Fertility and Birth Outcomes in Rheumatoid Arthritis: A Narrative Review

Abstract

Rheumatoid arthritis (RA) is a systemic rheumatic disease that often impacts women of childbearing age. Women and men with RA experience higher rates of subfertility compared to the general population. Disease activity, treatment, psychosocial concerns, and sexual dysfunction contribute to subfertility, delayed childbearing, and reduced family size in the RA population. Assisted reproductive technology (ART) procedures are safe and effective options for patients who experience subfertility or are interested in preserving future fertility while continuing pregnancy-incompatible medications. Women with RA also experience increased risk of various adverse pregnancy outcomes compared to the general population, including preterm delivery and having small-for-gestational-age infants. Achieving well-controlled disease on pregnancy-compatible medications prior to conception optimizes maternal and neonatal outcomes. For patients with childbearing potential taking teratogenic medication, contraception is important; there are no RA-specific contraindications to the use of hormonal birth control. Sexual and reproductive health care for women and men with RA requires a multidisciplinary, patient-centered approach. Future studies are needed to elucidate mechanisms of impaired fertility and adverse pregnancy outcomes in RA, to investigate the safety of non-tumor necrosis factor inhibitor biologic disease‑modifying antirheumatic drugs (non-TNFi bDMARDs) during pregnancy and lactation, and to illuminate patient perspectives and priorities regarding their reproductive health across the lifespan.

Key Summary Points

People with rheumatoid arthritis (RA) experience higher rates of subfertility than the general population, driven by various disease-related and psychosocial factors

Assisted reproductive technology procedures (ART) are safe for women with RA, without the need to modify RA treatment when pregnancy is not the immediate goal

Women with RA are at increased risk of adverse maternal and neonatal outcomes, including preterm delivery and small-for-gestational-age infants, compared to the general population

Most women with RA have healthy pregnancies, especially when conception occurred during a period of low disease activity on pregnancy-compatible medications

There are no RA-specific contraindications to any form of contraception

Introduction

Rheumatoid arthritis (RA) is a chronic autoimmune disease defined by polyarticular inflammatory arthritis. Global prevalence of RA is 0.5–1% [1], and it is typically diagnosed at 30–50 years of age and occurs two- to threefold more frequently in females than in males [2, 3]. Given the disease prevalence and affected demographics, it is important to understand the relationship between RA and reproductive health.

Women diagnosed with RA face disproportionate risk of both impaired fertility and adverse maternal and neonatal pregnancy outcomes [4–10]. Careful pregnancy planning is recommended, emphasizing the importance of quiescent disease and the use of pregnancy-compatible medications prior to conception [11, 12]. The association between RA and male reproductive health is less well understood [13, 14].

This review synthesizes current evidence on fertility, birth outcomes, and other sexual and reproductive health topics as they relate to RA. PubMed was searched for studies related to sexual and reproductive health in patients with RA, using keywords including “rheumatoid arthritis,” “juvenile idiopathic arthritis,” “fertility,” “pregnancy,” and “disease activity.” Priority was given to recent studies and clinical trials when available. This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors.

Rheumatoid Arthritis and Fertility

Subfertility is defined as prolonged time to pregnancy (TTP), while infertility is the failure to achieve pregnancy after 12 months of unprotected intercourse [15, 16]. An estimated 36–42% of female patients with RA experience infertility, compared to 10–17% of the general population [5]. The burden of subfertility in women with juvenile idiopathic arthritis (JIA) is similar to that in women with adult-onset RA [17].

The Pregnancy-induced Amelioration of Rheumatoid Arthritis (“PARA” study), a large prospective cohort study carried out in the Netherlands, demonstrated that women with RA have lower ovarian reserve (defined by Anti-Müllerian hormone [AMH] levels) than do healthy controls [18].

Subfertility in RA is multifactorial. Direct factors include both disease and treatment-related factors; indirect factors impacting family planning include pain, fatigue, sexual dysfunction, and psychosocial concerns (Fig. 1) [4, 5, 19, 20].

Fig. 1.

Contributors to subfertility in women and men with rheumatoid arthritis. ACPA Anti-citrullinated protein antibodies, ASA antisperm antibodies, COX-2 cyclooxygenase-2, GCs glucocorticoids, NSAID nonsteroidal anti-inflammatory drugs, RA rheumatoid arthritis, RF rheumatoid factor, SSZ sulfasalazine

Direct Factors

Disease-Related Factors

The biological basis of subfertility in RA remains largely unknown but certain clinical associations have been identified.

The presence of RA autoantibodies (rheumatoid factor [RF] and anti-citrullinated protein antibodies [ACPAs]) may contribute to subfertility [21]. In the PARA study [18], RF and ACPA positivity were associated with a decreased likelihood of conception (90% of those who did not conceive vs 70% of those who did were RF-positive, p = 0.01; 80% of those who did not conceive vs 63% of those who did were ACPA-positive, p = 0.05); however, autoantibody status was no longer significant in the multivariable regression analysis. ACPA positivity (but not RF positivity) was associated with TTP > 12 months (73% vs. 60%; p = 0.042) [19]. Longitudinal follow-up identified a steeper decline in AMH levels in patients with RA compared to age-matched healthy controls, with no RA-related variable (i.e., disease duration, ACPA/RF positivity, presence of erosions, methotrexate [MTX] use) exerting a significant effect on this finding [22].

Anti-ovarian antibodies (AOAs) have been investigated as potential markers for premature ovarian insufficiency due to autoimmunity, but a relationship between RA and AOAs has not been established [23].

Data demonstrate that increasing RA disease activity is independently associated with decreasing likelihood of achieving pregnancy [19] (Table 1). Interactions between cytokines, chemokines, and growth factors may alter communication between the blastocyst and receptive endometrium, impeding implantation [24]. Interleukin (IL)-6, a key inflammatory cytokine implicated in RA pathogenesis, has been associated with subfertility in women with RA, with increased TTP reported to be associated with higher IL-6 levels (hazard ratio [HR] 0.66, 95% confidence interval [CI] 0.43–0.99; p = 0.044), adjusting for age, disease activity, nulliparity, nonsteroidal anti-inflammatory drug (NSAID) use, and prednisone use [25]. Whether IL-6 directly impacts fertility or serves as a proxy for other pathogenic mechanisms is unknown.

Table 1.

Impact of disease activity on fertility and pregnancy outcomes for women with rheumatoid arthritis

Outcome	Study	Study design	N (patients with RA)	Disease activity measure	Key results
Fertility	Brouwer et al. [19]	Cohort	245	DAS28-CRP-3	• Fertility progressively declined with increasing disease activity: every 1-point increase in DAS-28 reduced the likelihood of pregnancy by 19% (HR: 0.81, 95% CI 0.71–0.93), adjusting for age, nulliparity, medication use
Pregnancy and postpartum flare	de Man et al. [90]	Cohort	84	DAS28-CRP-3	• 48% with moderate/high disease activity in first trimester had moderate improvement in disease activity during pregnancy (mean DAS-28 score reduction of 0.54 ± 0.92 [p < 0.001]) • Low disease activity in the first trimester stable for remainder of the pregnancy (mean change in DAS28 of + 0.23 ± 0.92 [p = 0.21)]) • Disease activity increased post-partum (mean DAS-28 scores increased 0.3 [95% CI 0.07–0.48, p = 0.01] from 6 to 12 weeks) • 39% experienced a moderate or severe flare postpartum
	Nakamura et al.[91]	Cohort	27	DAS28-CRP-3, DAS28-CRP-4, SDAI, CDAI, PD score	• Disease activity before and during pregnancy (based on SDAI, CDAI, PD) correlated with disease activity postpartum • Disease activity in third trimester only correlated with postpartum (based on DAS-CRP-3)
Maternal and neonatal pregnancy complications	Vegas et al. [7]	Cohort	11,792	Initiation of csDMARD, b/tsDMARDs and/or ≥ 1 dose systemic or intra-articular corticosteroid, and/or hospitalization for RA flare	• Active disease (vs non-active) was associated with preterm delivery (OR 2.02, 95% CI 1.71–2.38), SGA (OR 1.53; 95% CI 1.28–1.83) and cesarean delivery (OR 1.25; 95% CI 1.11–1.40)
	Lv et al. [8]	Meta-analysis	HAQ-DI: 487 DAS-28: 143	DAS-28, HAQ-DI, PS, PGS	• Active disease (HAQ-DI > 0.5) was associated with preterm delivery (OR 1.82, 95% CI 1.12–2.97) • Moderate/high disease activity (DAS-28 > 3.2) was associated with preterm delivery (OR 5.61, 95% CI 2.20–14.30) and cesarean delivery (OR 2.29, 95% CI 1.02–5.15)
	Hellgren et al. [81]	Cohort	1,739	DAS28-CRP-3, HAQ-DI	• Moderate vs low disease active (DAS-28 ≥ 4.1 vs < 3.2) was associated with preterm delivery (OR 3.38, 95% CI 1.52–7.55) and SGA (OR 3.90, 95% CI 1.46–10.4)
	Atta et al. [83]	Cohort	47	DAS28-CRP-3	• High disease activity (DAS-28 > 5.1) was more frequent for participants with preterm vs full-term delivery (64.7% vs 3.3%; p = 0.001) as well as more common among patients with SGA vs. non-SGA infants (37.5% vs 19.4%; p = 0.043)

bDMARDs Biological disease-modifying antirheumatic drugs, CDAI Clinical Disease Activity Index, csDMARD conventional synthetic disease-modifying antirheumatic drugs, CI confidence interval, DAS-28 Disease Activity Score-28, DAS28-CRP-3 Disease Activity Score-28-C-reactive protein assessed with 3 variables, DAS28-CRP-4 Disease Activity Score-28-C-reactive protein assessed with 4 variables (includes patient global assessment), HAQ-DI Health Assessment Questionnaire (Disability Index), HR hazard ratio, OR odds ratio, PD power Doppler ultrasound, PGS patient global scale, PS pain score, SDAI Simplified Disease Activity Index, SGA small for gestational age, tsDMARDs targeted synthetic disease-modifying antirheumatic drugs

Current data are mixed regarding a relationship between RA and male fertility. A cross-sectional study in the Netherlands, including 628 individuals with inflammatory arthritis (IA)—RA, JIA, and spondyloarthritis (SpA)—found that men diagnosed with IA at  ≤ 30 years of age had fewer children (1.32 [SD {standard deviation} 1.14]) than men diagnosed 31–40 years of age (1.60 [SD 1.35]) and ≥ 41 years (1.88 [SD 1.14]) [13]. In contrast, a nationwide population-cohort study in Norway found that men with IA—RA, psoriatic arthritis (PsA), and SpA— did not have fewer children than population controls, before or after diagnosis [26].

Some studies have identified an association between disease activity in men and low testosterone levels [27, 28]. One study found that five of 70 males with systemic rheumatic diseases (SRDs), including one of 32 with RA, had anti-sperm antibodies (ASA), compared to none (0) of the 80 controls [29]. Given the small numbers of patients in this study, it is difficult to draw conclusions from the results.

Treatment-Related Factors

Nonsteroidal anti-inflammatory drugs and glucocorticoids (GCs) have been associated with increased TTP [19]. NSAIDs inhibit prostaglandin synthesis, impacting ovulation, implantation, and placentation, and can cause reversible infertility through induction of luteinized unruptured follicle syndrome (LUFS) [30]. Selective cyclooxygenase-2 (COX-2) inhibitors, such as etoricoxib, induce subfertility more than nonselective agents [31].

GC-related infertility is likely driven by suppression of the hypothalamic–pituitary–ovarian axis, with the degree of impact depending on dose, duration, and underlying disease [32]. Direct impacts on reproductive organs also have been suggested: one murine study showed that GC exposure does not damage oocyte quality or development, but may adversely impact the uterus, impeding implantation and increasing the likelihood of embryo loss [33].

While animal studies have suggested MTX may diminish female fecundity (the biologic capacity to reproduce) [34], human studies have found no effect of MTX on female fertility [19, 35]. Concerns had been raised regarding a potential impact of MTX on male fertility [36, 37]. However, a rigorous prospective cohort study in the Netherlands found no difference in the semen parameters of men prior to and following MTX exposure, or when comparing MTX users with unexposed controls [38]. Sulfasalazine (SSZ) treatment in men may lead to reversible azoospermia [39]. For men who aim to father a child, the American College of Rheumatology (ACR) Reproductive Health Guideline (RHG) and European Alliance of Associations for Rheumatology (EULAR) guideline conditionally recommend continuing low-dose MTX (≤ 25 mg/week) and SSZ. If fertility issues arise with continued SSZ, a semen analysis is recommended [11, 12].

Data are limited but overall reassuring regarding the relationship between biologic disease-modifying antirheumatic drug (bDMARD) treatment and fertility outcomes in women with RA. In uncontrolled studies, women receiving treat-to-target (T2T) therapy, including tumor necrosis factor inhibitors (TNFis), were found to have better fertility outcomes than non-TNFi-treated women [40, 41]. A retrospective Japanese study of 25 RA pregnancies found that continuing TNFi therapy (certolizumab and etanercept), versus discontinuing bDMARDs and conventional synthetic DMARDs (csDMARDs), was associated with lower TTP (5.9 ± 3.8 vs 11.0 ± 6.5 months; p = 0.04) [40]. A prospective study reaffirmed this finding by comparing 215 patients from the Preconception Counseling in Active Rheumatoid Arthritis (“PreCARA”) cohort to 245 from the historical PARA cohort. The PreCARA cohort had a T2T approach utilizing pregnancy-compatible DMARDs (69% on SSZ, 65% on hydroxychloroquine [HCQ]) and TNFis (53%), avoiding NSAIDs and prednisone > 7.5 mg per day; the PARA cohort was managed with standard of care (36% on no medications, 17% on prednisone > 7.5 mg daily, 32% on SSZ, 4% on TNFis). TTP in the PreCARA versus PARA cohort was significantly shorter (91 vs. 251 days) and comparable to general population rates; 23% in PreCARA vs. 42% in PARA had TTP > 12 months [41]. These findings may reflect the impact of improved disease control rather than a direct fertility benefit of a given treatment.

Little data are available on the impact of bDMARD treatment on male fertility; however, a 2018 systematic review reported no evidence that paternal exposure to TNFis, abatacept, or rituximab adversely affects fertility [42].

Indirect Factors

Psychosocial Factors

Women with RA may conceive later in life than do women without RA [17, 19, 43], and infertility increases significantly with age: 75% of women trying to conceive at 30 years of age have a live birth in 12 months; this declines to 44% by age 40 [44]. Women and men with RA may limit family size or delay conception for many reasons, including concerns regarding the physical aspects of childcare, the potential for disease or medications to harm their child, and concern that their offspring will develop RA [4, 13, 45].

Sexual Dysfunction

Women and men with RA experience sexual dysfunction to a greater degree than the general population. Approximately half of women with RA experience sexual dysfunction [20], attributed to pain, fatigue, limited mobility, vaginal dryness, anxiety and depression, and altered body image [46]. A meta-analysis including 44,745 patients (7 studies) found that females were 73% more likely to experience sexual dysfunction compared to controls (relative risk [RR] 1.73, 95% CI 1.36–2.22; p < 0.001) and males were 99% more likely (RR 1.99, 95% CI 1.64–2.43, p < 0.001) [47]. One questionnaire-based study found that among women with RA who aimed to conceive (n = 30), there was no significant difference in the frequency of sexual intercourse between those who became pregnant and those who did not [48].

Individuals with JIA may also experience sexual dysfunction more frequently than their healthy peers. A study of 246 adults with longstanding JIA found that approximately half reported negative body image due to their disease, and over half of those with previous sexual experiences had encountered disease-related sexual problems [49]. A questionnaire-based study of males with JIA suggested they experienced greater difficulty than both healthy males and females with JIA in establishing relationships with the opposite sex [50].

Assisted Reproductive Technologies

Women with RA may choose to utilize assisted reproductive technologies (ART)—including intrauterine insemination (IUI) and in vitro fertilization (IVF)—when experiencing subfertility. Oocyte/embryo cryopreservation facilitates fertility preservation when childbearing is delayed due to either personal or medical considerations (Fig. 2). IVF can also be used for embryo transfer to a gestational surrogate when childbearing is not an option.

Fig. 2.

Pathways to pregnancy for an individual with rheumatoid arthritis. ART Assisted reproductive technologies, RA rheumatoid arthritis, IUI intrauterine insemination, IVF in vitro fertilization

The ACR RHG supports ART for pregnancy in women with RA who are clinically stable on pregnancy-compatible medications. For patients pursuing cryopreservation, the recommendation is to continue current DMARD and/or bDMARD therapy (other than cyclophosphamide, not generally used for RA) [11]. For patients with antiphospholipid antibodies (approximately 10% of patients with RA [51]), the guideline recommends prophylactic anticoagulation during ART [11].

IVF success rates may differ for patients with RA compared to the general population. A recent meta-analysis found that patients with RA have an estimated 18% live birth per embryo transfer rate compared to 25% in controls (odds ratio [OR] 0.71, 95% CI 0.61–0.83). IVF outcomes in RA were found to be similar to those in other SRDs [52].

Rheumatoid Arthritis and Pregnancy

Women with RA experience a higher rate of adverse maternal and neonatal outcomes when compared to the general population [6, 9, 10]. A meta-analysis of 50 million people (18 studies) demonstrated an increased risk of various adverse outcomes (listed here from the highest to lowest magnitude estimate): preterm delivery (OR 1.58; 95% CI 1.44–1.74), small-for-gestational-age (SGA) infants (OR 1.49; 95% CI 1.22–1.82), preeclampsia (OR 1.48, 95% CI 1.19–1.83), low birth weight (OR 1.45; 95% CI 1.30–1.63), cesarean delivery (OR 1.39, 95% CI 1.24–1.55), stillbirths (OR 1.38; 95% CI 1.09–1.74), congenital anomalies (OR 1.36; 95% CI 1.01–1.83), gestational hypertension (OR 1.34; 95% CI 1.07–1.68), and spontaneous abortion (OR 1.16; 95% CI 1.04–1.29) [9]. The studies included in this meta-analysis did not uniformly adjust for parity, which could confound results as a first birth is associated with increased risk of adverse pregnancy outcomes in all women, and even more so in women with RA [53]. In addition, the reported OR for congenital malformations in RA is 1.36, with a wide 95% CI beginning just above 1. Multiple rigorous registry studies did not show an increased risk for this outcome [6, 10, 53]. The magnitude of risk for pregnancy complications associated with RA is notably less than that observed among women with systemic lupus erythematosus (SLE), who are reported to have 6.7-fold higher odds of preterm delivery (95% CI 4.31–10.55) and a 3.22-fold higher odds of preeclampsia (95% CI 1.83–5.66) than controls [54].

Women with JIA have a comparable risk of preterm delivery to those with RA [55]. Women with JIA persisting into adulthood may face higher pregnancy risks than those with RA and with childhood-limited JIA. In a Swedish population-based cohort study, pediatric-only patients with JIA had less than twofold increased risks of preterm delivery (adjusted odds ratio [aOR] 1.74, 95% CI 1.35–2.67), cesarean delivery (aOR 1.42, 95% CI 1.66–1.73), and induction of labor (aOR 1.45, 95% CI 1.18–1.77) compared to controls. In another study, patients with JIA persisting into adulthood were fourfold more likely to have preterm deliveries (aOR 4.12, 95% CI 2.76–6.15), threefold more likely to have very preterm deliveries (aOR 3.14, 95% CI 1.58–6.24), sixfold more likely to have early preeclampsia (aOR 6.28, 95% CI 2.68–13.81), and twofold more likely to have late-onset preeclampsia compared to controls (aOR 1.96, 95% CI 1.31–2.91) [56].

Medication in Pregnancy

A summary of RA medications and their compatibility with pregnancy, lactation, and paternal use is given in Table 2.

Table 2.

Rheumatoid arthritis medications and compatibility with pregnancy, lactation, and paternal use

Class	Medication	Pregnancy	Lactation	Paternal use	Notes
csDMARDs	Hydroxychloroquine	Yes	Yes	Yes	Reduces risk of congenital heart block in anti-Ro/SSA+ pregnancies
	Azathioprine	Yes	Yes	Yes	Low transfer during lactation, conditional recommendation in ACR guidelines
	Sulfasalazine	Yes	Yes	Yes	Paternal use: consider semen analysis if delayed conception
	Methotrexate	No	No	Yes	Lactation (EULAR): MTX ≤ 25 mg/week may be considered if no alternative medication can be used Paternal use (EULAR): MTX ≤ 25 mg/week is compatible
	Leflunomide	No	No	Yes	Pregnancy (ACR): stop and give cholestyramine washout
bDMARDs: TNFi	Infliximab	Yes	Yes	Yes	Pregnancy (EULAR): Based on risk–benefit discussion, TNFis can be used throughout pregnancy
	Etanercept	Yes	Yes	Yes
	Adalimumab	Yes	Yes	Yes
	Golimumab	Yes	Yes	Yes
	Certolizumab	Yes	Yes	Yes	Pregnancy (ACR): minimal placental transfer, preferred TNFi prior to and during pregnancy
bDMARDs: non-TNFi	Rituximab	Yes (in absence of pregnancy-compatible alternative)	Yes	Yes	Pregnancy (ACR): avoid unless organ- or life-threatening disease
	Anakinra	Yes (in absence of pregnancy-compatible alternative)	Yes	Yes
	Abatacept	Yes (in absence of pregnancy-compatible alternative)	Yes	Yes
	Tocilizumab	Yes (in absence of pregnancy-compatible alternative)	Yes	Yes
tsDMARDs	JAK inhibitors	No	No	Consider alternative	Insufficient data to support use
Glucocorticoids	Prednisone, methylprednisolone	Yes (lowest dose needed)	Taper to < 20 mg/day	Yes, if < 20 mg/day	Pregnancy (ACR): ≤ 10 mg/day of prednisone equivalent if needed to treat active disease Lactation (ACR): After a ≥ 20 mg dose, delay breastfeeding for 4 h (or discard milk expressed in that timeframe)
NSAIDs	Non-COX-2 selective	Yes (until 20 weeks gestation)	Yes	Yes	Pregnancy (EULAR): Intermittent use permitted but should be stopped at week 28 of gestation Lactation (ACR): Non-COX-2 selective NSAIDs preferred over COX-2 inhibitors: Ibuprofen preferred
	COX-2 inhibitors	No	Yes	Yes

Designation of compatibility derived from synthesis of published guidelines and expert opinion

ACR American College of Rheumatology, bDMARDs biological disease-modifying antirheumatic drugs, COX-2 cyclooxygenase-2, csDMARD conventional synthetic disease-modifying antirheumatic drugs, EULAR European Alliance of Associations for Rheumatology, JAK Janus kinase, MTX methotrexate, NSAIDs nonsteroidal anti-inflammatory drugs, SSA Sjögren’s-syndrome-related antigen A, TNFi tumor necrosis factor inhibitor, tsDMARDs targeted synthetic disease-modifying antirheumatic drugs

Maternal Medication: DMARDs

Pregnancy- and lactation-compatible medications used to treat RA include HCQ, SSZ, azathioprine (AZA), and TNFis; incompatible medications include MTX, leflunomide, and Janus kinase (JAK) inhibitors [11, 12]. Given their small size and low molecular weight, JAK inhibitors likely cross the placenta throughout pregnancy; their effects are unknown [57].

Placental passage of TNFis varies by agent; certolizumab has minimal placental transfer due to not binding to the neonatal Fc receptor (FcRn), and etanercept has significantly less placental transfer than infliximab, adalimumab, and golimumab [58, 59].

Guidelines previously discouraged the use of non-TNFi bDMARDs during pregnancy due to a lack of safety data [11, 60, 61]. However, the 2024 EULAR guideline supports continued use of several non-TNFi bDMARDs during pregnancy—including rituximab, abatacept, tocilizumab, and sarilumab—if needed to control disease [12]. Given their molecular weights and structures, early transplacental passage and related teratogenicity is mechanistically unlikely. Research is needed to determine whether fetal exposure to these agents later in pregnancy confers risk of neonatal immunosuppression or other adverse outcomes.

Maternal Medication: NSAIDs and GCs

Judicious use of NSAIDs and GCs during pregnancy is recommended. In October 2020, the U.S. Food and Drug Administration (FDA) advised against NSAID use beyond 20 weeks gestation due to risk of oligohydramnios [62]; preceding ACR and EULAR guidelines had recommended avoidance in the third trimester due to associated risk of premature closure of the ductus arteriosus [11, 12, 63]. Guidelines support the use of nonselective NSAIDs over selective COX-2 inhibitors in pregnancy [11, 12].

Low-dose GCs (i.e., ≤ 10 mg/day of prednisone equivalent) can be utilized during pregnancy when needed to treat active disease [11]. Nonfluorinated GCs (e.g., prednisone and methylprednisolone) are used for maternal treatment: they are largely metabolized by placental 11β-hydroxysteroid dehydrogenase enzyme. Fluorinated GCs (e.g., dexamethasone and betamethasone) are used exclusively for fetal treatment, as they readily cross the placenta [64]. Results from animal studies raised concern for the risk of oral cleft development due to maternal GC treatment [65], and a 2000 meta-analysis of case–control studies found fetal GC exposure to be associated with a 3.4-fold risk (summary OR 3.35, 95% CI 1.97–5.69) [66]. More recent studies, however, have refuted this finding [67, 68]. A meta-analysis found no association between fetal GC exposure and congenital heart defects, with the authors acknowledging a lack of high-quality evidence. [69]

GC usage during pregnancy is associated with various adverse outcomes, including preeclampsia, preterm delivery, SGA infants, and infectious and thrombotic maternal complications [55, 70, 71]. In two observational cohort studies from the MotherToBaby Pregnancy Studies, higher prednisone doses in RA were associated with risk of preterm delivery [72, 73]. A 2024 systematic review reported no association between maternal prednisone/prednisolone up to 10 mg per day and congenital abnormalities or adverse neonatal outcomes [74].

Maternal Medications: Additional Considerations

For women with risk factors for preeclampsia, including SLE and antiphospholipid syndrome, the American College of Obstetricians and Gynecologists (ACOG) recommends low-dose aspirin (81 mg/day) initiated between 12 and 16 weeks gestation and continued through delivery [75]. Pregnant women with RA should discuss their individual risk of preeclampsia with their rheumatologist and obstetrician/gynecologist (OB/GYN) to determine the treatment course.

Approximately 6% of patients with RA have anti-Ro/Sjögren’s-syndrome-related antigen A (SSA) and/or anti-La/Sjögren’s-syndrome-related antigen B (SSB) antibodies [76]. Up to 20% of women with these antibodies may have an infant with mild, typically self-limited manifestations of “neonatal lupus”; up to 2% of infants develop congenital heart block [11, 77, 78]. The ACR RHG suggests testing patients with RA for Sjögren’s antibodies prior to or early in pregnancy and, if positive, initiating HCQ to decrease the risk of congenital heart block (Table 3) [11, 77].

Table 3.

Pre-pregnancy assessment for women with RA

Essential elements of care
Disease activity
Medication safety in pregnancy
Sjögren’s antibody status
Joint limitations (hips, C-spine)

Paternal Medication

For male teratogens, there are two theoretical exposure pathways: preconception, with the impacted sperm fertilizing the egg, or post-conception, via transfer of a drug via the semen to the fetus. No commonly used RA medication is an established teratogen with paternal use via either pathway. Animal studies have found that paternal MTX treatment can alter sperm messenger RNA (mRNA), possibly causing adverse birth outcomes [79]; however, human studies have not supported this finding [11, 36, 80]. Theoretical concern regarding post-conception teratogenic exposure is unlikely given the minimal concentrations of medications transferred in the seminal fluid [11].

The ACR RHG strongly recommends continued paternal use of HCQ, AZA, and TNFis, conditionally recommends the use of NSAIDs, SSZ, MTX, leflunomide, and rituximab, and does not comment on the use of abatacept, tocilizumab, sarilumab, or JAK inhibitors [11].

EULAR considers HCQ, AZA, leflunomide, MTX, SSZ, NSAIDs, TNFi, and non-TNFi biologics to be compatible with male efforts to conceive. Regarding JAK inhibitors, the EULAR guideline recommends considering alternative medications given insufficient safety data. [12]

Disease Activity and Damage in Pregnancy

Active disease preceding or during pregnancy is highly associated with adverse pregnancy outcomes in RA. Studies have found that patients with RA with high disease activity compared to those with quiescent disease during pregnancy are up to 5.6-fold more likely to have preterm deliveries and up to 3.9-fold more likely to have SGA infants [7, 8, 81]. Two separate studies demonstrated that higher IL-6 levels were associated with lower birth weights, while higher (anti-inflammatory) IL-10 levels in the first trimester were associated with higher birth weights (Table 1) [82, 83]. Maintaining well-controlled disease during pregnancy is associated with pregnancy outcomes comparable to those of the general population [7, 71, 81].

Increasing use of bDMARDs in pregnancy has led to improved RA disease control [84]. Despite the established relationship between disease control and improved pregnancy outcomes, many individuals with RA discontinue biologic medications prior to or during pregnancy [85], leading to disease flares and preterm delivery [86, 87]. However, discontinuation may be appropriate for some patients. A study of 397 women with RA and 93 with JIA found no clinically relevant worsening of patient-reported outcomes by the third trimester of pregnancy following TNFi discontinuation prior to gestational week 20 among patients with well-controlled disease [88].

Pregnancy appears to decrease RA disease activity in many patients, with one meta-analysis estimating that 60% experience improvement [7, 89]. For patients with low disease activity during the first trimester, disease activity often remains stable [90]. Disease activity before and during pregnancy may predict postpartum disease activity [91]. Postpartum flares are common, however, with one meta-analysis suggesting a rate of 46.7% [89, 90]. Results of studies may differ among populations examined due to variable access to bDMARDs and to prenatal care.

In rare cases, joint damage may impact mode of delivery. Women with severe hip arthritis may be advised to avoid vaginal delivery [92]. Women with severe cervical spine disease face risk associated with the potential need for intubation during a complicated delivery (Table 3) [93].

Contraception

Contraception use is important for women with childbearing potential prescribed teratogenic medications, or when pregnancy is not desired. The uptake of prescription contraception among patients with SRD is suboptimal [94, 95]. A single-center database study including 2455 reproductive-aged women with SRD (70% of whom were taking ≥ 1 teratogenic medication) found that 32.1% used prescription contraception; only 7.9% used highly effective methods. The frequency of prescription contraception use did not differ based on teratogenic medication use [94]. Contraceptive counseling occurs more frequently for women prescribed teratogenic medications than for those who are not [96], but remains inadequate and inconsistent [97].

The ACR RHG does not include RA-specific contraindications to any form of contraception. Intrauterine devices (IUDs) and subdermal progestin implants—the most effective reversible contraception—are recommended as first-line for all women with SRD [11]. Contraception requiring self-insertion (e.g., intravaginal ring insert and diaphragm) may pose issues for patients with limited dexterity due to arthritis. Depot medroxyprogesterone acetate, administered either as an intramuscular or subcutaneous injection every 3 months, has been linked to loss of bone mineral density. As RA and GC treatment are independent risk factors for osteoporosis, alternative contraceptive methods may be preferable [98]. There are no contraindications to any form of emergency contraception.

Clinical Considerations and Future Directions

Multidisciplinary Care

Comprehensive sexual and reproductive health care for individuals with RA involves multidisciplinary collaboration. Reproductive-aged women with SRD want their rheumatologists to initiate discussions regarding their sexual and reproductive health, including disease- and treatment-related risks, and may feel they are the intermediary between their rheumatologist and OB/GYN [99]. Rheumatologists should initiate such conversations and revisit these topics over time, as patients’ goals and desires may evolve [11].

Future Directions

Important knowledge gaps exist pertaining to RA and reproductive health. The biologic basis for impaired fertility and adverse pregnancy outcomes in RA is incompletely understood, and studies are often limited due to inconsistent assessment of disease activity. More studies are needed to examine the impact of emerging and current non-TNFi bDMARDs on maternal and neonatal outcomes, including long-term impacts of in-utero exposure. The relationship between RA and male sexual and reproductive health is understudied. Finally, reasons for the suboptimal uptake of contraception among patients with SRD, including RA, particularly in the context of treatment with teratogenic medication, are unknown. Patient perspectives can inform counseling and quality improvement efforts to optimize care delivery and reproductive health outcomes.

Conclusion

The relationship between RA and reproductive health is multifaceted. Subfertility is more frequently observed among individuals with RA than in healthy comparators. For individuals with RA who face subfertility or choose to delay pregnancy, ART is safe and may facilitate pregnancy, fertility preservation, or surrogacy. While many women with RA experience uncomplicated pregnancies, RA is associated with some increased risk of various adverse maternal and neonatal outcomes. Established risks are minimized when disease is well-controlled on pregnancy-compatible medications prior to and during pregnancy. For reproductive-aged women prescribed teratogenic medications or who do not desire pregnancy, contraception is important; there are no disease-specific contraindications to available hormonal contraceptive methods. Patients look to rheumatologists to initiate conversations regarding their reproductive health and for ongoing guidance throughout the reproductive lifespan.

Author Contributions

Noel L. Ermer, Lisa R. Sammaritano, and Caroline H. Siegel, contributed to the conception and design of this study. The first draft of the manuscript was written by Noel L. Ermer, and the work was critically reviewed for intellectual content by Caroline H. Siegel and Lisa R. Sammaritano. All authors read and approved of the final manuscript.

Funding

No funding or sponsorship was received for this study or publication of this article. NE, LS, and CS are supported by the Barbara Volcker Center for Women and Rheumatic Diseases, Hospital for Special Surgery, New York, NY, USA.

Declarations

Conflict of Interest

Noel L. Ermer and Lisa R. Sammaritano have nothing to disclose. Caroline H. Siegel has received honoraria from the Broth Agency and has served as a consultant for Bristol Myers Squibb.

Ethical Approval

This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors.