Introduction

Rheumatoid arthritis (RA) is a chronic immune-mediated inflammatory disease which can cause significant disability, morbidity, and mortality. RA affects women three times more often than men, commonly in their childbearing years [1]. There are concerns about the teratogenic effects of many traditional disease-modifying anti-rheumatic drugs (DMARDs) and an ever-growing list of new therapeutic options with limited data in pregnancy and breastfeeding.

Active RA in pregnancy is associated with a number of negative outcomes for both mother and baby. These include increased incidence of low birth weight, pre-term delivery, cesarean section, and pre-eclampsia [2, 3]. But, thankfully, outcomes for women with well-controlled RA are comparable to the general population [4].

Before pregnancy, a key aim is to establish the RA patient in remission on medications that are relatively safe in pregnancy; this is usually achieved by the judicious use of synthetic and biological DMARDs. A specific withdrawal period is required for teratogenic medications such as methotrexate and leflunomide. Clinicians should be encouraged to enquire about family planning at the first consultation and each review thereafter, to allow all patients opportunity to discuss any concerns they may have.

Pre-conceptual risk assessment and counseling should be ideally performed in every woman with systemic autoimmune diseases before attempting pregnancy [5]. This is an opportune time to alter medication management if required and to refer for a pre-conceptual review with maternal medicine if available. This facilitates access to numerous specialities. Complex patients may benefit from a multidisciplinary approach from obstetrics, hematology, rheumatology, and respiratory or other specialties. This may be possible in a combined clinic.

Pregnancy itself may reduce the activity of RA [6]. In 1938, Hench suggested that remission rates during pregnancy were greater than 70% [7]. Later studies suggest that this rate is lower, with a recent prospective study giving a remission rate of 48% [3]. The exact mechanism of this improved disease control is unclear; one theory is downregulation of the maternal immune system with the presence of the fetus. It can be tempting to withdraw anti-rheumatic medications and treat symptomatically with steroids during pregnancy. Recent data would suggest that this may not be the best approach [8].

The postpartum period can be a difficult for the patient, the baby, and the treating healthcare providers. It is important to explain this to patients, their partners, and/or family. There is an increased rate of disease flare. A 2008 study showed a deterioration in RA control in 39% of patients postpartum [3]. One should also consider the additional strain of caring for an infant.

It may be difficult to differentiate what is normal postpartum from a disease flare, particularly for first time mothers. Breastfeeding and medication safety is another consideration. Postpartum complications such as wound infection may delay re-institution of RA medications.

Methods

Upon commencement of a multidisciplinary Rheumatology and Reproductive Health Service, a systematic approach to prescribing anti-rheumatic drugs in women of childbearing age was required. Thus, the published data and guidelines were reviewed to develop a unified approach.

Methotrexate and leflunomide are completely contraindicated at conception and in pregnancy. They require specific washout periods of 3 months recommended for methotrexate and 2 years for leflunomide [9, 10]. An elimination protocol using cholestyramine or activated charcoal may also be used when circumstances warrant more rapid drug elimination of leflunomide such as with pregnancy [10]. Thus, we carefully consider whether to use these agents in women of childbearing age and always stress to women on these medications the importance of adequate contraception during any period of use and the withdrawal period.

Steroids are considered generally safe if required in pregnancy. Fetal risks with steroids include a slight increase risk of pre-term delivery and a small risk of oral cleft with first trimester use. There is also of course the well-known side effect profile to the mother (including increased risk of infection). Thus, we aim to use the lowest effective dose for the shortest time possible in active disease. Non-fluorinated steroids, such as prednisolone or hydrocortisone, are generally preferred as they are metabolized by the placenta and have less fetal effects.

NSAIDs can contribute to the infertility and subfertility seen in RA due to anovulation [11]. Their use in early pregnancy can be associated with increased risk of miscarriage. In the third trimester, they may cause premature closure of ductus arteriosus.

Tumor necrosis factor (TNF) inhibitors may be safer than previously believed although we should not underestimate the risks. In 2010, a 4-month-old baby died from disseminated BCG [12]. His 28-year-old mother was treated with infliximab [TNF alpha inhibitor] throughout pregnancy for inflammatory bowel disease. The previously healthy infant received his BCG at 3 months of age.

Yet, there is now extensive experience and guidelines to support the use of biologics around and during pregnancy. Many rheumatologists would continue their use for at least the initial stages of pregnancy.

The updated BSR guidelines advise on timing of discontinuation of TNF inhibitors in pregnancy and breastfeeding. It is important to notice the differing timelines for the different biologic agents in these guidelines. Certolizumab pegol is compatible with all three trimesters of pregnancy and has reduced placental transfer compared with other TNF inhibitors. Infliximab may be continued until 16 weeks. Etanercept and adalimumab may be continued until the end of the second trimester. Golimumab is unlikely to be harmful in the first trimester. If these drugs are continued later in pregnancy to treat active disease, then live vaccines should be avoided in the infant until 7 months of age [9].

There is little data available for the use of non-TNFi biologics in pregnancy or breastfeeding. BSR guidelines suggest stopping rituximab 6 months and tocilizumab 3 months prior to conception. Unintentional exposure to anakinra or abatacept in the first trimester is unlikely to be harmful. There are no data on the use of any of these agents in breastfeeding. EULAR guidelines suggest discontinuing tofacitinib 2 months prior to conception and to avoid breastfeeding while on the medication.

Lactation

Guidelines consider numerous anti-rheumatic drugs compatible with breastfeeding. Our approach is summarized in the chart below.

Compatible with breastfeeding

Inadequate data about lactation

Contraindicated while breastfeeding

Corticosteroids

TNF inhibitors

Methotrexate

NSAIDs

Abatacept

Leflunomide

Hydroxychloroquine

Anakinra

 

Sulfasalazinea

Rituximab

 

Azathioprine

Tocilizumab

 
 

Tofacitinib

 
  1. aConcerns with prematurity, glucose-6-phosphate deficiency, and hyperbilirubinemia

Results

From reviewing previous studies and guidelines, we have created a joint Saint Vincent’s University Hospital/National Maternity Hospital approach to medications for RA in women of childbearing age. The table summarizes our approach to managing RA in and around pregnancy:

 

DMARDs

Biologics

Steroids

Analgesics

Before pregnancy

Stop MTX 3 months prior to conception

Continue TNF inhibitors

None/as low as possible

Stop NSAIDs if difficulties in conceiving

Wash out leflunomide (two years)

Consider HCQ/SSZ

Stop other biologics before conception

 

Use paracetamol

During pregnancy

Continue HCQ/SSZ, may taper

Often stopped during trimester 2

None/as low as possible

Avoid NSAIDs

Consider certolizumab throughout pregnancy

 

Use paracetamol

After pregnancy

Continue HCQ/SSZ

Avoid leflunomide, MTX if breastfeeding

Aim to restart biologics within 2 weeks (consider wound healing, infection, and breastfeeding)

None/as low as possible

Consider restarting NSAIDs, ideally ibuprofen if breastfeeding

Use paracetamol

  1. DMARDs disease-modifying anti-rheumatic drugs, MTX methotrexate, with 5 mg folic acid weekly, HCQ hydroxychloroquine, SSZ sulfasalazine (with 5 mg folic acid daily), TNF tumor necrosis factor, NSAIDs non-steroidal anti-inflammatory drugs

Conclusions

Women with active RA might have increased subfertility and infertility. Patients should be encouraged to discuss their pregnancy plans with their healthcare providers at every consultation. Good disease control at all stages of reproduction ensures best outcomes for mother and baby. RA tends to improve during pregnancy and flare postpartum. Consideration should be given to the treatment of disease flares during pregnancy. There are now numerous anti-rheumatic drug options during pregnancy and breastfeeding with more widespread use of anti TNF agents in this group.