The management of women of childbearing age with rheumatoid arthritis: an expert report

ABSTRACT

Introduction

The introduction of biologic therapies and a treat-to-target approach has transformed the management of rheumatoid arthritis (RA), which has led to improved outcomes for women with RA who wish to become pregnant. However, guidelines for the management of reproductive health in female patients with RA are still lacking.

Areas covered

A task force (Women of Childbearing Age [WoCBA]-Rheumatoid Arthritis in Japan) comprising 10 experts in the fields of rheumatology, obstetrics and orthopedic surgery developed 10 clinical questions (CQ) related to the management of WoCBA with RA. For each CQ, a systematic literature review was conducted to identify relevant evidence. Based on this evidence, a set of recommendations for each CQ were drafted and evaluated using the modified Delphi method. This article describes the agreed recommendations along with the supporting evidence.

Expert opinion

There are many ongoing challenges associated with the provision of reproductive healthcare in WoCBA with RA. It is hoped that the consensus-based recommendations provided here can be implemented in clinical practice in order to increase collaboration between rheumatologists and obstetricians/gynecologists and to improve reproductive health outcomes for WoCBA with RA.

KEYWORDS:

• Childbearing
• consensus recommendations
• pregnancy
• reproductive care
• rheumatoid arthritis
• systematic literature review

1. Introduction

The reproductive healthcare management of rheumatoid arthritis (RA) in women of childbearing age (WoCBA) has changed in recent decades because of the development of various anti-rheumatoid drugs. In particular, a treat-to-target (T2T) strategy using biologic therapies has led to improvements in disease control before, during, and after pregnancy [1,2], which may contribute to improved pregnancy outcomes for patients with RA.

Although guidelines for reproductive care in patients with rheumatic diseases have been proposed [3], these are predominantly focused on systemic lupus erythematosus (SLE) and antiphospholipid antibody-positive patients. Recommendations for reproductive healthcare specifically for women with RA have been limited to a few consensus recommendations [4–6]. Therefore, there is a need for a comprehensive healthcare and treatment plan for the management of reproductive health in female patients with RA by rheumatologists, obstetricians, orthopedic surgeons, and other medical staff that is based on the latest evidence.

In this report, a volunteer task force (WoCBA-Rheumatoid Arthritis in Japan [WoCBA-RAJ]) comprising rheumatologists, obstetricians and gynecologists (OB/GYN), and orthopedic surgeons was established. This task force identified clinical questions (CQs), then developed and evaluated recommendations based on the current evidence.

2. Methods

The WoCBA-RAJ was established as a task force of 10 volunteers representing the fields of rheumatology, OB/GYN, and orthopedics. Each participating specialist had to be currently involved and experienced in the care of WoCBA with RA (either from a rheumatology or an OB/GYN perspective) and/or involved in the development of past or present guidelines/consensus statements (rheumatology or OB/GYN guidelines) [7]. This task force developed preliminary CQs based on national guidelines and overseas consensus reports related to WoCBA with RA. Subsequently, these were closely examined at an online meeting in August 2021, and a final set of 10 CQs was selected.

For each CQ, a Systematic Literature Review (SLR) was conducted in September 2021 in accordance with the methods specified in the Minds Clinical Practice Guideline Development Manual 2020 version 3.0 [8]. The PubMed and Scopus databases were searched and relevant articles were collected to address each CQ. Full details of the SLR are shown in Supplementary Figure 1. For each CQ, the level of evidence was defined according to the Grading of Recommendations, Assessment, Development and Evaluations framework [9] (Supplementary Table S1). Based on the evidence available, a recommendation for each CQ was drafted, and anonymized comments were collected from each of the 10 taskforce members. These comments were discussed at an online meeting in March 2022 and the draft recommendations were evaluated using the modified Delphi method. A consensus was reached for each draft decision upon the agreement of at least 8 out of 10 members. Draft recommendations that did not reach a consensus were revised and repeated for up to three rounds of review. A summary of the consensus agreement process is shown in Supplementary Figure 2.

3. Results

CQ1: When should pregnancy education be started for WoCBA with RA?

Recommendation:

• Pregnancy education should be provided to WoCBA with RA early after diagnosis, regardless of their current plans for conception.

Level of evidence D; Agreement: 90%.

3.1.1. Importance of pregnancy education for RA patients

For patients with RA, new treatment approaches such as the T2T strategy have significantly improved outcomes, including improved functional capacity and quality of life. These advances have strengthened the opinion that safe pregnancy is possible in women with RA, especially if pregnancy planning and screening for maternal and fetal risks are implemented and the pregnancy occurs in the context of good disease control [10,11]. To achieve this, it is important that the rheumatologist providing the initial care instigates a positive discussion with the patient, recognize the need for family planning counseling, consult with an OB/GYN specialist at an early stage, and initiate appropriate patient education.

3.1.2. Contraceptive education

In WoCBA with RA, because optimal control of disease activity of RA has an impact on fertility, continuation of pregnancy and normal delivery, it is important to plan for pregnancies after the patient has achieved and maintained remission or low disease activity [4]. Therefore, it is strongly recommended to educate patients at an early stage on the importance of appropriate contraceptive use until disease activity is sufficiently low. In surveys of WoCBA with chronic inflammatory diseases in the US, UK, Germany, Italy, and Spain, more than 70% of rheumatologists had discussed family planning with their female patients, but less than half consulted their patients’ general practitioners or GYN about these topics. Moreover, many patients felt that they received inconsistent advice from the healthcare professionals managing different aspects of their care [12]. This failure to provide consistent information to female patients may potentially lead to high rates of unplanned pregnancies. This is illustrated by a survey of patients with autoimmune diseases in Japan, which reported that only 52.5% of pregnancies in patients with RA were planned [13].

3.1.3. Collaboration between rheumatologists and OB/GYN specialists

To address these issues, rheumatologists treating WoCBA should establish a relationship with an OB/GYN (see CQ4). Rheumatologists should also initiate discussions on reproductive issues, as it can be difficult for patients to initiate these discussions. In a survey of rheumatologists, many physicians were hesitant to provide consultations concerning contraception and preferred this to be handled by an OB/GYN specialist [14]. However, in a survey of female patients with RA, the patients’ preference was for their rheumatologist to communicate directly with OB/GYN specialists [15].

In Japan, networking between rheumatologists and OB/GYNs regarding female patients with RA is not yet well established, and preconception care for these patients has not been standardized. Therefore, it is necessary to promote the future development of networks and standardization of education programs (see CQ2) that can be practiced in primary care and disseminated.

3.1.4. Counseling RA patients who wish to conceive

If a patient with RA wishes to conceive, the rheumatologist should counsel the patient on the importance of controlling disease activity before attempting pregnancy. For the management of pregnancy in patients with RA, adherence to a clinical path is recommended that includes (1) a diagnostic pathway involving blood and antibody testing; (2) a treatment pathway that includes an appropriate selection of anti-rheumatic drugs; and (3) a follow-up pathway consisting of at least one prenatal rheumatologist visit that can reduce the risk of adverse pregnancy events, such as birth complications or miscarriage, to the same level as that expected in the general population [16]. Because patients with RA tend to be older at the time of delivery than women without RA [17], counseling should be initiated at the appropriate time if the patient wishes to become pregnant. The rheumatologist, in collaboration with an OB/GYN specialist, should begin family planning consultations (CQ3) and a preconception care program (CQ5).

CQ2: What assessments should be performed early after diagnosing RA in WoCBA?

Recommendations:

• In addition to assessing disease activity and joint status, it is recommended to check for comorbidities, organ damage, and pregnancy-related risk factors.

• Screening for cervical cancer is recommended.

Level of evidence C; Agreement: 100%.

3.2.1. Considerations for the rheumatologist

3.2.1.1. Monitoring disease activity and joint status of patients with RA (Table 1)

All WoCBA diagnosed with RA should be assessed for the possibility of pregnancy, including unplanned pregnancies. Newly diagnosed patients should be treated with drugs that can achieve remission or low disease activity and then switched to maintenance medications that are compatible with pregnancy (CQ3). Even if the patient’s RA is considered to be in remission, birth outcomes may still be affected if the range of motion of the joints (e.g. hip, knee, ankle, wrist) is worsening or if the patient has cervical spine lesions. The rheumatologist should assess for restriction of hip opening and closing and lower extremity loading and share this information with the patient’s OB/GYN specialist.

3.2.1.2. Comorbidities/medical history (Table 1)

Femalepatients with RA have been shown to have a higher frequency of thyroid disease compared with healthy control women. In addition, the frequencies of other risk factors in pregnancy, including hypertension, diabetes mellitus, and renal impairment, also increase with higher maternal age [1,17]. Therefore, it is important to control these comorbidities regardless of the patient’s immediate reproductive plans [4]. Rheumatologists should also conduct relevant health screenings, including rubella immunization status and screening for other autoimmune diseases, that may affect pregnancy [4].

3.2.2. Considerations for the OB/GYN specialist

3.2.2.1. Previous pregnancies (Table 1)

In addition to the patient’s general obstetric history, any previous pregnancy-related complications and miscarriages should be identified as they may affect subsequent pregnancies [4]. If there is a history of more than two miscarriages or stillbirths, gynecological problems or diseases such as antiphospholipid syndrome should be suspected.

3.2.2.2. Cervical cancer screening

Women in Japan are at high risk of cervical cancer because of unique social circumstances and the discontinuation of the human papillomavirus (HPV) vaccine. From 2009 until 2013, the HPV vaccination rate in Japan was approximately 70%; however, the Japanese government subsequently discontinued active recommendation of the vaccine and the vaccination rate dropped to less than 1% [18]. This unvaccinated generation is now reaching the starting age (20 years) for cervical cancer screening in Japan [18,19]. In addition, most women born before the introduction of the vaccine (before 1993) are also unvaccinated [20]. In Japan, the HPV vaccination program resumed in 2022. HPV vaccination is reported to protect against both cervical cancer and cervical dysplasia [21–24]. The low vaccination rate in Japan is expected to have a significant impact on rates of cervical cancer, so at the time of OB/GYN consultation, patients should be recommended to undergo screening for cervical cancer every 2 years. Considerations for the rheumatologist and OB/GYN specialist for WoCBA at RA diagnosis are shown in Table 1.

Table 1. Considerations at RA diagnosis in WoCBA.

Item	Description
Considerations for the rheumatologist
Disease activity	Confirm remission or low disease activity
Assessing the condition of the joints	Check the range of motion of the joints
Comorbidities/history	Screen for complications such as thyroid disease, hypertension, diabetes, and obesity Screen for immunization status (e.g. rubella) and other autoimmune diseases that may affect pregnancy Screen for autoimmune diseases that may affect pregnancy
Considerations for the OB/GYN specialist
Past pregnancies	Determine past fertility and pregnancy history, and pregnancy-related complications (e.g. miscarriage, stillbirths, preterm birth, hypertensive disorders of pregnancy, gestational diabetes mellitus)
Cervical cancer	Recommend screening for cervical cancer every 2 years, regardless of immediate conception plans
Co-morbid diseases	Screen for sexually transmitted infections (if patients have symptoms)
Other	Check for any other factors (e.g. smoking, family history of genetic disorders) that may affect pregnancy

CQ3: What pregnancy-related education should be provided to patients at the time of RA diagnosis?

Recommendations:

• If a patient with RA wishes to conceive, pregnancy education on the importance of controlling disease activity and the potential risk of complications should be provided before attempting conception.

• Education is recommended on the importance of contraception until disease remission or stable low disease activity is achieved.

Level of evidence B; Agreement: 100%.

3.3.1. Considerations for the rheumatologist

3.3.1.1. Disease activity and pregnancy in patients with RA

In treating WoCBA with RA, it is important to counsel the patient that conception should only be attempted after achieving remission or stable low disease activity [4]. In female patients with RA, high disease activity can lead to prolonged time to pregnancy and reduced fertility [25,26]. In addition, active RA in the third trimester of pregnancy has been reported to be an independent risk factor for low birth weight newborns [27]. Furthermore, in a survey performed in the Japan Maternal Fetal Intensive Care Units, patients with RA had a higher frequency of preterm birth (27.5% vs. 5.6%, p < .001) and low birth weight (51.6% vs. 9.5%, p < .001) than the general population [13]. Conversely, when RA is well-controlled, pregnancy outcomes are comparable with that of the general population and there is no increase in the risk of preterm delivery or infertility [25].

3.3.1.2. Anti-rheumatic drugs for the preconception period

When treating female patients with RA who wish to conceive immediately, anti-rheumatic drugs that can be used during pregnancy after achieving remission or low disease activity should be selected [11]. Adherence to anti-rheumatic drugs should also be confirmed [11]. Information on medications that can be used during pregnancy can be found in the Treatment Guidelines for Pregnancy and Childbirth in Female Patients with SLE, RA, Juvenile Idiopathic Arthritis (JIA) and Inflammatory Bowel Disease (IBD) [28]; and the American College of Rheumatology (ACR) Guideline for the Management of Reproductive Health in Rheumatic and Musculoskeletal Diseases [3]. In treating patients with RA who wish to conceive immediately, methotrexate (MTX), leflunomide, and Janus kinase (JAK) inhibitors should be avoided because of the increased risk of congenital abnormalities and miscarriage [28]. Sulfasalazine and hydroxychloroquine can be used throughout pregnancy (hydroxychloroquine is not approved to treat RA in Japan). Among the biologic disease-modifying antirheumatic drugs (bDMARDS), tumor necrosis factor (TNF) inhibitors can be used continuously throughout the second trimester of pregnancy with little placental transfer [3,29]; they can also be used in the third trimester under certain circumstances when considering the risk – benefit profile of the patient [3,30].

The use of TNF inhibitors during pregnancy is supported by a study that showed that maternal and neonatal outcomes were not different in patients treated with TNF inhibitors compared with patients receiving other DMARDs or no DMARDs [13]. Moreover, several studies showed that discontinuation of TNF inhibitors in early pregnancy was identified as a risk factor for RA disease flares during pregnancy [31,32]. Conversely, a study comparing patients who discontinued TNF inhibitors before gestational week 20 or continued to receive them beyond week 20 showed no significant difference in disease activity in late pregnancy [33].

All three guidelines note that certolizumab pegol is compatible with all trimesters of pregnancy [3,30,34]. Certolizumab pegol does not have an Fc region and placental transfer is reported to be very low [35], with no increase in adverse pregnancy outcomes or risk of congenital malformations in certolizumab pegol-exposed pregnancies reported in a large cohort safety database analysis [36,37]. Regarding other TNF inhibitors, the ACR guidelines suggest that treatment with infliximab, etanercept, adalimumab, and golimumab should be discontinued in the third trimester of pregnancy [3]. The EULAR and British Society of Rheumatology (BSR) guidelines state that etanercept can be continued up to week 30–32 of gestation [30,34] because it has a low rate of trans-placental transfer [38]. Additionally, both guidelines recommend discontinuation of infliximab after 20 weeks of gestation [30,34]. Limited data are available on the safe use of abatacept, tocilizumab, and rituximab in pregnancy; therefore, these bDMARDs should be discontinued while pregnant [3,30,34] (rituximab is not approved for the treatment of RA in Japan). However, we note that unintentional exposure early in the first trimester may not be harmful [34].

If a female patient with RA does not plan to immediately conceive and is receiving MTX or JAK inhibitors, reliable forms of contraception should be discussed with the patient. If a patient receiving MTX or JAK inhibitors wishes to conceive, the patient should be instructed to discontinue these medications and wait for at least one menstrual cycle before attempting to conceive [3,4].

3.3.2. Considerations for the OB/GYN specialist

3.3.2.1. Family planning counseling

OB/GYN physicians who are consulted by patients with RA should collaborate with the patient’s rheumatologist to obtain information on current disease activity and drug treatments. The OB/GYN should then take this information into account when discussing the patient’s intentions concerning pregnancy and family planning.

There are cases in which patients may be reluctant to receive pharmacological treatments during pregnancy and may discontinue medication at their discretion. Conversely, patients may continue to take drugs that are contraindicated during pregnancy. These scenarios should be avoided through appropriate education.

It is well established that female fertility declines with age [39]. For example, in a Japanese in vitro fertilization embryo transfer study, fertility rates declined from 45.1% for those 30 years of age to 28.3% for those 40 years of age and 8.5% for those 45 years of age [40]. Therefore, patients with RA need to be offered a plan based on these age-related issues.

3.3.2.2. Contraceptive counseling

Condoms are the most widely used contraceptive method in Japan but have a lower contraceptive efficacy compared with other methods of contraception. Therefore, more reliable methods, such as oral contraceptives and intrauterine devices, are recommended for patients with RA. The OB/GYN should also educate patients on the effectiveness of emergency contraceptives, which can be used for up to 72 hours after unprotected intercourse [3,11].

3.3.2.3. Unintended (unplanned) pregnancy

In the case of an unintended (unplanned) pregnancy, the rheumatologist should review drug exposure and disease activity status, share the situation with the OB/GYN specialist, assess maternal and fetal risks, and inform the patient of those risks. MTX should be discontinued immediately for any patient who is found to be pregnant while taking this drug. Previous reports where MTX was immediately discontinued upon identification of pregnancy have shown that, although miscarriages were more frequent, the teratogenicity rate was only 3%–4% higher than in patients not taking this drug, and 80.9% of infants were healthy at birth [41]. Patients should be provided with this information and assisted in making their own decisions. If the patient wishes for the pregnancy to continue, the OB/GYN team should assess for structural abnormalities using ultrasonography and provide this information to the patient. If an unintended pregnancy is identified during RA treatment and the patient is unsure as to their next steps, the Japan Drug Information Institute in Pregnancy (https://www.ncchd.go.jp/kusuri/) offers consultations with specialized physicians and pharmacists at hospitals throughout Japan to provide information and assistance in making decisions. Similarly, in Europe and the US, information is available via the European Network of Teratology Information Services (https://www.entis-org.eu/) and MotherToBaby (https://mothertobaby.org/), respectively.

CQ4: How to support patients with RA who wish to become pregnant?

Recommendations:

• For patients with RA who wish to become pregnant, early collaboration between rheumatologists and OB/GYN specialists is recommended, as well as the establishment of a support team including other medical staff.

• If pregnancy has not been achieved after 1 year of regular, unprotected sexual intercourse, it is recommended to refer the patient to fertility specialists.

Level of evidence D; Agreement: 90%.

3.4.1. Multidisciplinary care team for RA patients who wish to conceive

Patients with RA who are pregnant should be managed by a multidisciplinary medical team who are familiar with autoimmune diseases [4]. Specifically, in addition to a rheumatologist and OB/GYN specialist, allied medical staff, including RA nurses and dietitians, should be involved in patient management before conception. However, it can be difficult for medical staff such as nurses to mediate between rheumatologists and OB/GYN specialists for each patient. Therefore, flexibility in the team structure will be required to adjust to the specific situation within each facility. When a decision is made to attempt a pregnancy, all relevant information on the patient’s health during the preconception period, including changes in anti-rheumatic drugs, should be shared between the rheumatologist and OB/GYN specialist (see CQ5) [4]).

3.4.2. Support for the treatment of infertility in patients with RA

For patients with RA who wish to conceive, infertility treatment should be initiated if a pregnancy has not been achieved within 1 year of regular, unprotected sexual intercourse [42]. In the absence of regular OB/GYN visits, the rheumatologist should advise patients to consult an OB/GYN specialist if pregnancy is not achieved within 1 year.

CQ5: What assessments and care are required during the preconception period for patients with RA?

Recommendations

• In addition to monitoring disease activity and treatment, an assessment of comorbidities and risk factors potentially affecting pregnancy is recommended.

• Assessment of reproductive function and risk factors for pregnancy complications is recommended.

Level of evidence B; Agreement: 100%.

3.5.1. Considerations for the rheumatologist (Table 2)

3.5.1.1. RA disease activity

When a patient with RA plans to become pregnant, it is important to maintain remission or low disease activity. Recommended forms of assessment for RA disease activity during the preconception period and pregnancy include non-erythrocyte sedimentation indexes, such as the Clinical Disease Activity Index (CDAI) (see CQ6). It is also important to ensure that any RA medications in use are not contraindicated for use during pregnancy (see CQ3). If a patient has received MTX, a contraceptive period of one menstrual cycle should be provided after discontinuation of MTX [4].

3.5.1.2. Comorbidities/medical history

If the patient has a limited range of motion due to pelvic and hip deformity, this should continue to be assessed as it may affect the choice of vaginal delivery or Cesarean section [4]. The patient should also be checked for risk factors for pregnancy complications such as a history of thrombosis, hypertension, or renal failure, and this information should be shared with the treating OB/GYN specialist. If the patient’s menstrual cycle is irregular, anovulatory cycles are suspected and patients should be instructed to consult with an OB/GYN specialist.

3.5.2. Considerations for the OB/GYN specialist (Table 1)

3.5.2.1. Preconception checklist

The patient’s history of previous pregnancies and deliveries should be checked, including the number of miscarriages (including approximate age of gestation at the time of miscarriage) and any other previous pregnancy-related complications (e.g. gestational diabetes mellitus, hypertensive disorders of pregnancy). If the patient’s menstrual cycle is irregular, anovulatory cycles should be suspected and basal body temperature and female hormone levels should be monitored. Folic acid intake is recommended to reduce the risk of neural tube defects. In addition, medical risk factors that may adversely affect pregnancy outcomes, such as obesity, hypertension, and diabetes mellitus, should be assessed and treated. A preliminary interview should also be conducted to evaluate the patient’s exercise habits, smoking and alcohol consumption, vaccination history, etc., and to provide appropriate lifestyle guidance. Moreover, accurate information about the disease should also be provided to the partner and their family members so that the patient does not feel isolated.

3.5.2.2. Infertility and recurrent pregnancy loss (RPL) management

If no pregnancies are achieved after 1 year of regular, unprotected sexual intercourse, and if the RA disease activity is controlled, infertility treatment should be initiated (see CQ4). Fertility assessments should be performed as needed. Multiple studies have found that anti-Müllerian hormone (AMH) levels in patients with RA are comparable to healthy controls, suggesting that reduced fertility in patients with RA is not due to reduced ovarian reserve [25,43]. Of note, AMH is a biomarker of ovarian reserve [44], but it is not an indicator of oocyte quality [45].

The frequency of RPL, defined as a history of two or more miscarriages or stillbirths, is reported to be 1%–4% overall [46]. In Japan, the frequency of RPL is reported to be 4.2%, which is slightly higher than in Western countries; of these patients, 8.7% were reported to be positive for antiphospholipid antibodies [47,48]. Therefore, patients with RA should also be screened for antiphospholipid syndrome if reproductive issues are suspected. Patients who are antiphospholipid positive should be referred to a specialist for evaluation of their antibody profile and titers.

3.5.2.3. Indications for Assisted Reproductive Technology (ART)

ART is indicated in female patients with RA who are receiving drugs compatible with pregnancy, have stable disease activity, and have no pregnancy complications [49,50]. Oocyte cryopreservation is also an option in patients with high RA disease activity and/or who are receiving MTX. Continuation of necessary immunosuppressive and/or biologic therapies (except cyclophosphamide) is not an issue when the purpose of ovarian stimulation is oocyte retrieval for oocyte cryopreservation [3].

3.5.3. Common considerations (rheumatologist, OB/GYN specialist, Table 2)

3.5.3.1. Antibody profile

3.5.3.1.1. Thyroid function tests, anti-thyroid antibodies

An increased incidence of hypothyroidism in RA patients compared with healthy controls has been reported in both cross-sectional [51] and case – control studies [52], and elevated levels of antithyroid antibodies have also been reported in patients with RA in a meta-analysis [53]. It has also been shown that there is an increased incidence of hypothyroidism during the 5 years before the diagnosis of RA [52]. Therefore, screening for thyroid dysfunction and anti-thyroid antibodies should be required in patients with RA. If hypothyroidism is detected, a referral to a perinatal medical center or an endocrinologist/thyroid specialist should be considered.

3.5.3.1.2. Anti-SSA antibodies

Screening for anti-SSA antibodies in RA patients is recommended in the ACR guidelines to improve counseling regarding pregnancy and fetal risk [3]. The prevalence of anti-SSA antibodies has been noted to be higher in RA patients compared with the general population, reported as 4%–20% in a study of RA patients [13,54]. In addition, there is insufficient evidence for the effectiveness of screening, as the incidence of congenital heart block among fetuses in women who are positive for anti-SSA antibodies is only approximately 1% and early detection and management does not improve the outcome [55]. Therefore, the effectiveness of screening for anti-SSA antibodies in patients with RA should be reevaluated in the future.

3.5.3.1.3. Antiphospholipid antibodies

There is insufficient evidence to support screening of all female RA patients for antiphospholipid antibodies, as reference values vary by report and results are variable [56]. In Japan, the number of patients who have antiphospholipid antibodies is extremely small, and measurement should only be considered when there is a history of miscarriage, abnormal blood coagulation times, or other complications that may indicate antiphospholipid antibody syndrome. Considerations for the rheumatologist and OB/GYN specialist for WoCBA with RA in the preconception period are shown in Table 2

Table 2. Considerations in the preconception period for WoCBA with RA [5,11].

Item	Assessment Contents
Considerations for the rheumatologist
RA medical history and disease activity	Assess disease activity: indicators such as CDAI are recommended Aim for a certain period of remission before conception Medication review: wash out teratogenic drugs thoroughly, check treatment adherence, recommend multivitamin use
Comorbidities/history	Check for bone deformities (e.g. pelvis) to determine any impact on pregnancy success
Considerations for the OB/GYN specialist
Reproductive history	Review past fertility and pregnancy history, and pregnancy-related complications (e.g. miscarriage, stillbirth, preterm birth, hypertensive disorders of pregnancy, gestational diabetes mellitus)
Comorbidities/history	Recommend cervical cancer screening every 2 years
Risk factors for pregnancy complications	Check risk factors for pregnancy complications such as a history of thrombosis, hypertension, renal failure, etc.
Confirmation of infertility and infertility	If pregnancy is not achieved within 1 year with controlled disease activity, begin infertility treatment
Fertility	Fertility: ovarian reserve: AMH Infertility
Common considerations
Antibody profile	Anti-thyroid antibodies (anti-TG and anti-TPO antibodies) Anti-SSA antibodies (1% of fetuses of positive women are at risk of congenital heart block) Antiphospholipid antibodies when there are factors that may lead to suspicion of complications of antiphospholipid syndrome (e.g. complication of systemic lupus erythematosus, history of miscarriage or stillbirth, abnormal blood clotting times)

.

CQ6: How should patients with RA be managed during pregnancy?

Recommendations

• For pregnant patients with RA, it is recommended to assess disease activity using indices such as CDAI.

• Management with attention to gestational hypertension, preterm delivery, and fetal growth restriction is recommended.

Level of evidence A; Agreement: 100%.

3.6.1. Considerations for the rheumatologist (Table 3)

3.6.1.1. Disease activity and pregnancy outcomes during pregnancy

Elevated RA disease activity during pregnancy increases the risk of adverse pregnancy outcomes [31]. Therefore, control of disease activity with appropriate medications is important during pregnancy. The preferred method for assessing disease activity during pregnancy is to use indices such as CDAI [57] that do not require blood sedimentation, as blood sedimentation is known to be affected by pregnancy. A database study of 31,439 United States obstetric inpatients with RA reported a significantly increased risk of pregnancy-induced hypertension (odds ratio [OR] = 1.16), premature rupture of membranes (OR = 1.55), antepartum hemorrhage (OR = 1.23), preterm delivery (OR = 1.46), intrauterine growth restriction (OR = 1.93), and Cesarean section (OR = 1.17) compared with a control group without RA [17]. In addition, a retrospective cohort study in the United States suggested that pre-eclampsia/eclampsia and gestational diabetes may occur more frequently in patients with RA than in those without RA [1]. However, it is important to note that these data are likely to include cases in which disease activity was not well controlled. Poor control of disease activity has also been reported to be associated with preterm delivery and shorter gestational age [58], as well as intrauterine growth restriction, and increased risk of Cesarean section [59]. It is therefore important that disease activity be well controlled before and during pregnancy.

3.6.1.2. Use of anti-rheumatic drugs during pregnancy

Information on medications that can be used during pregnancy can be found in the Japan College of Rheumatology (JCR) Clinical Practice Guidelines for the Management of Rheumatoid Arthritis [60], the Treatment Guidelines for Pregnancy and Childbirth in Female Patients with SLE, RA, JIA and IBD [28], and the ACR Guideline for the Management of Reproductive Health in Rheumatic and Musculoskeletal Diseases [3], as described in CQ3. Biologics are conditionally recommended before and during pregnancy, and specifically may be discontinued in the third trimester of pregnancy in the ACR guidelines [3]. If biologics need to be used during the third trimester due to inadequately controlled RA, it is recommended that biologics with less placental transfer be used [3]. The phenomenon of transient improvement in disease activity during pregnancy has been previously reported. For example, in a meta-analysis in 2018, RA disease activity improved during pregnancy in approximately 60% of patients [61]. However, in the same study, postpartum disease flares occurred in 46.7% of pregnancies [61].

3.6.1.3. Assessment of joint condition

Joint status should continue to be evaluated throughout pregnancy. However, radiographic evaluation should not be performed unless deemed necessary. In the case of undiagnosed pregnancies that have been radiographed, the Guidelines for Gynecological Practice in Japan state that exposure up to 10 days after fertilization does not increase the incidence of malformations, and fetal exposure from 11 days after fertilization to 10 weeks’ gestation does not increase the incidence of malformations at doses below 50 mGy [62]. Moreover, the Diagnostic Imaging Guidelines also state that the incidence of malformations does not increase at doses below 50 mGy [63] and that a single computed tomography scan under normal imaging conditions will not result in fetal complications.

3.6.2. Considerations for the OB/GYN specialist (Table 3)

3.6.2.1. Pregnancy complications in patients with RA

Although there are no reports of an increased risk of pregnancy complications in patients with RA when disease activity is adequately controlled, signs of pregnancy complications should be monitored appropriately. The use of an adjunctive marker to predict the short-term onset of preeclampsia should be considered if the patient has symptoms that suggest pregnancy-induced hypertension (e.g. blood pressure of 130/80 mmHg or higher, intrauterine growth restriction, abnormal umbilical artery blood flow wave type) [64,65].

3.6.2.2. Prevention of thrombosis

Patients with RA are generally at higher risk of thrombosis (including venous thromboembolism [VTE], pulmonary embolism, and deep vein thrombosis), with the risk of VTE being highest in the first year after RA diagnosis [66]. The risk of VTE during pregnancy is increased in patients with inflammatory polyarthritis, according to the Guidelines for Gynecological Practice in Japan [62]. Both the Royal College of Obstetricians and Gynecologists and the American College of Chest Physicians call for careful observation of pregnant patients with RA based on the presence or absence of a thrombogenic predisposition and the cause of any previous VTE [67,68]. General care, such as observation for dehydration, should be provided. In addition, prophylactic anticoagulation, such as heparin, should be considered if there is a combination of risks, such as gestational hypertension, older age, and/or high body mass index [62].

3.6.2.3. Anti-SSA antibodies

Patients with SSA antibodies should be carefully monitored by fetal echocardiography because of the risk of congenital heart block. However, as SSA antibody-associated fetal heart block can progress from Grade I – II to complete atrioventricular block in only 24–48 hours, it is diagnosed in very few cases where treatment can be initiated [3], e.g. with dexamethasone as indicated in the ACR guidelines. As such, the clinical significance of screening for anti-SSA antibodies and the use of fetal echocardiography in anti-SSA antibody-positive patients remains controversial [55].

Testing for SSA antibodies is effective for counseling regarding pregnancy and fetal risk [3], and early referral to a perinatal center may be considered for patients with a positive anti-SSA antibody result. Considerations for the rheumatologist and OB/GYN specialist or the management of pregancy in RA are shown in Table 3.

Table 3. Management of pregnancy in patients with RA [11].

Item	Monitoring
Considerations for the rheumatologist
Frequency	Visit every 4–6 weeks If disease activity increases or flare-ups are observed, the frequency of visits should be increased
Parameters	General laboratory tests: total blood count, serum uric acid, liver function, urea, creatinine, electrolyte levels, urinalysis Disease activity: CDAI recommended Confirmation of joint condition
Pharmacotherapy	Continue drug therapy Monitor adherence to treatment TNF inhibitors in the third trimester of pregnancy may be reduced or discontinued if symptoms are stable
Considerations for the OB/GYN specialist
Frequency	Once every 4 weeks until Week 23 + 6, once every 2 weeks from Week 24 to Week 35 + 6, and once a week thereafter as with general uncomplicated pregnancies
Parameters	Fetal evaluation: performed between Weeks 18 and 20 to screen for fetal abnormalities Routinely assess fetal development and well-being Prevention of thrombosis: avoid dehydration; consider heparin in patients with overlapping thrombosis risks such as gestational hypertension, older age, and high body mass index
Pregnancy complications	Monitor for signs of pregnancy complications (e.g. hypertensive disorders of pregnancy, gestational diabetes mellitus, renal function)
High-risk cases	Preeclampsia: recommend inpatient management and routine evaluation of blood pressure, maternal weight, blood tests, fetal growth, and fetal well-being Intrauterine growth restriction: increase the frequency of developmental monitoring by ultrasound or other means Patients with anti-SSA antibodies should be carefully monitored using fetal echocardiography; when an anti-SSA antibody-positive RA patient becomes pregnant, referral to a perinatal center is recommended
Nutritional state	Consider the need for nutritional or vitamin supplements, including folic acid [69]

CQ7: How should patients with RA be supported when they lose a pregnancy?

Recommendation

• Comprehensive medical and mental health support by obstetricians, rheumatologists, and medical staff is recommended after pregnancy loss.

Level of evidence D; Agreement: 100%.

3.7.1. Miscarriage rate in patients with RA

The rate of miscarriage in patients with RA with controlled disease activity and a planned pregnancy is not markedly higher than in the general population. This is supported by a prospective cohort study that reported a miscarriage rate of 17% in a cohort of patients with RA; this is similar to the miscarriage rate in the general population [25]. Of note, women who experienced miscarriages tended to have a higher frequency of anti-citrullinated protein antibodies or MTX exposure and a higher Disease Activity Score 28 than women who had not miscarried, although none of these differences were significant. After a miscarriage, 68% of women became pregnant again within 1 year, and the live birth rate was 90%.

3.7.2. Handling pregnancy loss

Miscarriage or RPL is emotionally taxing for all patients and their families. In a longitudinal survey, women who experienced perinatal loss had nearly four-fold higher odds of having a positive screen for depression and seven-fold higher odds of a positive screen for post-traumatic stress disorder compared with control women. However, only a minority of these women received any type of psychiatric treatment [70]. Therefore, adequate perinatal bereavement care, both medical and emotional, is needed for the patient and their family at the time of pregnancy loss [71]. All necessary information about the patient’s pregnancy loss should be shared with the rheumatologist, with the obstetrician responsible for notification and counseling concerning the possible causes. The rheumatologist should then reexamine the previously described risk factors, and with the support of a clinical psychologist and medical staff, should support the patient to think positively about subsequent pregnancies, while being attentive to the patient’s feelings and understanding their emotional distress.

CQ8: How should patients with RA be supported during delivery?

Recommendation

• Relevant information, including the condition of the patient’s joints, should be shared among physicians and allied medical staff to ensure the safe delivery of patients with RA.

Level of evidence C; Agreement: 100%.

3.8.1. Delivery in the case of joint disorders

Patients with RA may have restricted joint motion and are at risk of fracture or dislocation during manipulation under critical anesthesia of the hip, cervical spine, or lumbar spine, complicating pregnancy, childbirth, and subsequent childcare [49]. Therefore, rheumatologists need to share information regarding the patient’s joint condition with obstetricians, pediatricians, orthopedic surgeons, anesthesiologists, and medical staff.

Depending on the condition of the patient’s pelvis and other conditions, vaginal delivery may not be possible, in which case other delivery method options and birthing positions should be considered [4]. The rheumatologist should also inform the obstetrician if the patient has an artificial joint in the lower extremities, such as hip, knee, or ankle joints.

It should be noted that in RA patients, as in the general population, an increase in body mass index has been reported to increase the Cesarean section rate [58]. After a Cesarean section, if there is no risk of infection, biologic agents can be resumed within 48 hours after delivery. After a vaginal delivery, biologic agents can be resumed within 24 hours [72].

CQ9: What assessment and support is needed postpartum for patients with RA?

Recommendations

• Because patients with RA have an increased flare risk in the postpartum period, monitoring of disease activity at a certain frequency is recommended.

• If the patient received a biologic before delivery, it is suggested to consult with a pediatrician about the risks of administering live attenuated vaccines to the newborn during the first 6 months of life.

Level of evidence C; Agreement: 80%.

3.9.1. Considerations for the rheumatologist (Table 4)

3.9.1.1. Management of RA disease activity

Disease activity in RA patients often flares up during the postpartum period and careful monitoring should be performed. This is supported by a meta-analysis, in which 46.7% of patients with RA who underwent pregnancy and childbirth showed an increase in disease activity in the postpartum period [61]. In general, RA is more likely to flare between 6 weeks and 6 months postpartum [73,74]. Risk factors for postpartum flares include seropositive RA and discontinuation of RA medications (particularly TNF inhibitors) early in pregnancy [75].

Patients with RA also experience childcare difficulties associated with joint symptoms, with difficulties such as carrying and standing up with the child correlating with disease activity [76]. Therefore, physical or occupational therapy related to childcare should also be considered. It should also be noted that sleep deprivation due to childcare may increase disease activity and pain [4].

3.9.1.2. Restarting anti-rheumatic drugs that had been discontinued during pregnancy

Anti-rheumatic drugs that were discontinued during pregnancy should be considered for restart before relapse occurs or if there are any signs of an increase in disease activity. Rheumatologists should consider resuming treatment, especially for biologics and other drugs that are approved for use in lactation (see CQ10) [3]. MTX is not recommended during breastfeeding due to limited data showing a low level of drug transfer in breast milk (See CQ 10) [3,34,77–79]. If signs of relapse of disease activity are observed, breastfeeding abstinence should be discussed with the patient in order to permit the resumption of MTX.

3.9.2. Considerations for the OB/GYN specialist (Table 4)

3.9.2.1. Obstetric monitoring

At the checkup after delivery, the patient should be assessed for joint symptoms (e.g. pain) and this information should be shared with the rheumatologist. The risk of postpartum wound complications and VTE has been reported to be increased in RA patients and should be monitored appropriately [1] (see CQ6 for management of perinatal thrombosis). Thyroid function should be checked between 2 and 6 months postpartum in patients with RA who are positive for anti-thyroglobulin or anti-thyroid peroxidase antibodies (Hashimoto’s disease), or who have known hypothyroidism or hyperthyroidism. At 1 month postpartum for patients with RA, if there are no problems with childcare issues or breastfeeding, the joint care of the OB/GYN specialist and rheumatologist ends and the patient is then transferred primarily to the rheumatologist’s care. Considerations for the rheumatologist and OB/GYN specialist for the postpartum management of patients with RA are shown in Table 4

Table 4. Postpartum management of patients with RA.

Item	Assessment Contents
Considerations for the rheumatologist
Clinical examination	Carefully monitor for a flare-up of disease activity up to 6 months postpartum
Pharmacotherapy	Ensure that the patient is receiving treatment with a drug that is not contraindicated during breastfeeding (e.g. MTX, JAK inhibitors)
Considerations for the OB/GYN specialist
Management of perinatal complications	Monitor for wound complications and VTE
Thyroid function	Check thyroid function because of the risk of developing Hashimoto’s disease or postpartum thyroiditis
Vaccination of newborns	Newborns exposed to biological agents in the second and third trimesters of pregnancy should not receive an attenuated live vaccine for the first 6 months of life Other immunization programs may be implemented in the same manner as for the general population

3.9.2.2. Newborn vaccinations

The OB/GYN specialist should be aware of exposure to biologics and should educate parents concerning the use of live vaccines for the newborn. This information should be shared with the pediatrician if the mother received biologics before delivery. Biologics have been detected in newborns up to 6 months of age following maternal exposure to TNF inhibitors before delivery [11,80]. In a postmarketing pharmacokinetic study, zero-to-minimal placental transfer of certolizumab pegol was observed from mothers to infants, suggesting a lack of in utero fetal exposure during the third trimester [35]. Similarly, following etanercept treatment during pregnancy in a patient with RA, cord blood levels (considered to represent serum levels in the infant) were approximately only 1/30 of maternal levels [38]. However, because no data on vaccination of neonates with live vaccines have been reported for either of these drugs [11], live vaccination should be handled in the same way as for patients receiving other TNF inhibitors. Guidelines from the Japanese Society for Pediatric Infectious Disease currently recommend avoiding vaccination with live vaccines during the first 6 months of life if the mother has received a biologic until late pregnancy [81]. Rotavirus vaccine is generally recommended to be administered within the first 15 weeks of life [82]; therefore, it is not recommended in infants whose mothers continued to receive biologics until late pregnancy. Similarly, the BCG vaccination should only be administered after 6 months of age in infants whose mothers received biologics during late pregnancy [11]. EULAR guidelines also recommend that newborns exposed to biologics in the second and third trimester should not receive attenuated live vaccines for the first 6 months of life [30]. Other immunization programs may be implemented in the same manner as in the general population.

CQ10: What lactation education should be provided to RA patients?

Recommendations

• Provision of information on whether current medications are compatible with breastfeeding is recommended.

• Lactation support by allied medical staff is recommended.

Level of evidence C; Agreement: 100%.

3.10.1. Lactation education for RA patients

Similar to women in the general population, the majority of patients with RA want to breastfeed [83]. However, many patients with RA do not implement breastfeeding despite using anti-rheumatoid drugs that are compatible with breastfeeding [84]. This is often because of concerns, based on inaccurate information, about the effects of RA medications on infants [85]. Therefore, it is necessary to provide patients with correct information about breastfeeding and to assist them in making the appropriate choice of breastfeeding or formula milk for their infant. The patient, rheumatologist, OB/GYN specialist, and allied medical staff should agree on whether breastfeeding is feasible before delivery [4]. Breastfeeding is not known to adversely affect disease activity [84].

3.10.2. Lactation-compatible RA medications

For information on RA medications compatible with breastfeeding, see the JCR Clinical Practice Guidelines for the Management of Rheumatoid Arthritis [60], the Treatment Guidelines for Pregnancy and Childbirth in Female Patients with SLE, RA, JIA and IBD [28], and the ACR Guideline for the Management of Reproductive Health in Rheumatic and Musculoskeletal Diseases [3]. Prednisolone and non-steroidal anti-inflammatory drugs, e.g. ibuprofen, diclofenac, indomethacin, naproxen, and piroxicam, are compatible with breastfeeding [11], whereas MTX and JAK inhibitors are not recommended [30,41]. There are limited data showing that MTX is present in low concentrations in breast milk [77–79]; therefore, the use of MTX should be avoided while breastfeeding [3,34]. A prospective study reported that the TNF inhibitor certolizumab pegol has low transferability to breast milk [85] along with poor absorption from the gastrointestinal tract of the newborn [86]. Thus, certolizumab pegol is considered compatible with breastfeeding [3,30,34]. Etanercept is another TNF inhibitor that is present at low levels in breast milk of lactating patients with RA [38] and is suggested to be compatible with breastfeeding in several guidelines, as are several other TNF inhibitors [3,30,34]. It is reported that abatacept, tocilizumab, and rituximab are present at a low concentration in breast milk [87,88] and are conditionally recommended as compatible with breastfeeding [3]. When resuming or adding drugs after childbirth based on disease activity, the rheumatologist should share information with the OB/GYN and pediatrician and provide advice such as breastfeeding abstinence where needed.

4. Conclusion

Throughout the development of this consensus report, it was clarified that most women with RA can conceive and deliver safely if they maintain disease remission and are compliant with appropriate medications. However, we understand that these concepts are not fully understood and practiced in a clinical setting. To overcome these gaps in clinical practice, it is important to establish strategic care pathways and share the necessary reproductive healthcare information with both patients and their healthcare providers. Furthermore, it is important to encourage multidisciplinary collaboration between rheumatologists and OB/GYN specialists. Based on this consensus report, we intend to provide a range of assistance in building this new protocol (guidelines) for reproductive healthcare in patients with RA. We hope that our pragmatic approach will contribute to improving the quality of care for WoCBA with RA in the preconception, prenatal, and postnatal periods.

5. Expert opinion

Reproductive healthcare in patients with RA presents a variety of challenges that must be overcome. Birru Talabi et al. reported that rheumatologists feel a sense of responsibility to provide family planning counseling to WoCBA with RA, but they are reluctant to manage high-risk pregnancies or prescribe contraceptives and prefer to collaborate with OB/GYN specialists [14]. While rheumatologists found OB/GYNs to be an important resource, they rarely consult with them regarding the management of patients with RA. Admiraal et al. also reported that there is a gap between the patient and the healthcare professional level, and that realization of preconception care remains difficult, even though patients are interested in this and physicians think it is important to contribute to preconception care [89]. In a recent survey, it was reported that while most clinicians agreed that controlled disease reduced the risk of pregnancy complications, consistent implementation of controlled disease activity was not a reality in current clinical practice. The survey also reported that 69% of rheumatologists were ‘very comfortable’ prescribing TNF inhibitors for patients who are WoCBA, compared with 29% of obstetricians [90]. The frequency also differed across Australia, Japan, and the Asia-Pacific region. These findings support a varied knowledge of the treatment of rheumatic diseases among obstetricians from different countries and regions.

We conducted an online survey on preconception care among rheumatologists (including orthopedic surgeons) treating WoCBA with RA (n = 230) and female RA outpatients (n = 124) aged 18–45 years to understand the actual clinical situation in Japan [90]. The results of this survey showed that 91% of rheumatologists were aware of preconception care (defined as providing information about the mutual impact of pregnancy and RA and supporting life-planning treatment choices) and almost all rheumatologists thought ‘preconception care was necessary’ for WoCBA with RA. In addition, 80%–90% confirmed the ‘wish to conceive in the future’ and ‘possibility of pregnancy’ at the beginning of treatment. However, 48% of the rheumatologists responded that they ‘conducted life planning based preconception care for WoCBA with RA’ and only 10% of them ‘consulted and collaborated with an OB/GYN.’ This is lower than that reported by Murray et al (55%) [5], suggesting that consultations with OB/GYN specialists are difficult in Japan. These results indicate that barriers to the dissemination of reproductive health care for WoCBA with RA include the lack of comprehensive information and standard counseling methods, and difficulty in developing collaborations between rheumatologists and OB/GYN specialists.

The WoCBA-RAJ committee also commented that not all OB/GYN specialists are experts in pregnancy and delivery in patients with RA and that it is necessary to establish a network to refer patients to OB/GYN specialists with appropriate experience.

In a survey of patients, information desired by WoCBA with RA included ‘whether I can live my life like a healthy woman,’ ‘the possibility of RA inheritance,’ ‘the effect of chronic disease on gynecological disorders’ and ‘the impact of RA medications on children’ (both the fetus and during breastfeeding). The survey also showed a gap between patients and their rheumatologists: 46% of the respondents were aware that their doctors confirmed their ‘wish to have a baby in the future’ at the time of RA diagnosis, and 43% were aware that their doctors confirmed their ‘possibility of pregnancy.’ Furthermore, only 8% of patients discussed their treatment plan with their doctors from the viewpoint of their life plan as a woman, and the awareness rate of preconception care was extremely low at 3%. The results suggest that low awareness of preconception care and inadequate information provision are the main barriers to the dissemination of reproductive healthcare among WoCBA with RA.

The committee first organized these issues, developed CQs according to the steps of the practice, and reviewed the current evidence for each CQ. Based on this, the committee also proposed recommendations and suggested a standard process of reproductive healthcare for WoCBA with RA and organized information to be shared in the collaboration between rheumatologists and OB/GYN specialists. As a result, we have developed practical guidance that can be applied in daily clinical practice.

However, in order to put this guidance into practice, we recognize the need to further develop clinical pathways and other tools for physicians and patients that can be used in daily clinical practice, and to promote information provision and sharing. Briggs et al. recently reported recommendations for real-world multidisciplinary support for best-practice care of WoCBA with RA [4], with particular emphasis on ‘how to provide care’ in addition to ‘what to care for’ in their recommendations. Murray et al. also developed a multidisciplinary reproductive care pathway for WoCBA with RA and reported that, in fact, 70% of women who wanted to conceive gave birth to healthy children using this pathway, and 90% of patients were ‘very satisfied’ with this service [5]. In the UK, it has been shown that the management of patients who are WoCBA by a joint obstetric and rheumatology clinic improves pregnancy outcomes [91].

In high-income countries, preconception care remains remarkably low despite countermeasures against the declining birthrate attracting attention. In order to promote preconception care, it will be necessary to make changes to the medical system. For instance, for patients with intractable conditions such as RA and other autoimmune diseases, it may be necessary to design and rapidly implement a system that allows for additional fees to be paid for the provision of preconception medical education and guidance and for referrals to OB/GYN specialists.

Over the next five years, we believe that supporting the development of regional networks of rheumatologists and OB/GYN specialists will be necessary. Over this time, it is expected that the comprehensive care of WoCBA with RA will be improved by listing facilities that can provide preconception care for rheumatic disease patients, especially obstetricians and gynecologists, and by promoting education on preconception care for physicians. It will also be important to raise awareness that safe pregnancy is achievable for WoCBA with RA as long as appropriate rheumatologic treatment and preconception care are provided. Through these activities, it is hoped that more WoCBA will receive comprehensive care from rheumatologists and OB/GYN specialists and that reproductive healthcare for WoCBA with RA will become widely established in clinical practice.

Article highlights

• Through the development of this consensus report, it became clear that with recent advances in antirheumatic drugs, most women with rheumatoid arthritis (RA) are able to maintain disease remission or low disease with appropriate treatment, thereby enabling them to proceed with safe pregnancy and childbirth.

• This consensus report provides practical guidance that can be applied in daily clinical practice when treating women of childbearing age (WoCBA) with RA and is expected to improve reproductive health outcomes for these women.

• There is a need for a comprehensive healthcare and treatment plan for the management of reproductive health in female patients with RA. This plan should be developed and supported by rheumatologists, obstetricians, and other medical staff, and should be based on the latest clinical evidence.

• Optimal control of RA disease activity in WoCBA is crucial for fertility, full-term pregnancy, and normal childbirth. Thus, it is important that a patient achieves and maintains remission or low disease activity prior to planning to become pregnant. Furthermore, it is strongly recommended that, early in their RA diagnosis, patients are educated on the importance of practicing effective contraception use, which should be maintained until disease activity is sufficiently low.

• Treatment of patients with RA who are considering becoming pregnant or who are already pregnant should be managed by a multidisciplinary medical team that includes rheumatologists, obstetrician/gynecology specialists, RA nurses, dietitians, and other allied medical staff who are familiar with autoimmune diseases.

Declaration of interest

Y Tanaka reports grants or contracts from AbbVie, Asahi Kasei, Nippon Boehringer Ingelheim, Chugai Pharmaceuticals, Daiichi Sankyo, Eisai, and Takeda Pharmaceuticals and honoraria from AbbVie, AstraZeneca, Nippon Boehringer Ingelheim, Bristol-Myers Squibb, Chugai Pharmaceuticals, Daiichi Sankyo, Eisai, Eli Lilly Japan, Gilead Sciences, GSK, Mitsubishi Tanabe, and Pfizer Japan. A Murashima reports grants or contracts from Chugai Pharmaceuticals and honoraria from Chugai Pharmaceuticals, Asahi Kasei Pharma UCB Japan, and Astellas. T Atsumi reports consulting fees from Sanofi, GSK, AbbVie, AstraZeneca, Chugai Pharmaceuticals, Nippon Boehringer Ingelheim, Janssen, Gilead Sciences, Eli Lilly Japan, and Ono Pharmaceutical Co.; honoraria from Takeda Pharmaceuticals, Astellas, Mitsubishi Tanabe, Chugai Pharmaceuticals, Daiichi Sankyo, Pfizer Japan, Alexion, Teijin Pharma, Novartis, Eli Lilly Japan, Kyowa Kirin, AbbVie, Nippon Boehringer Ingelheim, Amgen, UCB Japan, AstraZeneca, and Eisai; and payment for expert testimony from Novartis, GSK, Eisai, Idorsia Pharmaceuticals, and Otsuka Pharmaceuticals. H Dobashi reports honoraria from Ayumi Pharmaceuticals, UCB Japan, and Asahi Kasei Pharma. Y Murakawa reports grants or contracts from Asahi Kasei, Chugai Pharmaceuticals, Eisai, Nihon Kayaku, Taisho Pharmaceuticals, AbbVie, Teijin Pharma, and Mitsubishi Tanabe and honoraria from AbbVie, Asahi Kasei, Astellas, Nippon Boehringer Ingelheim, Bristol-Myers Squibb, Chugai Pharmaceuticals, Eisai, Eli Lilly Japan, GSK, Janssen, Pfizer Japan, Sanofi, Teijin Pharma, and UCB Japan. S Momohara reports honoraria from AbbVie, Asahi Kasei Pharma, Astellas, Chugai Pharmaceuticals, Eisai, Eli Lilly Japan, Mitsubishi Tanabe Pharma, Ono Pharmaceutical Co., and Pfizer Japan. S Tanigaki reports consulting fees from UCB Japan and Kaken Pharmaceuticals; honoraria from Johnson & Johnson, Astellas, and Konica Minolta; and payment for expert testimony and support for attending meetings from UCB Japan. S Saito reports consulting fees from UCB Japan, Japan Blood Products Organization, Roche Diagnostics, and Kyowa Kirin; honoraria from UCB Japan, Astellas, Asahi Kasei, Shino-Test Corp, Kaken Pharmaceuticals, Otsuka Pharmaceuticals, Tsumura, AstraZeneca, Alexion, Roche Diagnostics, TOA Biopharma, Fuji Pharma, Chugai Pharmaceuticals, Mochida Pharmaceuticals, ASKA Pharmaceuticals, and Shibuya; payment for expert testimony from Japan Blood Products Organization, Roche Diagnostics, and Kyowa Kirin; and an unpaid leadership role in the Japan Society of Perinatal and Neonatal Medicine. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Acknowledgments

We thank Mr. Hajimu Shiba (Infront Medical Publications) and Dr. Stephanie Carter of Edanz (www.edanz.com) for providing medical writing support, which was funded by UCB Japan Co. Ltd. and Astellas Pharma Inc., in accordance with Good Publication Practice (GPP) 2022 guidelines (http://www.ismpp.org/gpp-2022).

Supplemental data

Supplemental data for this article can be accessed online at https://doi.org/10.1080/1744666X.2023.2197212.

Additional information

Funding

The expert meeting was funded by UCB Japan Co. Ltd. and Astellas Pharma Inc.