eMedicine Specialties > Rheumatology > Rheumatoid Arthritis

Rheumatoid Arthritis and Pregnancy

Author: Katherine Temprano, MD, Assistant Professor of Internal Medicine, Associate Program Director, Rheumatology Fellowship Program, Division of Rheumatology, University of Kentucky Medical Center
Coauthor(s): Shannon Colleen Florea, MD, Fellow, Department of Internal Medicine, Division of Rheumatology, University of Kentucky Medical Center; Elizabeth Scarbrough, MSN, Rheumatology Nurse Practitioner, University of Kentucky Chandler Medical Center
Contributor Information and Disclosures

Updated: Jun 22, 2009

Introduction

Background

Rheumatoid arthritis (RA) is a systemic, chronic, autoimmune inflammatory disease that affects about 1% of the US population. The disease is approximately 3 times more common in women than in men and often affects women during their reproductive years.

Pregnancy alters the immune state, possibly contributing to a change in the course of RA. For decades, the ameliorating effects of pregnancy on the disease activity in women with RA have been observed. In 1998, Barrett et al reported on a large prospective study of RA in women from late pregnancy to 6 months postpartum. In retrospect, 63% of the study patients reported improvement in disease activity, but only 16% were in remission at the third trimester.1

In a 2008 study, de Man et al monitored 84 patients with RA for disease activity before conception, if possible, at each trimester of pregnancy, and at 6, 12, and 26 weeks postpartum. Disease activity was found to decrease during pregnancy but to increase after delivery. Among patients with at least moderate disease activity in the first trimester, at least 48% had a moderate response during pregnancy, while patients with low disease activity in the first trimester reported that their disease activity remained stable during pregnancy. Thirty-nine percent of patients had at least one moderate flare postpartum.2

Pathophysiology

The pathophysiology of the ameliorating effect of pregnancy on RA activity during pregnancy remains unknown, but various theories have been proposed. Nonetheless, no single mechanism satisfactorily explains the observed improvement, and multiple factors are probably responsible for the decreased disease severity.

Some of the proposed theories are as follows:

  • The effect of pregnancy on cell-mediated immunity (eg, decreased cell-mediated immunity, predominance of helper T-cell 2 [TH2] cytokine profile)3
  • Elevated levels of anti-inflammatory cytokines, such as interleukin-1 receptor antagonist (IL-1Ra) and soluble tumor necrosis factor-alpha receptors (sTNFRs), and down-regulation of Th1 cytokines during pregnancy4
  • The effect of hormonal changes during pregnancy (eg, increased cortisol, estrogen, and progestin levels)
  • The effect of pregnancy on humoral immunity (eg, a proportional decrease in immunoglobulin G lacking terminal galactose units, an elevated serum alpha-2 pregnancy-associated globulin [PAG] level)5,6,7
  • Altered neutrophil function during pregnancy (eg, decreased neutrophil respiratory burst)8,9
  • The degree of HLA disparity between the mother and the fetus (the less genetically similar the mother and fetus, the more likely the RA will remit)10

Possible causes for flare-ups during the postpartum period include the following:

  • A decrease in the anti-inflammatory steroid levels
  • Elevated levels of prolactin (ie, proinflammatory hormone)11
  • Change in the neuroendocrine axis
  • Change from a TH2 to a helper T-cell 1 cytokine profile

Frequency

United States

RA is observed in 1%-2% of the general population. Women of reproductive age are commonly affected; hence, pregnancy complicated by RA is not rare.

Mortality/Morbidity

  • Effect of RA on pregnancy: Few studies have addressed the effects of RA on pregnancy. A 2006 study suggests that RA during pregnancy does not affect the rate of spontaneous abortion.12
  • Effect of RA on fetal outcome: There has been some controversy regarding fetal complications in mothers with RA; however, a 2006 study showed an increased risk for prematurity but no increased risk for low birth weight after adjusting for gestational age.12 In contrast, another 2006 study did show an increased rate of intrauterine growth restriction associated with RA.13
  • Effect of RA on fertility: RA does not appear to affect the likelihood of fertility; however, lower birth rates among women with RA have been reported. This may reflect choices by women to limit family sizes, as a recent study found that women diagnosed with RA prior to the birth of their first child had the fewest pregnancies and children.14

Sex

  • RA is 2-3 times more common in women than in men.

Clinical

History

History is targeted toward identifying the activity of rheumatoid arthritis (RA), complications related to pregnancy, and adverse effects of the various medications.

  • Features of RA disease activity include the following:
    • Constitutional symptoms may be present.
    • In most patients, morning stiffness and fatigue are diminished during pregnancy.
    • The likelihood of developing extra-articular manifestations of RA during pregnancy is not increased.
    • Many patients notice improvement in joint pain or stiffness. Most patients who have a favorable response notice the decrease in pain as early as the first trimester and have durable relief throughout pregnancy. In some patients, this improvement occurs later, during the second or third trimester. Some patients (16%) achieve remission.1
  • Symptoms due to pregnancy include the following:
    • Nausea, vomiting, and morning sickness can occur during the first trimester. These symptoms may prevent absorption of medications.
    • Pedal edema and back pain unrelated to RA can occur in the later stages of pregnancy.

Physical

  • Examination for RA disease activity and structural damage
    • Pallor may be present. Patients with RA may have anemia of chronic disease. Pregnancy could further lower the hematocrit value following volume expansion.
    • Joint examination is performed to assess disease activity. Activity is assessed based on the number of swollen tender joints. The pattern of the joint involvement in pregnant patients is the same as in the nonpregnant state (ie, involving small joints of the hands, wrists, shoulders, neck, knees, and ankles in a bilaterally symmetric pattern). Range of motion in the hip and neck joints is assessed (1) to determine if the patient needs to abduct and externally rotate their hips for vaginal delivery and (2) to identify patients with ligamental instability of the atlantoaxial joint.
    • Assess for extra-articular symptoms, including dry eyes, scleritis, dry mouth, pulmonary fibrosis, pleural effusion, and vasculitis.
    • Examination to assess fetal growth and development and maternal health: No specific guidelines address obstetric monitoring in patients with RA. Because little available data suggest a significant risk for preterm birth, pre-eclampsia, or fetal growth restriction in pregnant patients with RA, no special obstetric monitoring is indicated beyond what is performed for usual obstetric care.15

Causes

  • Current data suggest that parity has no consistent effect on the risk or severity of RA.16
  • A 2004 report suggested that breastfeeding protected against the development of RA in parous women, with longer duration of breastfeeding conferring greater protection.17

More on Rheumatoid Arthritis and Pregnancy

Overview: Rheumatoid Arthritis and Pregnancy
Differential Diagnoses & Workup: Rheumatoid Arthritis and Pregnancy
Treatment & Medication: Rheumatoid Arthritis and Pregnancy
Follow-up: Rheumatoid Arthritis and Pregnancy
References
[ CLOSE WINDOW ]

References

  1. Barrett JH, Brennan P, Fiddler M, Silman AJ. Does rheumatoid arthritis remit during pregnancy and relapse postpartum? Results from a nationwide study in the United Kingdom performed prospectively from late pregnancy. Arthritis Rheum. Jun 1999;42(6):1219-27. [Medline].

  2. de Man YA, Dolhain RJ, van de Geijn FE, Willemsen SP, Hazes JM. Disease activity of rheumatoid arthritis during pregnancy: results from a nationwide prospective study. Arthritis Rheum. Sep 15 2008;59(9):1241-8. [Medline].

  3. Wegmann TG, Lin H, Guilbert L, Mosmann TR. Bidirectional cytokine interactions in the maternal-fetal relationship: is successful pregnancy a TH2 phenomenon?. Immunol Today. Jul 1993;14(7):353-6. [Medline].

  4. Ostensen M, Forger F, Nelson JL, Schuhmacher A, Hebisch G, Villiger PM. Pregnancy in patients with rheumatic disease: anti-inflammatory cytokines increase in pregnancy and decrease post partum. Ann Rheum Dis. Jun 2005;64(6):839-44. [Medline].

  5. Unger A, Kay A, Griffin AJ, Panayi GS. Disease activity and pregnancy associated alpha 2-glycoprotein in rheumatoid arthritis during pregnancy. Br Med J (Clin Res Ed). Mar 5 1983;286(6367):750-2. [Medline].

  6. Quinn C, Mulpeter K, Casey EB, Feighery CF. Changes in levels of IgM RF and alpha 2 PAG correlate with increased disease activity in rheumatoid arthritis during the puerperium. Scand J Rheumatol. 1993;22(6):273-9. [Medline].

  7. Alavi A, Arden N, Spector TD, Axford JS. Immunoglobulin G glycosylation and clinical outcome in rheumatoid arthritis during pregnancy. J Rheumatol. Jun 2000;27(6):1379-85. [Medline].

  8. Crocker IP, Baker PN, Fletcher J. Neutrophil function in pregnancy and rheumatoid arthritis. Ann Rheum Dis. Jul 2000;59(7):555-64. [Medline].

  9. Crouch SP, Crocker IP, Fletcher J. The effect of pregnancy on polymorphonuclear leukocyte function. J Immunol. Dec 1 1995;155(11):5436-43. [Medline].

  10. van der Horst-Bruinsma IE, de Vries RR, de Buck PD, et al. Influence of HLA-class II incompatibility between mother and fetus on the development and course of rheumatoid arthritis of the mother. Ann Rheum Dis. May 1998;57(5):286-90. [Medline].

  11. Zoli A, Lizzio MM, Ferlisi EM, et al. ACTH, cortisol and prolactin in active rheumatoid arthritis. Clin Rheumatol. Aug 2002;21(4):289-93. [Medline].

  12. Reed SD, Vollan TA, Svec MA. Pregnancy outcomes in women with rheumatoid arthritis in Washington State. Matern Child Health J. Jul 2006;10(4):361-6. [Medline].

  13. Chakravarty EF, Nelson L, Krishnan E. Obstetric hospitalizations in the United States for women with systemic lupus erythematosus and rheumatoid arthritis. Arthritis Rheum. Mar 2006;54(3):899-907. [Medline].

  14. Katz PP. Childbearing decisions and family size among women with rheumatoid arthritis. Arthritis Rheum. Apr 15 2006;55(2):217-23. [Medline].

  15. Branch DW. Pregnancy in patients with rheumatic diseases: obstetric management and monitoring. Lupus. 2004;13(9):696-8. [Medline].

  16. Golding A, Haque UJ, Giles JT. Rheumatoid arthritis and reproduction. Rheum Dis Clin North Am. May 2007;33(2):319-43, vi-vii. [Medline].

  17. Karlson EW, Mandl LA, Hankinson SE, Grodstein F. Do breast-feeding and other reproductive factors influence future risk of rheumatoid arthritis? Results from the Nurses' Health Study. Arthritis Rheum. Nov 2004;50(11):3458-67. [Medline].

  18. Temprano KK, Bandlamudi R, Moore TL. Antirheumatic drugs in pregnancy and lactation. Semin Arthritis Rheum. Oct 2005;35(2):112-21. [Medline].

  19. Vermillion ST, Scardo JA, Lashus AG, Wiles HB. The effect of indomethacin tocolysis on fetal ductus arteriosus constriction with advancing gestational age. Am J Obstet Gynecol. Aug 1997;177(2):256-9; discussion 259-61. [Medline].

  20. Park-Wyllie L, Mazzotta P, Pastuszak A, et al. Birth defects after maternal exposure to corticosteroids: prospective cohort study and meta-analysis of epidemiological studies. Teratology. Dec 2000;62(6):385-92. [Medline].

  21. Blanford AT, Murphy BE. In vitro metabolism of prednisolone, dexamethasone, betamethasone, and cortisol by the human placenta. Am J Obstet Gynecol. Feb 1 1977;127(3):264-7. [Medline].

  22. Brent RL. Teratogen update: reproductive risks of leflunomide (Arava); a pyrimidine synthesis inhibitor: counseling women taking leflunomide before or during pregnancy and men taking leflunomide who are contemplating fathering a child. Teratology. Feb 2001;63(2):106-12. [Medline].

  23. Mogadam M, Dobbins WO 3rd, Korelitz BI, Ahmed SW. Pregnancy in inflammatory bowel disease: effect of sulfasalazine and corticosteroids on fetal outcome. Gastroenterology. Jan 1981;80(1):72-6. [Medline].

  24. Francella A, Dyan A, Bodian C, Rubin P, Chapman M, Present DH. The safety of 6-mercaptopurine for childbearing patients with inflammatory bowel disease: a retrospective cohort study. Gastroenterology. Jan 2003;124(1):9-17. [Medline].

  25. Moskovitz DN, Bodian C, Chapman ML, et al. The effect on the fetus of medications used to treat pregnant inflammatory bowel-disease patients. Am J Gastroenterol. Apr 2004;99(4):656-61. [Medline].

  26. Parke A, West B. Hydroxychloroquine in pregnant patients with systemic lupus erythematosus. J Rheumatol. Oct 1996;23(10):1715-8. [Medline].

  27. Buchanan NM, Toubi E, Khamashta MA, Lima F, Kerslake S, Hughes GR. Hydroxychloroquine and lupus pregnancy: review of a series of 36 cases. Ann Rheum Dis. Jul 1996;55(7):486-8. [Medline].

  28. Costedoat-Chalumeau N, Amoura Z, Duhaut P, et al. Safety of hydroxychloroquine in pregnant patients with connective tissue diseases: a study of one hundred thirty-three cases compared with a control group. Arthritis Rheum. Nov 2003;48(11):3207-11. [Medline].

  29. Motta M, Tincani A, Faden D, Zinzini E, Chirico G. Antimalarial agents in pregnancy. Lancet. Feb 9 2002;359(9305):524-5. [Medline].

  30. Treacy G. Using an analogous monoclonal antibody to evaluate the reproductive and chronic toxicity potential for a humanized anti-TNFalpha monoclonal antibody. Hum Exp Toxicol. Apr 2000;19(4):226-8. [Medline].

  31. Katz JA, et al. Outcome of pregnancy in patients receiving infliximab for the treatment of crohns disease and rheumatoid arthritis. Digestive disease Week 2003, May 17-22, 2003 Orlando Florida.

  32. Roux CH, Brocq O, Breuil V, Albert C, Euller-Ziegler L. Pregnancy in rheumatology patients exposed to anti-tumour necrosis factor (TNF)-alpha therapy. Rheumatology (Oxford). Apr 2007;46(4):695-8. [Medline].

  33. Sinha A, Patient C. Rheumatoid arthritis in pregnancy: successful outcome with anti-TNF agent (Etanercept). J Obstet Gynaecol. Oct 2006;26(7):689-91. [Medline].

  34. Skomsvoll JF, Wallenius M, Koksvik HS, et al. Drug insight: Anti-tumor necrosis factor therapy for inflammatory arthropathies during reproduction, pregnancy and lactation. Nat Clin Pract Rheumatol. Mar 2007;3(3):156-64. [Medline].

  35. Chambers CD, et al. Pregnancy Outcome in Women Exposed to Anti-TNF-alpha Medications: The OTIS Rheumatoid Arthritis in Pregnancy Study [abstract]. Arthritis Rheum. 50(9):s479-s480.

  36. Chambers CD, et al. Pregnancy outcome in women exposed to adalimumab: the OTIS autoimmune diseases in pregnancy project. University of California at San Diego. June 2007.

  37. Chambers CD, et al. Pregnancy outcomes in women exposed to etanercept: the OTIS autoimmune diseases in pregnancy project. [abstract]. J Am Acad Derm. Feb 2007;56(2):AB10.

  38. Genentech & Biogen. Prescribing Information. Retrieved on October 17,2008 from http://www.gene.com/gene/products/information/pdf/rituxan-prescribing.pdf. (2008).

  39. Rey J, Coso D, Roger V, et al. Rituximab combined with chemotherapy for lymphoma during pregnancy. Leuk Res. Mar 2009;33(3):e8-9. [Medline].

  40. Herold M, Schnohr S, Bittrich H. Efficacy and safety of a combined rituximab chemotherapy during pregnancy. J Clin Oncol. Jul 15 2001;19(14):3439. [Medline].

  41. Kimby E, Sverrisdottir A, Elinder G. Safety of rituximab therapy during the first trimester of pregnancy: a case history. Eur J Haematol. Apr 2004;72(4):292-5. [Medline].

  42. Klink DT, van Elburg RM, Schreurs MW, van Well GT. Rituximab administration in third trimester of pregnancy suppresses neonatal B-cell development. Clin Dev Immunol. 2008;2008:271363. [Medline].

  43. Friedrichs B, Tiemann M, Salwender H, Verpoort K, Wenger MK, Schmitz N. The effects of rituximab treatment during pregnancy on a neonate. Haematologica. Oct 2006;91(10):1426-7. [Medline].

  44. Decker M, Rothermundt C, Holländer G, Tichelli A, Rochlitz C. Rituximab plus CHOP for treatment of diffuse large B-cell lymphoma during second trimester of pregnancy. Lancet Oncol. Aug 2006;7(8):693-4. [Medline].

  45. Amgen. (2008). Kineret®. Personal communication with Kijung Sung-Thay, PharmD.

  46. Bristol-Myers Squibb. Use of Orencia during pregnancy and effects on fertility. Personal communication with Kelly S. Park, Pharm.D., MBA, representative of Bristol-Myers Squibb. (2008).

  47. Ost L, Wettrell G, Bjorkhem I, Rane A. Prednisolone excretion in human milk. J Pediatr. Jun 1985;106(6):1008-11. [Medline].

  48. Canadian Rheumatology Association. Canadian Consensus Conference on hydroxychloroquine. J Rheumatol. Dec 2000;27(12):2919-21. [Medline].

  49. Johns DG, Rutherford LD, Leighton PC, Vogel CL. Secretion of methotrexate into human milk. Am J Obstet Gynecol. Apr 1 1972;112(7):978-80. [Medline].

  50. Jarnerot G, Into-Malmberg MB. Sulphasalazine treatment during breast feeding. Scand J Gastroenterol. 1979;14(7):869-71. [Medline].

  51. American Academy of Pediatrics Committee on Drugs: The transfer of drugs and other chemicals into human milk. Pediatrics. Jan 1994;93(1):137-50. [Medline].

  52. European best practice guidelines for renal transplantation. Section IV: Long-term management of the transplant recipient. IV.10. Pregnancy in renal transplant recipients. Nephrol Dial Transplant. 2002;17 Suppl 4:50-5. [Medline].

  53. Peltier M, James D, Ford J, et al. Infliximab levels in breast-milk of a nursing Crohn's patient (poster). American College of Gastroenterology 66th Annual Scientific Meeting; Las Vegas, NV: Poster. October 22-24, 2001;P258.

  54. Ostensen M, Eigenmann GO. Etanercept in breast milk. J Rheumatol. May 2004;31(5):1017-8. [Medline].

[ CLOSE WINDOW ]

Further Reading

[ CLOSE WINDOW ]

Keywords

rheumatoid arthritis and pregnancy, RA, arthritis, DMARDs and pregnancy, disease-modifying anti-rheumatic drugs, disease-modifying antirheumatic drugs, spontaneous abortions, preeclampsia, preterm delivery, pregnancy complications, pregnancy management, adverse fetal outcome, decreased sexual drive, ovulation dysfunction, impaired hypothalamic-pituitary-adrenal axis, impaired HPA axis

[ CLOSE WINDOW ]

Contributor Information and Disclosures

Author

Katherine Temprano, MD, Assistant Professor of Internal Medicine, Associate Program Director, Rheumatology Fellowship Program, Division of Rheumatology, University of Kentucky Medical Center
Katherine Temprano, MD is a member of the following medical societies: American College of Physicians-American Society of Internal Medicine and American College of Rheumatology
Disclosure: Nothing to disclose.

Coauthor(s)

Shannon Colleen Florea, MD, Fellow, Department of Internal Medicine, Division of Rheumatology, University of Kentucky Medical Center
Shannon Colleen Florea, MD is a member of the following medical societies: American College of Rheumatology
Disclosure: Nothing to disclose.

Elizabeth Scarbrough, MSN, Rheumatology Nurse Practitioner, University of Kentucky Chandler Medical Center
Elizabeth Scarbrough, MSN is a member of the following medical societies: American College of Rheumatology, Council for the Advancement of Nursing Science, and Sigma Theta Tau International
Disclosure: Nothing to disclose.

Medical Editor

Bryan L Martin, DO, Chief, Allergy Immunology Department, Walter Reed Army Medical Center; Associate Professor of Medicine and Pediatrics, Uniformed Services University of the Health Sciences; United States Army Consultant in Allergy Immunology and Immunizations
Bryan L Martin, DO is a member of the following medical societies: American Academy of Allergy Asthma and Immunology, American College of Allergy, Asthma and Immunology, American College of Osteopathic Internists, American College of Physicians, American Medical Association, and American Osteopathic Association
Disclosure: Nothing to disclose.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: eMedicine Salary Employment

Managing Editor

Ajay K Singh, MB, MRCP, MBA, Associate Professor of Medicine, Harvard Medical School; Clinical Chief, Renal Division, Director of Dialysis, Brigham and Women's Hospital; Consulting Staff, Faulkner Hospital
Disclosure: Nothing to disclose.

CME Editor

Frederick B Gaupp, MD, Consulting Staff, Department of Family Practice, Hancock Medical Center
Frederick B Gaupp, MD is a member of the following medical societies: American Academy of Family Physicians
Disclosure: Nothing to disclose.

Chief Editor

David Chelmow, MD, Professor of Obstetrics and Gynecology, Tufts University School of Medicine; Program Director, Tufts University Affiliated Hospitals Obstetrics/Gynecology Residency Program; Chair, Tufts University Health Sciences Campus Institutional Review Board; Vice Chair for Research and Education, Department of Obstetrics/Gynecology, Tufts Medical Center
David Chelmow, MD is a member of the following medical societies: American College of Obstetricians and Gynecologists, American Medical Association, Association of Professors of Gynecology and Obstetrics, Massachusetts Medical Society, Phi Beta Kappa, Sigma Xi, Society for Gynecologic Investigation, and Society for Medical Decision Making
Disclosure: Nothing to disclose.

 
 
HONcode

We subscribe to the
HONcode principles of the
Health On the Net Foundation

All material on this website is protected by copyright, Copyright© 1994- by Medscape.
This website also contains material copyrighted by 3rd parties.

DISCLAIMER: The content of this Website is not influenced by sponsors. The site is designed primarily for use by qualified physicians and other medical professionals. The information contained herein should NOT be used as a substitute for the advice of an appropriately qualified and licensed physician or other health care provider. The information provided here is for educational and informational purposes only. In no way should it be considered as offering medical advice. Please check with a physician if you suspect you are ill.