Rheumatoid Arthritis in Pregnancy

1. What every clinician should know

Rheumatoid arthritis (RA) affects approximately 1% of the population, occurs more frequently in women than men and presents during childbearing age. RA is a chronic inflammatory disease that usually affects the small joints of the hands and feet but can also form rheumatoid nodules, vasculitis, and have heart and lung involvement. The disease course can fluctuate and result in progressive joint destruction, deformity, disability and even death.

2. Diagnosis and differential diagnosis

Establishing the diagnosis

RA is usually diagnosed and managed by a rheumatologist. There is no specific test to diagnose RA, but rather the American College of Rheumatology has created a list of criteria to assist with the diagnosis. They recommend that the patient have at least four of the following signs and symptoms.

Morning stiffness in and around the joints for at least 1 hour.
Swelling or fluid around three or more joints simultaneously.
At least one swollen area in the wrist, hand or finger joints.
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Arthritis involving the same joint on both sides of the body (symmetric arthritis).
Rheumatoid nodules, firm lumps in the skin. Usually these are in the pressure points of the body.
Abnormal amount of rheumatoid factor in the blood.
X-ray changes in the hands and wrists typical of rheumatoid arthritis, with destruction of the bone around the involved joints.

Differential diagnosis

The differential diagnosis includes osteoarthritis, gout, fibromyalgia, systemic lupus erythematosus and infectious joint inflammation. Sorting out the differential diagnosis is not straightforward and consultation with a rheumatologist should be considered.

3. Management

The majority of RA patients experience suppression of their disease during pregnancy with recurrence during the postpartum period. Treatment during pregnancy and the postpartum period is limited due to the potential effects of the medications on the fetus.

NSAIDs are commonly taken to relieve RA symptoms. There is a potential risk of cardiac septal defects and gastroschisis to fetuses exposed to NSAIDs. Many NSAIDs also have been associated with renal dysgenesis and oligohydramnios during the third trimester. NSAIDs also can promote premature closure of the ductus arteriosis. Given the above considerations, the current recommendations are low dose NSAIDs up to 32 weeks.

Corticosteroids can be used to suppress acute flareups during pregnancy. These are FDA category C. The lowest doses of corticosteroids are recommended to reduce risk of maternal and fetal side effects. There is no evidence for cleft palate.

Disease modifying anti-rheumatic drugs (DMARD) can be used to suppress disease activity, but their mechanism of actions are not fully understood. This class of medications includes Methotrexate, Sulfasalazine, Leflunomide, Hydroxychloroquine, Azathioprine and Cyclosporin.

Methotrexate works as a folate antagonist. It is FDA category X and associated with growth restriction, hypoplasia of the supraorbital ridges, abnormal cranial ossification, small low set ears, micrognathia and limb abnormalities. Women should wait at least 3 months after taking methotrexate prior to conception.

Sulfasalazine is also a folate antagonist. It has mostly been used for treating inflammatory bowel disease. There are conflicting studies regarding the safety of sulfasalazine, but generally low doses are considered safe in pregnancy. The patient should be given folic acid supplements while taking it.

Leflunomide inhibits pyrimidine synthesis. It is FDA category X although there is limited data regarding its safety. It is recommended that women stop taking leflunomide 2 years prior to conception or undergo washout procedure.

Hydroxychloroquine is an antimalarial medication and is thought to be safe during pregnancy. It is FDA category C due to potential ocular and ototoxicity.

Azathioprine is a second line agent for RA but has limited data regarding pregnancy, and most of it comes from transplant patients. There is potential for growth restriction and prematurity, but it is difficult to distinguish if the risks are from transplant status or the medication.

Cyclosporine is also a second line agent and most of the data comes from transplant patients. It also may be associated with prematurity and growth restriction, but, as with azathioprine, it is difficult to tell whether the transplant status or the medication is the cause of the increased risk. However, cyclosporine is considered safe during pregnancy.

Biologics are a new class of drugs with limited data. They include tumor necrosis factor (TNF) inhibitors, rituximab and abatacept. Most data regarding TNF inhibitors is from retrospective series and most patients stopped after conception. TNF inhibitors are FDA category B and generally regarded as safe at conception, but should be stopped at that time, as they may increase the risk of prematurity and growth restriction.

Rituximab is a monoclonal antibody that binds to B-lymphocyte CD20 surface antigens. It can cross the placenta and has been associated with neonatal lymphopenia. It is FDA category C and recommended that it be stopped 1 year before conception.

Abatacept selectively modulates and alters T-cell activation. There is no data regarding the effects in pregnant women, but there have been no adverse events noted in animal studies. However it is recommended to stop the medication at least 10 weeks prior to conception.

4. Complications

Most patients experience improvement in their disease during the first trimester. Despite this RA can affect the pregnancy through several mechanisms. Inflammation may affect the placenta, increasing the risk of prematurity and growth restriction. Women with RA have 1.5-2.2-fold increase in premature delivery and low birth weight infants. Treatment of flares also increases the risk to the fetus depending on which medication is used as well as timing of the medication.

5. Prognosis and outcome

A. Maternal and fetal/neonatal outcomes

In one study reviewing births in Denmark and Sweden, patients with RA had a moderate preterm (32-36 week) birth rate of 7.8% and very preterm (fewer than 32 weeks) birthrate of 1.4%, compared with 5.3% and 0.9%, respectively, for women without RA. This same study also found a 5.9% prevalence of SGA in mothers with RA. The prevalence of stillbirth was 0.9%, compared to 0.4% of the control population.

Frequently women experience a flare in the postpartum period and restart treatment to reduce the inflammation and joint damage.

B. Impact on long term health

RA can lead to significant joint injury and damage that is irreversible. Early diagnosis and treatment with newer medications may reduce the long term effects of the disease.

6. What is the evidence for specific management and treatment recommendations

Partlett, R, Roussou, E. “The treatment of rheumatoid arthritis during pregnancy”. Rheumatol Int. vol. 31. 2011. pp. 445-9. (This is the most current and comprehensive review on medical management of RA.)

Nørgaard, M, Larsson, H, Pederson, L. “Rheumatoid arthritis and birth outcomes: a Danish and Swedish nationwide prevalence study”. Journal of Internal Medicine. vol. 268. 2010. pp. 329-37. (This is one of the largest studies looking at birth outcomes in women with RA.)

Märker-Hermann, E, Fischer-Betz, R. “Rheumatic diseases and pregnancy”. Current Opinion in OB and Gyn. vol. 22. 2010. pp. 458-65. (This is the most recent and comprehensive review of obstetrical literature evaluating complications, prognosis and treatment of RA.)

Silman, AJ. “The 1987 revised American rheumatism and association criteria for rheumatoid arthritis”. British Journal of Rheumatology. vol. 27. 1988. pp. 341-3. (This is the current diagnostic criteria for RA.)

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Rheumatoid arthritis in pregnancy