A bulk of investigations imply that women with rheumatoid arthritis (RA) deliver fewer children in comparison to healthy women.
This review article attempts to clarify the involvement of infertility-related issues in both RA men and women. Moreover, the effect of RA disease on the fertility quality and quantity will be discussed.
Declined fertility rate in RA women seems to stem from modified inflammatory settings, advanced maternal age, limited sexual activity, and adverse effects of drugs on ovarian function. Women with RA may have smaller families and seem to be slower to conceive relative to their peer women. The chance of gestation in RA women may drop due to suppressed sexual function through pain and fatigue. In addition, treatment of RA women with non-steroidal anti-inflammatory drugs (NSAIDs) may prevent ovulation and therefore hinder the conception.
A complex interaction between RA disease and fertility related issues is present. Despite an increase rate of infertility in RA females or males, the mechanisms involved in this outcome is still unknown. Plausible causes of the decreased fertility rate in RA patients might be due to inflammatory cytokines, suppressed sexual activity, drug treatments, mother age, personal choice, or a combination of these elements.
This is a preview of subscription content, access via your institution.
Buy single article
Instant access to the full article PDF.
Price excludes VAT (USA)
Tax calculation will be finalised during checkout.
Wallenius M, Skomsvoll JF, Irgens LM, Salvesen KÅ, Nordvåg B-Y, Koldingsnes W, et al. Fertility in women with chronic inflammatory arthritides. Rheumatology. 2011;50:1162–7.
Wallenius M, Skomsvoll J, Irgens L, Salvesen K, Nordvåg B, Koldingsnes W, et al. Parity in patients with chronic inflammatory arthritides childless at time of diagnosis. Scand J Rheumatol. 2012;41:202–7.
Skomsvoll JF, Ostensen M, Baste V, Irgens LM. Number of births, interpregnancy interval, and subsequent pregnancy rate after a diagnosis of inflammatory rheumatic disease in Norwegian women. J Rheumatol. 2001;28:2310–4.
Förger F, Vallbracht I, Helmke K, Villiger PM, Ostensen M. Pregnancy mediated improvement of rheumatoid arthritis. Swiss Med Wkly. 2012;142:w13644.
Østensen M, Villiger PM, Förger F. Interaction of pregnancy and autoimmune rheumatic disease. Autoimmun Rev. 2012;11:A437–A446446.
Østensen M, Villiger PM. The remission of rheumatoid arthritis during pregnancy. Semin Immunopathol. 2007;29:185–91. https://doi.org/10.1007/s00281-007-0072-5.
Förger F, Villiger PM. Immunological adaptations in pregnancy that modulate rheumatoid arthritis disease activity. Nat Rev Rheumatol. 2020;16:113–22. https://doi.org/10.1038/s41584-019-0351-2.
Del Junco D, Annegers J, Coulam C, Luthra HS. The relationship between rheumatoid arthritis and reproductive function. Br J Rheumatol. 1989;28:33.
Tsepelidis S, Devreker F, Demeestere I, Flahaut A, Gervy C, Englert Y. Stable serum levels of anti-Müllerian hormone during the menstrual cycle: a prospective study in normo-ovulatory women. Hum Reprod. 2007;22:1837–40.
Leverenz DL, Eudy AM, Jayasundara M, Haroun T, McDaniel G, Nowell WB, et al. Contraception methods used by women with rheumatoid arthritis and psoriatic arthritis. Clin Rheumatol. 2019;38:1207–12.
Provost M, Eaton JL, Clowse ME. Fertility and infertility in rheumatoid arthritis. Curr Opin Rheumatol. 2014;26:308–14.
Katz PP. Childbearing decisions and family size among women with rheumatoid arthritis. Arthritis Care Res. 2006;55:217–23.
Clowse ME, Chakravarty E, Costenbader KH, 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. 2012;64:668–74.
Eudy AM, McDaniel G, Hurd WW, Clowse ME. Fertility and ovarian reserve among women with rheumatoid arthritis. J Rheumatol. 2019;46:455–9.
Brouwer J, Laven JS, Hazes JM, Schipper I, Dolhain RJ. Levels of Serum anti-müllerian hormone, a marker for ovarian reserve, in women with rheumatoid arthritis. Arthritis Care Res. 2013;65:1534–8.
Silman A, Roman E, Beral V, Brown A. Adverse reproductive outcomes in women who subsequently develop rheumatoid arthritis. Ann Rheum Dis. 1988;47:979.
Spector TD, Silman A. Is poor pregnancy outcome a risk factor in rheumatoid arthritis? Ann Rheum Dis. 1990;49:12.
Nørgård BM, Larsen MD, Friedman S, Knudsen T, Fedder J. Decreased chance of a live born child in women with rheumatoid arthritis after assisted reproduction treatment: a nationwide cohort study. Ann Rheum Dis. 2019;78:328–34.
Chakravarty EF, Nelson L, Krishnan E. Obstetric hospitalizations in the United States for women with systemic lupus erythematosus and rheumatoid arthritis. Arthritis Rheumatol. 2006;54:899–907.
Lin H, Chen S, Lin H, et al. Increased risk of adverse pregnancy outcomes in women with rheumatoid arthritis: a nationwide population-based study. Ann Rheum Dis. 2010;69:715–7.
Bowden AP, Barrett JH, Fallow W, Silman AJ. Women with inflammatory polyarthritis have babies of lower birth weight. J Rheumatol. 2001;28:355–9.
Kishore S, Mittal V, Majithia V. Obstetric outcomes in women with rheumatoid arthritis: results from nationwide inpatient sample database 2003–2011✰. Semin Arthritis Rheum. 2019;49(2):236–40.
Aljary H, Czuzoj-Shulman N, Spence AR, Abenhaim HA. Pregnancy outcomes in women with rheumatoid arthritis: a retrospective population-based cohort study. J Maternal-Fetal Neonatal Med. 2020;33(4):618–24. https://doi.org/10.1080/14767058.2018.1498835.
Jethwa H, Lam S, Smith C, Giles I. Does rheumatoid arthritis really improve during pregnancy? A systematic review and metaanalysis. J Rheumatol. 2019;46:245–50.
Jabbour H, Sales K. Prostaglandin receptor signalling and function in human endometrial pathology. Trends Endocrinol Metab. 2004;15:398–404.
Rashid NA, Lalitkumar S, Lalitkumar PG, Gemzell-Danielsson K. Endometrial receptivity and human embryo implantation. Am J Reprod Immunol. 2011;66:23–30.
Gemzell-Danielsson K, Hamberg M. Endocrinology: the effect of antiprogestin (RU 486) and prostaglandin biosynthesis inhibitor (naproxen) on uterine fluid prostaglandin F2α concentrations. Hum Reprod. 1994;9:1626–30.
King AE, Critchley HO. Oestrogen and progesterone regulation of inflammatory processes in the human endometrium. J Steroid Biochem Mol Biol. 2010;120:116–26.
Dawood MY. Nonsteroidal anti-inflammatory drugs and reproduction. Am J Obstet Gynecol. 1993;169:1255–65.
Eppig JJ. Prostaglandin E2 stimulates cumulus expansion and hyaluronic acid synthesis by cumuli oophori isolated from mice. Biol Reprod. 1981;25:191–5.
Hizaki H, Segi E, Sugimoto Y, Hirose M, Saji T, Ushikubi F, et al. Abortive expansion of the cumulus and impaired fertility in mice lacking the prostaglandin E receptor subtype EP2. Proc Natl Acad Sci. 1999;96:10501–6.
Reich R, Daphna-Iken D, Chun S, Popliker M, Slager R, Adelmann-Grill B, et al. Preovulatory changes in ovarian expression of collagenases and tissue metalloproteinase inhibitor messenger ribonucleic acid: role of eicosanoids. Endocrinology. 1991;129:1869–75.
Markosyan N, Duffy DM. Prostaglandin E2 acts via multiple receptors to regulate plasminogen-dependent proteolysis in the primate periovulatory follicle. Endocrinology. 2008;150:435–44.
Hester KE, Harper MJ, Duffy DM. Oral administration of the cyclooxygenase-2 (COX-2) inhibitor meloxicam blocks ovulation in non-human primates when administered to simulate emergency contraception. Hum Reprod. 2009;25:360–7.
Duffy DM, Stouffer RL. Follicular administration of a cyclooxygenase inhibitor can prevent oocyte release without alteration of normal luteal function in rhesus monkeys. Hum Reprod. 2002;17:2825–31.
Duffy DM, Stouffer RL. The ovulatory gonadotrophin surge stimulates cyclooxygenase expression and prostaglandin production by the monkey follicle. MHR Basic Sci Reprod Med. 2001;7:731–9.
McCann NC, Lynch TJ, Kim SO, Duffy DM. The COX-2 inhibitor meloxicam prevents pregnancy when administered as an emergency contraceptive to nonhuman primates. Contraception. 2013;88:744–8.
Yoshinaga K. Uterine receptivity for blastocyst implantation. Ann N Y Acad Sci. 1988;541:424–31.
Dimitriadis E, White C, Jones R, Salamonsen L. Cytokines, chemokines and growth factors in endometrium related to implantation. Human Reprod Update. 2005;11:613–30.
Brouwer J, Hazes JMW, Laven JSE, et al. Fertility in women with rheumatoid arthritis: influence of disease activity and medication. Ann Rheum Dis. 2015;74:1836–41.
Akintayo RO, Aworinde OO, Ojo O, Akintayo FC, Akinlade OM, Awodun RO, et al. Is rheumatoid arthritis an innocent bystander in female reproductive problems? A comparative study of fertility in Nigerian women with and without rheumatoid arthritis. European J Rheumatol. 2018;5:179.
Ince-Askan H, Dolhain RJ. Pregnancy and rheumatoid arthritis. Best Pract Res Clin Rheumatol. 2015;29:580–96.
Saketos M, Sharma N, Santoro NF. Suppression of the hypothalamic–pituitary–ovarian axis in normal women by glucocorticoids. Biol Reprod. 1993;49:1270–6.
Whirledge S, Cidlowski JA. A role for glucocorticoids in stress-impaired reproduction: beyond the hypothalamus and pituitary. Endocrinology. 2013;154:4450–68.
Gordon D, Beastall G, Thomson J, Sturrock R. Androgenic status and sexual function in males with rheumatoid arthritis and ankylosing spondylitis. QJM Int J Med. 1986;60:671–9.
O'moráin C, Smethurst P, Doré CJ, Levi A. Reversible male infertility due to sulphasalazine: studies in man and rat. Gut. 1984;25:1078–84.
Visser K, Katchamart W, Loza E, Martinez-Lopez J, Salliot C, Trudeau J, et al. Multinational evidence-based recommendations for the use of methotrexate in rheumatic disorders with a focus on rheumatoid arthritis: integrating systematic literature research and expert opinion of a broad international panel of rheumatologists in the 3E Initiative. Ann Rheum Dis. 2009;68:1086–93.
Wallenius M, Lie E, Daltveit AK, Salvesen KÅ, Skomsvoll JF, Kalstad S, et al. Brief report: no excess risks in offspring with paternal preconception exposure to disease-modifying antirheumatic drugs. Arthritis Rheumatol. 2015;67:296–301.
Weber-Schoendorfer C, Hoeltzenbein M, Wacker E, Meister R, Schaefer C. No evidence for an increased risk of adverse pregnancy outcome after paternal low-dose methotrexate: an observational cohort study. Rheumatology. 2013;53:757–63.
Millsop JW, Heller MM, Eliason MJ, Murase JE. Dermatological medication effects on male fertility. Dermatol Ther. 2013;26:337–46.
Puchner R, Danninger K, Puchner A, Pieringer H. Impact of TNF-blocking agents on male sperm characteristics and pregnancy outcomes in fathers exposed to TNF-blocking agents at time of conception. Clin Exp Rheumatol. 2012;30:765–7.
Ramonda R, Foresta C, Ortolan A, Bertoldo A, Oliviero F, Lorenzin M, et al. Influence of tumor necrosis factor α inhibitors on testicular function and semen in spondyloarthritis patients. Fertil Steril. 2014;101:359–65.
Micu MC, Micu R, Surd S, Gîrlovanu M, Bolboacă SD, Ostensen M. TNF-α inhibitors do not impair sperm quality in males with ankylosing spondylitis after short-term or long-term treatment. Rheumatology. 2014;53:1250–5.
Whirledge S, Cidlowski JA. Glucocorticoids, stress, and fertility. Minerva Endocrinol. 2010;35:109.
Martini AC, Molina RI, Tissera AD, Ruiz RD, De Cuneo MF. Analysis of semen from patients chronically treated with low or moderate doses of aspirin-like drugs. Fertil Steril. 2003;80:221–2.
Reed SD, Vollan TA, Svec MA. Pregnancy outcomes in women with rheumatoid arthritis in Washington State. Matern Child Health J. 2006;10:361–6.
Wolfberg AJ, Lee-Parritz A, Peller AJ, Lieberman ES. Association of rheumatologic disease with preeclampsia. Obstet Gynecol. 2004;103:1190–3.
Nørgaard M, Larsson H, Pedersen L, Granath F, Askling J, Kieler H, et al. Rheumatoid arthritis and birth outcomes: a Danish and Swedish nationwide prevalence study. J Intern Med. 2010;268:329–37.
Bharti B, Lee SJ, Lindsay SP, Wingard DL, Jones KL, Lemus H, 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. 2015;42:1376–82.
Ince-Askan H, Mandaviya PR, Felix JF, Duijts L, van Meurs JB, Hazes JM, et al. Altered DNA methylation in children born to mothers with rheumatoid arthritis during pregnancy. Ann Rheum Dis. 2019;78:1198–204.
de Man YA, Hazes JM, van der Heide H, Willemsen SP, de Groot CJ, Steegers EA, et al. Association of higher rheumatoid arthritis disease activity during pregnancy with lower birth weight: results of a national prospective study. Arthritis Rheumatol. 2009;60:3196–206.
Ong KK, Dunger DB. Perinatal growth failure: the road to obesity, insulin resistance and cardiovascular disease in adults. Best Pract Res Clin Endocrinol Metab. 2002;16:191–207.
Leunissen RW, Kerkhof GF, Stijnen T, Hokken-Koelega A. Timing and tempo of first-year rapid growth in relation to cardiovascular and metabolic risk profile in early adulthood. JAMA. 2009;301:2234–42.
Steenwinkel F, Hokken-Koelega A, Ridder MA, Hazes JM, Dolhain RJ. Rheumatoid arthritis during pregnancy and postnatal catch-up growth in the offspring. Arthritis Rheumatol. 2014;66:1705–11.
de Steenwinkel FD, Hokken-koelega AC, Hazes J, Dolhain RJ. Does elevated disease activity or medication use influence the bone density of the prepubertal offspring in pregnant women with rheumatoid arthritis? Arthritis Rheum. 2013;65:S172.
Ince-Askan H, Hazes JMW, Dolhain R. Breastfeeding among women with rheumatoid arthritis compared with the general population: results from a nationwide prospective cohort study. J Rheumatol. 2019;46(9):1067–74. https://doi.org/10.3899/jrheum.180805.
Murray KE, Moore L, O’Brien C, Clohessy A, Brophy C, Minnock P, et al. Updated pharmacological management of rheumatoid arthritis for women before, during, and after pregnancy, reflecting recent guidelines. Ir J Med Sci. 2019;188:169–72 (1971-).
Østensen M, Andreoli L, Brucato A, Cetin I, Chambers C, Clowse ME, et al. State of the art: reproduction and pregnancy in rheumatic diseases. Autoimmun Rev. 2015;14:376–86.
Østensen M, Khamashta M, Lockshin M, Parke A, Brucato A, Carp H, et al. Anti-inflammatory and immunosuppressive drugs and reproduction. Arthritis Res Ther. 2006;8:209.
Bermas BL. Non-steroidal anti inflammatory drugs, glucocorticoids and disease modifying anti-rheumatic drugs for the management of rheumatoid arthritis before and during pregnancy. Curr Opin Rheumatol. 2014;26:334–40.
Skorpen CG, Hoeltzenbein M, Tincani A, Fischer-Betz R, Elefant E, Chambers C, et al. The EULAR points to consider for use of antirheumatic drugs before pregnancy, and during pregnancy and lactation. Ann Rheum Dis. 2016;75:795–810.
Weber-Schoendorfer C, Chambers C, Wacker E, Beghin D, Bernard N, NoFP C, et al. Pregnancy outcome after methotrexate treatment for rheumatic disease prior to or during early pregnancy: a prospective multicenter cohort study. Arthritis Rheumatol. 2014;66:1101–10.
Brent RL. Utilization of animal studies to determine the effects and human risks of environmental toxicants (drugs, chemicals, and physical agents). Pediatrics. 2004;113:984–95.
Cassina M, Johnson D, Robinson L, Braddock S, Xu R, Jimenez J, et al. Pregnancy outcome in women exposed to leflunomide before or during pregnancy. Arthritis Rheum. 2012;64:2085–94.
Chambers CD, Johnson DL, Robinson LK, Braddock SR, Xu R, Lopez-Jimenez J, et al. Birth outcomes in women who have taken leflunomide during pregnancy. Arthritis Rheum. 2010;62:1494–503.
Weber-Schoendorfer C, Oppermann M, Wacker E, Bernard N, centres noFp, Beghin D, et al. Pregnancy outcome after TNF-α inhibitor therapy during the first trimester: a prospective multicentre cohort study. Br J Clin Pharmacol. 2015;80:727–39.
Chaudrey KH, Kane SV. Safety of immunomodulators and anti-TNF therapy in pregnancy. Curr Treat Options Gastroenterol. 2015;13:77–89.
Eworuke E, Panucci G, Goulding M, Neuner R, Toh S. Use of tumor necrosis factor-alpha inhibitors during pregnancy among women who delivered live born infants. Pharmacoepidemiol Drug Saf. 2019;28:296–304.
Kawai Y, Tsuchiya T, Aoki S. Pregnancy outcomes of patients exposed to adalimumab in Japan. Dig Dis. 2019;37:123–30.
Malek A, Sager R, Kuhn P, Nicolaides KH, Schneider H. Evolution of maternofetal transport of immunoglobulins during human pregnancy. Am J Reprod Immunol. 1996;36:248–55.
Mahadevan U, Wolf DC, Dubinsky M, Cortot A, Lee SD, Siegel CA, et al. Placental transfer of anti–tumor necrosis factor agents in pregnant patients with inflammatory bowel disease. Clin Gastroenterol Hepatol. 2013;11:286–92.
Berthelsen BG, Fjeldsøe-Nielsen H, Nielsen CT, Hellmuth E. Etanercept concentrations in maternal serum, umbilical cord serum, breast milk and child serum during breastfeeding. Rheumatology. 2010;49:2225–7.
Hyrich KL, Verstappen SM. Biologic therapies and pregnancy: the story so far. Rheumatology. 2013;53:1377–85.
Brooks P. Use and benefits of nonsteroidal anti-inflammatory drugs. Am J Med. 1998;104:9S–13S.
Wood SF. Women’s health and the FDA. N Engl J Med. 2005;353:1650–1.
Østensen ME, Skomsvoll JF. Anti-inflammatory pharmacotherapy during pregnancy. Expert Opin Pharmacother. 2004;5:571–80.
Østensen M. Nonsteroidal anti-inflammatory drugs during pregnancy. Scand J Rheumatol. 1998;27:128–32.
Akil M, Amos R, Stewart P. Infertility may sometimes be associated with NSAID consumption. Rheumatology. 1996;35:76–8.
Smith G, Roberts R, Hall C, Nuki G. Reversible ovulatory failure associated with the development of luteinized unruptured follicles in women with inflammatory arthritis taking non-steroidal anti-inflammatory drugs. Rheumatology. 1996;35:458–62.
Van der Weiden R, Wouters J. Infertility may sometimes be associated with non-steroidal anti-inflammatory drug consumption. Br J Rheumatol. 1997;36:605.
Nielsen GL, Sørensen HT, Larsen H, Pedersen L. Risk of adverse birth outcome and miscarriage in pregnant users of non-steroidal anti-inlammatory drugs: population based observational study and case-control study. BMJ Br Med J. 2001;322(7281):266–70.
Li D-K, Liu L, Odouli R. Exposure to non-steroidal anti-inflammatory drugs during pregnancy and risk of miscarriage: population based cohort study. BMJ. 2003;327:368.
Nakhai-Pour HR, Broy P, Sheehy O, Bérard A. Use of nonaspirin nonsteroidal anti-inflammatory drugs during pregnancy and the risk of spontaneous abortion. CMAJ. 2011;183:1713–20.
Edelman AB, Jensen JT, Doom C, Hennebold JD. Impact of the prostaglandin synthase-2 inhibitor celecoxib on ovulation and luteal events in women. Contraception. 2013;87:352–7.
Bata M, Al-Ramahi M, Salhab A, Gharaibeh M, Schwartz J. Delay of ovulation by meloxicam in healthy cycling volunteers: a placebo-controlled, double-blind, crossover study. J Clin Pharmacol. 2006;46:925–32.
Brouwer J, Hazes J, Laven J, Dolhain R. FRI0145 High disease activity and preconceptional use of prednisone and non-steroidal anti-inflammatory drugs impair fertility in women with rheumatoid arthritis. Ann Rheum Dis. 2013;72:A419–A419419.
Brubaker W, Li S, Baker L, Eisenberg M. Increased risk of autoimmune disorders in infertile men: analysis of US claims data. Andrology. 2018;6:94–8.
Conflict of interest
Abolfazl Fattah, Soheila Nouraei, Mohammad Reza Hooshangi Shayesteh, Forough Hatefi Hesari, Sirous Jamalzehi, Mojtaba Abbasi, Mohammad Javad Mousavi, and Saeed Aslani declare that they have no conflict of interest.
Responsible Editor: John Di Battista.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
About this article
Cite this article
Fattah, A., Asadi, A., Shayesteh, M.R.H. et al. Fertility and infertility implications in rheumatoid arthritis; state of the art. Inflamm. Res. 69, 721–729 (2020). https://doi.org/10.1007/s00011-020-01362-w