Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Stratifying management of rheumatic disease for pregnancy and breastfeeding

Abstract

The management of inflammatory rheumatic diseases during pregnancy and breastfeeding has undergone considerable change in the past few years. Modern therapeutics, including biologic and targeted synthetic DMARDs, have enabled substantial improvements in the control of rheumatic diseases, resulting in more patients with severe disease considering pregnancy. Therefore, management of disease for these patients needs to be discussed with clinicians before, during and after pregnancy and patients need to know what complications they might experience before they become pregnant. This Review summarizes the effects pregnancy has on various rheumatic diseases and the effects these diseases have on pregnancy, as well as providing advice regarding the alteration and monitoring of therapy before, during and after pregnancy.

Key points

  • Various inflammatory rheumatic diseases carry an increased burden of adverse pregnancy outcomes.

  • Pregnancy can exacerbate some but not all inflammatory rheumatic diseases.

  • Pre-pregnancy counselling is required to evaluate and reduce risks of adverse pregnancy outcomes for each patient.

  • Some therapies must be altered before, during and/or after pregnancy.

  • Careful monitoring is required throughout pregnancy by a multidisciplinary team.

  • Vigilance for disease flare is required post-partum.

This is a preview of subscription content, access via your institution

Access options

Buy this article

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Transplacental transfer of IgG antibodies from maternal blood into the fetal circulation.
Fig. 2: Treat-to-target strategy for management of inflammatory rheumatic diseases in pregnancy.
Fig. 3: Optimization of management of inflammatory rheumatic diseases in pregnancy.

Similar content being viewed by others

References

  1. Symmons, D. et al. The prevalence of rheumatoid arthritis in the United Kingdom: new estimates for a new century. Rheumatology 41, 793–800 (2002).

    CAS  PubMed  Google Scholar 

  2. Rees, F. et al. The incidence and prevalence of systemic lupus erythematosus in the UK, 1999–2012. Ann. Rheum. Dis. 75, 136–141 (2016).

    PubMed  Google Scholar 

  3. Ogdie, A. et al. Prevalence and treatment patterns of psoriatic arthritis in the UK. Rheumatology 52, 568–575 (2013).

    PubMed  Google Scholar 

  4. Haroon, N. N., Paterson, J. M., Li, P. & Haroon, N. Increasing proportion of female patients with ankylosing spondylitis: a population-based study of trends in the incidence and prevalence of AS. BMJ Open 4, e006634 (2014).

    PubMed  PubMed Central  Google Scholar 

  5. Royle, J. G., Lanyon, P. C., Grainge, M. J., Abhishek, A. & Pearce, F. A. The incidence, prevalence, and survival of systemic sclerosis in the UK Clinical Practice Research Datalink. Clin. Rheumatol. 37, 2103–2111 (2018).

    PubMed  PubMed Central  Google Scholar 

  6. Ostensen, M. et al. State of the art: reproduction and pregnancy in rheumatic diseases. Autoimmun. Rev. 14, 376–386 (2015).

    PubMed  Google Scholar 

  7. Flint, J. et al. BSR and BHPR guideline on prescribing drugs in pregnancy and breastfeeding— part I: standard and biologic disease modifying anti-rheumatic drugs and corticosteroids. Rheumatology 55, 1693–1697 (2016).

    CAS  PubMed  Google Scholar 

  8. Flint, J. et al. BSR and BHPR guideline on prescribing drugs in pregnancy and breastfeeding— part II: analgesics and other drugs used in rheumatology practice. Rheumatology 55, 1698–1702 (2016).

    PubMed  Google Scholar 

  9. Gotestam Skorpen, C. et al. The EULAR points to consider for use of antirheumatic drugs before pregnancy, and during pregnancy and lactation. Ann. Rheum. Dis. 75, 795–810 (2016).

    PubMed  Google Scholar 

  10. de Man, Y. A. et al. Association of higher rheumatoid arthritis disease activity during pregnancy with lower birth weight: results of a national prospective study. Arthritis Rheum. 60, 3196–3206 (2009).

    PubMed  Google Scholar 

  11. Clowse, M. E. B., Magder, L. S., Witter, F. & Petri, M. The impact of increased lupus activity on obstetric outcomes. Arthritis Rheum. 52, 514–521 (2005).

    PubMed  Google Scholar 

  12. Ko, H. S. et al. Pregnancy outcomes and appropriate timing of pregnancy in 183 pregnancies in Korean patients with SLE. Int. J. Med. Sci. 8, 577–583 (2011).

    PubMed  PubMed Central  Google Scholar 

  13. Urowitz, M. B., Gladman, D. D., Farewell, V. T., Stewart, J. & Mcdonald, J. Lupus and pregnancy studies. Arthritis Rheum. 36, 1392–1397 (1993).

    CAS  PubMed  Google Scholar 

  14. 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).

    PubMed  Google Scholar 

  15. Cortes-Hernandez, J. et al. Clinical predictors of fetal and maternal outcome in systemic lupus erythematosus: a prospective study of 103 pregnancies. Rheumatology 41, 643–650 (2002).

    CAS  PubMed  Google Scholar 

  16. Clowse, M. E. B., Magder, L., Witter, F. & Petri, M. Hydroxychloroquine in lupus pregnancy. Arthritis Rheum. 54, 3640–3647 (2006).

    PubMed  Google Scholar 

  17. Andreoli, L. et al. EULAR recommendations for women’s health and the management of family planning, assisted reproduction, pregnancy and menopause in patients with systemic lupus erythematosus and/or antiphospholipid syndrome. Ann. Rheum. Dis. 76, 476–485 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. 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. 64, 668–674 (2012).

    Google Scholar 

  19. Helland, Y., Dagfinrud, H. & Kvien, T. K. Perceived influence of health status on sexual activity in RA patients: associations with demographic and disease-related variables. Scand. J. Rheumatol. 37, 194–199 (2008).

    CAS  PubMed  Google Scholar 

  20. Schmidt, R. J. & Holley, J. L. Fertility and contraception in end-stage renal disease. Adv. Ren. Replace Ther. 5, 38–44 (1998).

    CAS  PubMed  Google Scholar 

  21. Morel, N. et al. Study of anti-Mullerian hormone and its relation to the subsequent probability of pregnancy in 112 patients with systemic lupus erythematosus, exposed or not to cyclophosphamide. J. Clin. Endocrinol. Metab. 98, 3785–3792 (2013).

    CAS  PubMed  Google Scholar 

  22. Khnaba, D. et al. Sexual dysfunction and its determinants in Moroccan women with rheumatoid arthritis. Pan Afr. Med. J. 24, 16 (2016).

    PubMed  PubMed Central  Google Scholar 

  23. Hansen, K. R. et al. A new model of reproductive aging: the decline in ovarian non-growing follicle number from birth to menopause. Hum. Reprod. 23, 699–708 (2008).

    PubMed  Google Scholar 

  24. Ostensen, M. Sexual and reproductive health in rheumatic disease. Nat. Rev. Rheumatol. 13, 485–493 (2017).

    PubMed  Google Scholar 

  25. Martinez, F. Update on fertility preservation from the Barcelona International Society for Fertility Preservation-ESHRE-ASRM 2015 expert meeting: indications, results and future perspectives. Hum. Reprod. 32, 1802–1811 (2017).

    PubMed  PubMed Central  Google Scholar 

  26. 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).

    PubMed  Google Scholar 

  27. Lin, H. C., Chen, S. F., Lin, H. C. & Chen, Y. H. Increased risk of adverse pregnancy outcomes in women with rheumatoid arthritis: a nationwide population-based study. Ann. Rheum. Dis. 69, 715–717 (2010).

    PubMed  Google Scholar 

  28. Skomsvoll, J. F., Ostensen, M., Irgens, L. M. & Baste, V. Obstetrical and neonatal outcome in pregnant patients with rheumatic disease. Scand. J. Rheumatol. Suppl. 107, 109–112 (1998).

    CAS  PubMed  Google Scholar 

  29. Wolfberg, A. J., Lee-Parritz, A., Peller, A. J. & Lieberman, E. S. Association of rheumatologic disease with preeclampsia. Obstet. Gynecol. 103, 1190–1193 (2004).

    PubMed  Google Scholar 

  30. Reed, S. D., Vollan, T. A. & Svec, M. A. Pregnancy outcomes in women with rheumatoid arthritis in Washington State. Matern. Child Health J. 10, 361–366 (2006).

    PubMed  Google Scholar 

  31. Zbinden, A., van den Brandt, S., Ostensen, M., Villiger, P. M. & Forger, F. Risk for adverse pregnancy outcome in axial spondyloarthritis and rheumatoid arthritis: disease activity matters. Rheumatology 57, 1235–1242 (2018).

    Google Scholar 

  32. Bowden, A. P., Barrett, J. H., Fallow, W. & Silman, A. J. Women with inflammatory polyarthritis have babies of lower birth weight. J. Rheumatol. 28, 355–359 (2001).

    CAS  PubMed  Google Scholar 

  33. 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, 5 (2008).

    Google Scholar 

  34. Buyon, J. P. et al. Predictors of pregnancy outcomes in patients with lupus: a cohort study. Ann. Intern. Med. 163, 153–163 (2015).

    PubMed  PubMed Central  Google Scholar 

  35. 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).

    PubMed  PubMed Central  Google Scholar 

  36. Arkema, E. V. et al. What to expect when expecting with systemic lupus erythematosus (SLE): a population-based study of maternal and fetal outcomes in SLE and pre-SLE. Arthritis Care Res. 68, 988–994 (2016).

    Google Scholar 

  37. Bundhun, P. K., Soogund, M. Z. & Huang, F. Impact of systemic lupus erythematosus on maternal and fetal outcomes following pregnancy: a meta-analysis of studies published between years 2001–2016. J. Autoimmun. 79, 17–27 (2017).

    PubMed  Google Scholar 

  38. Clowse, M. E. Lupus activity in pregnancy. Rheum. Dis. Clin. North Am. 33, 237–252 (2007).

    PubMed  PubMed Central  Google Scholar 

  39. Bharti, B. et al. Disease severity and pregnancy outcomes in women with rheumatoid arthritis: results from the Organization of Teratology Information Specialists Autoimmune Diseases in Pregnancy Project. J. Rheumatol. 42, 1376–1382 (2015).

    PubMed  Google Scholar 

  40. Polachek, A., Li, S., Polachek, I. S., Chandran, V. & Gladman, D. Psoriatic arthritis disease activity during pregnancy and the first-year postpartum. Semin. Arthritis Rheum. 46, 740–745 (2017).

    PubMed  Google Scholar 

  41. Mouyis, M. A., Thornton, C. C., Williams, D. & Giles, I. P. Pregnancy outcomes in patients with psoriatic arthritis. J. Rheumatol. 44, 128–129 (2017).

    PubMed  Google Scholar 

  42. Gupta, S. & Gupta, N. Sjogren syndrome and pregnancy: a literature review. Perm. J. 21, 16–047 (2017).

    PubMed  PubMed Central  Google Scholar 

  43. Lidar, M. & Langevitz, P. Pregnancy issues in scleroderma. Autoimmun. Rev. 11, A515–A519 (2012).

    PubMed  Google Scholar 

  44. Jethwa, H., Lam, S., Smith, C. & Giles, I. Does rheumatoid arthritis really improve during pregnancy? A systematic review and metaanalysis. J. Rheumatol. 46, 245–250 (2019).

    PubMed  Google Scholar 

  45. de Man, Y. A., Dolhain, R. J., van de Geijn, F. E., Willemsen, S. P. & Hazes, J. M. Disease activity of rheumatoid arthritis during pregnancy: results from a nationwide prospective study. Arthritis Rheum. 59, 1241–1248 (2008).

    PubMed  Google Scholar 

  46. Lockshin, M. D., Reinitz, E., Druzin, M. L., Murrman, M. & Estes, D. Lupus pregnancy. Case-control prospective study demonstrating absence of lupus exacerbation during or after pregnancy. Am. J. Med. 77, 893–898 (1984).

    CAS  PubMed  Google Scholar 

  47. Mintz, G., Niz, J., Gutierrez, G., Garcia-Alonso, A. & Karchmer, S. Prospective study of pregnancy in systemic lupus erythematosus. Results of a multidisciplinary approach. J. Rheumatol. 13, 732–739 (1986).

    CAS  PubMed  Google Scholar 

  48. Wong, K. L., Chan, F. Y. & Lee, C. P. Outcome of pregnancy in patients with systemic lupus erythematosus. A prospective study. Arch. Intern. Med. 151, 269–273 (1991).

    CAS  PubMed  Google Scholar 

  49. Petri, M., Howard, D. & Repke, J. Frequency of lupus flare in pregnancy. The Hopkins Lupus Pregnancy Center experience. Arthritis Rheum. 34, 1538–1545 (1991).

    CAS  PubMed  Google Scholar 

  50. 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).

    CAS  PubMed  Google Scholar 

  51. Teng, Y. K. O. et al. An evidence-based approach to pre-pregnancy counselling for patients with systemic lupus erythematosus. Rheumatology 57, 1707–1720 (2018).

    PubMed  Google Scholar 

  52. Eudy, A. M. et al. Effect of pregnancy on disease flares in patients with systemic lupus erythematosus. Ann. Rheum. Dis. 77, 855–860 (2018).

    PubMed  PubMed Central  Google Scholar 

  53. Ostensen, M. & Husby, G. A prospective clinical study of the effect of pregnancy on rheumatoid arthritis and ankylosing spondylitis. Arthritis Rheum. 26, 1155–1159 (1983).

    CAS  PubMed  Google Scholar 

  54. Ostensen, M. The effect of pregnancy on ankylosing spondylitis, psoriatic arthritis, and juvenile rheumatoid arthritis. Am. J. Reprod. Immunol. 28, 235–237 (1992).

    CAS  PubMed  Google Scholar 

  55. Ostensen, M. Pregnancy in psoriatic arthritis. Scand. J. Rheumatol. 17, 67–70 (1988).

    CAS  PubMed  Google Scholar 

  56. Franceschini, F. & Cavazzana, I. Anti-Ro/SSA and La/SSB antibodies. Autoimmunity 38, 55–63 (2005).

    CAS  PubMed  Google Scholar 

  57. Simister, N. E., Story, C. M., Chen, H. L. & Hunt, J. S. An IgG-transporting Fc receptor expressed in the syncytiotrophoblast of human placenta. Eur. J. Immunol. 26, 1527–1531 (1996).

    CAS  PubMed  Google Scholar 

  58. Costedoat-Chalumeau, N. et al. Outcome of pregnancies in patients with anti-SSA/Ro antibodies: a study of 165 pregnancies, with special focus on electrocardiographic variations in the children and comparison with a control group. Arthritis Rheum. 50, 3187–3194 (2004).

    PubMed  Google Scholar 

  59. Nield, L. E. et al. Endocardial fibroelastosis associated with maternal anti-Ro and anti-La antibodies in the absence of atrioventricular block. J. Am. Coll. Cardiol. 40, 796–802 (2002).

    CAS  PubMed  Google Scholar 

  60. Zuppa, A. A. et al. Neonatal lupus: follow-up in infants with anti-SSA/Ro antibodies and review of the literature. Autoimmun. Rev. 16, 427–432 (2017).

    CAS  PubMed  Google Scholar 

  61. 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).

    CAS  PubMed  Google Scholar 

  62. Cervera, R. et al. Morbidity and mortality in the antiphospholipid syndrome during a 10-year period: a multicentre prospective study of 1000 patients. Ann. Rheum. Dis. 74, 1011–1018 (2015).

    CAS  PubMed  Google Scholar 

  63. Alijotas-Reig, J. et al. The European Registry on Obstetric Antiphospholipid Syndrome (EUROAPS): a survey of 247 consecutive cases. Autoimmun. Rev. 14, 387–395 (2015).

    PubMed  Google Scholar 

  64. Pengo, V. et al. Clinical course of high-risk patients diagnosed with antiphospholipid syndrome. J. Thromb. Haemost. 8, 237–242 (2010).

    CAS  PubMed  Google Scholar 

  65. Ruffatti, A. et al. Antibody profile and clinical course in primary antiphospholipid syndrome with pregnancy morbidity. Thromb. Haemost. 96, 337–341 (2006).

    CAS  PubMed  Google Scholar 

  66. Wahl, D. G. et al. Risk for venous thrombosis related to antiphospholipid antibodies in systemic lupus erythematosus—a meta-analysis. Lupus 6, 467–473 (1997).

    CAS  PubMed  Google Scholar 

  67. Wahl, D. G. et al. Meta-analysis of the risk of venous thrombosis in individuals with antiphospholipid antibodies without underlying autoimmune disease or previous thrombosis. Lupus 7, 15–22 (1998).

    CAS  PubMed  Google Scholar 

  68. Reynaud, Q. et al. Risk of venous and arterial thrombosis according to type of antiphospholipid antibodies in adults without systemic lupus erythematosus: a systematic review and meta-analysis. Autoimmun. Rev. 13, 595–608 (2014).

    CAS  PubMed  Google Scholar 

  69. Alijotas-Reig, J. et al. The European Registry on Obstetric Antiphospholipid Syndrome (EUROAPS): A survey of 1000 consecutive cases. Autoimmun. Rev. 18, 406–414 (2019).

    PubMed  Google Scholar 

  70. Kallur, S. D., Patil Bada, V., Reddy, P., Pandya, S. & Nirmalan, P. K. Organ dysfunction and organ failure as predictors of outcomes of severe maternal morbidity in an obstetric intensive care unit. J. Clin. Diagn. Res. 8, OC06–OC08 (2014).

    PubMed  PubMed Central  Google Scholar 

  71. 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).

    PubMed  Google Scholar 

  72. Bramham, K. et al. Pregnancy outcome in women with chronic kidney disease: a prospective cohort study. Reprod. Sci. 18, 623–630 (2011).

    PubMed  Google Scholar 

  73. Imbasciati, E. et al. Pregnancy in CKD stages 3 to 5: fetal and maternal outcomes. Am. J. Kidney Dis. 49, 753–762 (2007).

    PubMed  Google Scholar 

  74. Nevis, I. F. et al. Pregnancy outcomes in women with chronic kidney disease: a systematic review. Clin. J. Am. Soc. Nephrol. 6, 2587–2598 (2011).

    PubMed  PubMed Central  Google Scholar 

  75. Jones, D. C. & Hayslett, J. P. Outcome of pregnancy in women with moderate or severe renal insufficiency. N. Engl. J. Med. 335, 226–232 (1996).

    CAS  PubMed  Google Scholar 

  76. Kiely, D. G., Condliffe, R., Wilson, V. J., Gandhi, S. V. & Elliot, C. A. Pregnancy and pulmonary hypertension: a practical approach to management. Obstet. Med. 6, 144–154 (2013).

    PubMed  PubMed Central  Google Scholar 

  77. King, T. E. Jr Restrictive lung disease in pregnancy. Clin. Chest Med. 13, 607–622 (1992).

    PubMed  Google Scholar 

  78. Anthony, J. & Sliwa, K. Decompensated heart failure in pregnancy. Card. Fail. Rev. 2, 20–26 (2016).

    PubMed  PubMed Central  Google Scholar 

  79. Handler, J. Managing chronic severe hypertension in pregnancy. J. Clin. Hypertens. 8, 738–743 (2006).

    Google Scholar 

  80. Murphy, V. E. et al. Metabolism of synthetic steroids by the human placenta. Placenta 28, 39–46 (2007).

    CAS  PubMed  Google Scholar 

  81. Hwang, J. L. & Weiss, R. E. Steroid-induced diabetes: a clinical and molecular approach to understanding and treatment. Diabetes Metab. Res. Rev. 30, 96–102 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  82. Smith, C. J. F., Forger, F. & Chambers, C. Predictors for preterm delivery among pregnant women with rheumatoid arthritis and juvenile idiopathic arthritis. Ann. Rheum. Dis. 77, 535 (2018).

    Google Scholar 

  83. Ostensen, M. et al. Anti-inflammatory and immunosuppressive drugs and reproduction. Arthritis Res. Ther. 8, 209 (2006).

    PubMed  PubMed Central  Google Scholar 

  84. Deguchi, M. et al. Factors associated with adverse pregnancy outcomes in women with systematic lupus erythematosus. J. Reprod. Immunol. 125, 39–44 (2018).

    CAS  PubMed  Google Scholar 

  85. Al Arfaj, A. S. & Khalil, N. Pregnancy outcome in 396 pregnancies in patients with SLE in Saudi Arabia. Lupus 19, 1665–1673 (2010).

    CAS  PubMed  Google Scholar 

  86. Clark, C. A., Spitzer, K. A., Nadler, J. N. & Laskin, C. A. Preterm deliveries in women with systemic lupus erythematosus. J. Rheumatol. 30, 2127–2132 (2003).

    PubMed  Google Scholar 

  87. Kemp, M. W., Newnham, J. P., Challis, J. G., Jobe, A. H. & Stock, S. J. The clinical use of corticosteroids in pregnancy. Hum. Reprod. Update 22, 240–259 (2016).

    CAS  PubMed  Google Scholar 

  88. Brucato, A. et al. Normal neuropsychological development in children with congenital complete heart block who may or may not be exposed to high-dose dexamethasone in utero. Ann. Rheum. Dis. 65, 1422–1426 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  89. Kelly, E. N., Sananes, R., Chiu-Man, C., Silverman, E. D. & Jaeggi, E. Prenatal anti-Ro antibody exposure, congenital complete atrioventricular heart block, and high-dose steroid therapy impact on neurocognitive outcome in school-age children. Arthritis Rheumatol. 66, 2290–2296 (2014).

    CAS  PubMed  Google Scholar 

  90. Chambers, C. D. et al. Birth outcomes in women who have taken leflunomide during pregnancy. Arthritis Rheum. 62, 1494–1503 (2010).

    PubMed  PubMed Central  Google Scholar 

  91. Coscia, L. A. et al. Update on the teratogenicity of maternal mycophenolate mofetil. J. Pediatr. Genet. 4, 42–55 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  92. Leroy, C. et al. Immunosuppressive drugs and fertility. Orphanet J. Rare Dis. 10, 136 (2015).

    PubMed  PubMed Central  Google Scholar 

  93. Cassina, M. et al. Pregnancy outcome in women exposed to leflunomide before or during pregnancy. Arthritis Rheum. 64, 2085–2094 (2012).

    CAS  PubMed  Google Scholar 

  94. Weber-Schoendorfer, C., Beck, E., Tissen-Diabate, T. & Schaefer, C. Leflunomide — a human teratogen? A still not answered question. An evaluation of the German Embryotox pharmacovigilance database. Reprod. Toxicol. 71, 101–107 (2017).

    CAS  PubMed  Google Scholar 

  95. Berard, A., Zhao, J. P., Shui, I. & Colilla, S. Leflunomide use during pregnancy and the risk of adverse pregnancy outcomes. Ann. Rheum. Dis. 77, 500–509 (2018).

    CAS  PubMed  Google Scholar 

  96. Keating, G. M. Apremilast: a review in psoriasis and psoriatic arthritis. Drugs 77, 459–472 (2017).

    CAS  PubMed  Google Scholar 

  97. Dhillon, S. Tofacitinib: a review in rheumatoid arthritis. Drugs 77, 1987–2001 (2017).

    CAS  PubMed  Google Scholar 

  98. Al-Salama, Z. T. & Scott, L. J. Baricitinib: a review in rheumatoid arthritis. Drugs 78, 761–772 (2018).

    CAS  PubMed  Google Scholar 

  99. Palmeira, P., Quinello, C., Silveira-Lessa, A. L., Zago, C. A. & Carneiro-Sampaio, M. IgG placental transfer in healthy and pathological pregnancies. Clin. Dev. Immunol. 2012, 985646 (2012).

    PubMed  Google Scholar 

  100. Nesbitt, A., Kevorkian, L. & Baker, T. Lack of FcRn binding in vitro and no measurable levels of ex vivo placental transfer of certolizumab pegol. Hum. Reprod. 29, 127 (2014).

    Google Scholar 

  101. Herrera-Esparza, R., Bollain-y-Goytia, J. J. & Avalos-Díaz, E. Pathogenic effects of maternal antinuclear antibodies during pregnancy in women with lupus. Rheumatol. Rep. 6, 5545 (2014).

    Google Scholar 

  102. Hyrich, K. L. & Verstappen, S. M. M. Biologic therapies and pregnancy: the story so far. Rheumatology 53, 1377–1385 (2014).

    CAS  PubMed  Google Scholar 

  103. Murashima, A., Watanabe, N., Ozawa, N., Saito, H. & Yamaguchi, K. Etanercept during pregnancy and lactation in a patient with rheumatoid arthritis: drug levels in maternal serum, cord blood, breast milk and the infant’s serum. Ann. Rheumat. Dis. 68, 1793–1794 (2009).

    CAS  PubMed  Google Scholar 

  104. Berthelsen, B. G., Fjeldsoe-Nielsen, H., Nielsen, C. T. & Hellmuth, E. Etanercept concentrations in maternal serum, umbilical cord serum, breast milk and child serum during breastfeeding. Rheumatology 49, 2225–2227 (2010).

    CAS  PubMed  Google Scholar 

  105. Zaretsky, M. V., Alexander, J. M., Byrd, W. & Bawdon, R. E. Transfer of inflammatory cytokines across the placenta. Obstet. Gynecol. 103, 546–550 (2004).

    CAS  PubMed  Google Scholar 

  106. Kumar, M., Ray, L., Vemuri, S. & Simon, T. A. Pregnancy outcomes following exposure to abatacept during pregnancy. Semin. Arthritis Rheum. 45, 351–356 (2015).

    CAS  PubMed  Google Scholar 

  107. Cheent, K. et al. Case report: fatal case of disseminated BCG infection in an infant born to a mother taking infliximab for Crohn’s disease. J. Crohns Colitis 4, 603–605 (2010).

    PubMed  Google Scholar 

  108. Mariette, X. et al. Lack of placental transfer of certolizumab pegol during pregnancy: results from CRIB, a prospective, postmarketing, pharmacokinetic study. Ann. Rheum. Dis. 77, 228–233 (2018).

    CAS  PubMed  Google Scholar 

  109. Clowse, M. E. et al. Minimal to no transfer of certolizumab pegol into breast milk: results from CRADLE, a prospective, postmarketing, multicentre, pharmacokinetic study. Ann. Rheum. Dis. 76, 1890–1896 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  110. Hoeltzenbein, M. et al. Tocilizumab use in pregnancy: analysis of a global safety database including data from clinical trials and post-marketing data. Semin. Arthritis Rheum. 46, 238–245 (2016).

    CAS  PubMed  Google Scholar 

  111. Youngstein, T. et al. International multi-centre study of pregnancy outcomes with interleukin-1 inhibitors. Rheumatology 56, 2102–2108 (2017).

    PubMed  Google Scholar 

  112. Norman, R. J. & Wu, R. The potential danger of COX-2 inhibitors. Fertil. Steril. 81, 493–494 (2004).

    CAS  PubMed  Google Scholar 

  113. National Collaborating Centre for Women’s and Children’s Health (UK). Hypertension in pregnancy: the management of hypertensive disorders during pregnancy. 4: Management of pregnancy with chronic hypertension. NCBI https://www.ncbi.nlm.nih.gov/books/NBK62651/ (2010).

  114. Atallah, A. et al. Aspirin for prevention of preeclampsia. Drugs 77, 1819–1831 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  115. Asayama, K. & Imai, Y. The impact of salt intake during and after pregnancy. Hypertens. Res. 41, 1–5 (2018).

    CAS  PubMed  Google Scholar 

  116. Podymow, T. & Joseph, G. Preconception and pregnancy management of women with diabetic nephropathy on angiotensin converting enzyme inhibitors. Clin. Nephrol. 83, 73–79 (2015).

    CAS  PubMed  Google Scholar 

  117. Ruiz-Irastorza, G., Khamashta, M. A., Nelson-Piercy, C. & Hughes, G. R. Lupus pregnancy: is heparin a risk factor for osteoporosis? Lupus 10, 597–600 (2001).

    CAS  PubMed  Google Scholar 

  118. Henderson, J. T. et al. Low-dose aspirin for prevention of morbidity and mortality from preeclampsia: a systematic evidence review for the U.S. Preventive Services Task Force. Ann. Intern. Med. 160, 695–703 (2014).

    PubMed  Google Scholar 

  119. Carlin, A. & Alfirevic, Z. Physiological changes of pregnancy and monitoring. Best Pract. Res. Clin. Obstet. Gynaecol. 22, 801–823 (2008).

    PubMed  Google Scholar 

  120. Yee, C. S. et al. The BILAG2004-Pregnancy index is reliable for assessment of disease activity in pregnant SLE patients. Rheumatology 51, 1877–1880 (2012).

    PubMed  Google Scholar 

  121. Bramham, K. et al. Pregnancy outcomes in systemic lupus erythematosus with and without previous nephritis. J. Rheumatol. 38, 1906–1913 (2011).

    PubMed  Google Scholar 

  122. Espinoza, J. et al. Should bilateral uterine artery notching be used in the risk assessment for preeclampsia, small-for-gestational-age, and gestational hypertension? J. Ultrasound Med. 29, 1103–1115 (2010).

    PubMed  PubMed Central  Google Scholar 

  123. Levine, R. J. et al. Soluble endoglin and other circulating antiangiogenic factors in preeclampsia. N. Engl. J. Med. 355, 992–1005 (2006).

    CAS  PubMed  Google Scholar 

  124. Kim, M. Y. et al. Angiogenic factor imbalance early in pregnancy predicts adverse outcomes in patients with lupus and antiphospholipid antibodies: results of the PROMISSE study. Am J. Obstet. Gynecol. 214, 108.e1–108.e14 (2016).

    CAS  Google Scholar 

  125. Kattah, A. G. & Garovic, V. D. The management of hypertension in pregnancy. Adv. Chron. Kidney Dis. 20, 229–239 (2013).

    Google Scholar 

  126. Soh, M. C. & Nelson-Piercy, C. High-risk pregnancy and the rheumatologist. Rheumatology 54, 572–587 (2015).

    PubMed  Google Scholar 

  127. Orbai, A. M. et al. Anti-C1q antibodies in systemic lupus erythematosus. Lupus 24, 42–49 (2015).

    CAS  PubMed  Google Scholar 

  128. Eudy, A. M. et al. Reasons for cesarean and medically indicated deliveries in pregnancies in women with systemic lupus erythematosus. Lupus 27, 351–356 (2018).

    CAS  PubMed  Google Scholar 

  129. Lee, J. J. & Pope, J. E. A meta-analysis of the risk of venous thromboembolism in inflammatory rheumatic diseases. Arthritis Res. Ther. 16, 435 (2014).

    PubMed  PubMed Central  Google Scholar 

  130. Cohen, H., Arachchillage, D. R., Middeldorp, S., Beyer-Westendorf, J. & Abdul-Kadir, R. Management of direct oral anticoagulants in women of childbearing potential: guidance from the SSC of the ISTH. J. Thromb. Haemost. 14, 1673–1676 (2016).

    CAS  PubMed  Google Scholar 

  131. Izmirly, P. M. et al. Maternal and fetal factors associated with mortality and morbidity in a multi-racial/ethnic registry of anti-SSA/Ro-associated cardiac neonatal lupus. Circulation 124, 1927–1935 (2011).

    PubMed  PubMed Central  Google Scholar 

  132. Clowse, M. E. B. et al. The prevention, screening and treatment of congenital heart block from neonatal lupus: a survey of provider practices. Rheumatology 57, v9–v17 (2018).

    PubMed  Google Scholar 

  133. Izmirly, P. M. et al. Maternal use of hydroxychloroquine is associated with a reduced risk of recurrent anti-SSA/Ro-antibody-associated cardiac manifestations of neonatal lupus. Circulation 126, 76–82 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  134. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  135. Martinez-Sanchez, N. et al. Obstetric and perinatal outcome in anti-Ro/SSA-positive pregnant women: a prospective cohort study. Immunol. Res. 65, 487–494 (2017).

    CAS  PubMed  Google Scholar 

  136. Silverman, E. & Jaeggi, E. Non-cardiac manifestations of neonatal lupus erythematosus. Scand. J. Immunol. 72, 223–225 (2010).

    CAS  PubMed  Google Scholar 

  137. Webster, P. et al. Tacrolimus is an effective treatment for lupus nephritis in pregnancy. Lupus 23, 1192–1196 (2014).

    CAS  PubMed  Google Scholar 

  138. Clark, A. L. Clinical uses of intravenous immunoglobulin in pregnancy. Clin. Obstet. Gynecol. 42, 368–380 (1999).

    CAS  PubMed  Google Scholar 

  139. Ruffatti, A. et al. Plasma exchange in the management of high risk pregnant patients with primary antiphospholipid syndrome. A report of 9 cases and a review of the literature. Autoimmun. Rev. 6, 196–202 (2007).

    PubMed  Google Scholar 

  140. Kurkinen-Raty, M., Koivisto, M. & Jouppila, P. Preterm delivery for maternal or fetal indications: maternal morbidity, neonatal outcome and late sequelae in infants. BJOG 107, 648–655 (2000).

    CAS  PubMed  Google Scholar 

  141. Ostensen, M., Brown, N. D., Chiang, P. K. & Aarbakke, J. Hydroxychloroquine in human breast milk. Eur. J. Clin. Pharmacol. 28, 357 (1985).

    CAS  PubMed  Google Scholar 

  142. Bates, S. M. et al. VTE, thrombophilia, antithrombotic therapy, and pregnancy: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 141, e691S–e736S (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Contributions

All authors made substantial contributions to the research and discussion of the content. I.G. drafted the article and C.-S.Y. and C.G. edited/reviewed the article.

Corresponding author

Correspondence to Caroline Gordon.

Ethics declarations

Competing interests

I.G. declares that he has received honoraria and travel grants from UCB and Lupus Academy to speak at educational meetings on topics related to pregnancy in rheumatic disease. C.S.Y. declares that he has consulted for Bristol Myers Squibb, Immupharma and EMD Serono. C.G. declares that she has consulted for and received honoraria from Bristol-Myers Squibb, GlaxoSmithKline, EMD Serono and UCB in relation to lupus clinical trial design and analysis, and has been a member of the speakers’ bureau for GlaxoSmithKline and UCB. C.G. also declares that she has participated in clinical trials sponsored by UCB and funded by Arthritis Research UK with drugs supplied by GlaxoSmithKline.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Glossary

Intrauterine growth restriction

(IUGR). Reduced fetal growth resulting in an estimated weight below the 10th percentile for gestational age.

Cyclophosphamide-induced gonadal toxicity

Gonadal damage induced by cyclophosphamide, leading to reduced ovarian function.

Gestational hypertension

New-onset hypertension presenting after 20 weeks’ gestation without significant proteinuria.

Pre-eclampsia

New-onset hypertension presenting after 20 weeks’ gestation with significant proteinuria. Indicative of maternoplacental dysfunction.

Small for gestational age

Term used to describe a baby who is smaller than usual for the number of weeks of pregnancy. These babies usually have birthweights below the 10th percentile for gestational age.

Endocardial fibroelastosis

A rare heart disorder of infants and children that is characterised by a thickening within the muscular lining of the heart chambers due to an increase in the amount of supporting connective tissue (inelastic collagen) and elastic fibres.

Placental insufficiency

Failure of the placenta to deliver sufficient nutrients and oxygen to the fetus during pregnancy.

Minimum tolerable dose of corticosteroid

The minimum dose required to maintain disease control and reduce complications such as steroid-induced diabetes mellitus, hypertension and infections in the mother.

Rescue therapy

Treatment given after a patient has failed to respond to standard therapy.

Ductus arteriosus

A blood vessel in the fetus connecting the main pulmonary artery to the proximal descending aorta, allowing most blood from the right ventricle to bypass the lungs. Premature closure of this blood vessel leads to progressive right heart dysfunction, congestive heart failure and intrauterine death.

Uterine artery Doppler ultrasound

A technique used to measure uterine artery blood flow between mother and baby.

Thromboprophylaxis

In this context, the prevention of thromboembolic disease by pharmacological means.

Fetal cardiac ultrasound

Technique used to evaluate the structure of the fetal heart.

Screening for congenital heart block

The use of fetal cardiac ultrasound at the 16th to 20th week of pregnancy in anti-SSA/Ro-positive mothers.

Cardiac pacing

Technique used to regulate heart rate involving the fitting of a pacemaker.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Giles, I., Yee, CS. & Gordon, C. Stratifying management of rheumatic disease for pregnancy and breastfeeding. Nat Rev Rheumatol 15, 391–402 (2019). https://doi.org/10.1038/s41584-019-0240-8

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41584-019-0240-8

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing