Rheumatoid arthritis and pregnancy

INTRODUCTION — There is a female predominance among patients with rheumatoid arthritis (RA), and many of these patients are of childbearing age [1]. Thus, the management of RA during conception and pregnancy is a common challenge for rheumatologists and obstetricians. In many patients with RA, disease activity will improve in the gravid state. However, in patients whose RA flares or remains active during pregnancy, modification of treatment to minimize potential fetal toxicity while maintaining adequate disease control can be challenging.

The influence of RA upon fertility and pregnancy, the influence of pregnancy upon the disease, and the management of RA during conception, pregnancy, and lactation will be reviewed here. The use of antiinflammatory and immunosuppressive drugs in patients with rheumatic diseases during pregnancy and lactation, paternal use of antirheumatic drugs, and general principles in the management of RA are discussed in detail separately. (See "Safety of rheumatic disease medication use during pregnancy and lactation" and "Effects of antiinflammatory and immunosuppressive drugs on gonadal function and teratogenicity in men with rheumatic diseases" and "General principles and overview of management of rheumatoid arthritis in adults".)

EFFECT OF RHEUMATOID ARTHRITIS ON FERTILITY — Smaller family size has been observed in women with rheumatoid arthritis (RA) [2-4]. The reasons for this appear multifactorial and include patient choice, medication use during the usual period of family planning, and subfertility related to disease activity [2-7]:

●Patient preferences – According to two telephone surveys involving a total of approximately 1000 female patients, having RA negatively affected their decision to have children [2,3]; reasons cited included concerns over carrying the child, caring for the child, and passing RA on to biologic offspring, as well as concern that disease activity would be adversely impacted. Women diagnosed before age 18 and those who had not yet had children were more likely to have fewer pregnancies and children, compared with women diagnosed after age 30. Similarly, a Norwegian registry-based study also reported fewer pregnancies in women who were diagnosed with RA before having children [4].

●Reduced fertility in women with rheumatoid arthritis – In one survey of women with RA, over half of the respondents had fewer pregnancies than intended; of these women, 42 percent cited infertility as a reason [3]. Disease activity and medications have been cited as factors associated with reduced fertility in women with RA [3,7-9]. Additionally, one study [8], but not another [5], found evidence for reduced ovarian reserve in women with RA, based upon low age-adjusted serum anti-Müllerian hormone (AMH) levels. A more recent study demonstrated that increase in disease activity correlated with lower AMH levels; however, there was no significant difference in AMH levels between patients with RA and controls from the general population [10].

●Longer time to conceive – Women with RA attempting to conceive have been found to have a longer time to pregnancy compared with women without RA [9]. A nationwide prospective cohort study in the Netherlands involving 245 women with RA attempting pregnancy or in their first trimester found that time to pregnancy exceeded 12 months in 42 percent of patients [7]; in addition to increased maternal age and nulliparity, RA-related factors associated with a longer time to pregnancy included increased disease activity and preconception use of nonsteroidal antiinflammatory drugs (NSAIDs) and prednisone (greater than 7.5 mg/day). These findings suggest that maintaining good disease control prior to conception may decrease time to pregnancy. Factors that were not associated with a prolonged time to pregnancy included disease duration, smoking, being seropositive for rheumatoid factor (RF) or anti-citrullinated peptide antibodies (ACPA), use of sulfasalazine (SSZ), and past use of methotrexate (MTX).

●Reduced fertility in men with rheumatoid arthritis – Few antirheumatic medications decrease sperm production. Cyclophosphamide, a cytotoxic alkylating agent that is rarely used for rheumatoid vasculitis, can cause irreversible azoospermia that may induce permanent infertility. In addition, SSZ can cause reversible oligospermia but has a limited impact on fertility. The adverse effects of these medications on male fertility are described in more detail separately. (See "Effects of antiinflammatory and immunosuppressive drugs on gonadal function and teratogenicity in men with rheumatic diseases", section on 'Adverse effects on spermatogenesis'.)

EFFECTS OF PREGNANCY ON DISEASE ACTIVITY

Disease activity during pregnancy — Approximately 50 to 70 percent of women with rheumatoid arthritis (RA) improve during pregnancy [11-15]. The decrease in disease activity generally starts in the first trimester and lasts through the duration of pregnancy. Though they may improve, half of women continue to have moderately to severely active RA through pregnancy [16].

Disease characteristics, such as duration of disease and functional class, do not appear to predict whether a patient will remit during pregnancy [17,18]. However, some data suggest that patients who lack both rheumatoid factor (RF) and anti-citrullinated peptide antibodies (ACPA) are more likely to improve during pregnancy when compared with patients with either or both autoantibodies [18]. Other factors that may impact disease activity during pregnancy include the degree of human leukocyte antigen (HLA) class II disparity between mother and fetus. Several studies have shown that increased HLA class II disparity between mother and fetus is more likely to be associated with improvement in disease activity [19,20].

The immunologic effects of pregnancy, including the maternal-fetal immune interface and the systemic maternal immune response, are reviewed in detail separately. (See "Immunology of the maternal-fetal interface".)

Not all studies have found improvement in symptoms with pregnancy. As an example, one report that evaluated the clinical course of 140 pregnant women with RA noted only minimal improvement in Health Assessment Questionnaire (HAQ) scores and in joint symptoms [21]. However, the results of the study should be interpreted with caution as the HAQ as an estimate of functionality is likely impacted by pregnancy itself [22].

Postpartum flare — Disease flares of RA are common during the several months postpartum, occurring in nearly half of patients according to a 2019 meta-analysis [15]. In addition, one study suggested an increased risk of newly developing RA in the first three months postpartum, approaching 11-fold after a woman's first pregnancy [13].

RA pregnancies are associated with higher cesarean delivery rates. Whether this is driven by patient choice, provider choice, obstetrical factors, or medical indication is unclear [23].

PREGNANCY OUTCOME — Pregnancy outcomes in women with well-controlled rheumatoid arthritis (RA) are comparable to those in the general population. However, patients with active disease may be at higher risk of adverse obstetric outcomes; overall, these risks are increased 1.4- to 2.2-fold compared with controls, including hypertensive disorders (11.1 versus 7.8 percent), intrauterine growth restriction (3.4 versus 1.6 percent), and cesarean delivery (37.2 versus 26.5 percent) [23]. Similarly, in a Danish study of 1739 RA pregnancies, women with higher levels of disease activity had a greater risk of preterm birth and small for gestational age infants [24].

Most reports have failed to show any increase in fetal morbidity or fetal losses in women with RA [25,26]. In a nationwide cohort study in Denmark of 1,917,723 children born between 1977 and 2008, including 13,556 children exposed to maternal RA or maternal preclinical RA [27], children born to mothers with RA were more likely to be born preterm (odds ratio [OR] 1.48, 95% CI 1.20-1.84), as were children of mothers in whom the diagnosis of RA was made following but not before the birth (OR 1.32, 95% CI 1.07-1.64). Even after adjusting for maternal age at birth, parity (one, two, or three), maternal education, smoking status, and mother's country of origin (Denmark or outside Denmark), the effects of several factors associated with preterm birth were not analyzed, including medication use and disease activity during pregnancy. The birth weight of children of mothers with RA or preclinical RA was also slightly reduced (87 grams) compared with children of mothers without RA. Paternal RA did not affect rates of either preterm birth or birth weight.

MANAGEMENT APPROACH — For women with rheumatoid arthritis (RA), counseling prior to conception, coordinated care among specialists, and medication management with shared decision-making are all important. Therapeutic choices are governed not only by disease severity but also by concerns regarding fetal teratogenicity and toxicity. Thus, the benefits and risks of antirheumatic therapeutics for the individual patient and her fetus are important considerations [28-31].

The approach to management is described here, and a more detailed discussion of the evidence regarding the safety and use of specific antiinflammatory and immunosuppressive medications in pregnancy and during lactation are presented in more detail elsewhere. (See "Safety of rheumatic disease medication use during pregnancy and lactation".)

Our approach to the treatment of patients with RA prior to and during pregnancy is generally consistent with the recommendations of the American College of Rheumatology (ACR) [32] and other major professional organizations (table 1) [33,34]:

Prior to pregnancy

Preconception counseling and testing

●In patients with RA who are contemplating pregnancy, it is helpful for the rheumatologist, obstetrician, and patient to discuss potential fertility issues, pregnancy outcomes in RA, disease activity during pregnancy and in the postpartum period, and medication use in the preconception period and during pregnancy and lactation. The benefits of keeping disease under good control must be balanced with the risk of any medications that are used.

●Patients with active RA should be managed by both a rheumatologist and a maternal fetal medicine specialist during pregnancy.

●Patients should plan pregnancy when their disease is under good control on medications compatible with pregnancy (eg, sulfasalazine [SSZ], hydroxychloroquine [HCQ], a tumor necrosis factor [TNF] alpha inhibitor) (table 1). Patients who are receiving medications for RA with a moderate to high risk of fetal harm (eg, methotrexate [MTX] and leflunomide [LEF]) should use highly effective contraceptive methods such as long-acting reversible contraceptives (LARCs). (See "Contraception: Counseling and selection", section on 'Discuss method characteristics' and "Intrauterine contraception: Background and device types" and "Contraception: Etonogestrel implant".)

●As recommended by the ACR, patients with RA should be tested for anti-Ro/SSA and anti-La/SSB antibodies once before or early in pregnancy, due to their associated increase in risk for neonatal lupus [32]. Given the relative persistence of these antibodies when present, repeat testing during pregnancy is not required. Screening and testing for these antibodies and for fetal heart block and other features of neonatal lupus are described in detail separately. (See "Neonatal lupus: Epidemiology, pathogenesis, clinical manifestations, and diagnosis", section on 'Screening and surveillance'.)

●Women with extensive cervical spine involvement due to RA should have an anesthesiology evaluation in case urgent surgery requiring intubation occurs. (See "Cervical subluxation in rheumatoid arthritis" and "Preoperative evaluation and perioperative management of patients with rheumatic diseases", section on 'Rheumatoid arthritis'.)

Medication management before pregnancy

●Folic acid supplementation – Patients should start folic acid supplementation prior to pregnancy once conception is being attempted; the appropriate dose is included in a prenatal multivitamin. (See "Preconception and prenatal folic acid supplementation".)

●NSAIDs – In women who have had recurrent (ie, two or more) first trimester losses and in those experiencing difficulty in conceiving, one can consider discontinuing nonsteroidal antiinflammatory drugs (NSAIDs) (table 1). There are case reports and some small series that have shown transient infertility, which appears to be mediated by inhibition of the rupture of the luteinized follicle, in some women treated with NSAIDs. Data in animals have also suggested that NSAIDs may interfere with ovulation and implantation. There are conflicting data regarding an increased risk of spontaneous abortion after NSAID use during the first trimester. (See "Safety of rheumatic disease medication use during pregnancy and lactation", section on 'NSAIDs'.)

●Glucocorticoids – The fluorinated glucocorticoids, such as betamethasone and dexamethasone, cross the placenta at higher concentrations without significant metabolism to inactive metabolites, and they can be used to hasten lung maturity in cases of expectant delivery of premature infants, but would not be used routinely for the management of active RA, particularly during pregnancy (table 1). Glucocorticoids (eg, prednisone, prednisolone, and methylprednisolone) should be maintained at the lowest dose possible. Nonfluorinated glucocorticoids, including prednisone, prednisolone, and methylprednisolone, cross the placenta at very low concentrations and are largely metabolized to inactive metabolites in the placenta before reaching the fetus; thus, they are relatively safe to use during pregnancy in low to moderate doses. Dosing should kept as low as possible as doses of oral glucocorticoids of >10 mg prednisone equivalent has been associated with increased risk of preterm birth [35]. (See "Safety of rheumatic disease medication use during pregnancy and lactation", section on 'Glucocorticoids' and "Pregnancy in women with systemic lupus erythematosus", section on 'Selective use allowed during pregnancy'.)

●Hydroxychloroquine – HCQ crosses the placenta (table 1). However, most studies have not described fetal toxicity with HCQ doses used for the treatment of systemic lupus erythematosus (SLE) or other rheumatic diseases [36-38]. One population-based cohort study of rheumatic disease patients involving 2045 HCQ-exposed pregnancies and 21,679 matched pregnancies not exposed to HCQ showed that HCQ use during the first trimester was associated with a small increased risk of major congenital malformations (adjusted relative risk 1.26, 95% CI 1.04-1.54) [39]. The absolute risk for exposed infants was slightly higher than in unexposed infants of autoimmune rheumatic disease patients (5.48 versus 4.32 percent). However, no particular pattern of malformations was identified. Moreover, this study did not account for variables not included in the data set, such as use of alcohol, tobacco, folic acid, other drugs, and over-the-counter medications, as well as unidentified confounders [40]. The benefits of HCQ during pregnancy discussed below outweigh the potential risks raised by the aforementioned study.

●Methotrexate – MTX should be stopped at least one to three months prior to conception in women because of its teratogenic risk and should be avoided throughout pregnancy (table 1). If conception occurs in a woman taking MTX, the medication should be stopped immediately and folic acid 5 mg/day taken for the duration of the pregnancy. Referral to a high-risk obstetrician can be useful to ascertain the risk for congenital anomalies and determine optimal pregnancy management in this situation. (See "Safety of rheumatic disease medication use during pregnancy and lactation", section on 'Methotrexate'.)

The use of MTX in men prior to or around the time of conception does not appear to have adverse consequences for fertility or pregnancy outcomes and is discussed in more detail separately. (See "Effects of antiinflammatory and immunosuppressive drugs on gonadal function and teratogenicity in men with rheumatic diseases".)

●Leflunomide – Pregnancy should be avoided in patients on LEF until undetectable serum concentrations (<0.02 mg/L) are verified because of reports of teratogenicity in animals (table 1) (see "Safety of rheumatic disease medication use during pregnancy and lactation", section on 'Leflunomide'). This can be achieved by discontinuation of this medication two years prior to conception or by the use of an enhanced drug elimination procedure using cholestyramine. (See "Pharmacology, dosing, and adverse effects of leflunomide in the treatment of rheumatoid arthritis".)

Despite these concerns, there have been several reassuring studies that have not shown an increased risk of congenital anomalies or spontaneous abortions in pregnancies with LEF exposure. One report of data from a Canadian registry did not find an increased incidence of congenital anomalies or spontaneous abortions in their cohort of 72 pregnancies and births exposed to LEF [41]. Several other studies also reported no increased risk of congenital anomalies in LEF-exposed pregnancies [42-44].

●TNF inhibitors, other biologics, and targeted synthetic disease-modifying antirheumatic drugs (tsDMARDs) – In patients with active disease who are on tumor necrosis factor (TNF) alpha inhibitors, these medications can be continued (table 1). Most professional societies recommend discontinuing these medications in the third trimester, although in patients with active disease, one may continue these medications through delivery if critically important for disease control. Certolizumab is pegylated and does not cross the placenta in significant amounts and can be continued throughout pregnancy. (See 'During pregnancy' below.)

There are insufficient data to draw conclusions regarding the safety of the other biologics or tsDMARDs (ie, Janus kinase [JAK] inhibitors) during pregnancy; thus, these medications should be discontinued prior to pregnancy.

During pregnancy

General and obstetric care — Several issues may modify routine obstetric practice and care in women with RA:

●Patients with RA can be seen at typical intervals for pregnancy management except in the case of active RA or for a specific obstetric concern that requires more frequent care.

●Patients with pregnancy complications such as gestational diabetes, pregnancy-induced hypertension, and preeclampsia should be followed accordingly based upon usual obstetric practice. (See "Gestational diabetes mellitus: Obstetric issues and management" and "Gestational hypertension" and "Preeclampsia: Antepartum management and timing of delivery".)

●Patients with anti-Ro/SSA and anti-La/SSB antibodies should be screened and managed accordingly. (See 'Preconception counseling and testing' above and "Neonatal lupus: Epidemiology, pathogenesis, clinical manifestations, and diagnosis", section on 'Screening and surveillance'.)

●Women with RA should not be delivered early unless indicated for obstetric reasons.

●Usual management is performed for patients who require a cesarean delivery, other than particular attention to the risks of intubation in patients with cervical spine disease. (See 'Preconception counseling and testing' above and "Cervical subluxation in rheumatoid arthritis" and "Preoperative evaluation and perioperative management of patients with rheumatic diseases", section on 'Rheumatoid arthritis'.)

●Recommendations for exercise and physical activity do not differ for most patients with RA from other pregnant women, except when modifications may be required because of limitations due to active arthritis or prior joint injury or deformity. (See "Exercise during pregnancy and the postpartum period" and "Nonpharmacologic therapies for patients with rheumatoid arthritis", section on 'Physical activity and exercise'.)

Medication management during pregnancy

●NSAIDs, including aspirin – In patients whose RA becomes active during pregnancy, nonsteroidal antiinflammatory drugs (NSAIDs) can be used and are generally considered safe until week 20; however, from 20 weeks on, NSAIDs should be avoided, with the exception of low-dose aspirin being given for obstetric-related indications, because of the rare risk of fetal renal compromise and oligohydramnios (table 1). After week 30, there is an increased risk of premature closure of the ductus arteriosus and inhibition of labor. (See "Safety of rheumatic disease medication use during pregnancy and lactation", section on 'Aspirin (low dose)'.)

There are insufficient data on the safety of selective cyclooxygenase 2 (COX-2) inhibitors during pregnancy; therefore, these drugs should be avoided.

There are only limited data regarding moderate- to high-dose aspirin, which should be avoided throughout pregnancy. This is in distinction to low-dose aspirin (81 mg/day), which is sometimes used as part of the management of antiphospholipid syndrome and for prevention of preeclampsia. Adverse effects reported in the fetus following maternal use of high-dose aspirin include mortality, intrauterine growth retardation, salicylate intoxication, bleeding abnormalities, and neonatal acidosis [45-47]. Use of high-dose aspirin close to delivery may cause premature closure of the ductus arteriosus. Adverse effects reported in the mother include anemia, hemorrhage, prolonged gestation, and prolonged labor.

Evidence regarding the safety of NSAIDs and low-dose aspirin use during pregnancy is discussed in detail separately. (See "Safety of rheumatic disease medication use during pregnancy and lactation", section on 'NSAIDs'.)

●Glucocorticoids – In patients in whom NSAIDs are inadvisable or inadequate, we use the lowest dose of prednisone necessary for disease control (table 1). We try to limit prednisone dosing to no more than 10 mg/day. Our approach to the use of stress-dose glucocorticoids for women undergoing a cesarean delivery is described in detail separately. (See "The management of the surgical patient taking glucocorticoids" and 'Medication management before pregnancy' above and "Safety of rheumatic disease medication use during pregnancy and lactation", section on 'Glucocorticoids'.)

●Conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) – HCQ, sulfasalazine (SSZ), and azathioprine (AZA) can be continued and used in patients with an inadequate response to NSAIDs or prednisone (table 1). For moderately active disease, patients can be maintained on HCQ and/or SSZ. Evidence regarding the safety of these medications is described separately. (See "Safety of rheumatic disease medication use during pregnancy and lactation", section on 'Hydroxychloroquine' and "Safety of rheumatic disease medication use during pregnancy and lactation", section on 'Sulfasalazine' and "Safety of rheumatic disease medication use during pregnancy and lactation", section on 'Azathioprine and 6-mercaptopurine'.)

Neither MTX nor LEF should be used during pregnancy, as discussed in detail separately. (See 'Medication management before pregnancy' above and "Safety of rheumatic disease medication use during pregnancy and lactation", section on 'Methotrexate' and "Safety of rheumatic disease medication use during pregnancy and lactation", section on 'Leflunomide'.)

●TNF inhibitors – Tumor necrosis factor (TNF) inhibitors may be continued during pregnancy (table 1). However, the duration of use depends upon the specific agent and the balance of individual risks and benefits. Our approach to the use of TNF inhibitors is generally consistent with the guidelines of the ACR, the European Alliance of Associations for Rheumatology (formerly the European League Against Rheumatism; EULAR), and the British Society for Rheumatology (BSR)/British Health Professionals in Rheumatology (BHPR) [32-34]:

•Infliximab, adalimumab, golimumab, and etanercept should be discontinued in the third trimester [33], although the use of these drugs can be extended, if necessary, to a later gestational age if benefits of disease control outweigh potential risks for an individual patient [34]. The major concern has been that continuing TNF alpha blockade may increase the risk of neonatal infection; however, available data have not shown a statistically significant increased risk of infection in neonates after exposure in utero to TNF alpha blockade [48,49]. (See "Safety of rheumatic disease medication use during pregnancy and lactation", section on 'Tumor necrosis factor inhibitors'.)

•Certolizumab may be continued throughout pregnancy. It crosses the placenta in low to undetectable amounts.

●Other biologics and targeted synthetic disease-modifying antirheumatic drugs (tsDMARDs) – Biologics that contain an immunoglobulin, such as rituximab, abatacept, and tocilizumab, do not cross the placenta in significant amounts until week 12 of gestation. Thus, these medications can be continued up until conception. There are insufficient data to conclude pregnancy safety for the small molecule tsDMARDs such as the JAK inhibitors (table 1).

Resistant or flaring disease activity

●Glucocorticoids (oral or intraarticular) can be used to manage disease flares or persistent moderately to highly active disease that is not adequately controlled with other medications. Glucocorticoid therapy during pregnancy may increase the risk of premature rupture of the membranes (PROM) and intrauterine growth restriction [50,51]. In addition, oral glucocorticoids can increase the risk of preterm birth [35]. In the mother, oral glucocorticoids may increase the risk of pregnancy-induced hypertension, gestational diabetes, osteoporosis, and infection [47]. The lowest effective dose of glucocorticoids should be used. (See 'Medication management before pregnancy' above and "Safety of rheumatic disease medication use during pregnancy and lactation", section on 'Glucocorticoids'.)

●In patients with disease refractory to routine management or with continued flares during pregnancy despite the use of glucocorticoids, if not already taking these medications, TNF inhibitors can be used (table 1). (See 'Medication management during pregnancy' above and "Safety of rheumatic disease medication use during pregnancy and lactation", section on 'Tumor necrosis factor inhibitors'.)

POSTPARTUM MANAGEMENT

Postpartum management of rheumatoid arthritis — For patients who are clinically quiescent in the postpartum period, the pregnancy medication regimen can be continued. For women who flare postpartum or who have a high likelihood of flaring, their prepregnancy regimen can be resumed with adjustment to medications for women who are breastfeeding. (See 'Medication use during breastfeeding' below.)

The demands of caring for a newborn can be particularly challenging in women with rheumatoid arthritis (RA) who are flaring in the postpartum period or who have restricted joint mobility. Patients with RA may need additional support or help during this time.

Medication use during breastfeeding — The majority of antirheumatic medications are compatible with breastfeeding, although there are certain antirheumatic medications that should be avoided during breastfeeding. Many of these restrictions pertain to the same medications for which use is restricted during pregnancy (table 1) [32]. The evidence regarding the safety of maternal use of antirheumatic disease medications during lactation is reviewed in detail separately. (See "Safety of rheumatic disease medication use during pregnancy and lactation".)

●Nonsteroidal antiinflammatory drugs (NSAIDs) can be used, but aspirin should be avoided.

●Prednisone can be taken in low doses. In patients taking 20 mg/day or greater, waiting at least four hours after the dose prior to nursing is sufficient to substantially reduce exposure to the nursing child.

●Hydroxychloroquine (HCQ) is compatible with nursing.

●Sulfasalazine (SSZ) is generally compatible with breastfeeding in healthy, full-term infants. SSZ is transferred in low concentration into breast milk and is considered compatible with breastfeeding However, women taking SSZ should avoid breastfeeding premature infants or those with hyperbilirubinemia or glucose-6-phosphate dehydrogenase (G6PD) deficiency. A case of bloody diarrhea has been reported in a newborn exposed to this medication during nursing, and diarrhea during breastfeeding may require discontinuation of nursing. (See "Safety of rheumatic disease medication use during pregnancy and lactation", section on 'Sulfasalazine'.)

●Biologics such as tumor necrosis factor (TNF) alpha inhibitors, abatacept, anakinra, rituximab, sarilumab, and tocilizumab can be continued or initiated during lactation. These biologic agents are large molecules and therefore reach the breast milk in low concentration. Furthermore, they are unlikely to be effectively absorbed orally by the newborn.

●Azathioprine (AZA) is considered compatible with breastfeeding. Excretion in breast milk is very low in most patients. (See "Safety of rheumatic disease medication use during pregnancy and lactation", section on 'Azathioprine and 6-mercaptopurine'.)

●Methotrexate (MTX), leflunomide (LEF), cyclosporine, and cyclophosphamide should be avoided in nursing women.

●The Janus kinase (JAK) inhibitors and other targeted synthetic disease-modifying antirheumatic drugs (tsDMARDs) should be avoided in lactating women as these agents readily transfer into breast milk.

In patients who flare during the postpartum period, attention should be given to the use of medications compatible with nursing. In those patients who choose not to breastfeed, their prepregnancy medications can be resumed.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Rheumatoid arthritis".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topics (see "Patient education: Rheumatoid arthritis and pregnancy (The Basics)")

●Beyond the Basics topics (see "Patient education: Rheumatoid arthritis and pregnancy (Beyond the Basics)" and "Patient education: Disease-modifying antirheumatic drugs (DMARDs) in rheumatoid arthritis (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●Pregnancy and disease activity – Approximately 50 to 70 percent of women with rheumatoid arthritis (RA) experience a reduction in disease activity during pregnancy. This reduction generally starts in the first trimester and lasts for several weeks or months into the postpartum period. However, roughly one-half of patients eventually flare during the postpartum period, usually within the first three months. There may also be an increased risk of developing RA in the first three months postpartum, particularly after a woman’s first pregnancy. (See 'Disease activity during pregnancy' above and 'Postpartum flare' above.)

●Pregnancy outcomes – RA does not increase fetal losses. There is a higher rate of intrauterine growth restriction, pregnancy-induced hypertension, and cesarean delivery among RA patients compared with the general population. (See 'Pregnancy outcome' above.)

●Chronic medication management in the preconception, prenatal, and breastfeeding period

•Patients using glucocorticoids – Most patients can continue or use glucocorticoids during pregnancy and breastfeeding, using the lowest dose necessary for disease control (table 1). Nonfluorinated glucocorticoids (eg, prednisone, prednisolone, methylprednisolone) do not cross the placenta and are safe to use at low to moderate doses. However, prednisone doses greater than 10 mg/day (or equivalent glucocorticoid) may be associated with preterm birth.

Fluorinated glucocorticoids (eg, betamethasone, dexamethasone) cross the placenta and are not typically used in pregnant patients with RA. (See 'Medication management during pregnancy' above and 'Medication use during breastfeeding' above.)

•Patients using nonsteroidal antiinflammatory drugs – Women who have had two or more first trimester losses or have difficulty conceiving should stop taking nonsteroidal antiinflammatory drugs (NSAIDs), which have been associated with transient infertility. NSAIDs can be used safety through week 20 of gestation but should not be used during the second half of pregnancy because of the risk for oligohydramnios (table 1). Moderate- to high-dose aspirin should be avoided throughout pregnancy. NSAIDs other than aspirin can be used safely during breastfeeding. (See 'Medication management before pregnancy' above and 'Resistant or flaring disease activity' above.)

•Patients using conventional synthetic disease-modifying antirheumatic drugs (csDMARDs)

-Methotrexate – Methotrexate (MTX) should be stopped one to three months prior to conception and should not be restarted until the patient is no longer breastfeeding (table 1).

-Leflunomide – Pregnancy should be avoided in patients on leflunomide (LEF) until undetectable serum concentrations are verified (table 1). LEF should not be restarted until the patient is no longer breastfeeding.

-Hydroxychloroquine and azathioprine – Both hydroxychloroquine (HCQ) and azathioprine (AZA) are safe for use during pregnancy and breastfeeding (table 1).

-Sulfasalazine – Sulfasalazine (SSZ) may be used throughout pregnancy (table 1). SSZ may also be used during breastfeeding except when the infant has hyperbilirubinemia, has glucose-6-phosphate dehydrogenase deficiency, or is premature. (See 'Medication management before pregnancy' above and 'Medication management during pregnancy' above and 'Medication use during breastfeeding' above.)

•Patients using biologic (b) DMARDs

-Tumor necrosis factor inhibitors – These can be continued through the first two trimesters of pregnancy (table 1). Infliximab, adalimumab, golimumab, and etanercept should generally be discontinued in the third trimester because of a theoretical risk of neonatal infection, although they can be used in late pregnancy on a case-by-case basis. Certolizumab may be continued during the entire pregnancy, since PEGylation prevents it from crossing the placenta. All tumor necrosis factor (TNF) inhibitors are compatible with breastfeeding.

-Other bDMARDs – Biologics that contain an immunoglobulin, such as rituximab, abatacept, and tocilizumab, do not cross the placenta in significant amounts until week 12 of gestation. Thus, these medications may be used throughout pregnancy and breastfeeding (table 1). (See 'Medication management during pregnancy' above and 'Medication use during breastfeeding' above.)

●Patients using targeted synthetic (ts) DMARDs – Janus kinase (JAK) inhibitors should be discontinued prior to pregnancy and should not be restarted until the patient is no longer breastfeeding. (See 'Medication management before pregnancy' above and 'Medication use during breastfeeding' above.)

●Flare management during pregnancy – In patients whose RA becomes active during pregnancy, we advise limited use of NSAIDs, which can be given up to week 20. If NSAIDs are inadequate, we try to use no more than 10 mg/day prednisone to achieve disease control. HCQ and SSZ can be used in patients with an inadequate response to NSAIDs or prednisone. TNF inhibitors can be initiated if patients flare. (See 'During pregnancy' above and 'Resistant or flaring disease activity' above.)

●Flare management while breastfeeding – Women who are breastfeeding can use NSAIDs, but aspirin should be avoided. Prednisone can be taken in low doses; when the dose is 20 mg/day or more, patients should wait at least four hours prior to nursing. In patients whose symptoms recur during the postpartum period, TNF inhibitors, HCQ, and AZA may be used. SSZ is also compatible with nursing except when the infant has hyperbilirubinemia, has glucose-6-phosphate dehydrogenase deficiency, or is premature. Breastfeeding patients should avoid MTX, LEF, JAK inhibitors, cyclosporine, and cyclophosphamide. (See 'Medication use during breastfeeding' above.)