Systemic lupus erythematosus (SLE) is an autoantibody-mediated systemic autoimmune disease, predominantly affecting young females. Pregnancy is increasingly common in the setting of SLE, as survival and quality of life of patients improve. Although live births can be achieved in the most cases, pregnancy in patients with SLE remains a high-risk condition. Maternal and fetal mortality and morbidity are considerably increased, compared with the general population. Aberrations in pregnancy-related maternal immune adaptations are likely contributors. Active maternal disease, renal involvement, specific autoantibody subsets and advanced organ damage are predictors of poor outcome. Therapeutic options are limited during pregnancy as maternal benefit has to be weighed against fetal risk. Prevention of preterm birth and refractory pregnancy loss, as well as management of established neonatal heart block remain unmet needs. Further research should address these important issues that affect young patients with SLE and their babies.
Pregnancy in the setting of systemic lupus erythematosus (SLE) is increasingly common
Physiological immune adaptations of pregnancy are altered in women with SLE
Successful pregnancies are possible in most young women with SLE, but active disease at conception is associated with poor outcomes
Preconception assessment is necessary to risk-stratify patients
Disease flares, pre-eclampsia, fetal loss, prematurity, intra-uterine growth restriction and neonatal lupus syndromes remain the main issues
Treatment of neonatal heart block and refractory pregnancy loss, in the presence of antiphospholipid antibodies, remain far from optimal
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Chakravarty, E. F., Nelson, L. & Krishnan, E. Obstetric hospitalizations in the United States for women with systemic lupus erythematosus and rheumatoid arthritis. Arthritis Rheum. 54, 899–907 (2006).
Vinet, E. et al. Decreased live births in women with systemic lupus erythematosus. Arthritis Care Res. (Hoboken) 63, 1068–1072 (2011).
Clowse, M. E., Chakravarty, E., Costenbader, K. H., Chambers, C. & Michaud, K. Effects of infertility, pregnancy loss, and patient concerns on family size of women with rheumatoid arthritis and systemic lupus erythematosus. Arthritis Care Res. (Hoboken) 64, 668–674 (2012).
Hunt, J. S. Stranger in a strange land. Immunol. Rev. 213, 36–47 (2006).
Doria, A. et al. Effect of pregnancy on serum cytokines in SLE patients. Arthritis Res. Ther. 14, R66 (2012).
Torricelli, M. et al. High levels of maternal serum IL-17 and activin A in pregnant women affected by systemic lupus erythematosus. Am. J. Reprod. Immunol. 66, 84–89 (2011).
Doria, A. et al. Steroid hormones and disease activity during pregnancy in systemic lupus erythematosus. Arthritis Rheum. 47, 202–209 (2002).
Verthelyi, D., Petri, M., Ylamus, M. & Klinman, D. M. Disassociation of sex hormone levels and cytokine production in SLE patients. Lupus 10, 352–358 (2001).
Tower, C., Crocker, I., Chirico, D., Baker, P. & Bruce, I. SLE and pregnancy: the potential role for regulatory T cells. Nat. Rev. Rheumatol. 7, 124–128 (2011).
Salmon, J. E. & Girardi, G. Antiphospholipid antibodies and pregnancy loss: a disorder of inflammation. J. Reprod. Immunol. 77, 51–56 (2008).
Cohen, D. et al. Classical complement activation as a footprint for murine and human antiphospholipid antibody-induced fetal loss. J. Pathol. 225, 502–511 (2011).
Carvalheiras, G. et al. Pregnancy and systemic lupus erythematosus: review of clinical features and outcome of 51 pregnancies at a single institution. Clin. Rev. Allergy Immunol. 38, 302–306 (2010).
Cortes-Hernandez, J. et al. Clinical predictors of fetal and maternal outcome in systemic lupus erythematosus: a prospective study of 103 pregnancies. Rheumatology (Oxford) 41, 643–650 (2002).
Petri, M. Prospective study of systemic lupus erythematosus pregnancies. Lupus 13, 688–689 (2004).
Petri, M., Howard, D. & Repke, J. Frequency of lupus flare in pregnancy. The Hopkins Lupus Pregnancy Center experience. Arthritis Rheum. 34, 1538–1545 (1991).
Ruiz-Irastorza, G. et al. Increased rate of lupus flare during pregnancy and the puerperium: a prospective study of 78 pregnancies. Br. J. Rheumatol. 35, 133–138 (1996).
Smyth, A. et al. A systematic review and meta-analysis of pregnancy outcomes in patients with systemic lupus erythematosus and lupus nephritis. Clin. J. Am. Soc. Nephrol. 5, 2060–2068 (2010).
Buyon, J. P. et al. Assessing disease activity in SLE patients during pregnancy. Lupus 8, 677–684 (1999).
Ruiz-Irastorza, G. et al. Measuring systemic lupus erythematosus activity during pregnancy: validation of the lupus activity index in pregnancy scale. Arthritis Rheum. 51, 78–82 (2004).
Imbasciati, E. et al. Pregnancy in women with pre-existing lupus nephritis: predictors of fetal and maternal outcome. Nephrol. Dial. Transplant. 24, 519–525 (2009).
Gladman, D. D., Tandon, A., Ibanez, D. & Urowitz, M. B. The effect of lupus nephritis on pregnancy outcome and fetal and maternal complications. J. Rheumatol. 37, 754–758 (2010).
Saavedra, M. A. et al. Impact of previous lupus nephritis on maternal and fetal outcomes during pregnancy. Clin. Rheumatol. 31, 813–819 (2012).
Petri, M. Hopkins Lupus Pregnancy Center: to 1996. Rheum. Dis. Clin. North Am. 23, 1–13 (1997).
Clowse, M. E., Jamison, M., Myers, E. & James, A. H. A national study of the complications of lupus in pregnancy. Am. J. Obstet. Gynecol. 199, 127 e1–e6 (2008).
Bramham, K. et al. Pregnancy outcomes in systemic lupus erythematosus with and without previous nephritis. J. Rheumatol. 38, 1906–1913 (2011).
Chakravarty, E. F. et al. Factors that predict prematurity and preeclampsia in pregnancies that are complicated by systemic lupus erythematosus. Am. J. Obstet. Gynecol. 192, 1897–1904 (2005).
Kwok, L. W., Tam, L. S., Zhu, T., Leung, Y. Y. & Li, E. Predictors of maternal and fetal outcomes in pregnancies of patients with systemic lupus erythematosus. Lupus 20, 829–836 (2011).
Lateef, A., Magder, L. & Petri, M. Decrease in complement (C3) levels during systemic lupus erythematosus pregnancy is associated with higher rates of pre-eclampsia. Arthritis Rheum. 62 (Suppl. 10), S193 (2010).
Verghese, L. et al. Antenatal screening for pre-eclampsia: evaluation of the NICE and pre-eclampsia community guidelines. J. Obstet. Gynaecol. 32, 128–131 (2012).
Le Thi Huong, D. et al. The second trimester Doppler ultrasound examination is the best predictor of late pregnancy outcome in systemic lupus erythematosus and/or the antiphospholipid syndrome. Rheumatology (Oxford) 45, 332–338 (2006).
Cnossen, J. S. et al. Use of uterine artery Doppler ultrasonography to predict pre-eclampsia and intrauterine growth restriction: a systematic review and bivariable meta-analysis. CMAJ 178, 701–711 (2008).
Kleinrouweler, C. et al. Accuracy of circulating placental growth factor, vascular endothelial growth factor, soluble fms-like tyrosine kinase 1 and soluble endoglin in the prediction of pre-eclampsia: a systematic review and meta-analysis. BJOG 119, 778–787 (2012).
Qazi, U., Lam, C., Karumanchi, S. A. & Petri, M. Soluble Fms-like tyrosine kinase associated with preeclampsia in pregnancy in systemic lupus erythematosus. J. Rheumatol. 35, 631–634 (2008).
Clark, C. A., Spitzer, K. A. & Laskin, C. A. Decrease in pregnancy loss rates in patients with systemic lupus erythematosus over a 40-year period. J. Rheumatol. 32, 1709–1712 (2005).
Clowse, M. E., Magder, L. S., Witter, F. & Petri, M. The impact of increased lupus activity on obstetric outcomes. Arthritis Rheum. 52, 514–521 (2005).
Clowse, M. E., Magder, L. S. & Petri, M. The clinical utility of measuring complement and anti-dsDNA antibodies during pregnancy in patients with systemic lupus erythematosus. J. Rheumatol. 38, 1012–1016 (2011).
Wagner, S. J. et al. Maternal and foetal outcomes in pregnant patients with active lupus nephritis. Lupus 18, 342–347 (2009).
Clowse, M. E., Magder, L. S., Witter, F. & Petri, M. Early risk factors for pregnancy loss in lupus. Obstet. Gynecol. 107, 293–299 (2006).
Lockshin, M. D. et al. Lupus anticoagulant, but not anticardiolipin antibody, predicts adverse pregnancy outcome in patients with antiphospholipid antibodies. Arthritis Rheum. 64, 2311–2318 (2012).
Stagnaro-Green, A. et al. Thyroid disease in pregnant women with systemic lupus erythematosus: increased preterm delivery. Lupus 20, 690–699 (2011).
Petri, M. The Hopkins Lupus Pregnancy Center: ten key issues in management. Rheum. Dis. Clin. North Am. 33, 227–235 (2007).
Yasmeen, S., Wilkins, E. E., Field, N. T., Sheikh, R. A. & Gilbert, W. M. Pregnancy outcomes in women with systemic lupus erythematosus. J. Matern. Fetal Med. 10, 91–96 (2001).
Lee, L. A. & Weston, W. L. Cutaneous lupus erythematosus during the neonatal and childhood periods. Lupus 6, 132–138 (1997).
Silverman, E. & Jaeggi, E. Non-cardiac manifestations of neonatal lupus erythematosus. Scand. J. Immunol. 72, 223–225 (2010).
Neiman, A. R., Lee, L. A., Weston, W. L. & Buyon, J. P. Cutaneous manifestations of neonatal lupus without heart block: characteristics of mothers and children enrolled in a national registry. J. Pediatr. 137, 674–680 (2000).
Brucato, A. et al. Pregnancy outcome in 100 women with autoimmune diseases and anti-Ro/SSA antibodies: a prospective controlled study. Lupus 11, 716–721 (2002).
Izmirly, P. M. et al. Cutaneous manifestations of neonatal lupus and risk of subsequent congenital heart block. Arthritis Rheum. 62, 1153–1157 (2010).
Llanos, C. et al. Recurrence rates of cardiac manifestations associated with neonatal lupus and maternal/fetal risk factors. Arthritis Rheum. 60, 3091–3097 (2009).
Spence, D., Hornberger, L., Hamilton, R. & Silverman, E. D. Increased risk of complete congenital heart block in infants born to women with hypothyroidism and anti-Ro and/or anti-La antibodies. J. Rheumatol. 33, 167–170 (2006).
Hornberger, L. K. & Al Rajaa, N. Spectrum of cardiac involvement in neonatal lupus. Scand. J. Immunol. 72, 189–197 (2010).
Jaeggi, E., Laskin, C., Hamilton, R., Kingdom, J. & Silverman, E. The importance of the level of maternal anti-Ro/SSA antibodies as a prognostic marker of the development of cardiac neonatal lupus erythematosus a prospective study of 186 antibody-exposed fetuses and infants. J. Am. Coll. Cardiol. 55, 2778–2784 (2010).
Salomonsson, S. et al. Ro/SSA autoantibodies directly bind cardiomyocytes, disturb calcium homeostasis, and mediate congenital heart block. J. Exp. Med. 201, 11–17 (2005).
Buyon, J. P., Clancy, R. M. & Friedman, D. M. Cardiac manifestations of neonatal lupus erythematosus: guidelines to management, integrating clues from the bench and bedside. Nat. Clin. Pract. Rheumatol. 5, 139–148 (2009).
Hutter, D., Silverman, E. D. & Jaeggi, E. T. The benefits of transplacental treatment of isolated congenital complete heart block associated with maternal anti-Ro/SSA antibodies: a review. Scand. J. Immunol. 72, 235–241 (2010).
Rein, A. J. et al. Early diagnosis and treatment of atrioventricular block in the fetus exposed to maternal anti-SSA/Ro-SSB/La antibodies: a prospective, observational, fetal kinetocardiogram-based study. Circulation 119, 1867–1872 (2009).
Friedman, D. M. et al. Utility of cardiac monitoring in fetuses at risk for congenital heart block: the PR Interval and Dexamethasone Evaluation (PRIDE) prospective study. Circulation 117, 485–493 (2008).
Mevorach, D., Elchalal, U. & Rein, A. J. Prevention of complete heart block in children of mothers with anti-SSA/Ro and anti-SSB/La autoantibodies: detection and treatment of first-degree atrioventricular block. Curr. Opin. Rheumatol. 21, 478–482 (2009).
Sonesson, S. E. Diagnosing foetal atrioventricular heart blocks. Scand. J. Immunol. 72, 205–212 (2010).
Chia, E. L., Ho, T. F., Rauff, M. & Yip, W. C. Cardiac time intervals of normal fetuses using noninvasive fetal electrocardiography. Prenat. Diagn. 25, 546–552 (2005).
Yazdany, J. et al. Contraceptive counseling and use among women with systemic lupus erythematosus: a gap in health care quality? Arthritis Care Res. (Hoboken) 63, 358–365 (2011).
Petri, M. et al. Combined oral contraceptives in women with systemic lupus erythematosus. N. Engl. J. Med. 353, 2550–2558 (2005).
Sanchez-Guerrero, J. et al. A trial of contraceptive methods in women with systemic lupus erythematosus. N. Engl. J. Med. 353, 2539–2549 (2005).
Shaarawy, M., El-Mallah, S. Y., Seoudi, S., Hassan, M. & Mohsen, I. A. Effects of the long-term use of depot medroxyprogesterone acetate as hormonal contraceptive on bone mineral density and biochemical markers of bone remodeling. Contraception 74, 297–302 (2006).
Saleeb, S., Copel, J., Friedman, D. & Buyon, J. P. Comparison of treatment with fluorinated glucocorticoids to the natural history of autoantibody-associated congenital heart block: retrospective review of the research registry for neonatal lupus. Arthritis Rheum. 42, 2335–2345 (1999).
Friedman, D. M. et al. Prospective evaluation of fetuses with autoimmune-associated congenital heart block followed in the PR Interval and Dexamethasone Evaluation (PRIDE) Study. Am. J. Cardiol. 103, 1102–1106 (2009).
Breur, J. M., Visser, G. H., Kruize, A. A., Stoutenbeek, P. & Meijboom, E. J. Treatment of fetal heart block with maternal steroid therapy: case report and review of the literature. Ultrasound Obstet. Gynecol. 24, 467–472 (2004).
Jaeggi, E. T. et al. Transplacental fetal treatment improves the outcome of prenatally diagnosed complete atrioventricular block without structural heart disease. Circulation 110, 1542–1548 (2004).
Kaaja, R. & Julkunen, H. Prevention of recurrence of congenital heart block with intravenous immunoglobulin and corticosteroid therapy: comment on the editorial by Buyon et al. Arthritis Rheum. 48, 280–281 (2003).
Friedman, D. M. et al. Evaluation of fetuses in a study of intravenous immunoglobulin as preventive therapy for congenital heart block: results of a multicenter, prospective, open-label clinical trial. Arthritis Rheum. 62, 1138–1146 (2010).
Pisoni, C. N. et al. Failure of intravenous immunoglobulin to prevent congenital heart block: findings of a multicenter, prospective, observational study. Arthritis Rheum. 62, 1147–1152 (2010).
Routsias, J. G. et al. Association of the idiotype:antiidiotype antibody ratio with the efficacy of intravenous immunoglobulin treatment for the prevention of recurrent autoimmune-associated congenital heart block. Arthritis Rheum. 63, 2783–2789 (2011).
Izmirly, P. M. et al. Evaluation of the risk of anti-SSA/Ro-SSB/La antibody-associated cardiac manifestations of neonatal lupus in fetuses of mothers with systemic lupus erythematosus exposed to hydroxychloroquine. Ann. Rheum. Dis. 69, 1827–1830 (2010).
Miyakis, S. et al. International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS). J. Thromb. Haemost. 4, 295–306 (2006).
Girardi, G. Role of tissue factor in the maternal immunological attack of the embryo in the antiphospholipid syndrome. Clin. Rev. Allergy Immunol. 39, 160–165 (2010).
Meroni, P. L. et al. Anti-phospholipid antibody mediated fetal loss: still an open question from a pathogenic point of view. Lupus 19, 453–456 (2010).
Di Simone, N. et al. Pathogenic role of anti-beta2-glycoprotein I antibodies on human placenta: functional effects related to implantation and roles of heparin. Hum. Reprod. Update 13, 189–196 (2007).
Girardi, G., Redecha, P. & Salmon, J. E. Heparin prevents antiphospholipid antibody-induced fetal loss by inhibiting complement activation. Nat. Med. 10, 1222–1226 (2004).
Salmon, J. E. et al. Mutations in complement regulatory proteins predispose to preeclampsia: a genetic analysis of the PROMISSE cohort. PLoS Med. 8, e1001013 (2011).
Cervera, R. et al. Morbidity and mortality in the antiphospholipid syndrome during a 5-year period: a multicentre prospective study of patients. Ann. Rheum. Dis. 68, 1428–1432 (2009).
Yasuda, M., Takakuwa, K., Tokunaga, A. & Tanaka, K. Prospective studies of the association between anticardiolipin antibody and outcome of pregnancy. Obstet. Gynecol. 86, 555–559 (1995).
Petri, M. & Qazi, U. Management of antiphospholipid syndrome in pregnancy. Rheum. Dis. Clin. North Am. 32, 591–607 (2006).
Empson, M., Lassere, M., Craig, J. & Scott, J. Prevention of recurrent miscarriage for women with antiphospholipid antibody or lupus anticoagulant. Cochrane Database of Systematic Reviews, Issue 2. Art. No.: CD002859 http://dx.doi.org/10.1002/14651858.CD002859.pub2.
Mak, A., Cheung, M. W., Cheak, A. A. & Ho, R. C. Combination of heparin and aspirin is superior to aspirin alone in enhancing live births in patients with recurrent pregnancy loss and positive anti-phospholipid antibodies: a meta-analysis of randomized controlled trials and meta-regression. Rheumatology (Oxford) 49, 281–288 (2010).
Sephton, V. et al. A longitudinal study of maternal dose response to low molecular weight heparin in pregnancy. Obstet. Gynecol. 101, 1307–1311 (2003).
Bates, S. M. et al. Venous thromboembolism, thrombophilia, antithrombotic therapy, and pregnancy: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest 133 (Suppl. 6) 844S–886S (2008).
Cowchock, F. S., Reece, E. A., Balaban, D., Branch, D. W. & Plouffe, L. Repeated fetal losses associated with antiphospholipid antibodies: a collaborative randomized trial comparing prednisone with low-dose heparin treatment. Am. J. Obstet. Gynecol. 166, 1318–1323 (1992).
Dendrinos, S., Sakkas, E. & Makrakis, E. Low-molecular-weight heparin versus intravenous immunoglobulin for recurrent abortion associated with antiphospholipid antibody syndrome. Int. J. Gynaecol. Obstet. 104, 223–225 (2009).
Triolo, G. et al. Randomized study of subcutaneous low molecular weight heparin plus aspirin versus intravenous immunoglobulin in the treatment of recurrent fetal loss associated with antiphospholipid antibodies. Arthritis Rheum. 48, 728–731 (2003).
Branch, D. W. et al. A multicenter, placebo-controlled pilot study of intravenous immune globulin treatment of antiphospholipid syndrome during pregnancy. The Pregnancy Loss Study Group. Am. J. Obstet. Gynecol. 182, 122–127 (2000).
El-Haieg, D. O., Zanati, M. F. & El-Foual, F. M. Plasmapheresis and pregnancy outcome in patients with antiphospholipid syndrome. Int. J. Gynaecol. Obstet. 99, 236–241 (2007).
Abadi, S., Einarson, A. & Koren, G. Use of warfarin during pregnancy. Can. Fam. Physician 48, 695–697 (2002).
Østensen, M. et al. Anti-inflammatory and immunosuppressive drugs and reproduction. Arthritis Res. Ther. 8, 209 (2006).
Clowse, M. E., Magder, L., Witter, F. & Petri, M. Hydroxychloroquine in lupus pregnancy. Arthritis Rheum. 54, 3640–3647 (2006).
Levy, R. A. et al. Hydroxychloroquine (HCQ) in lupus pregnancy: double-blind and placebo-controlled study. Lupus 10, 401–404 (2001).
Sperber, K., Hom, C., Chao, C. P., Shapiro, D. & Ash, J. Systematic review of hydroxychloroquine use in pregnant patients with autoimmune diseases. Pediatr. Rheumatol. Online J. 7, 9 (2009).
Cassina, M. et al. Pregnancy outcome in women exposed to leflunomide before or during pregnancy. Arthritis Rheum. 64, 2085–2094 (2012).
Chambers, C. D. et al. Birth outcomes in women who have taken leflunomide during pregnancy. Arthritis Rheum. 62, 1494–1503 (2010).
Østensen, M. et al. Update on safety during pregnancy of biological agents and some immunosuppressive anti-rheumatic drugs. Rheumatology (Oxford) 47 (Suppl. 3), iii28–iii31 (2008).
Nielsen, G. L., Sorensen, H. T., Larsen, H. & Pedersen, L. Risk of adverse birth outcome and miscarriage in pregnant users of non-steroidal anti-inflammatory drugs: population based observational study and case–control study. BMJ 322, 266–270 (2001).
Koren, G., Florescu, A., Costei, A. M., Boskovic, R. & Moretti, M. E. Nonsteroidal antiinflammatory drugs during third trimester and the risk of premature closure of the ductus arteriosus: a meta-analysis. Ann. Pharmacother. 40, 824–829 (2006).
Al-Aqeedi, R. F. & Al-Nabti, A. D. Drug-eluting stent implantation for acute myocardial infarction during pregnancy with use of glycoprotein IIb/IIIa inhibitor, aspirin and clopidogrel. J. Invasive Cardiol. 20, E146–E149 (2008).
Kuczkowski, K. M. Clopidogrel and pregnancy: a situation pregnant with danger? Arch. Gynecol. Obstet. 280, 693–694 (2009).
Bell, A. D. et al. The use of antiplatelet therapy in the outpatient setting: Canadian Cardiovascular Society guidelines. Can. J. Cardiol. 27 (Suppl. A), S1–S59 (2011).
Cooper, W. O. et al. Major congenital malformations after first-trimester exposure to ACE inhibitors. N. Engl. J. Med. 354, 2443–2451 (2006).
Tabacova, S., Little, R., Tsong, Y., Vega, A. & Kimmel, C. A. Adverse pregnancy outcomes associated with maternal enalapril antihypertensive treatment. Pharmacoepidemiol. Drug Saf. 12, 633–646 (2003).
Lindheimer, M. D., Taler, S. J., Cunningham, F. G. & American Society of Hypertension. ASH position paper: hypertension in pregnancy. J. Clin. Hypertens. (Greenwich) 11, 214–225 (2009).
Frishman, W. H. Beta-adrenergic receptor blockers. Adverse effects and drug interactions. Hypertension 11, II21–II29 (1988).
Al-Balas, M., Bozzo, P. & Einarson, A. Use of diuretics during pregnancy. Can. Fam. Physician 55, 44–45 (2009).
Stathopoulos, I. P. et al. The use of bisphosphonates in women prior to or during pregnancy and lactation. Hormones (Athens) 10, 280–291 (2011).
The authors declare no competing financial interests.
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Lateef, A., Petri, M. Management of pregnancy in systemic lupus erythematosus. Nat Rev Rheumatol 8, 710–718 (2012). https://doi.org/10.1038/nrrheum.2012.133
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