease) groups was not significantly different (Table 1). A total of 234 infants (70% of live born infants) received the study-related physical examination. The proportion of children with 3 or more minor malformations in the three groups did not differ, and there was no specific pattern of minor malformations identified (120). The rate of preterm delivery did not differ significantly among groups,
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nor did the proportion of infants who were small for gestational age. In spite of the small sample size,
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these results provide reassuring data to women with RA who require treatment with ADA. A follow-up questionnaire study examined outcomes of children exposed to TNF inhibitors in utero
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during the first 24 months after birth. Eleven children exposed were compared to nine children not exposed in utero to TNF inhibitors. The preliminary analysis of this ongoing study showed that children exposed in utero to anti-TNFα had a good birth outcome, normal growth and a normal response to vaccinations with no significant differences between exposed and non-exposed children born by
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mothers with chronic arthritis (121). Some infectious disorders were reported in the first year of life in several children, but with a benign course.
In men, cytotoxic and immunosuppressive drugs can impair spermatogenesis resulting in infertility or chromosomal defects in spermatozoa. At present, there are limited data to confirm or refute the risk of congenital malformations induced by antirheumatic drugs given to men.The majority of male patients with spondyloarthropathies (SpA) are affected during their peak reproductive years. Treatment with TNFα inhibitors has proved highly effective in patients with SpA. TNF-alpha plays a role in spermatogenesis – moderate levels in the testes appear to promote spermatogenesis whereas high levels inhibit it. In a prospective study of 23 men with AS and a comparison group of 46 healthy men, the influence of TNF-inhibitors on spermatogenesis was investigated (122). Sperm samples were analyzed prior to starting a TNF-inhibitor, and three and 12 months after therapy. Normal sperm quality was present in AS patients at baseline, and did not change significantly during three and 12 months of anti-TNF treatment. Together with two additional studies, this study suggests that TNFinhibitors do not impair sperm quality (123).
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ACCEPTED MANUSCRIPT Counselling and pregnancy planning Planning is essential to increase the probability of success of pregnancies. Planned pregnancies have demonstrated reduced flare rates and better obstetric outcomes in women with SLE (124). Thus, preconceptional risk assessment and counselling should be ideally performed in every woman with
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systemic autoimmune diseases before attempting pregnancy.
In the preconceptional visit, several issues should be assessed in order to estimate the risk for
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complications: the age of the patient; the outcome of previous pregnancies; the extent of organ involvement and the presence of irreversible damage; the degree of disease activity and the occurrence of recent flares; the presence of antiphospholipid antibodies / syndrome and of anti-Ro / anti-La antibodies; the current treatment, with special attention to any drugs forbidden during
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pregnancy. Highly active disease or a high degree of irreversible damage, especially in vital organs such as the kidneys, the lungs or the heart, should discourage conception. Drugs contraindicated during pregnancy must be stopped at the preconceptional visit and replaced by safe ones. However,
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any change in treatment before pregnancy should be given for at least two or three months to assure that disease keeps in remission with the new therapeutic combination (125). It is essential to bear in mind that hydroxychloroquine must not be stopped because of pregnancy or pregnancy planning,
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given its safety and the high risk for severe lupus flares after withdrawal (126).
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Active disease in the preconceptional visit must be treated. Pregnancy-compatible drugs like pulsemethyl prednisolone, medium-low dose prednisone, hydroxychloroquine and azathioprine can be used
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if needed. Once activity is controlled for at least three months, women can try to conceive. However, severe activity (for instance, lupus nephritis, neuropsychiatric lupus, vasculitis affecting vital organs, scleroderma lung disease), should be aggressively treated with drugs such as cyclophosphamide or mycophenolate, and pregnancy should be delayed for at least one year after remission. In patients
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with nephritis, the goal is achieving normal renal function with no significant proteinuria, or at least lower than 1 gr in 24 h (46). Progressive changes in therapy should then be started to assure a good control with drugs allowed during pregnancy. On the other hand, if a woman with a systemic autoimmune disease is in sustained remission taking hydroxychloroquine, low-dose prednisone -or no prednisone at all- or any other drug allowed during pregnancy, treatment should not be modified in the preconceptional visit given the risk of triggering a disease flare with not much to gain. All women with previous renal disease should be given low-dose aspirin within the first trimester of pregnancy up to delivery in order to decrease the risk of preeclampsia (127). Likewise, adequate prophylaxis for preeclampsia and thrombosis must be given to women with antiphospholipid antibodies taking into acount their immunological and clinical profile as well as the current guidelines (77). Placental Doppler studies are important predictors of preeclampsia and placental insufficiency, and should be planned in advance (128). It is important that rheumatologists raise the need for contraceptives with their female patients, particularly when potentially teratogenic medications like methotrexate, leflunomide, mycophenolate mofetil, and cyclophosphamide are prescribed to fertile women. There are many effective
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ACCEPTED MANUSCRIPT contraceptive options for women with rheumatic disease – no woman should be left with the impression that she cannot use birth control due to her rheumatologic diagnosis. Long-active contraceptives, like intrauterine devices ( IUD) and implantable progesterone, provide effective pregnancy prevention and will allow patients and physicians to plan pregnancies during periods of
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disease quiescence and when only safe medications are in use (6).
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Female patients with systemic inflammatory diseases have important family planning and pregnancy
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(FPP) concerns that need to be addressed by their treating physicians. Two online surveys performed in rheumatologists and gastroenterologists in Europe and the US showed that 49%-65% of physicians spontaneously reported having discussed FPP with their female patients of child-bearing age (129). Across specialties less than half of physicians who discussed FPP with their patients reported
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discussing FPP with the general practitioner treating the patient. More than 60% of patients reported their concerns relating to FPP are not adequately settled during their medical appointments. Many patients experienced a lack of consistency in communication on FPP across healthcare professionals
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revealing that there is low interaction between different caregivers. These data show that comprehensive pre-pregnancy counselling is the first step to managing pregnancy in women with chronic disease.
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Conclusion
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Reproduction issues including fertility and pregnancy are of great importance for women and men with rheumatic disease. Due to an increasing recognition of risk factors and an interdisciplinary approach
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women with rheumatic diseases can undergo successful infertility treatment and can have successful pregnancies. New therapeutic options are available both for the management of lupus complications and the APS during pregnancy. Increasing experience with the effect of TNF inhibitors on pregnancy will allow their use, when indicated, in women and men who desire children. Pre- pregnancy
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counselling and risk assessment remains a critical first step to achieve good pregnancy outcomes.
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Disclosure statement
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The authors declare no conflict of interest.
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ACCEPTED MANUSCRIPT 84. Andreoli L, Chighizola CB, Banzato A, Pons-Estel GJ, de Jesus GR, Erkan D The estimated frequency of antiphospholipid antibodies in patients with pregnancy morbidity, stroke, myocardial infarction, and deep vein thrombosis. Arthritis Care Res 2013; 65: 1869–1873.
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87. Mak A, Cheung MW, Cheak AA, Ho RC. 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 metaregression. Rheumatology (Oxford) 2010; 49:281–288.
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88. Lockshin MD, Kim M, Laskin CA,et al. Prediction of adverse pregnancy outcome by the presence of lupus anticoagulant, but not anticardiolipin antibody, in patients with antiphospholipid antibodies. Arthritis Rheum. 2012; 64(7):2311-8.
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89. Ruffatti A, Tonello M, Visentin MS, et al. Risk factors for pregnancy failure in patients with antiphospholipid syndrome treated with conventional therapies: a multicentre, case-control study. Rheumatology (Oxford) 2011;50(9):1684 e 9.
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90. Angela Tincani & Laura Andreoli, “personal communication 2014
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91. Bramham K, Thomas M, Nelson-Piercy C,et al. First-trimester low-dose prednisolone in refractory antiphospholipid antibody-related pregnancy loss. Blood. 2011;117: 6948-51.
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5/74 (6.8)
0.91 (0.24,3.03)
4/72 (5.6)
6/77 (7.8)
0.71 (0.16,2.27)
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4/65 (6.2)
1.14 (0.26,4.93)
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Crude RR (95% CI)
Adjusted OR (95% CI)
Crude RR (95% CI)
Adjusted OR (95% CI)
---10/197 (5.1)
1.21 (0.40,3.54)
11/201 (5.5)
1.02 (0.34,2.94)
1.10 (0.32,3.82)
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1.26 (0.29,5.54)
NonDiseased Comparison n/N (%)
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Major Birth Defects in All Pregnancies Excluding Lost-ToFollow-Up
RA Comparison n/N (%)
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Major Birth Defects in Live Born Infants
ADA Exposed n/N (%)
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Birth Defects
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Table 1. Major Birth Defects in 1st Trimester-Adalimumab-Exposed Pregnancies Among Women with Rheumatoid Arthritis (RA) Compared to Disease-Matched and Non-Diseased Pregnancies Not Exposed to Adalimumab
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ACCEPTED MANUSCRIPT Text figure 1:
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Figure 1 is a modified version of the model for preeclampsia pathogenesis presented in Redman and Sargent (98). A stage of pre-conceptual immunological priming is followed by a stage 1 of immunological acceptance. Poor immunoregulation may lead to poor placentation and later to systemic inflammation. Preeclampsia is understood as part of a continuum. For the early stages this continuum ranges from miscarriage to normal pregnancy, whereas in the later stages, dominated by inflammation, maternal clinical complications range from hypertension and mild preeclampsia to severe preeclamptic manifestations in pregnancy. Maternal constitutional factors contribute to the development and outcome of all stages of placental pathology, and may also account for the increased risk of cardiovascular diseases later in life seen in women with preeclampsia.
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Abbreviations: Treg cells: T-regulatory cells, IDO: idoleamine 2,3 dioxygenase, FGR: fetal growth restriction, ER-stress: Endoplasmatic reticulum stress
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Figure 1. Pathogenesis of miscarriage, Intrauterine growth restriction, and preeclampsia (modified after Redman and Sargent 2010)
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