Rheumatoid Arthritis and Pregnancy 

Updated: May 11, 2018
  • Author: Katherine K Temprano, MD; Chief Editor: Christine Isaacs, MD  more...
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Effects of Pregnancy on Rheumatoid Arthritis

Pregnancy alters the immune state, possibly contributing to a change in the course of rheumatoid arthritis (RA). [1, 2]  Approximately 50% of pregnant women with RA have low disease activity, and 20% to 40% achieve remission by the third trimester; however, nearly 20% will have worse or moderate-to-high disease activity during pregnancy that may require further therapeutic intervention. [3]

Women also experience postpartum flares. One study reported that disease activity decreased during pregnancy but increased after delivery. [4] The investigators monitored 84 patients with RA for disease activity before conception; at each trimester of pregnancy, if possible; and at 6, 12, and 26 weeks postpartum. Among patients with at least moderate disease activity in the first trimester, at least 48% had a moderate response during pregnancy, whereas patients with low disease activity in the first trimester reported that their disease activity remained stable during pregnancy. [4] Thirty-nine percent of patients had at least 1 moderate flare postpartum.

No specific guidelines address obstetric monitoring in patients with RA. Because few available data suggest a significantly increased risk for preterm birth, preeclampsia, or fetal growth restriction, no special obstetric monitoring is indicated beyond what is performed for usual obstetric care. [5]

Go to Rheumatoid Arthritis for more complete information on this topic.

Possible causes for the effects of pregnancy on rheumatoid arthritis

The reasons behind the ameliorating effect of pregnancy on RA activity remain 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) [6]

  • Elevated levels of anti-inflammatory cytokines, such as interleukin-1 receptor antagonist (IL-1Ra) and soluble tumor necrosis factor-alpha receptors (sTNFRs), as well as down-regulation of Th1 cytokines during pregnancy [7]

  • 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) [8, 9, 10, 11]

  • Altered neutrophil function during pregnancy (eg, decreased neutrophil respiratory burst) [12, 13]

  • 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) [14]

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) [15]

  • Change in the neuroendocrine axis

  • Change from a TH2 to a helper T-cell 1 cytokine profile

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Preconception Counseling

It is important to counsel women of childbearing age about the teratogenicity and adverse effects of the medications used to treat rheumatoid arthritis (RA) before starting therapy. These patients may need a reminder about the importance of using contraception during therapy with disease-modifying antirheumatic drugs (DMARDs), especially methotrexate, leflunomide, and cyclophosphamide. Educate patients that because of a prolonged half-life, some of these medications may need to be discontinued several months before conception is planned. In addition to discontinuation, some patients who take DMARDs may require treatment with other medications to enhance their clearance.

Fertility is compromised in women with RA. They report having fewer children than they intended to have and they are more often nulliparous that women without RA. In women with RA diagnosed before family completion, 36% to 42% will experience a time to pregnancy (TTP) greater than 12 months. 

Adjustments to antirheumatic treatment before women start trying to conceive coupled with longer TTP can result in a prolonged period with less adequately controlled disease and consequently an increased risk for permanent damage to the joints. [16]  Factors associated with longer time to pregnancy included age, nulliparous state, and preconception use of nonsteroidal anti-inflammatory drugs (NSAIDs) and prednisone (>7.5 mg/day). Thus preconception treatment strategies should aim at maximum suppression of disease activity, while taking into account possible negative effects of NSAID use and higher prednisone doses. [17]

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Peripartum Concerns

Miscarriage

The miscarriage rate is comparable to that in the general population. In one study, within 1 year after miscarriage, the majority of patients with rheumatoid arthritis (RA) who continued trying to conceive achieved a pregnancy resulting in a live birth. [17]

Cesarean delivery

Cesarean delivery does not appear to be performed more commonly in patients with RA.

Diet and supplements

A low-fat, high-carbohydrate, high-fiber diet is recommended in pregnant patients with RA. Fish oils in moderate quantities can be taken during pregnancy. Over-the-counter (OTC) herbal remedies should probably be avoided. Routine oral calcium and vitamin D supplementation is recommended.

Specialist consultations

The physician providing obstetric care needs to work closely with the patient's rheumatologist, especially if the patient is taking disease-modifying antirheumatic drugs (DMARDs) or steroids. Patients on hydroxychloroquine (HCQ) may need an eye examination by an ophthalmologist to assess for drug toxicity.

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Medication Safety

None of the medications used in the treatment of rheumatoid arthritis (RA) is absolutely safe during pregnancy. Hence, the decision to use medications should be made after careful assessment of the risks and benefits in consultation with the patient. Pain control through nonpharmacologic management (eg, paraffin baths, decreased physical activity, splinting, cold packs) can be used as adjunctive care.

Guidelines for the use of antirheumatic drugs during pregnancy have been released by the European League Against Rheumatism (EULAR) [18] and jointly by the British Society of Rheumatology (BSR) and British Health Professionals in Rheumatology (BHPR). [19]

Nonsteroidal anti-inflammatory drugs

Nonsteroidal anti-inflammatory drugs (NSAIDs) should be stopped at the beginning of a menstrual cycle when conception is planned, because these agents have been shown in animal studies to interfere with blastocyst implantation. Most traditional NSAIDs are considered category B medications but should be used with caution in pregnancy. [20]

Possible effects on the mother include prolonged gestation and labor, increased peripartum blood loss, and increased anemia. The potential adverse effects to the fetus include impaired fetal renal function with oligohydramnios and increased cutaneous and intracranial bleeding. Monitoring for oligohydramnios should be considered if the pregnant patient is on prolonged NSAID therapy.

NSAIDs are contraindicated in the third trimester, because they promote premature closure of the ductus arteriosus, leading to fetal pulmonary hypertension. Ductal constriction can occur at any gestational age; however, one study noted a dramatic increase in indomethacin-induced ductal constriction at 31 weeks’ gestation. [21]

Stopping NSAID therapy before 31 weeks’ gestational age is prudent for potentially avoiding adverse effects to the fetus. Short-acting NSAIDs (eg, ibuprofen, indomethacin, diclofenac) are preferred over long-acting agents.

Cyclooxygenase-2 (COX-2) inhibitors are generally considered category C medications and potentially share the same adverse effects as traditional NSAIDs.

The EULAR guidelines make the following recommendations regarding the use of NSAIDS [18] :

  • Non-selective (classic) NSAIDS: Can be continued during the first and second trimesters based on current evidence indicating no increased rate of congenital malformations. 
  • Selective COX-2 inhibitors: Should be avoided in pregnancy due to insufficient evidence of fetal safety

Corticosteroids

Corticosteroids are potent anti-inflammatory agents. They are considered relatively safe in pregnancy when used in low doses and are designated as category B medications. Nonetheless, corticosteroids may increase the maternal risk of hypertension, edema, gestational diabetes, osteoporosis, premature rupture of membranes, and small-for-gestational-age babies. [22]

One meta-analysis found a 3.5-fold increase in the risk of cleft palate in fetuses with first-trimester exposure to corticosteroids. [23]

The choice of glucocorticoid depends on whether the mother or the fetus needs to be treated. Hydrocortisone and cortisone cross the placenta, but 11 beta-dehydrogenase, a placental enzyme, converts hydrocortisone to cortisone, which is biologically inactive; thus, the fetus is exposed to only approximately 10% of the maternal dose. [24] Therefore, if steroid treatment is desired for the mother, hydrocortisone, cortisone, or prednisone should be chosen.

Dexamethasone and betamethasone cross the placenta with similar maternal and fetal concentrations; thus, they are the treatment of choice for fetal respiratory distress.

The lowest possible steroid dose needed to control disease activity should be used in pregnancy. Stress doses of steroids should be used during labor and delivery if the mother received steroids (even low-dose) for more than 2-3 weeks during pregnancy, and the neonate should be monitored for evidence of adrenal insufficiency and infection.

The EULAR guidelines make the following recommendations for use of corticosteroids [18] :

  • Prednisone:  Can be continued at the lowest effective dose throughout pregnancy, based on current evidence indicating no increased rate of congenital malformations 
  • Glucocorticoids: Can be given, when required, throughout pregnancy, based on current evidence indicating no increased rate of congenital malformations 

BSR-BHPR guidelines find prednisone use acceptable in each trimester of pregnancy. The guidelines notes that methylprednisolone has rates of placental transfer similar to prednisolone with equivalent anti-inflammatory effects at 80% of prednisolone dose. Therefore its use is expected to be compatible with pregnancy, [19]

Methotrexate

Methotrexate (MTX), a folic acid antagonist, is contraindicated in pregnancy (category X), because it is an abortifacient and has teratogenic effects, such as causing the development of craniofacial abnormalities, limb defects, and such CNS defects as anencephaly, hydrocephaly, and meningomyelopathy, especially with first-trimester exposure. [20] Because its active metabolites have a long half-life, methotrexate must be discontinued at least 3 months before conception; compensatory treatment with folic acid should be continued during that period and throughout pregnancy. Male partners should also discontinue methotrexate at least 3 months prior to attempting to conceive.

Pregnancy outcomes in women taking MTX (≤30 mg/week) either after conception or within 12 weeks before conception were evaluated in a prospective observational multicenter cohort study and compared with disease-matched women and women without autoimmune diseases. Major birth defects were more common in women with MTX exposure postconception than in the nondiseased comparison group (odds ratio [OR] 3.1, 1.03–9.5). However, there was no significant increase when compared with disease-matched controls. There was no difference in birth defects among women with exposure only in preconception and the two comparison groups. No birth defects in either exposure group were consistent with MTX embryopathy. [25]  While this information is helpful in risk managmenet counseling if an unplanned pregnancy occurs, MTX should always be discontinued prior to conception when pregnancy is being planned (category X). If a woman is receiving MTX, she should be using concomitant contraception.

Both the EULAR and BSR-BHPR guidelines recommend MTX at any dose should be avoided in pregnancy and stopped 3 months in advance of conception. [18, 19]   BSR-BHPR guidelines further recommend that women treated with low-dose MTX within 3 months of conception receive folic acid supplementation prior to and throughout pregnancy. In the case of accidental pregnancy in a woman on low-dose MTX, the drug should be stopped immediately, folic acid supplementation continued, and a careful evaluation of fetal risk carried out by local experts. [19]  

Leflunomide

Leflunomide (LEF), a pyrimidine synthesis inhibitor, is also a category X medication; it is extremely teratogenic and is absolutely contraindicated in pregnancy. Its half-life is 14-15 days, but the active metabolite undergoes extensive enterohepatic circulation; thus, the drug takes up to 2 years to be undetectable in plasma. Consequently, discontinuation of the drug before conception is insufficient. The drug needs to be eliminated with administration of cholestyramine (8 g tid for 11 d). Plasma levels of less than 0.02 mg/L should be verified with 2 separate tests at least 2 weeks apart. [26] If unacceptably high levels persist, additional cholestyramine may be given.

A study by Chambers et al of 64 women who became pregnant while taking leflunomide and underwent cholestyramine treatment found no significant increase in adverse pregnancy outcomes. These authors suggested that although the sample size was small, the findings can provide some reassurance to women in this situation. [27]

Both the EULAR and BSR-BHPR guidelines recommend avoiding leflunomide in pregnancy and completing a cholestyramine washout procedure prior to conception. [18, 19]  BSR-BHPR guidelines further recommend that if accidental conception occurs during leflunomide therapy, the drug should be stopped immediately and cholestyramine washout given until plasma levels are undetectable. [19]

Sulfasalazine

Sulfasalazine (SSZ), a dihydrofolate reductase inhibitor, is a category B medication; it does not increase fetal morbidity or mortality and is considered safe in pregnancy. [28]  

Both EULAR and BSR-BHPR guidelines support continuation of sulfasalazine wtith folic acid supplementation throughout pregnancy, based on current evidence indicating no increased rate of congenital malformations. [18, 19]

Azathioprine

Azathioprine (AZA), although a category D medication, can be used if the benefits outweigh the risks. AZA crosses the placenta, but the fetal liver lacks the enzyme inosinate pyrophosphorylase, which converts AZA to its active metabolite, 6-mercaptopurine; thus, the fetus is protected from the agent's teratogenic effects.

A meta-analysis of four studies that evaluated AZA/6-mercaptopurine use in 312 pregnant women with inflammatory bowel disease (IBD) found no increased risk for spontaneous abortion, prematurity or low birth weight. However, an increased risk for congenital abnormalities was found in women taking the drug, compared with women with IBD not on medications (OR, 2.95; 95% CI, 1.03-8.43). [29]

Both EULAR and BSR-BHPR guidelines support continuation of AZA throughout pregnancy in doses 18</ref> [19]

Hydroxychloroquine

HCQ, an antimalarial agent, is considered a category C medication. Previous reports of fetal toxicity with this agent were based on the effects of chloroquine, which has 2.5 times the amount of tissue deposition as HCQ. No fetal toxicity is associated with HCQ at the dosage used for RA and connective-tissue disease (6.5 mg/kg body weight). [30] Several studies and case series have provided further evidence that no fetal toxicity is associated with HCQ therapy in mothers. [31, 32, 33]

BSR-BHPR guidelines find HCQ the antimalarial of choice in women with rheumatic disease who are planning a pregnancy and recommend continuing use during pregnancy. [19]  EULAR guidelines also support use throughout pregnancy, based on current evidence indicating no increased rate of congenital malformations. [18]

Tumor necrosis factor–alpha antagonists

Medications in the anti–tumor necrosis factor (TNF)-alpha class (eg, etanercept, adalimumab, infliximab, golimumab, and certolizumab) are commonly used in the treatment of RA. These agents have been labeled as class B medications; animal studies have shown no harm to the fetus, [34, 35] but thus far, no randomized, blinded, placebo-controlled trials on potential teratogenicity in humans have been completed. Numerous case reports have shown positive outcomes with anti–TNF-alpha use in pregnancy, with an incidence of spontaneous abortion and birth defects similar to that in the general population. [4, 6, 7, 8, 36, 37, 38, 39]

Pregnancy outcomes of 495 women on adalimumab, infliximab, etanercept, certolizumab pegol or golimumab were evaluated in a prospective observational multicenter cohort study and compared with 1532 outcomes from a non-exposed random sample. Major birth defects were reported in 5% of the exposed group as compared to 1.5% in nondiseased controls. The risk of preterm birth was increased, but not the risk of spontaneous abortion. Birth weights adjusted for gestational age and sex were significantly lower in the exposed group compared to the non-exposed cohort (P = 0.02). [40]

A meta-analysis of 13 studies evaluating the risk of pregnancy outcomes in patients with various immune-mediated diseases (including RA, IBD, and others) treated with anti–TNF-α agents found that anti-TNF treated patients were at risk for preterm birth, spontaneous abortion and low birth weight compared with the general population, but the risks were comparable to those in female patients with immune-mediated diseases who were not treated with anti–TNF-α agents. [41]

The death of a 4.5-month-old infant from disseminated tuberculosis following routine bacillus Calmette-Guerin (BCG) vaccination at 3 months of age has been linked to the mother’s treatment with infliximab during pregnancy. It has been suggested that clinicians exercise caution in the use of anti-TNF in late pregnancy and that neonates who have had exposure to anti-TNF agents in utero should not receive any live vaccines for the first 6 months of life. [42]

The individual TNF inhibitors differ in terms of placental transfer. Certolizumab may have a safety advantage, as smaller amounts of the drug are known to pass into fetal circulation. [29]

A comparison of pregnancy outcomes of 74 women exposed to adalimumab and 80 women with RA not exposed found no difference in the frequency or relative risk of major birth defects between adalimumab-exposed women, unexposed women with RA, and healthy women. Among the specific birth defects in the adalimumab cohort, no pattern was evident. Preterm delivery occurred at similar rates in the adalimumab-exposed and RA comparison groups (adjusted hazard ratio [HR]=1.08, 95% CI 0.41 to 2.83). [43]

The EULAR guidelines make the following recommendations for use of anti-TNF medications [18] :

  • Infliximab/adalimumab:  Can be continued up to 20 weeks gestation; if indicated, it can be used throughout pregnancy, based on current evidence indicating no increased rate of congenital malformations 
  • Golimumab: Because of limited evidence, alternative medications should be considered for treatment throughout pregnancy
  • Etanercept: Can be continued up to 30–32 weeks of gestation; if indicated, it can be used throughout pregnancy, based on current evidence indicating no increased rate of congenital malformations 
  • Certolizumab: Can be used throughout pregnancy, based on current evidence indicating no increased rate of congenital malformations

BSR-BHPR guidelines include the following recommendations [19] :

  • Infliximab (IFX) may be continued until 16 weeks and etanercept (ETA) and adalimumab (ADA) may be continued until the end of the second trimester 
  • To ensure low/no levels of drug in cord blood at delivery, ETA and ADA should be avoided in the third trimester and IFX stopped at 16 weeks. 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
  • Certolizumab is compatible with all three trimesters of pregnancy and has less placental transfer than other TNF inhibitors (TNFs) 
  • Golimumab is unlikely to be harmful in the first trimester 

Rituximab

Rituximab (Rituxan), a monoclonal antibody that inhibits CD20 antigen on B lymphocytes, is indicated for the treatment for moderate to severe RA. It is a pregnancy category C medication and should be stopped 12 months prior to attempting conception. 

Case reports have also shown that rituximab therapy results in detectable levels of the drug in cord blood and results in B-cell depletion in the mother and the neonate. [44, 45, 46, 47, 48, 49]

Recovery of B-cell levels in the neonate has been reported to occur at age 3-4 months and does not appear to impair antibody formation in response to immunizations. The dosing of rituximab in case reports was 375 mg/m2 for 1-6 cycles. Mothers and newborns exposed to rituximab during second and third trimester should be monitored for the risk of infections, since neutropenia and B-cell depletion have been described in newborns. [44, 48, 49]

The EULAR guidelilnes recommend use in exceptional cases early in gestation; use at later stages of pregnancy increase risk of B cell depletion and other cytopenias in the neonate. [18]  BSR-BHPR guidelines recommend stopping rituximab 6 months before conception. [19]  

Anakinra

Anakinra (Kineret), an interleukin 1 receptor antagonist, is used to treat severe RA. Anakinra is a pregnancy category B medication. No adverse effects have been reported in rats and rabbits receiving up to 100 times the recommended human dose. No data are available to indicate whether anakinra is excreted in human milk. 

Very little information is available on its effects in pregnancy.  Less than 20 cases have been reported in the literature. The largest series evaluated 9 births to women with cryopyrin-associated periodic syndromes and anakinra exposure. There was a single fetus of a twin pregnancy that died in the setting of renal agenesis with an NLRP3 mutation. No other birth defects or premature delivery were noted. [50]

Citing an insufficient documentation of fetal safety,  EULAR recommends use of anakinra before and during pregnancy when there are no other well-studied options available for treatment. [18]  BSR-BHPR guidelines note there is limited evidence on which to base a recommendation for use of anakinra in pregnancy, but unintentional exposure in the first trimester is unlikely to be harmful. [19]  

Abatacept

Abatacept (Orencia) is a selective co-stimulation modulator that binds to CD80 and CD86, thereby inhibiting activation of T lymphocytes and interactions with CD28. This drug is indicated for the treatment of moderate to severe RA. Abatacept is considered a pregnancy risk factor C and should be used during pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus. Attempts to conceive should occur 14 weeks after the last abatacept dose, which would correlate with five half-lives of abatacept. [3]

The largest series of maternal exposure to abatacept is 151 pregnancies with 86 live births. [51]  Spontaneous abortion was reported in 40 pregnancies (over half of patients were also receiving MTX) and 19 women chose elective abortion. Two of the mothers were also receiving LEF and mycophenolate. Seven (8.1%) congenital anomalies were identified:

  • Cleft lip/palate
  • Congenital aortic anomaly
  • Meningocele
  • Pyloric stenosis
  • Skull malformation
  • Trisomy 21 with premature rupture of membranes at 17 weeks and subsequent infant death
  • Ventricular septal defect and congenital arterial malformation

Both EULAR and BSR-BHPR guidelines recommend avoiding treatment with abatacept during pregnancy, due to the lack of data on fetal safety. [18, 19]

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Postpartum and Breastfeeding

Patients with rheumatoid arthritis (RA) must be monitored closely following delivery, because they have the potential to have arthritis flare-ups during the postpartum period. Hyperprolactinemia has been associated with worsening of RA. Thus, breastfeeding may increase the likelihood of arthritis flare-ups.

Nonsteroidal anti-inflammatory drugs

NSAIDs can be used with caution, provided newborns do not have jaundice, because NSAIDs can displace bilirubin and predispose patients to kernicterus. If NSAIDs must be used during breastfeeding, only NSAIDs with a known safety record should be used. [20]

EULAR guidelines find non-selective NSAIDS compatible with breastfeeding. The selective COX-2 inhibitor celecoxib has sufficient data to recommend use while breastfeeding. [18]

Prednisone

Prednisone can be used safely during breastfeeding, because only small amounts (5% of the glucocorticoid dose) are secreted in breast milk. Nursing mothers taking doses higher than prednisone 20 mg once or twice daily should pump and discard breast milk for 4 hours following the steroid dose to minimize drug exposure to the infant. [52]

BSR-BHPR guidelines find prednisolone compatible with breastfeeding. [19]

Hydroxychloroquine

HCQ is found in human breast milk, and the infant may be exposed to 2% of the maternal dose per kilogram per day. Although the elimination is slow and there is a potential risk for accumulation in the infant, most experts believe that the drug may be continued during breastfeeding. HCQ can potentially displace bilirubin and result in the development of kernicterus. The drug should be discontinued if the neonate has jaundice.

Both EULAR and BSR-BHPR guidelines find HCQ compatible with breastfeeding. [18, 19]

Methotrexate

Methotrexate is excreted in breast milk in low concentrations and can accumulate in neonatal tissues; thus, it is contraindicated during breastfeeding. [53]  Both EULAR and BSR-BHPR guidelines recommend that nursing mothers avoid methotrexate. [18, 19]

Leflunomide

Leflunomide should not be used during breastfeeding. Leflunomide is excreted into animal milk; whether it is excreted into human milk is unknown, [54]

Sulfasalazine

Only negligible amounts of SSZ were found to transfer into breast milk. [55] SSZ is believed to be safe during nursing, although the American Academy of Pediatrics has cited a reported case of bloody diarrhea in an infant as a reason to use caution with this drug during nursing. [56]

Both EULAR and BSR-BHPR guidelines find SSZ compatible with breastfeeding in healthy, full-term infants. [18, 19]

Other medications

Although it is unknown whether rituximab is excreted in human milk, immunoglobulin G is present in human milk, and rituximab has been detected in the milk of monkeys. [44, 48, 49]  According to EULAR recommendations, when rituximab is administered before 22 weeks, vaccinations can be performed according to local guidelines (live vaccines included). When administered later in pregnancy, live vaccines should be avoided till 6 months of age. Due to the lack of data, lactation should be avoided. [18]  

Until more data are available on TNF-alpha antagonists and lactation, breastfeeding should probably be avoided during therapy with these agents. A prospective study in three nursing mothers treated with infliximab for Crohn disease found that infliximab was not detectable in their breast milk or in their infants' sera. [57]  These authors suggest that mothers who are taking infliximab should not be discouraged from breastfeeding. In case reports, however, small amounts of etanercept were found in the breast milk of lactating patients with RA; the risk this may pose is unknown. [58, 59]  

The EULAR guidelines find TNF-alpha agents compatible with breastfeeding; BSR-BHPR guidelines advise use with caution until further information is available. [18] [19]

Because no data are available on the use of anakinra or abatacept in breastfeeding, both EULAR and BSR-BHPR guidelines recommend lactation be avoided during therapy with these agents. [18, 19]

Up to date information on medication safety in breastfeeding is available at the Drugs and Lactation Database (LactMed).

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