A clinical care pathway for managing pregnancy in patients with inflammatory arthritis

Abstract

Inflammatory arthritis (IA) disproportionately affects women and is particularly concerning in those of childbearing age, where unique considerations are required in their management. Existing practice guidelines provide recommendations on managing IA before, during, and after pregnancy. However, there is a lack of Canadian clinical resources to support shared decision-making between clinicians and patients with IA. A comprehensive care plan for women of childbearing age with IA should include preconception counselling, a 40-week pregnancy plan, and postpartum care. Preconception counselling should address contraception to reduce the risk of unplanned pregnancy, as well as the bidirectional impact of disease on pregnancy outcomes. The 40-week pregnancy plan includes monitoring disease activity, assessing medication safety, and planning delivery. The postpartum care plan should emphasize medication management, particularly in the context of breastfeeding and vaccinations for infants exposed to biologic medications in utero. The goal of this clinical care pathway is to provide a resource for managing patients with IA who are contemplating pregnancy, are pregnant, or are in the postpartum period.

Key Points • Managing women of childbearing age with inflammatory arthritis (IA) requires a unique set of considerations. • There is a lack of Canadian clinical resources to guide the management of women of childbearing age with IA. • This clinical care pathway is intended as a resource for multidisciplinary teams managing patients with IA who are contemplating pregnancy, are pregnant, or are in the postpartum period. • The proposed care pathway includes preconception counselling, a 40-week pregnancy plan, and postpartum care for women of childbearing age with IA.

Introduction

Arthritis affects approximately 6 million Canadians, making it the most prevalent chronic health condition in the country, and prevalence is expected to increase by another 3 million by 2040 [1]. Inflammatory arthritides (IA) include conditions such as rheumatoid arthritis (RA), psoriatic arthritis (PsA), spondyloarthritis (SpA), and juvenile idiopathic arthritis. Prevalence varies by etiology, with RA representing the most common autoimmune IA, affecting approximately 1.2% of the Canadian population (about 375,000 individuals) [2]. More women than men are affected by IA, with a reported female-to-male ratio of 3:1 in RA [3]. The predominance of most rheumatic diseases in women is thought to result from several factors, including sex hormones, epigenetics, and differences in the gut microbiome [3, 4]. This disproportionate prevalence significantly affects many aspects of women’s lives, including family planning [5, 6].

Many women with inflammatory arthritis who are considering pregnancy have unaddressed anxiety and concerns that often delay their decision to become a mother [7].

Common concerns include managing disease activity during and after pregnancy, and the impact of disease on pregnancy outcomes and infant health [7–9]. Women also seek reliable information on the potential effects of IA medications on infants exposed in utero and their safety during breastfeeding [8–10]. These questions and concerns highlight the need for an evidence-based clinical resource to guide the management of IA before, during, and after pregnancy. Practice guidelines from the British Society of Rheumatology (BSR), American College of Rheumatology (ACR), and the European League Against Rheumatism (EULAR) provide thorough evaluations of evidence and recommendations on family planning, pregnancy, and breastfeeding in the context of rheumatic disease management [11–16]. However, there are no Canadian guidelines, and a resource is still needed to support shared decision-making among clinicians and patients with IA in everyday practice.

Herein, we present a comprehensive clinical care pathway for managing pregnancy in patients with IA, specifically RA, PsA, and SpA. Patients with other rheumatic diseases, such as vasculitis and connective tissue diseases (e.g., myositis, scleroderma, and systemic lupus erythematosus), are not included within the scope of this pathway and may require additional considerations. This pathway is intended for use by rheumatologists, obstetricians, and other healthcare providers caring for women with rheumatic diseases in the peri-pregnancy period (preconception, pregnancy, and postpartum). Our guidance is based on a review of the latest evidence, best practice recommendations, and expert input from relevant disciplines. The goal is to provide healthcare providers with an evidence-based, practical approach to managing the complex needs of these patients, while empowering patients to make informed decisions about family planning in consultation with their care team.

Figure 1 outlines the proposed clinical care pathway for managing pregnancy in patients with IA, highlighting three distinct stages of the care continuum with associated counselling topics at each stage.

Fig. 1.

Inflammatory arthritis care continuum during pregnancy. IA, inflammatory arthritides

Family planning and preconception counseling

General counselling

A survey of 439 women with inflammatory arthritis in Canada found that only 46% received counselling from their rheumatologists on pregnancy risks and medication safety prior to conception [17]. Rheumatologists should continually address the reproductive needs of their patients, particularly early in care and when medication changes are made [11, 18]. They should also discuss contraception and plans for pregnancy with all women of reproductive age, disease and medication management during pregnancy, and refer patients to other specialists and allied healthcare providers when needed [18].

The care team is not the only source of pregnancy-related information for patients. A patient’s current beliefs and knowledge may be revealed through high-quality discussions and can provide insight into important knowledge gaps. Consider asking the patient what they have read, what they have been told, and what they have seen on the internet during a consultation. This information can facilitate a productive conversation between physicians and patients preparing for pregnancy. Figure 2 summarizes key considerations for family planning and preconception counselling in patients with IA.

Fig. 2.

Preconception planning in women with inflammatory arthritis. Anti-Ro/SSA, Sjogren syndrome type A antigen; anti-RO/SSB, Sjogren syndrome type B antigen; HCQ, hydroxychloroquine; IA, inflammatory arthritides; LEF, leflunomide; MTX, methotrexate; RSV, respiratory syncytial virus; SSZ, sulfasalazine; Tdap, Tetanus, diphtheria, and acellular pertussis

Contraception

Contraception is widely underutilized among women with IA [11, 19]. Reliable contraception is recommended until pregnancy is clinically appropriate, ideally once the patient achieves low disease activity or remission on pregnancy-compatible medications [11, 19, 20]. This reduces the risks associated with an unplanned pregnancy, such as disease flare, birth defects associated with teratogenic medication use, and adverse pregnancy outcomes (e.g., pregnancy loss, prematurity and growth restriction) [11]. Contraception recommendations will be influenced by clinical factors, such as potential drug-drug interactions, comorbidities and presence of antiphospholipid antibodies [11]. Long-acting reversible contraceptives are encouraged as first-line options for all women with IA because of safety and efficacy (failure rate of < 1% per year) [11]. These options include intrauterine devices (copper or progestin-releasing such as Mirena® or Kyleena®) or subdermal progestin implants (such as Nexplanon®). The transdermal patch, vaginal ring, depot medroxyprogesterone acetate (DMPA) IM injection, and combined estrogen–progesterone contraceptives are effective and safe in all women with IA, with the exception of women with SLE who have moderate to high disease or those who are positive for antiphospholipid antibodies (aPL) [11]. The progestin-only pill is also safe in women with IA. However, the strict dosing regimen and higher rates of breakthrough bleeding make it a less attractive option [11, 21]. Emergency hormonal contraceptives (e.g., Plan B) are safe for all patients with IA [11]. These are approved for use up to 72 h after unprotected intercourse, with evidence of efficacy up to 5 days, and are available over-the-counter in Canadian pharmacies without a prescription [22].

Genetic risks

Patients with IA often inquire about the risk of disease in their offspring. It is important to consider that the prevalence of IA in the general population is low [2, 23, 24]. While there may be some genetic heritability, IA develops through a complex interplay of genetic predisposition, environmental factors, and social behaviors (e.g., smoking) [25–27]. Overall, more data are required on specific risks to children born to parents with IA. Patients should be reassured that most children who are born to parents with IA do not develop IA. Genetic or autoantibody testing in children in the absence of clinical symptoms is not recommended.

Fertility

IAs are not known to be associated with infertility. However, women with RA tend to have fewer children than healthy women of similar age [28], which may be attributable to sexual dysfunction related to disease activity, NSAID use, and personal reproductive choices [29–31]. Increased disease activity measured through DAS28 has been associated with prolonged time to pregnancy (defined as > 1 year) in women with RA [32]. Pikwer et al. demonstrated an association between the occurrence of menopause before the age of 45 and the development of RA (OR 2.42, 95% CI: 1.32,4,45), suggesting a link between the inflammation present before diagnosis and a reduction of ovarian reserve, leading to premature menopause [33]. This was further supported by an analysis of the French prospective multi-centered observational cohort EPSOIR, which showed that RA and inflammation in women of reproductive age negatively affected their ovarian reserve, as indicated by lower serum anti-Müllerian hormone (AMH) levels [34]. Studies have yet to disentangle the impact of each of these factors on a woman’s reproductive health and shed light on the complex interactions between them.

NSAID (non-steroidal anti-inflammatory medications) use has been associated with prolonged time to pregnancy in RA and SpA [31, 35]. NSAIDs may cause unruptured follicle syndrome [11, 16]. If a patient with IA experiences an unexplained delay in conceiving, NSAID use should be addressed and minimized [11]. Cyclophosphamide (CYC) can also cause premature ovarian failure with the highest risk in those who receive cyclophosphamide after the age of 30 [36]. Based on the findings of several studies in women with systemic lupus erythematosus (SLE) receiving CYC, clinicians may consider using concurrent gonadotropin-releasing hormone agonists to preserve ovarian function [37]. However, the authors note that CYC is not routinely used in patients with IA and therefore recommend seeking further information elsewhere in the literature. Referral to a reproductive medicine specialist is recommended for patients under the age of 35 years who cannot achieve a pregnancy after 1 year of unprotected intercourse, and patients over the age of 35 who have not been able to conceive after 3 months [38]. If a woman over the age of 40 is considering pregnancy, we recommend baseline assessment by reproductive medicine [38].

We agree with the 2020 ACR guidelines for managing reproductive health in patients with rheumatic disease which recommend that patients who are considering artificial reproductive techniques to facilitate pregnancy should achieve 6 months of stable inactive or low-level disease state prior to assisted reproductive technology procedures [11]. For patients whose disease activity is assessed to be moderate or severe, artificial reproductive techniques should ideally be postponed to reduce rates of adverse pregnancy outcomes. However, embryo or oocyte cryopreservation can still be considered [11].

Fertility and medication use in men with inflammatory arthritis

The impact of IA on male fertility remains an area of ongoing research. The iFAME-Fertility multicentre cross-sectional study found that men with IA have lower fertility and higher rates of childlessness [39].

Use of disease-modifying antirheumatic drugs (DMARDs) in men has not been shown to be teratogenic to the developing fetus [15, 16, 40]. Sulfasalazine (SSZ) may rarely induce reversible oligospermia and impair sperm motility [11, 16]. If a couple has difficulty conceiving, or if semen analysis indicates oligospermia, consider discontinuing paternal SSZ [13]. In addition, cyclophosphamide (CYC) also affects spermatogenesis and may cause temporary or permanent oligo/azoospermia [16, 36]. Sperm banking prior to CYC exposure may be considered [11]. Otherwise, attempted conception should be deferred until 3 months after completion of CYC treatment [41].

Lifestyle and diet

Lifestyle factors can also affect pregnancy and birth outcomes [42]. All women should take 0.4–1.0 mg of folic acid daily for at least 3 months before conception and continue until at least 12 weeks’ gestation to reduce the risk of neural tube defects [43–45].

Women with PsA have higher rates of tobacco use, increased pre-pregnancy BMI, and pre-existing depression, hypertension, and diabetes, which may contribute to a higher-risk pregnancy profile [46, 47]. Alcohol consumption and tobacco smoking negatively affect the developing fetus [48, 49], and pregnant women should abstain during the gestational period [50]. Evidence regarding marijuana use during pregnancy and breastfeeding is limited. The American College of Obstetricians and Gynecologists (ACOG) advises against marijuana use during pregnancy and breastfeeding [51].

Weight management should also be considered [42, 52]. Clinicians are encouraged to consult the Society of Obstetricians and Gynaecologists of Canada (SOGC) guidelines for recommendations on weight management in pregnancy [52].

Maternal immunizations

Women with IA at any stage of pregnancy should receive the inactivated influenza and COVID-19 vaccines [53–58]. Influenza and COVID-19 are associated with higher rates of adverse maternal and neonatal outcomes—including maternal hospitalization, mechanical ventilation, premature delivery, low birth weight, and NICU admission—and the corresponding vaccines have demonstrated efficacy and safety in pregnancy [53–57].

All pregnant women should also receive a pertussis-containing vaccine (Tdap) in every pregnancy, ideally between 27 and 32 weeks’ gestation, irrespective of prior Tdap history [54]. In line with public health guidance (e.g., CDC and Health Canada), administration of the respiratory syncytial virus (RSV) vaccine between 32 and 36 weeks’ gestation can prevent severe RSV disease in infants [54, 59]. For other vaccine recommendations, refer to the Journal of Obstetrics and Gynaecology Canada (JOGC) clinical practice guidelines [60]. Live vaccines are contraindicated in pregnancy [60]. These recommendations apply regardless of medication use (including biologics) during pregnancy.

Disease management

The adage that RA improves during pregnancy dates back to observations made over half a century ago [61]. Initial reports suggested improvements in disease activity in up to 90% of patients [62]. More recent prospective studies using objective disease activity measures suggest a more modest improvement (≈60%) during pregnancy [63], while others report stable disease activity [64]. SpA disease activity appears to peak in the second trimester [65]. Limited literature suggests PsA disease activity remains unchanged during pregnancy [66, 67].

Women with flares or high disease activity prior to conception are vulnerable to subsequent flares in pregnancy, impaired mobility, and pregnancy complications [5, 68]. By contrast, low disease activity at conception reduces rates of flares during pregnancy and postpartum [69].

Treatment adjustments should be made for women not taking pregnancy-compatible medications prior to conception. During this transition, patients should be closely monitored to assess the efficacy and tolerability of new medications. At least 6 months of remission or low disease activity is advisable prior to conception while on pregnancy-compatible medications [11].

Medications to avoid during the preconception period

Methotrexate (MTX) is teratogenic and abortifacient [11, 70]. In a prospective multicentre cohort study, MTX exposure after conception was associated with a spontaneous abortion rate of 42.5% (95% CI 29.2–58.7), compared with 14.4%, 22.4%, and 17.3% in the preconception-exposure, disease-matched, and non-autoimmune comparison cohorts, respectively [71]. The risk of major birth defects (6.6%) with post-conception MTX exposure was significantly higher than in the non-autoimmune cohort (2.9%) [71].

Ideally, MTX should be discontinued 3 months before planned conception and, when indicated, substituted with a pregnancy-compatible DMARD [11]. However, BSR guidelines allow maternal MTX exposure up to one month prior to conception [13]. If there is a history of maternal MTX exposure within 3 months of conception, a referral to Maternal–Fetal Medicine (MFM) should be made for close monitoring. If inadvertent exposure occurs after conception, MTX should be discontinued immediately. In our experience, most such pregnancies result in spontaneous miscarriage. Early referral to MFM is advised for monitoring, as therapeutic termination may be considered. There are no data to support increased folic acid or folinic acid supplementation in such cases.

Leflunomide (LEF) is embryotoxic and teratogenic in animal studies [72, 73]. LEF may persist in serum long after discontinuation due to enterohepatic circulation and a long half-life [74]. Therefore, a washout protocol is required to reduce serum LEF levels when indicated. The recommended protocol is cholestyramine 8 g three times daily for 11 days [75]. Although the 2020 ACR guidelines recommended a washout period of up to 2 years (or, alternatively, measurement of serum metabolite levels) before conception, the most recent EULAR recommendations accept discontinuation of LEF 3.5 months prior to conception [11, 15, 16]. If an unplanned pregnancy occurs while taking LEF, the drug should be discontinued and the cholestyramine washout completed as soon as possible [13]. In such cases, expectant management with referral to MFM is reasonable. Recent literature on in utero leflunomide exposure has been reassuring [72, 76, 77].

Special considerations

Anti-Ro/SSA and anti-La/SSB antibodies

Special consideration should be given to women with antibodies to Sjögren syndrome type A (Ro/SSA) and/or type B (La/SSB) antigens. These autoantibodies are detected in ~ 6% of patients with RA but are not typically seen in PsA or SpA [78]. They may also occur in asymptomatic individuals and in patients with other connective tissue diseases [79].

Positive SSA and/or SSB antibodies are associated with a 1–2% risk of congenital heart block and a 10–15% risk of neonatal lupus, due to passive antibody transfer across the placenta from ~ 16 weeks’ gestation [80]. This risk increases to 15–20% if there is a history of heart block in a previous pregnancy [80]. Currently, no interventions reliably reverse established heart block [79]. However, the PATCH study showed that hydroxychloroquine (HCQ) 400 mg daily, started before 10 weeks’ gestation in anti-Ro/SSA–positive women with a prior child with CHB, significantly reduced the risk of fetal congenital heart block [81]. Although data on HCQ for primary prevention (i.e., no prior affected child) are lacking, HCQ 400 mg daily may be offered before 10 weeks’ gestation in women with positive SSA antibodies. This approach is supported by the safety profile of HCQ in pregnancy and data extrapolated from the PATCH study [81], and is endorsed by the authors of this pathway.

Women who are anti-Ro/SSA positive should be referred to MFM for consideration of serial fetal echocardiography and/or heart rate monitoring between 16 and 26 weeks’ gestation, in accordance with local practice. If congenital heart block is detected, assessment and management by pediatric cardiology and MFM are advised.

Extra-articular disease

Patients with extra-articular manifestations of IA may require additional evaluation and monitoring. In patients with inflammatory bowel disease (IBD), it is essential to ensure remission or low disease activity before conception, and that they are followed by a gastroenterologist throughout pregnancy [82]. Similarly, in patients with interstitial lung disease, updated pulmonary function testing, echocardiography, and imaging should be performed within 6–12 months of pregnancy, with referral to respirology as appropriate [83].

Pregnancy plan

Monitoring disease activity

High disease activity during pregnancy may pose risks to both mother and infant. Patients with active RA in pregnancy are at increased risk of preeclampsia, preterm birth, low birth weight, and cesarean delivery [84–86]. A meta-analysis of more than 10 million pregnancies found that women with RA had a 66% higher risk of preeclampsia [87]. Women with PsA or SpA also face increased risks of preterm birth, cesarean delivery, and small-for-gestational-age infants [88, 89].

Rheumatologists should assess disease activity at least once per trimester, with closer monitoring in patients with high disease activity. Monitoring may include blood tests such as complete blood count, liver enzymes, kidney function, urinalysis, and C-reactive protein, as clinically indicated.

Medication risks/benefits during pregnancy

The baseline risk of congenital abnormalities in the general population is 3–5% [90]. Decisions about medication use during pregnancy should involve shared decision-making with patients and weigh potential effects on the fetus against the risks of maternal disease flare. Recommendations for medications used in the treatment of IA during pregnancy are summarized in Table 1.

Table 1.

Medication use during pregnancy and delivery

Medication	Considerations
Medications considered safe for use in pregnancy
Corticosteroids	● Prednisone and prednisolone are preferred for maternal indications ● Use the lowest effective dose; maintenance dose ≤ 5 mg/day when possible ● Monitor for side effects: nausea, vomiting, hypertension, headache, hyperglycemia, and sleep disturbance
NSAIDs	● Preferred agents: ibuprofen, naproxen ● May be used in the first and second trimesters; monitor for oligohydramnios in the second trimester ● Contraindicated in the third trimester due to risk of premature ductus arteriosus closure and neonatal pulmonary hypertension
Conventional DMARDS	Safe to continue throughout pregnancy: ● Hydroxychloroquine (HCQ) ● Chloroquine ● Colchicine ● Azathioprine or mercaptopurine ● Cyclosporine ● Tacrolimus ● Sulfasalazine (supplement folic acid 5 mg/day)
Anti-TNF Biologics (adalimumab, certolizumab, etanercept, infliximab, golimumab)	● All TNF inhibitors can be continued throughout pregnancy
Medications to avoid during pregnancy
Methotrexate	● Discontinue ≥ 3 months prior to conception ● Contraindicated in pregnancy
Leflunomide	● Discontinue ≥ 3.5 months prior to conception, as per updated EULAR guidance ● If discontinued more recently, confirm serum metabolite clearance (< 0.02 mg/L on two tests 14 days apart) or complete a cholestyramine washout protocol ● Contraindicated during pregnancy
Non-anti-TNF Biologics anti–IL-6 (tocilizumab, sarilumab) anti–IL-17 (secukinumab, ixekizumab) anti–IL-12/23 (ustekinumab) anti–IL-1 s (anakinra, canakinumab) anti–T-cell (abatacept) anti–B-cell (rituximab, belimumab)	● Use on an individual basis if needed to control maternal disease activity ● Placental transfer occurs in the second half of pregnancy
Other newer medications
Targeted Small Molecules JAKi, (baricitinib, tofacitinib, upadacitinib) PDE4i (apremilast)	● Limited human safety data; low molecular weight suggests placental transfer ● Contraindicated in pregnancy
Delivery Protocol
Steroids	● Consider stress dosing for women with prolonged prednisone exposure ● Dosing protocols vary; defer to anesthesiology/obstetrics team
Analgesia	● Pre-delivery anesthesia consult recommended ● Assess for cervical spine instability or temporomandibular joint (TMJ) involvement that may complicate intubation ● Flexion–extension cervical spine radiographs may be warranted in long-standing RA

DMARDs disease-modifying antirheumatic drugs, IL interleukin, JAKi Janus kinase inhibitor, NSAID non-steroidal anti-inflammatory drug, PDE4i phosphodiesterase-4 inhibitor, RA rheumatoid arthritis, TMJ temporomandibular joint, TNF tumor necrosis factor, TNFi tumor necrosis factor inhibitor

Medications considered compatible with pregnancy

Although glucocorticoids are not teratogenic, their use should be minimized during pregnancy [11, 15]. Glucocorticoid use in pregnancy has been associated with increased risk of preterm birth [91, 92], low birth weight [93], and maternal infections [94]. Steroid use may also contribute to excess weight gain, osteoporosis, hypertension, and diabetes [95]. For maternal indications, non-fluorinated glucocorticoids (e.g., prednisone and prednisolone) should be tapered where possible to a maintenance dose of ≤ 5 mg/day for the shortest possible duration when needed [11, 15]. Prednisone and prednisolone are preferred because the placenta inactivates much of the active drug, thereby limiting fetal exposure [13, 96, 97].

Nonselective NSAIDs with a short half-life (e.g., ibuprofen) may be used in the first and second trimesters [15, 16]. However, NSAID use should be minimized, particularly in the second trimester, due to the potential risk of oligohydramnios [98]. The effect of NSAIDs on fetal renal function appears dose-dependent but is usually reversible [98]. NSAIDs should be discontinued by the third trimester due to the risk of premature closure of ductus arteriosus and persistent pulmonary hypertension of the newborn [11, 98, 99].

Hydroxychloroquine (HCQ), chloroquine, colchicine, azathioprine (AZA), mercaptopurine, cyclosporine, tacrolimus, and sulfasalazine (SSZ) are considered compatible with use in pregnancy [11, 15, 16]. A recent population-based study among women with rheumatic disease showed that HCQ, AZA, and SSZ exposure before or during pregnancy was not associated with small-for-gestational age births [100]. No significant adverse outcomes were found in two recent population-based studies among women receiving HCQ during pregnancy [101, 102]. SSZ can affect folate absorption and therefore folate supplementation should be increased to 5 mg/day and encouraged during conception and throughout pregnancy [103, 104]. Multiple studies have not identified adverse outcomes with maternal or paternal azathioprine exposure [105–107]. However, there is no clear evidence on a dose limit, therefore use of azathioprine at an effective dose should be supported by blood tests and local guidelines [13].

Tumor necrosis factor inhibitors (TNFis) are the most studied biologics in pregnancy. Their use during the course of the pregnancy is considered safe [11, 13, 15, 16]. The 2020 ACR Guidelines, 2022 BSR Guidelines and the 2024 update of the EULAR recommendations provide thorough evaluations of available evidence [11, 13, 16]. Modest evidence suggests a low risk for pregnancy-related complications in anti-TNF users compared to non-users [11, 108–110]. In addition to active disease, TNFi discontinuation in early pregnancy is a risk factor for disease flare-ups in RA, SpA, and PsA during pregnancy [67, 69]. Most TNFis contain an Fc IgG1 construct that does not cross into fetal circulation in significant concentrations until the late second trimester, while high levels of placental transfer and significant drug levels are observed in the third trimester [111]. Certolizumab does not contain an Fc portion and thus has minimal placental transfer [11, 112]. Although infliximab, adalimumab, etanercept, and golimumab can cross the placenta, they may be continued throughout pregnancy [13, 96]. Decisions to stop or continue TNFi therapy should be made jointly by the rheumatologist, obstetrician, and patient.

Non-anti-TNF biologics such as anti–IL-6 (tocilizumab, sarilumab), anti–IL-17 (secukinumab and ixekizumab), anti–IL-12/23 (ustekinumab), anti–IL-1 (anakinra, canakinumab), anti-B-cell (rituximab and belimumab), and anti–T-cell (abatacept) agents are efficacious in IA and may be continued during pregnancy to control maternal disease activity [15, 16]. Rituximab and belimumab cross the placenta from 16 weeks of pregnancy and onwards [13, 15]. Use of these agents in the second half of pregnancy may result in transient B-cell depletion or other cytopenias in the neonate, typically without serious infections, with B-cell recovery within 6 months [11, 15, 16, 113].

Medications to avoid during pregnancy

Consistent with preconception guidance, neither MTX nor LEF should be used during pregnancy [11, 15]. Very limited or no data are available on anti–IL-23 s (risankizumab, guselkumab), anti–IL-5 (mepolizumab), complement C5 inhibitor (eculizumab), anti-IFNAR1 (Anifrolumab) in pregnancy [15]. These agents should only be used for the treatment of severe, refractory maternal disease, or when no alternative medications can be used [15]. The risks and benefits of non-anti-TNF biologics should be assessed by the rheumatologist and a joint decision should be made with the patient on a case-by-case basis.

Considerations on newer medications

Apremilast is a small molecule DMARD approved for use in PsA [114]. Apremilast inhibits phosphodiesterase-4 and blocks signaling of inflammatory pathways through degradation of cyclic AMP [114]. Given its low molecular weight and lack of safety data, apremilast should be avoided during pregnancy [11, 114].

Janus Kinase (JAK) inhibitors (e.g., Upadacitinib, baricitinib, tofacitinib) are small molecules approved for use in RA, PsA, and SpA [115–117]. There is limited human data available on the use of these agents during pregnancy [11]. These agents have low molecular weight and therefore are expected to passively cross the placenta, even early in pregnancy [96, 115–117]. Limited data on tofacitinib exposure in pregnancy suggest outcomes comparable to the general population and to patients treated with biologics, though conclusions remain limited by sample size [118]. Due to the lack of data, these agents should be discontinued at least 2 weeks before planned conception and avoided for the duration of pregnancy [13].

Special considerations

The ACOG, the Society for Maternal–Fetal Medicine, and the National Institute for Health and Science recommend ASA 75–150 mg for prophylaxis in women at high-risk for preeclampsia from 12 weeks of gestation until delivery [119, 120]. In Canada, ASA 81 mg or 162 mg is typically used from 12 to 36 weeks’ gestation for preeclampsia prophylaxis, depending on the center [120]. IA alone is not a risk factor for preeclampsia, but it may contribute to the overall risk profile when combined with other factors (history of preeclampsia, hypertension, multiple pregnancy, diabetes, chronic kidney disease, IVF, nulliparity, advanced maternal age, and obesity) in determining the need for ASA prophylaxis [14].

Delivery considerations

Mode of delivery should be determined by obstetric indication. Several issues related to underlying IA may require careful consideration as outlined below. Patients with JIA and prior hip replacements may have an increased likelihood of cesarean delivery [121]; however, previous arthroplasty is not an absolute indication for C-section delivery. Sacroiliac joint involvement in SpA is not an indication for C-section. Women with sacroiliac joint fusion or sacroiliitis can have vaginal deliveries. Drug considerations around delivery also warrant patient counselling. Stress-dose steroids may be required during labor and delivery for patients who used prednisone during pregnancy [11]. Based on the dose and duration of steroid therapy, the patient may be at risk of hypothalamic-pituitary axis (HPA) suppression, thus requiring exogenous stress glucocorticoids to meet the needs of perioperative stress [122]. The 2020 ACR Guidelines conditionally recommend against the routine administration of stress-dose glucocorticoids during vaginal delivery, but conditionally recommend their use at the time of surgical delivery in patients taking > 5 mg of prednisone or equivalent for > 4 weeks [11, 123]. No specific recommendations exist for steroid dosing around delivery, as institutional protocols vary. The decision should be guided by the anesthesia and obstetrical teams, taking into account the clinical suspicion for HPA axis suppression and the anticipated degree of surgical stress.

Use of analgesics and anesthetics may be affected by the underlying disease [103]. Syndesmophytes and spinal immobility are theoretical concerns that may complicate insertion of epidural anesthesia in patients with SpA. However, data are currently limited to case reports [124]. Furthermore, patients with long-standing RA should have flexion–extension views of the cervical spine to assess stability of the atlantoaxial joint, should intubation be required [125]. Similarly, temporomandibular joint involvement in JIA, SpA, or PsA may make intubation difficult. Pre-delivery anesthesia consultation is recommended.

Postpartum care plan

Reconsideration of medications

To minimize postpartum disease flares, biologic therapy should be resumed within 1–2 weeks of delivery, provided there is no infection and wound healing is satisfactory [126, 127]. Other DMARDs (HCQ, SSZ, AZA) can be continued through labor and delivery [11].

Breastfeeding

In general, practitioners should encourage breastfeeding with medications compatible with lactation [15]. Biologic DMARDs appear in low levels in breast milk and are minimally absorbed by the infant due to negligible oral bioavailability [15, 16]. As a result, anti-TNF and non-TNFi biologics are both considered compatible with breastfeeding, although anti-TNF agents remain the most well-studied [11, 15]. Mothers may continue breastfeeding on the same day as an injection or infusion. Prednisone, prednisolone and methylprednisolone are also compatible with breastfeeding [11, 13, 16, 96]. The ACR Guidelines and LACTMED® provide thorough summaries on drug compatibility while breastfeeding and are useful resources in practice during this period [11, 128, 129]. Medication compatibility with breastfeeding is summarized in Table 2.

Table 2.

Medications compatible with breastfeeding based on 2020 ACR guideline [11]

Compatible medications	Non-compatible medications
● Nonselective NSAIDs ● For prednisone ≥ 20 mg daily, discard breast milk obtained within 4 h following medication ● HCQ, chloroquine, colchicine, SSZ, AZA or mercaptopurine, cyclosporine, tacrolimus ● Anti-TNF biologics (infliximab, etanercept, adalimumab, golimumab, certolizumab) ● Other biologics (rituximab, abatacept, tocilizumab, secukinumab, ustekinumab)	● Leflunomide ● MMF ● CYC ● MTX ● JAKi

AZA azathioprine, CYC cyclophosphamide, HCQ hydroxychloroquine, JAKi janus kinase inhibitor, MMF mycophenolate mofetil/mycophenolic acid, MTX methotrexate, NSAID nonsteroidal anti-inflammatory drug, SSZ sulfasalazine, TNF tumor necrosis factor

Considerations for baby

Risk of infection

Due to the active transport of TNF-inhibitors across the placenta in the second and third trimester of pregnancy, there is a hypothetical risk of neonatal immunosuppression, potentially increasing the risk of neonatal infections [11, 13]. However, a recent study showed that infants exposed to adalimumab or infliximab in utero had normal T- and B-cell immunity and overall immune function [130]. Furthermore, increased infection or hospitalization rates have not been reported in children of women exposed to anti-TNF biologics in utero [131–134].

Vaccination

The Canadian immunization schedule may be followed for all infants exposed to anti-TNF-inhibitors in-utero. We also agree with the 2022 ACR Vaccination Guidelines’ conditional recommendation to administer live attenuated rotavirus vaccine within the first 6 months of life for infants exposed to TNFi’s during the second and/or third trimester [55]. For infants exposed to other biologics in the third trimester, rotavirus vaccination may be deferred [55]. In such cases, referral to the Special Immunization Clinic (SIC) Network is reasonable to assess vaccination safety. Similarly, for infants exposed to biologic DMARDs in the second-and/or third-trimester, Bacille Calmette-Guérin (BCG) vaccination (if indicated due to regional practice or risk factors) should be deferred until the infant is at least 6 months old, or the infant should be evaluated through a SIC Network prior to BCG administration [16, 135].

Considerations for mother

Postpartum flares are common in IA, particularly in RA [63, 129, 136, 137]. A tendency towards postpartum flares is seen within 3–4 months in patients with RA and within the first 6 months in SpA and PsA patients [67, 138, 139]. Flares may also be worsened during the postpartum period in patients discontinuing therapy [140]. Reduced adherence and persistence with therapy during the first year after reinitiation may further contribute to challenges in postpartum disease management [141]. Close monitoring of a patient’s disease state is required to reduce the occurrence of flares and ensure that mothers are in the best condition to provide care for their newborns.

Other specialists should also be involved in supporting the mother in the postnatal phase. A physiotherapist may be able to help with pelvic floor strengthening exercises and provide tips to recover from the birthing process [136]. An occupational therapist may be able to help mothers with the more practical considerations of caring for their baby or themselves [136]. Mental health resources should be offered to address common postpartum concerns, including anxiety, depression, sleep deprivation, and IA disease flares [136]. Contraception and planning for future pregnancies should also be discussed. Post-delivery care for mom and baby is summarized in Table 3.

Table 3.

Checklist for post-delivery care for mom and infant

Mother	Infant
● Monitor for disease flares ● Consult allied healthcare providers ○ Occupational therapy ○ Physiotherapy ○ Mental health support	● Routine vaccinations as per recommended immunization schedule for infants exposed to csDMARDs and anti-TNF biologics ● Withhold live vaccines within the first 6–12 month of life in those with in utero exposure to non-TNF biologics

csDMARDS conventional disease modifying antirheumatic drugs, TNF tumor necrosis factor

Summary

Women with inflammatory arthritis (IA) can have safe and healthy pregnancies when managed with a structured, multidisciplinary approach. This clinical care pathway helps address knowledge gaps in Canada and provides consistent, evidence-based guidance for this complex patient population.

For women of childbearing age with IA, the use of contraception should be considered to avoid the risks of unplanned pregnancy. Generally, intrauterine devices are considered first line, but there are many safe options available. The use of NSAIDs and prior exposure to cyclophosphamide should be addressed in women experiencing difficulty conceiving. Medications that should be avoided during the preconception period due to their teratogenic or abortifacient effect include methotrexate (ideally discontinue 3 months prior to conception) and leflunomide (discontinue at least 3.5 months prior to conception). For males with IA who are experiencing difficulty conceiving, SSZ can be held (or if indicated by semen analysis), and CYC should be held 3 months prior to conception. Patients considering assisted reproductive technologies should ideally have at least 6 months of stable or low disease activity.

During pregnancy, folic acid supplementation (0.4–1.0 mg daily) is recommended for all women with IA, and vaccination with influenza, COVID-19, Tdap, and RSV should be offered while avoiding live vaccines.

Anti-Ro/SSA or anti-La/SSB–positive women require fetal monitoring to assess for congenital heart block. Safe medication options include sulfasalazine, hydroxychloroquine, azathioprine, and TNF inhibitors, while non-TNF biologics may be used on a case-by-case basis and small molecule inhibitors should be avoided. Prednisone or prednisolone may be used at the lowest effective dose, and NSAIDs can be used in the first and second trimesters but must be stopped in the third trimester. Pre-delivery anesthesia consultation should be arranged when indicated.

Postpartum disease flares are common but can be minimized by timely reinitiation of therapy, with biologics restarted within 1–2 weeks if healing is adequate and infection excluded. Most medications—except methotrexate, leflunomide, and mycophenolate—are compatible with breastfeeding. Mothers benefit from postpartum supportive care including physiotherapy, occupational therapy, and mental health resources.

Infant care should follow the Canadian immunization schedule for those exposed to conventional DMARDs or TNF inhibitors. For infants exposed in utero to non-TNF biologics in the third trimester, rotavirus vaccination should be deferred, and BCG vaccination delayed until at least 6 months of age.

Developing an individualized, comprehensive care plan that integrates disease activity, medication safety, and maternal and infant health is essential to optimizing outcomes for both mother and child.

Author contribution

Conceptualization: Neda Amiri, MD; Maeve Gamble, MD; Viktoria Pavlova, MD; Sarah Troster, MD.

Literature search: Neda Amiri, MD; Maeve Gamble, MD; Viktoria Pavlova, MD; Sarah Troster, MD.

Data analysis: Neda Amiri, MD; Maeve Gamble, MD; Viktoria Pavlova, MD; Sarah Troster, MD.

Writing—original draft preparation: Neda Amiri, MD; Maeve Gamble, MD; Carl Laskin, MD; Viktoria Pavlova, MD; Sarah Troster, MD.

Writing—review and editing: Neda Amiri, MD; Maeve Gamble, MD; Carl Laskin, MD; Viktoria Pavlova, MD; Sarah Troster, MD.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: Financial support for medical writing services was provided by UCB Canada Inc.

Data availability

Data sharing not applicable to this article as no datasets were generated or analyzed during the current study.

Compliance with ethical standards

Ethics approval

The manuscript does not contain clinical studies or patient data.

Consent for publication

All authors read and approved the final manuscript.

Disclosures

None.