Prescribing Drugs in Pregnancy and Breastfeeding: Immunomodulatory Antirheumatic Drugs and Corticosteroids

Overview

This new Guidelines summary of the British Society for Rheumatology (BSR) guideline covers recommendations on prescribing antirheumatic drugs in pregnancy and breastfeeding. The following drug categories are included: antimalarials; corticosteroids; conventional synthetic disease-modifying antirheumatic drugs (DMARDs) and immunosuppressive therapies; biologic DMARDs; and targeted synthetic DMARDs.

This summary does not cover the management of infertility or the other indications for these drugs in specific rheumatic diseases in pregnancy. Other drug categories are considered in the BSR guideline on Prescribing drugs in pregnancy and breastfeeding: comorbidity medications used in rheumatology practice.

This summary only covers key recommendations for primary care. Refer to the full guideline for detailed information on data and studies used.

Reflecting on your Learnings

Reflection is important for continuous learning and development, and a critical part of the revalidation process for UK healthcare professionals. Click here to access the Guidelines Reflection Record.

Generic Recommendations on Prescribing Immunomodulatory Drugs and/or Corticosteroids in Rheumatic Disease in Pregnancy

• Pre-conception counselling should be addressed by all healthcare professionals, with referral to professionals with relevant expertise as appropriate, to optimise disease control before pregnancy; with advice on the timing of pregnancy, and drug therapy before, during, and after pregnancy, including contraception
• If a woman is planning pregnancy, avoid pregnancy-incompatible drugs
• The risks and benefits to the mother and fetus of drug treatment to control maternal disease should be discussed and clearly documented by all healthcare professionals involved in the patient’s care
• Immunomodulatory drugs that are contraindicated in pregnancy should be switched to a pregnancy-compatible alternative in advance of conception to ensure maintenance of disease control on the new medication
• When no pregnancy-compatible drugs are suitable, control of severe/life-threatening maternal disease should take priority over concerns for potential fetal outcomes
• All biologic DMARDs may be continued throughout pregnancy if required to control active/severe maternal disease
• Immunisation schedules in infants after in utero exposure to biologic DMARDs will depend on timing of exposure, bioavailability and persistence of the drug, and mechanism of action of drug and live vaccine
• Where possible, the minimum effective dose of immunomodulatory drug or corticosteroid should be used to maintain maternal disease suppression, and stopping the drug during pregnancy may be considered in women at low risk of disease flare on withdrawal of therapy
• Some drugs may reduce male fertility, but paternal drug exposure in humans has not convincingly been associated with adverse fetal development or pregnancy outcome. Although the evidence is weak, men who take rheumatological medicines should be reassured about the safety of conceiving.

Key Standards of Care

• Ideally, patients with rheumatic disease should receive tailored pre-pregnancy counselling and then be reviewed during pregnancy and the 4-month postpartum period by clinical practitioners with expertise in the management of rheumatic disease in pregnancy, in addition to their routine obstetric care
• Patients should have access to written information on relevant medications in pregnancy and breastfeeding that is accurate and allows them to make informed decisions regarding compatibility of certain drugs in pregnancy.

Antimalarials

• Hydroxychloroquine (HCQ) is the antimalarial drug most used to treat rheumatic disease and has been extensively studied in pregnancy 
• HCQ remains the antimalarial of choice in women planning a pregnancy with rheumatic disease in need of treatment, and should be continued during pregnancy at a dose of ≤400 mg/day
• HCQ is compatible with breastmilk exposure.

Corticosteroids

• Corticosteroids used to treat rheumatic disease (prednisolone, prednisone, and methylprednisolone) are metabolised in the placenta, and so 10% or less of the active drug reaches the fetus
• Prednisolone is compatible with pregnancy and is the preferred corticosteroid in the treatment of maternal rheumatological disease in pregnancy and requires shared care with obstetric teams to monitor maternal blood pressure and blood glucose
• Where possible, the dose of prednisolone should be <20 mg/day and tapered to the minimum effective dose to control maternal disease, in conjunction with steroid-sparing drugs compatible with pregnancy
• Prednisolone is compatible with breastmilk exposure
• Methylprednisolone has similar rates of placental transfer to prednisolone and would therefore be expected to be compatible with pregnancy and breastmilk exposure.

DMARDs and Immunosuppressive Therapies

Methotrexate

• Methotrexate (MTX) at any dose should be avoided in pregnancy and stopped at least 1 month in advance of planned conception, when it should be switched to another pregnancy-compatible drug to ensure maintenance of maternal disease suppression
• In women treated with low-dose (≤25 mg/week) MTX within 1 month prior to conception, folic acid supplementation (5 mg/day) should be continued up to 12 weeks of pregnancy
• In unintended pregnancy on low-dose (≤25 mg/week) MTX, there is minimal risk to the fetus; the drug should be stopped immediately, folic acid supplementation (5 mg/day) continued, and a careful evaluation of fetal risk with early referral to a fetal medicine department considered
• Although only minute amounts of MTX are excreted into breast milk, MTX cannot be recommended in breastfeeding because of theoretical risks and insufficient data on outcomes.

Sulfasalazine

• Sulfasalazine (SSZ) is compatible throughout pregnancy, with folic acid 5 mg/day recommended in the periconception period and during the first trimester
• SSZ is compatible with breastmilk exposure in healthy, full-term infants.

Leflunomide

• Leflunomide (LEF) may not be a human teratogen but there remains insufficient evidence to support use at the time of conception or during pregnancy
• Women on LEF considering pregnancy should stop and undergo a standard cholestyramine washout procedure, and switch to alternative medication compatible with pregnancy
• If unintended conception occurs on LEF, the drug should be stopped immediately and a standard cholestyramine washout procedure given, with early referral to a fetal medicine department considered
• LEF is not recommended whilst breastfeeding.

Azathioprine

• Azathioprine (AZA) is compatible throughout pregnancy
• AZA is compatible with breastmilk exposure.

Cyclosporine

• Cyclosporine (CsA) is compatible throughout pregnancy with monitoring of maternal blood pressure, renal function, blood glucose, and drug levels
• CsA is compatible with breastmilk exposure.

Tacrolimus

• Tacrolimus is compatible throughout pregnancy with monitoring of maternal blood pressure, renal function, blood glucose, and drug levels
• Tacrolimus is compatible with breastmilk exposure.

Cyclophosphamide

• Cyclophosphamide (CYC) is a known teratogen and gonadotoxic, and therefore should only be considered in pregnancy in cases of severe life/organ-threatening maternal disease when there is appreciable risk of maternal and fetal morbidity and mortality without this therapy
• CYC is not recommended whilst breastfeeding.

Mycophenolate Mofetil

• Mycophenolate mofetil (MMF) remains contraindicated during pregnancy, and should be avoided in women planning pregnancy or switched to a pregnancy compatible alternative at least 6 weeks before attempting to conceive
• In cases of unintended conception, switch MMF to a pregnancy-compatible alternative and refer to local experts for further advice and risk assessment
• MMF is not recommended whilst breastfeeding.

Intravenous Immunoglobulin

• Intravenous immunoglobulin (IVIG) is compatible with pregnancy
• IVIG is compatible with breastmilk exposure.

Biologic Drugs

• Biological therapies are commonly used as second-line agents to treat various forms of IRDs. Biologic drugs are often given alongside other DMARDs, and decisions regarding continuation of treatment should be taken for each drug independently.

Anti-TNF⍺ drugs

• Five biologic agents that inhibit tumor necrosis factor alpha (TNF⍺) are currently licenced to treat IRDs: etanercept (ETA), infliximab (INF), adalimumab (ADA), golimumab (GOL), and certolizumab pegol (CZP). These drugs have different half-lives, bioavailability, and rates of placental transfer, which are relevant when considering their potential use in pregnancy
• Women with no/low disease activity established on a tumour necrosis factor inhibitor (TNFi) with known placental transfer (INF, ADA, GOL) do not need to be switched to an alternative TNFi with established minimal placental transfer (CZP) either before or during pregnancy
• CZP is compatible with all three trimesters of pregnancy, has no to minimal placental transfer compared with other TNFi, and does not require any alteration to the infant vaccination schedule
• Women considered to have low risk of disease flare on withdrawal of TNFi in pregnancy could stop INF at 20 weeks, ADA and GOL at 28 weeks, and ETA at 32 weeks so that a full-term infant can have a normal vaccination schedule, with rotavirus vaccination at 8 weeks as per the UK schedule
• INF, ADA, ETA, or GOL may be continued throughout pregnancy to maintain maternal disease control; in these circumstances, live vaccines should be avoided in infants until they are 6 months of age
• If TNFi is stopped in pregnancy, it can be restarted as soon as practical post-partum in the absence of infections or surgical complications, regardless of breastfeeding status, to ensure control of maternal disease
• TNFi are compatible with breastmilk exposure.

Other Biologic Drugs (Non-TNFi)

Rituximab

• Limited evidence has not shown rituximab (RTX) to be teratogenic; however, there remains insufficient evidence to be confident that it is compatible with pregnancy. Consider stopping the drug at conception
• RTX may be considered to manage severe maternal disease in pregnancy if no other pregnancy-compatible drugs are suitable
• If RTX is used to treat severe maternal disease in the third trimester, it is currently recommended to avoid all live vaccines in the infant vaccination schedule until 6 months of age
• Based on limited evidence, maternal treatment with RTX is compatible with breastmilk exposure.

Interleukin-6 Inhibitors

• Limited evidence has not shown interleukin-6 inhibitors (IL-6i) to be teratogenic; however, there remains insufficient evidence to be confident that they are compatible with pregnancy. Consider stopping the drug at conception. Any exposure during pregnancy, however, is unlikely to be harmful
• IL-6i may be considered to manage severe maternal disease in pregnancy if no other pregnancy-compatible drugs are suitable
• If IL-6i are used to treat severe maternal disease in the third trimester, it is currently recommended to avoid all live vaccines in the infant vaccination schedule until 6 months of age
• Based on limited evidence, maternal treatment with IL-6i is compatible with breastmilk exposure.

Interleukin-1 Inhibitors

• Limited evidence has not shown IL-1 inhibitors (IL-1i) to be teratogenic; however, there remains insufficient evidence to be confident that they are compatible with pregnancy. Consider stopping the drug at conception. Any exposure during pregnancy, however, is unlikely to be harmful
• IL-1i may be considered to manage severe maternal disease in pregnancy if no other pregnancy-compatible drugs are suitable
• If IL-1i are used to treat severe maternal disease in the third trimester, it is currently recommended to avoid all live vaccines in the infant vaccination schedule until 6 months of age
• Based on limited evidence, maternal treatment with IL-1i is compatible with breastmilk exposure.

Abatacept

• Limited evidence has not shown abatacept (ABA) to be teratogenic; however, there remains insufficient evidence to be confident that it is compatible with pregnancy
• Consider stopping the drug at conception. Any exposure during pregnancy, however, is unlikely to be harmful
• ABA may be considered to manage severe maternal disease in pregnancy if no other pregnancy-compatible drugs are suitable
• If ABA is used to treat severe maternal disease in the third trimester, it is currently recommended to avoid all live vaccines in the infant vaccination schedule until 6 months of age
• Based on limited evidence, maternal treatment with ABA is compatible with breastmilk exposure.

Belimumab

• Limited evidence has not shown belimumab (BEL) to be teratogenic; however, there remains insufficient evidence to be confident that it is compatible with pregnancy. Consider stopping the drug at conception. Any exposure during pregnancy, however, is unlikely to be harmful
• BEL may be considered to manage severe maternal disease in pregnancy if no other pregnancy-compatible drugs are suitable
• If BEL is used to treat severe maternal disease in the third trimester, it is currently recommended to avoid all live vaccines in the infant vaccination schedule until 6 months of age
• Based on limited evidence, maternal treatment with BEL is compatible with breastmilk exposure.

Interleukin-17 Inhibitors

• Limited evidence has not shown interleukin-17 inhibitors (IL-17i) to be teratogenic; however, there remains insufficient evidence to be confident that they are compatible with pregnancy. Consider stopping the drug at conception. Any exposure during pregnancy, however, is unlikely to be harmful
• IL-17i may be considered to manage severe maternal disease in pregnancy if no other pregnancy-compatible drugs are suitable
• If IL-17i are used to treat severe maternal disease in the third trimester, it is currently recommended to avoid all live vaccines in the infant vaccination schedule until 6 months of age
• Based on limited evidence, maternal treatment with IL-17i is compatible with breastmilk exposure.

Interleukin-12/23 Inhibitors

• Ustekinumab (UST) is an IL-12/23 inhibitor with an IgG1 structure
• Limited evidence has not shown UST to be teratogenic; however, there remains insufficient evidence to be confident that it is compatible with pregnancy. Consider stopping the drug at conception. Any exposure during pregnancy, however, is unlikely to be harmful
• UST may be considered to manage severe maternal disease in pregnancy if no other pregnancy-compatible drugs are suitable
• If UST is used to treat severe maternal disease in the third trimester, it is currently recommended to avoid all live vaccines in the infant vaccination schedule until 6 months of age
• Based on limited evidence, maternal treatment with UST is compatible with breastmilk exposure. 

 Anifrolumab

• Current data on anifrolumab pregnancy exposure are insufficient to inform about potential drug-related risks and therefore post-authorisation pregnancy studies are planned
• Although there is no information regarding breastmilk exposure to anifrolumab, LactMed states that due to its large molecular weight, the amount in milk is likely to be very low, and it is also likely to be partially destroyed in the infant's gastrointestinal tract with minimal absorption by the infant. Based on this limited evidence, the BSR has not made any recommendations on this drug.

Targeted Synthetic DMARDs

JAK Inhibitors

• There are insufficient data to make a recommendation on Janus kinase inhibitor (JAKi) use during pregnancy and they should be stopped at least 2 weeks before planned conception
• There are insufficient data to recommend JAKi in breastfeeding and, given they are likely to transfer into breast milk, they should be avoided.

Paternal Exposures

• Due to the adverse effect of CYC on male fertility, semen cryopreservation is recommended for men prior to paternal exposure
• Men who take SSZ may have reduced fertility. There is little evidence to suggest that SSZ should be stopped pre-conception, unless conception is delayed by more than 12 months when stopping SSZ should be considered along with other causes of infertility
• Paternal exposure to the following antirheumatic medication is compatible with pregnancy: prednisolone, low-dose (≤25 mg/week) MTX, AZA, TNFi, CsA, HCQ, LEF, tacrolimus, MMF, IVIG, RTX, IL-6i, IL-1i, ABA, BEL, IL-17i, UST, and JAKi.