Use of Polynomial Reference Ranges for Atrioventricular Intervals Assessed by Fetal Echocardiography in Anti-Ro/SSA Antibody-Positive Pregnancies to Exclude Fetal Heart Blocks: A Pilot Study.

INTRODUCTION: Maternal anti-Ro/SSA antibodies can cause fetal atrioventricular blocks (AVB). This pilot study aims to apply previously published echocardiographic reference ranges of the fetal atrioventricular (AV) intervals in the setting of anti-Ro/SSA antibody-positive pregnancies in order to exclude a 1° AVB. MATERIALS AND METHODS: Between January 2018 and September 2022, we included all women with known anti-Ro/SSA antibodies followed up at the prenatal ultrasound department of the University Hospital of Bern. AV intervals were serially measured by two previously reported methods and plotted against previously created reference ranges. RESULTS: We included 23 pregnancies from 17 anti-Ro/SSA antibody-positive women with connective tissue diseases. 443 AV interval measurements were recorded between 16+3 and 38+4 weeks of gestation. 14 (3.2%) AV-intervals measured >150 ms, none measured >170 ms and 8 (1.8%) were found to be >95th percentile. In none of the pregnancies, serial AV-prolongations were noted. The postnatal electrocardiograms demonstrated normal sinus rhythm without AVB in all children. CONCLUSION: AV intervals of pregnancies followed up for anti-Ro/SSA antibodies without neonatal AVB lie within our published polynomial reference ranges. While diagnosing a 1° AVB remains controversial, more data are needed to prove that our reference ranges are helpful exclude a 1° AVB.

Immunology of pregnancy and reproductive health in autoimmune rheumatic diseases. Update from the 11th International Conference on Reproduction, Pregnancy and Rheumatic Diseases.

Autoimmune rheumatic diseases (ARD) can affect women and men during fertile age, therefore reproductive health is a priority issue in rheumatology. Many topics need to be considered during preconception counselling: fertility, the impact of disease-related factors on pregnancy outcomes, the influence of pregnancy on disease activity, the compatibility of medications with pregnancy and breastfeeding. Risk stratification and individualized treatment approach elaborated by a multidisciplinary team minimize the risk of adverse pregnancy outcomes (APO). Research has been focused on identifying biomarkers that can be predictive of APO. Specifically, preeclampsia and hypertensive disorders of pregnancy tend to develop more frequently in women with ARD. Placental insufficiency can lead to intrauterine growth restriction and small-for-gestational age newborns. Such APO have been shown to be associated with maternal disease activity in different ARD. Therefore, a key message to be addressed to the woman wishing for a pregnancy and to her family is that treatment with compatible drugs is the best way to ensure maternal and fetal wellbeing. An increasing number of medications have entered the management of ARD, but data about their use in pregnancy and lactation are scarce. More information is needed for most biologic drugs and their biosimilars, and for the so-called small molecules, while there is sufficient evidence to recommend the use of TNF inhibitors if needed for keeping maternal disease under control. Other issues related to the reproductive journey have emerged as "unmet needs", such as sexual dysfunction, contraception, medically assisted reproduction techniques, long-term outcome of children, and they will be addressed in this review paper. Collaborative research has been instrumental to reach current knowledge and the future will bring novel insights thanks to pregnancy registries and prospective studies that have been established in several Countries and to their joint efforts in merging data.

Pregnancy and neonatal outcomes in women with axial spondyloarthritis: pooled data analysis from the European Network of Pregnancy Registries in Rheumatology (EuNeP).

OBJECTIVE: To investigate outcome and course of pregnancies in women with axial spondyloarthritis (axSpA) in a pooled data analysis of pregnancy registries in rheumatology. METHODS: Prospectively followed women with axSpA, fulfilling ASAS classification criteria and for whom a pregnancy outcome was reported, were eligible for the analysis. Anonymised data of four registries was pooled. Rates of adverse pregnancy outcomes were calculated. Systemic inflammation, disease activity and treatment patterns with tumour necrosis factor inhibitor (TNFi) before, during and after pregnancy were analysed. RESULTS: In a total of 332 pregnancies from 304 axSpA women, 98.8% of the pregnancies resulted in live birth. Mean maternal age was 31 years and disease duration 5 years. Most of these patients received pre-conception counselling (78.4%). Before pregnancy, 53% received TNFi treatment, 27.5% in first and 21.4% in third trimester. Pregnancy and neonatal outcomes were favourable with rates of 2.2% for pre-eclampsia, 4.9% for preterm birth, 3.1% for low birth weight and 9.5% for small for gestational age. Neonates were delivered by caesarean section in 27.7% of pregnancies, of which 47.4% were emergencies. Pooled mean CRP was 4 mg/L before conception peaking in the second trimester at 9.4 mg/L. Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) was below 4 at all time-points. CONCLUSIONS: Pooled rates of most outcomes were better than what had been reported in the literature and within expected rates of those reported for the general population. Pre-conception counselling, planned pregnancies and a tight management in expert centres applying a tailored treatment approach may have contributed to the favourable pregnancy outcomes.

Pharmacovigilance pregnancy data in a large population of patients with chronic inflammatory disease exposed to certolizumab pegol.

Introduction: Chronic inflammatory diseases (CIDs), including rheumatic diseases and other inflammatory conditions, often affect women of reproductive age. Tumor necrosis factor inhibitors (TNFi) are widely used to treat CID, but there is limited information on outcomes of TNFi-exposed pregnancies. We evaluated pregnancy outcomes from 1392 prospectively reported pregnancies exposed to certolizumab pegol (CZP), a PEGylated, Fc-free TNFi with no to minimal placental transfer. Methods: CZP-exposed pregnancies in patients with CID from the UCB Pharmacovigilance global safety database were reviewed from the start of CZP clinical development (July 2001) to 1 November 2020. To limit bias, the analysis focused on prospectively reported cases with known pregnancy outcomes. Results: In total, 1392 prospective pregnancies with maternal CZP exposure and known pregnancy outcomes (n = 1425) were reported; 1021 had at least first-trimester CZP exposure. Live birth was reported in 1259/1425 (88.4%) of all prospective outcomes. There were 150/1425 (10.5%) pregnancy losses before 20 weeks (miscarriage/induced abortion), 11/1425 (0.8%) stillbirths, and 5/1392 (0.4%) ectopic pregnancies. Congenital malformations were present in 30/1259 (2.4%) live-born infants, of which 26 (2.1%) were considered major according to the Metropolitan Atlanta Congenital Defects Program criteria. There was no pattern of congenital malformations. Discussion and conclusion: No signal for adverse pregnancy outcomes or congenital malformations was observed in CZP-exposed pregnancies. Although the limitations of data collected through this methodology (including underreporting, missing information, and absence of a comparator group) should be considered, these data provide reassurance for women with CID who require CZP treatment during pregnancy, and their treating physicians.

Fertility and pregnancy outcomes in women with spondyloarthritis: a systematic review and meta-analysis.

OBJECTIVE: The aim of this study was to determine the impact of SpA and its treatments on fertility and pregnancy outcomes, as well as the impact of pregnancy on disease activity. METHODS: A systematic review and meta-analyses were performed, including studies in women with SpA [axial (axSpA) and peripheral SpA, including PsA]. The heterogeneity between studies was quantified (I2), and in the case of substantial heterogeneity, the results were reported in a narrative review. RESULTS: Of 4397 eligible studies, 21 articles were included, assessing a total of 3566 patients and 3718 pregnancies, compared with 42 264 controls. There is a lack of data on fertility in the literature. We found an increased risk of preterm birth [pooled odds ratio (OR) 1.64 (1.15-2.33), I2 =24% in axSpA and 1.62 (1.23-2.15), I2 =0.0% in PsA], small for gestational age [pooled OR 2.05 (1.09-3.89), I2 =5.8% in axSpA], preeclampsia [pooled OR 1.59 (1.11-2.27], I2 =0% in axSpA] and caesarean section [pooled OR 1.70 (1.44-2.00), I2 =19.9% in axSpA and 1.71 (1.14-2.55), I2 =74.3% in PsA], without any other unfavourable pregnancy outcome. Further analysis showed a significantly higher risk of elective caesarean section [pooled OR 2.64 (1.92-3.62), I2 =0.0% in axSpA and 1.47 [1.15-1.88], I2 =0,0% in PsA), without increased risk of emergency caesarean section in PsA. During pregnancy, there appears to be a tendency for unchanged or worsened disease activity in axSpA and unchanged or improved disease activity in PsA. Both conditions tend to flare in the postpartum period. CONCLUSION: SpA seems to be associated with an increased risk of preterm birth, small for gestational age, preeclampsia, and caesarean section.

[Current aspects of antirheumatic therapy in pregnancy planning, during pregnancy and breastfeeding]. / Aktuelles zur antirheumatischen Therapie bei Kinderwunsch, Schwangerschaft und Stillzeit.

Active rheumatic disease is a known factor for increased fetomaternal risks during pregnancy. Remission or inactive disease should therefore be targeted to reduce these risks by using pregnancy-compatible antirheumatic drugs as recommended by international guidelines. Teratogenic antirheumatic drugs, such as mycophenolate, methotrexate, cyclophosphamide and thalidomide should be stopped about 3 months prior to conception. Leflunomide is a weak human teratogen that should be stopped and eliminated with cholestyramine prior to conception. Furthermore, drugs with limited data, such as apremilast and JAK inhibitors as well as new biologics should be avoided during gestation. Pregnancy-compatible drugs are the antirheumatic drugs hydroxychloroquine, sulfasalazine, azathioprine, cyclosporine, tacrolimus, colchicine, non-selective NSAIDs, low-dose prednisone/prednisolone and TNF inhibitors. These drugs as well as other biologics, such as rituximab can be used during lactation. In a preconception counselling visit, the benefits and the international recommendations of pregnancy-compatible antirheumatic drugs should be discussed with the patient and be weighed against the possible fetomaternal risks of an active disease to enable a shared decision-making.

Rituximab and Canakinumab Use During Lactation: No Detectable Serum Levels in Breastfed Infants.

INTRODUCTION: In breastfeeding patients with chronic inflammatory rheumatic diseases, a postpartum flare may require the use of biologics. However, data on the safety of biologics during lactation are scarce, potentially impeding the decision-making process. CASE SERIES: We report two cases of women in whom treatment with a monoclonal IgG antibody (rituximab or canakinumab) was indicated during the lactation period. In both cases, breastfeeding was continued, and drug levels in the mother's serum, in serial breast milk samples and in the infant's serum were measured. Both rituximab and canakinumab showed minimal drug concentrations in breast milk and no detectable levels in the infants' sera. CONCLUSION: The lack of detectable levels of rituximab and canakinumab in the sera of breastfed infants reflects the poor oral bioavailability of these biologics and helps to promote their use in breastfeeding patients.

EULAR recommendations for a core data set for pregnancy registries in rheumatology.

BACKGROUND AND OBJECTIVE: There is an urgent need for robust data on the trajectories and outcomes of pregnancies in women with inflammatory rheumatic diseases (IRD). In particular when rare outcomes or rare diseases are to be investigated, collaborative approaches are required. However, joint data analyses are often limited by the heterogeneity of the different data sources.To facilitate future research collaboration, a European League Against Rheumatism (EULAR) Task Force defined a core data set with a minimum of items to be collected by pregnancy registries in rheumatology covering the period of pregnancy and the 28-day neonatal phase in women with any underlying IRD. METHODS: A stepwise process included a two-round Delphi survey and a face-to-face meeting to achieve consensus about relevant items. RESULTS: A total of 64 multidisciplinary stakeholders from 14 different countries participated in the two rounds of the Delphi process. During the following face-to-face meeting of the EULAR Task Force, consensus was reached on 51 main items covering 'maternal information', 'pregnancy' and 'treatment'. Generic instruments for assessment are recommended for every item. Furthermore, for the five most frequent IRDs rheumatoid arthritis, spondyloarthritis, juvenile idiopathic arthritis, systemic lupus erythematosus and other connective tissue diseases, disease-specific laboratory markers and disease activity measurements are proposed. CONCLUSION: This is the first consensus-based core data set for prospective pregnancy registries in rheumatology. Its purpose is to stimulate and facilitate multinational collaborations that aim to increase the knowledge about pregnancy course and safety of treatment in women with IRDs during pregnancy.

A questionnaire-based study on contraceptive practice in patients with rheumatic disease found no significant difference in age-matched healthy controls.

OBJECTIVE: Birth control is crucial in preventing unplanned pregnancy. The study analyzed contraceptive practice in women and men with rheumatic disease. METHODS: A questionnaire-based study investigated the actual contraceptive practices in patients of reproductive age from three European countries and compared them to age-matched healthy women and men. Associations between patient characteristics and contraception behavior were analyzed by association analysis. RESULTS: No significant difference in the frequency of contraception use was found in 133 rheumatic patients compared to 122 healthy controls. The main reason for not using contraception was lack of partner or the wish to become pregnant, whereas the current use of contraception was predominantly to limit family size in general or at this stage of life. Both patients and controls preferred barrier methods (48% and 45%, respectively) followed by hormonal contraceptives (31% and 38%, respectively). Characteristics associated with less use of contraception in patients were living single, having no children, and for being religious, whereas gender and education had no influence. Treatment with teratogenic drugs was no major patient concern, and 13 of 30 female patients using methotrexate, mycophenolate mofetil, or leflunomide did not practice birth control. CONCLUSION: Patients used contraception less frequently than healthy individuals, and the main reason for use was to limit family size. Contraception should be an integral part of counseling patients of fertile age, since the patient-preferred methods in case of active disease or therapy with teratogenic drugs were unreliable for the prevention of pregnancy.

Publisher Correction: Immunological adaptations in pregnancy that modulate rheumatoid arthritis disease activity.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Immunological adaptations in pregnancy that modulate rheumatoid arthritis disease activity.

During pregnancy, the fetus that grows within the maternal uterus is not rejected by the maternal immune system. To enable both tolerance towards the fetus and defence against pathogens, modifications of the maternal immune system occur during gestation. These modifications are able to bring about a natural improvement in disease activity of some autoimmune diseases, such as rheumatoid arthritis (RA). Various mechanisms of the immune system contribute to the phenomenon of pregnancy-related improvement of RA, and the cessation of these immunomodulatory mechanisms after delivery correlates with postpartum disease flare. HLA disparity between mother and fetus, glycosylation of IgG, immunoregulatory pathways, and alterations in innate and adaptive immune cells and their cytokines have important roles in pregnancy and in pregnancy-related amelioration of RA.

European Network of Pregnancy Registers in Rheumatology (EuNeP)-an overview of procedures and data collection.

BACKGROUND: The collaborative initiative of the European Network of Pregnancy Registers in Rheumatology (EuNeP) aims to combine data available in nationwide pregnancy registers to increase knowledge on pregnancy outcomes in women with inflammatory rheumatic diseases (IRD) and on drug safety during pregnancy and lactation. The objective of this study was to describe the similarities and differences of the member registers. METHODS: From all registers, information about their structure and design was collected, as well as which parameters regarding demographics, maternal outcomes, treatment, course and outcome of pregnancy, and development of the child were available in the respective datasets. Furthermore, the current recruitment status was reported. RESULTS: The four registers (EGR2 (France), RePreg (Switzerland), RevNatus (Norway), and Rhekiss (Germany)) collect information prospectively and nationwide. Patients can be enrolled before conception or during pregnancy. To date, more than 3500 patients in total have been included, and data on 2200 pregnancies with an outcome are available. The distribution of diagnoses in the respective registers varies considerably, and only three entities (rheumatoid arthritis, psoriatic arthritis, and spondyloarthritis) are captured by all the registers. Broad consistency was found in non-disease-specific data items, but differences regarding instruments and categories as well as frequency of data collection were revealed. Disease-specific data items are less homogeneously collected. CONCLUSION: Although the registers in this collaboration have similar designs, we found numerous differences in the variables collected. This survey of the status quo of current pregnancy registers is the first step towards identifying data collected uniformly across registers in order to facilitate joint analyses. TRIAL REGISTRATION: Not applicable.

No Association of Discontinuing Tumor Necrosis Factor Inhibitors Before Gestational Week Twenty in Well-Controlled Rheumatoid Arthritis and Juvenile Idiopathic Arthritis With a Disease Worsening in Late Pregnancy.

OBJECTIVE: To investigate whether the discontinuation of tumor necrosis factor inhibitors (TNFi) during pregnancy is associated with any changes of the disease course in women with rheumatoid arthritis (RA) and juvenile idiopathic arthritis (JIA). METHODS: Pregnant women with RA and JIA from the US and Canada were enrolled in the Organization of Teratology Information Specialists (OTIS) Autoimmune Diseases in Pregnancy Project, a prospective cohort study. Information about medication and disease activity (patient-reported outcome measures) was collected prior to gestational week 20 and at gestational week 32. Associations between patterns of TNFi continuation or discontinuation and disease activity changes were tested in unadjusted and multivariate analyses. RESULTS: Among 490 women (397 with RA, 93 with JIA) enrolled between 2005 and 2017, 122 (24.9%) discontinued a TNFi before gestational week 20, 201 (41.0%) received a TNFi beyond week 20, and 167 (34.1%) did not receive a TNFi during pregnancy. At the time of enrollment, disease activity was low to minimal in 72.9% of women. TNFi discontinuation was not associated with a clinically important worsening of patient reported outcome measures at the third trimester. Univariate but not multivariate analysis showed that women receiving TNFi beyond week 20 were more likely to experience improved disease activity scores at the third trimester. CONCLUSION: Discontinuing TNFi before gestational week 20 seems feasible in women with RA and JIA who enter pregnancy with well-controlled disease.

Factors Associated With Preterm Delivery Among Women With Rheumatoid Arthritis and Women With Juvenile Idiopathic Arthritis.

OBJECTIVE: Pregnant women with inflammatory arthritis may be at increased risk for preterm delivery (PTD), yet it is unclear what drives this risk. This aim of this prospective cohort study of pregnant women with rheumatoid arthritis (RA), juvenile idiopathic arthritis (JIA), or healthier comparison women was to analyze the independent effects of maternal disease activity, medication use, and comorbid pregnancy conditions on PTD risk. METHODS: Women were enrolled before 19 weeks completed gestation as part of the Organization of Teratology Information Specialists (OTIS) Autoimmune Disease in Pregnancy Project. Data on pregnancy events, medications, disease activity, and outcomes were obtained by maternal report and validated by medical records. Poisson regression with robust standard errors estimated risk ratios (RR), multivariable adjusted risk ratios (ARRs), and 95% confidence intervals (95% CIs). RESULTS: A total of 657 women with RA, 170 with JIA, and 564 comparison women without autoimmune disease who delivered live born infants, from 2004 to 2017 were included for analysis. Both the RA and JIA groups had an increased risk of PTD versus the comparison group (RR 2.09 [95% CI 1.50-2.91] and RR 1.81 [95% CI 1.14-2.89], respectively). Active RA at enrollment (ARR 1.58 [95% CI 1.10-2.27]) and any time during pregnancy (ARR 1.52 [95% CI 1.06-2.18]) was associated with PTD. Corticosteroid use in every trimester was associated with an approximate 2- to 5-fold increased risk for PTD for both arthritis groups, independent of disease activity. CONCLUSION: Women with RA and women with JIA are at increased risk for PTD. Maternal disease activity and corticosteroid use may contribute to some of this excess risk.

Role of reproductive and menopausal factors in functional and structural progression of rheumatoid arthritis: results from the SCQM cohort.

OBJECTIVES: To study the relationship between female reproductive and menopausal factors on functional and structural joint damage progression in women with RA. METHODS: This is an observational cohort study of RA patients enrolled in the Swiss Clinical Quality Management Program for Rheumatoid Arthritis. Information about female hormonal factors, such as pregnancies, menopause and hormonal therapy, were retrospectively retrieved using a specific questionnaire. The primary outcome was functional disability progression (HAQ) and the secondary outcome radiographic joint damage progression. We compared the functional progression between pre- and post-menopausal women using a multilevel regression model for longitudinal data, adjusting for potential confounders, such as baseline age, years of education, disease duration, seropositivity, DAS28 and treatment. RESULTS: A total of 1667 women were analysed, of whom 1025 (61%) were post-menopausal. Participants had a median of 6 HAQ assessments (interquartile range 3-10) during 5.1 (interquartile range 2.2-9.8) years of follow-up. At baseline, post-menopausal women had higher HAQ and erosion scores than pre-menopausal women. The evolution of HAQ scores over time differed between pre- and post-menopausal women (P < 0.001), with a less favourable evolution in post-menopausal women, particularly with earlier age at menopause. Erosion progression did not differ between pre- and post-menopausal women. CONCLUSION: In women with RA, functional disability progression differed between pre- and post-menopausal women. The more favourable evolution of function in pre-menopausal women was not explained by disease duration, age or radiographic damage.