Objective: To develop an evidence‐based guideline on contraception, assisted reproductive technologies (ART), fertility preservation with gonadotoxic therapy, use of menopausal hormone replacement therapy (HRT), pregnancy assessment and management, and medication use in patients with rheumatic and musculoskeletal disease (RMD).Methods: We conducted a systematic review of evidence relating to contraception, ART, fertility preservation, HRT, pregnancy and lactation, and medication use in RMD populations, using Grading of Recommendations Assessment, Development and Evaluation methodology to rate the quality of evidence and a group consensus process to determine final recommendations and grade their strength (conditional or strong). Good practice statements were agreed upon when indirect evidence was sufficiently compelling that a formal vote was unnecessary.Results: This American College of Rheumatology guideline provides 12 ungraded good practice statements and 131 graded recommendations for reproductive health care in RMD patients. These recommendations are intended to guide care for all patients with RMD, except where indicated as being specific for patients with systemic lupus erythematosus, those positive for antiphospholipid antibody, and/or those positive for anti‐Ro/SSA and/or anti‐La/SSB antibodies. Recommendations and good practice statements support several guiding principles: use of safe and effective contraception to prevent unplanned pregnancy, pre‐pregnancy counseling to encourage conception during periods of disease quiescence and while receiving pregnancy‐compatible medications, and ongoing physician‐patient discussion with obstetrics/gynecology collaboration for all reproductive health issues, given the overall low level of available evidence that relates specifically to RMD.Conclusion: This guideline provides evidence‐based recommendations developed and reviewed by panels of experts and RMD patients. Many recommendations are conditional, reflecting a lack of data or low‐level data. We intend that this guideline be used to inform a shared decision‐making process between patients and their physicians on issues related to reproductive health that incorporates patients’ values, preferences, and comorbidities.

Antiphospholipid syndrome (APS) is defined by recurrent pregnancy loss and thrombosis in the presence of antiphospholipid (aPL) Ab’s. Currently, therapy for pregnant women with APS is focused on preventing thrombosis, but anticoagulation is only partially successful in averting miscarriage. We hypothesized that complement activation is a central mechanism of pregnancy loss in APS and tested this in a model in which pregnant mice receive human IgG containing aPL Ab’s. Here we identify complement component C5 (and particularly its cleavage product C5a) and neutrophils as key mediators of fetal injury, and we show that Ab’s or peptides that block C5a–C5a receptor interactions prevent pregnancy complications. The fact that F(ab)′2 fragments of aPL Ab’s do not mediate fetal injury and that C4-deficient mice are protected from fetal injury suggests that activation of the complement cascade is initiated via the classical pathway. Studies in factor B–deficient mice, however, indicate that alternative pathway activation is required and amplifies complement activation. In contrast, activating FcγRs do not play an important role in mediating aPL Ab–induced fetal injury. Our findings identify the key innate immune effectors engaged by pathogenic autoantibodies that mediate poor pregnancy outcomes in APS and provide novel and important targets for prevention of pregnancy loss in APS.

The antiphospholipid syndrome (APS) is characterized by recurrent fetal loss, vascular thrombosis, and thrombocytopenia occurring in the presence of antiphospholipid (aPL) antibodies. The pathogenesis of fetal loss and tissue injury in APS is incompletely understood, but is thought to involve platelet and endothelial cell activation as well as procoagulant effects of aPL antibodies acting directly on clotting pathway components. Recent studies have shown that uncontrolled complement activation in the placenta leads to fetal death in utero. We hypothesized that aPL antibodies activate complement in the placenta, generating split products that mediate placental injury and lead to fetal loss and growth retardation. To test this hypothesis, we used a murine model of APS in which pregnant mice are injected with human IgG containing aPL antibodies. We found that inhibition of the complement cascade in vivo, using the C3 convertase inhibitor complement receptor 1–related gene/protein y (Crry)-Ig, blocks fetal loss and growth retardation. Furthermore, mice deficient in complement C3 were resistant to fetal injury induced by aPL antibodies. While antigenic epitopes recognized by aPL antibodies are important in the pathogenesis of APS, our data show that in vivo complement activation is required for aPL antibody-induced fetal loss and growth retardation.

Immune mechanisms have been implicated in placental dysfunction in patients with recurrent miscarriages and intrauterine growth restriction (IUGR), but the mediators are undefined. Here we show that complement activation, particularly C5a, is a required intermediary event in the pathogenesis of placental and fetal injury in an antibody-independent mouse model of spontaneous miscarriage and IUGR, and that complement activation causes dysregulation of the angiogenic factors required for normal placental development. Pregnancies complicated by miscarriage or growth restriction were characterized by inflammatory infiltrates in placentas, functional deficiency of free vascular endothelial growth factor (VEGF), elevated levels of soluble VEGF receptor 1 (sVEGFR-1, also known as sFlt-1; a potent anti-angiogenic molecule), and defective placental development. Inhibition of complement activation in vivo blocked the increase in sVEGFR-1 and rescued pregnancies. In vitro stimulation of monocytes with products of the complement cascade directly triggered release of sVEGFR-1, which sequesters VEGF. These studies provide the first evidence linking the complement system to angiogenic factor imbalance associated with placental dysfunction, and identify a new effector of immune-triggered pregnancy complications.

Objective: To investigate which serologic and clinical findings predict adverse pregnancy outcome in patients with antiphospholipid antibody (aPL) and to test the hypothesis that a pattern of clinical and serologic variables can identify women at highest risk of adverse pregnancy outcome.Methods: Women enrolled in a multicenter prospective observational study of risk factors for adverse pregnancy outcome in patients with aPL (lupus anticoagulant [LAC], anticardiolipin antibody [aCL], and/or antibody to β₂‐glycoprotein I [anti‐β₂GPI]) and/or systemic lupus erythematosus (SLE) were recruited for the present prospective study. Demographic, clinical, serologic, and treatment data were recorded at the time of the first study visit. The relationship between individual and combined variables and adverse pregnancy outcome was assessed by bivariate and multivariate analysis.Results: Between 2003 and 2011 we enrolled 144 pregnant patients, of whom 28 had adverse pregnancy outcome. Thirty‐nine percent of the patients with LAC had adverse pregnancy outcome, compared to 3% of those who did not have LAC (P < 0.0001). Among women with IgG aCL at a level of ≥40 units/ml, only 8% of those who were LAC negative had adverse pregnancy outcome, compared to 43% of those who were LAC positive (P = 0.002). IgM aCL, IgG anti‐β₂GPI, and IgM anti‐β₂GPI did not predict adverse pregnancy outcome. In bivariate analysis, adverse pregnancy outcome occurred in 52% of patients with and 13% of patients without prior thrombosis (P = 0.00005), and in 23% with SLE versus 17% without SLE (not significant); SLE was a predictor in multivariate analysis. Prior pregnancy loss did not predict adverse pregnancy outcome. Simultaneous positivity for aCL, anti‐β₂GPI, and LAC did not predict adverse pregnancy outcome better than did positivity for LAC alone.Conclusion: LAC is the primary predictor of adverse pregnancy outcome after 12 weeks' gestation in aPL‐associated pregnancies. Anticardiolipin antibody and anti‐β₂GPI, if LAC is not also present, do not predict adverse pregnancy outcome.

Objective: To develop an evidence‐based guideline on contraception, assisted reproductive technologies (ART), fertility preservation with gonadotoxic therapy, use of menopausal hormone replacement therapy (HRT), pregnancy assessment and management, and medication use in patients with rheumatic and musculoskeletal disease (RMD).Methods: We conducted a systematic review of evidence relating to contraception, ART, fertility preservation, HRT, pregnancy and lactation, and medication use in RMD populations, using Grading of Recommendations Assessment, Development and Evaluation methodology to rate the quality of evidence and a group consensus process to determine final recommendations and grade their strength (conditional or strong). Good practice statements were agreed upon when indirect evidence was sufficiently compelling that a formal vote was unnecessary.Results: This American College of Rheumatology guideline provides 12 ungraded good practice statements and 131 graded recommendations for reproductive health care in RMD patients. These recommendations are intended to guide care for all patients with RMD, except where indicated as being specific for patients with systemic lupus erythematosus, those positive for antiphospholipid antibody, and/or those positive for anti‐Ro/SSA and/or anti‐La/SSB antibodies. Recommendations and good practice statements support several guiding principles: use of safe and effective contraception to prevent unplanned pregnancy, pre‐pregnancy counseling to encourage conception during periods of disease quiescence and while receiving pregnancy‐compatible medications, and ongoing physician‐patient discussion with obstetrics/gynecology collaboration for all reproductive health issues, given the overall low level of available evidence that relates specifically to RMD.Conclusion: This guideline provides evidence‐based recommendations developed and reviewed by panels of experts and RMD patients. Many recommendations are conditional, reflecting a lack of data or low‐level data. We intend that this guideline be used to inform a shared decision‐making process between patients and their physicians on issues related to reproductive health that incorporates patients’ values, preferences, and comorbidities.