Risk for adverse pregnancy outcome in axial spondyloarthritis and rheumatoid arthritis: disease activity matters

Risk for adverse pregnancy outcome in axial spondyloarthritis and rheumatoid arthritis: disease... Abstract Objective To analyse pregnancy outcome and delivery mode in patients with RA and axial spondyloarthritis (axSpA) in relation to disease activity and anti-rheumatic drugs. Methods Patients with RA and axSpA were compared with age-matched healthy controls (HCs) with respect to pregnancy outcome and delivery mode. Disease activity (DAS28, ASDAS, CRP) and medication use of patients was assessed once at each trimester. ORs with 95% CI were calculated with univariate and multivariate regression models. Results We analysed 244 pregnancies, of which 96 occurred in patients with RA, 78 in patients with axSpA and 70 in HCs. The adjusted analysis showed that pregnant women with RA and axSpA had a higher risk of pregnancy complications (gestational diabetes, preeclampsia, infection, preterm premature rupture of membranes), small for gestational age infants and preterm deliveries (all P < 0.05). Active disease was a predictor for preterm delivery in both RA [odds ratio (OR) = 3.9, 95% CI: 1.25, 12.15] and axSpA (OR = 13.8, 95% CI: 1.33, 143.94). Regarding delivery mode, most patients had vaginal deliveries. However, women with RA revealed an increased risk of caesarean section compared with HC (P < 0.05), which was not seen in patients with axSpA. Conclusion Our findings show that disease activity of RA and axSpA during pregnancy influences pregnancy outcome. To allow for successful pregnancy a treatment strategy that targets inactive disease beyond conception should be followed. rheumatoid arthritis, axial spondyloarthritis, pregnancy Rheumatology key messages Women with RA and axial SpA are at risk for adverse pregnancy outcomes. Active disease is a predictor for preterm delivery in pregnant women with RA and axial SpA. Introduction Inflammatory rheumatic diseases such as RA and axial spondyloarthritis (axSpA) affect women of childbearing age. The interaction of pregnancy and the inflammatory rheumatic disease may influence maternal and foetal health. Pregnancy-mediated changes of the immune system may exert a positive effect on disease activity in about 48–65% of pregnant women with RA, yet remission is only seen in about 16–27% of these patients [1, 2]. In women with axSpA, pregnancy has no ameliorating effect on disease activity. Symptoms are reported in 60–80% of these women with a worsening of pain and morning stiffness around gestational week 20 [3–5]. In addition, the discontinuation of anti-rheumatic drugs around conception could be a risk factor for disease deterioration in RA and axSpA in the first or second trimester, respectively [6]. Active disease during pregnancy, however, not only poses a risk for future articular damage but could also be associated with pregnancy complications and adverse pregnancy outcome [7, 8]. To control disease symptoms in pregnant patients with RA and axSpA, therapy with pregnancy-compatible anti-rheumatic drugs is often needed [9]. In this context, the increase of reassuring data on the use of TNF inhibitors (TNFi) in pregnancy over time has resulted in a higher proportion of pregnant women with inflammatory rheumatic diseases being treated with TNFi [9, 10]. Both, the rheumatic disease and anti-rheumatic drugs can have an influence on pregnancy course and outcome as well as on delivery mode. In pregnant women with RA, the risk of adverse pregnancy outcome such as preterm delivery, infants being small for gestational age or having a reduced birth weight is elevated [7, 8, 11]. Two studies in RA patients have shown in a prospective way that disease activity contributes to these adverse pregnancy outcomes [7, 8]. In pregnant women with AS, retrospective data from a questionnaire study and two registry studies show inconsistent results ranging from no adverse effect on pregnancy outcome to increased rates of premature and small for gestational age infants [12–14]. Regarding delivery mode, most studies have found an increased rate of caesarean section (C-sections) in women with RA and axSpA versus reference subjects [8, 13, 14]. Prospective data on the outcome of pregnancies in patients with axSpA are lacking. Further studies in RA are necessary that include patients with TNFi use. The aim of this study was to analyse the outcome of pregnancy and the delivery mode in women with RA and axSpA vs healthy women as well as in relation to disease activity and therapy with anti-rheumatic drugs. Methods Patients All patients were prospectively followed at the Centre for Pregnancy in Rheumatic Diseases at the Department of Rheumatology of the University Hospital of Bern between 2000 and 2016. Age-matched healthy women not showing any pre-existing risk factors were included during the same time frame. The group of healthy women was recruited among pregnant employees of the University Hospital of Bern as well as at the Department of Obstetrics and Gynecology of the University Hospital of Bern. Patients with RA had to fulfil the revised 1987 ACR classification criteria for RA [15]. Patients with axSpA fulfilled the ESSG criteria for SpA [16]. All patients with SpA also fulfilled the Assessment of SpondyloArthritis international Society criteria for axSpA; for patients recruited before 2009, the Assessment of SpondyloArthritis international Society criteria were applied in retrospect [17]. The study was approved by the ethics committee of the Canton of Bern, Switzerland. Women were included after they provided written informed consent. Time points, assessments and definitions All patients were seen at each trimester during pregnancy (gestational weeks 10–12, 20–22 and 30–32) and after delivery, 6–8 weeks postpartum. The standard protocol consisted of a routine physical examination, assessment of diseases activity including the measurement of CRP (measured by NycoCard, Alere Technologies AS, Oslo, Norway) and recording of the current medication and complications. At the postpartum visit, information was collected on delivery mode, birth, neonatal health and complications such as preeclampsia, gestational diabetes, infection and preterm premature rupture of membranes. The data from healthy pregnant women were recorded twice: between gestational weeks 30–32 and at 8 weeks postpartum. All healthy women had normal CRP values at inclusion. Disease activity in RA was assessed using the three-variable DAS28-CRP since this score was shown to perform best in pregnancy [18]. Active disease in RA patients was defined as DAS28-CRP scores higher than 3.2. Disease activity in women with axSpA was assessed using the ASDAS-CRP [19]. In our experience, the ASDAS-CRP is able to reflect disease activity in pregnant patients with axSpA since it combines few subjective items with the CRP and is not biased by a fatigue question. Active disease in women with axSpA was defined by ASDAS-CRP scores higher than 2.1. In patients with axSpA recruited prior to the development of the ASDAS-CRP in 2009, the ASDAS-CRP scores were calculated retrospectively using the CRP, the scores of the patient global assessment (0–10) and the scores of the BASDAI questions about back pain, duration of morning stiffness and peripheral pain [20]. Preterm birth was defined as a live birth before gestational week 37. Small for gestational age (SGA) neonates were defined as those with a birth weight below the 10th percentile for gestational age. Statistical analysis Patients with RA and axSpA were compared with those of matched healthy controls (HCs) with respect to pregnancy complications, pregnancy outcome and delivery mode. To compare the two patients’ groups and the HCs, the Kruskal–Wallis test was used for continuous variables and the Fisher’s exact test for categorical variables. To identify risk factors for adverse pregnancy outcomes and delivery modes, univariate and multivariate logistic regression analyses were performed. Differences in birth weight of neonates in patients and references were examined in multivariate linear regression analyses. In the multivariate regression analyses, adjustments were made for age and gravidity. P < 0.05 was regarded as significant. Data were analysed using IBM SPSS Statistics 22 software package (IBM Corp., Armonk, NY, USA). Results Disease course and medication We analysed 244 pregnancies, of which 96 occurred in 86 RA patients, 78 in 70 axSpA patients and 70 in 70 age-matched healthy women (Table 1). Table 1 Descriptive information on mothers, pregnancies, deliveries and infants Characteristics Rheumatoid arthritis, n = 86 Axial spondyloarthritis, n = 70 Healthy controls, n = 70 P-valuea Maternal age at delivery, median (range), years 32 (22–44) 32 (23–41) 32 (20–41) 0.556 RF or ACPA positive, n (%)b 51 (59.3) HLA B-27, n (%)b 48 (68.6) SpA with peripheral arthritis, n (%)b 32 (45.7) Disease activity during pregnancyc     First trimester 2.3 2.5     Second trimester 2.4 2.4     Third trimester 2.3 2.2 Pregnancy 96 78 70     Twin pregnancy, n 4 2 0     Primigravidae, n (%)b 57 (66.3) 45 (64.3) 43 (61.4) 0.919 Pregnancy complications, n (%)d 11 (11.5) 14 (17.9) 1 (1.43) 0.002     Gestational diabetes 2 5 1     Preeclampsia 4 2 —     Infection 1 4 —     PPROM 4 3 — Delivery mode     Vaginal delivery, n (%)d 49 (51.0) 45 (57.8) 51 (72.9) 0.036     Caesarian section         Total, n (%) 43 (44.8) 31 (39.7) 19 (27.1) 0.036         Elective, n 21 14 9 0.267         Emergency, n 22 17 10 0.309         Unknown 4 2 — Infant     Live birth, n (%)e 99 (99.0) 79 (98.8) 70 (100)     Stillbirth/induced fetal demisef 1f 1 — Median birth weight (range), g 3100 (1250–4455) 3245 (1450–4740) 3460 (2620–4500) 0.000 Median birth weight percentile 32.4 (0.4–99.4) 38.2 (2.1–98.8) 72.5 (4.0–99.0) 0.193 SGA (<10th percentile), n (%)g 16 (16.2) 9 (11.4) 1 (1.4) 0.002 Preterm delivery, n (%)g 18 (18.2) 9 (11.4) 1 (1.4) 0.001 Congenital anomalies, n (%)e 3 (3.0) 3 (3.8) —     Hirschsprung disease 1 — —     Ventricular septal defect 1 — —     Unilateral kidney — 1 —     Down syndrome 1f 1 —     Di George Syndrome — 1 — Characteristics Rheumatoid arthritis, n = 86 Axial spondyloarthritis, n = 70 Healthy controls, n = 70 P-valuea Maternal age at delivery, median (range), years 32 (22–44) 32 (23–41) 32 (20–41) 0.556 RF or ACPA positive, n (%)b 51 (59.3) HLA B-27, n (%)b 48 (68.6) SpA with peripheral arthritis, n (%)b 32 (45.7) Disease activity during pregnancyc     First trimester 2.3 2.5     Second trimester 2.4 2.4     Third trimester 2.3 2.2 Pregnancy 96 78 70     Twin pregnancy, n 4 2 0     Primigravidae, n (%)b 57 (66.3) 45 (64.3) 43 (61.4) 0.919 Pregnancy complications, n (%)d 11 (11.5) 14 (17.9) 1 (1.43) 0.002     Gestational diabetes 2 5 1     Preeclampsia 4 2 —     Infection 1 4 —     PPROM 4 3 — Delivery mode     Vaginal delivery, n (%)d 49 (51.0) 45 (57.8) 51 (72.9) 0.036     Caesarian section         Total, n (%) 43 (44.8) 31 (39.7) 19 (27.1) 0.036         Elective, n 21 14 9 0.267         Emergency, n 22 17 10 0.309         Unknown 4 2 — Infant     Live birth, n (%)e 99 (99.0) 79 (98.8) 70 (100)     Stillbirth/induced fetal demisef 1f 1 — Median birth weight (range), g 3100 (1250–4455) 3245 (1450–4740) 3460 (2620–4500) 0.000 Median birth weight percentile 32.4 (0.4–99.4) 38.2 (2.1–98.8) 72.5 (4.0–99.0) 0.193 SGA (<10th percentile), n (%)g 16 (16.2) 9 (11.4) 1 (1.4) 0.002 Preterm delivery, n (%)g 18 (18.2) 9 (11.4) 1 (1.4) 0.001 Congenital anomalies, n (%)e 3 (3.0) 3 (3.8) —     Hirschsprung disease 1 — —     Ventricular septal defect 1 — —     Unilateral kidney — 1 —     Down syndrome 1f 1 —     Di George Syndrome — 1 — a P-values were calculated using the Kruskal–Wallis test for continuous variables and Fisher’s exact test for categorical variables. b Percentage based on number of women in each group. c Median DAS28-CRP in patients with RA, median ASDAS in patients with axSpA. d Percentage based on number of pregnancies. e Percentage based on number of fetuses. f Induced fetal demise because of Down syndrome. g Percentage based on number of live births. Hirschsprung disease: Congenital aganglionic megacolon; PPROM: preterm premature rupture of membranes; SGA: small for gestational age. Table 1 Descriptive information on mothers, pregnancies, deliveries and infants Characteristics Rheumatoid arthritis, n = 86 Axial spondyloarthritis, n = 70 Healthy controls, n = 70 P-valuea Maternal age at delivery, median (range), years 32 (22–44) 32 (23–41) 32 (20–41) 0.556 RF or ACPA positive, n (%)b 51 (59.3) HLA B-27, n (%)b 48 (68.6) SpA with peripheral arthritis, n (%)b 32 (45.7) Disease activity during pregnancyc     First trimester 2.3 2.5     Second trimester 2.4 2.4     Third trimester 2.3 2.2 Pregnancy 96 78 70     Twin pregnancy, n 4 2 0     Primigravidae, n (%)b 57 (66.3) 45 (64.3) 43 (61.4) 0.919 Pregnancy complications, n (%)d 11 (11.5) 14 (17.9) 1 (1.43) 0.002     Gestational diabetes 2 5 1     Preeclampsia 4 2 —     Infection 1 4 —     PPROM 4 3 — Delivery mode     Vaginal delivery, n (%)d 49 (51.0) 45 (57.8) 51 (72.9) 0.036     Caesarian section         Total, n (%) 43 (44.8) 31 (39.7) 19 (27.1) 0.036         Elective, n 21 14 9 0.267         Emergency, n 22 17 10 0.309         Unknown 4 2 — Infant     Live birth, n (%)e 99 (99.0) 79 (98.8) 70 (100)     Stillbirth/induced fetal demisef 1f 1 — Median birth weight (range), g 3100 (1250–4455) 3245 (1450–4740) 3460 (2620–4500) 0.000 Median birth weight percentile 32.4 (0.4–99.4) 38.2 (2.1–98.8) 72.5 (4.0–99.0) 0.193 SGA (<10th percentile), n (%)g 16 (16.2) 9 (11.4) 1 (1.4) 0.002 Preterm delivery, n (%)g 18 (18.2) 9 (11.4) 1 (1.4) 0.001 Congenital anomalies, n (%)e 3 (3.0) 3 (3.8) —     Hirschsprung disease 1 — —     Ventricular septal defect 1 — —     Unilateral kidney — 1 —     Down syndrome 1f 1 —     Di George Syndrome — 1 — Characteristics Rheumatoid arthritis, n = 86 Axial spondyloarthritis, n = 70 Healthy controls, n = 70 P-valuea Maternal age at delivery, median (range), years 32 (22–44) 32 (23–41) 32 (20–41) 0.556 RF or ACPA positive, n (%)b 51 (59.3) HLA B-27, n (%)b 48 (68.6) SpA with peripheral arthritis, n (%)b 32 (45.7) Disease activity during pregnancyc     First trimester 2.3 2.5     Second trimester 2.4 2.4     Third trimester 2.3 2.2 Pregnancy 96 78 70     Twin pregnancy, n 4 2 0     Primigravidae, n (%)b 57 (66.3) 45 (64.3) 43 (61.4) 0.919 Pregnancy complications, n (%)d 11 (11.5) 14 (17.9) 1 (1.43) 0.002     Gestational diabetes 2 5 1     Preeclampsia 4 2 —     Infection 1 4 —     PPROM 4 3 — Delivery mode     Vaginal delivery, n (%)d 49 (51.0) 45 (57.8) 51 (72.9) 0.036     Caesarian section         Total, n (%) 43 (44.8) 31 (39.7) 19 (27.1) 0.036         Elective, n 21 14 9 0.267         Emergency, n 22 17 10 0.309         Unknown 4 2 — Infant     Live birth, n (%)e 99 (99.0) 79 (98.8) 70 (100)     Stillbirth/induced fetal demisef 1f 1 — Median birth weight (range), g 3100 (1250–4455) 3245 (1450–4740) 3460 (2620–4500) 0.000 Median birth weight percentile 32.4 (0.4–99.4) 38.2 (2.1–98.8) 72.5 (4.0–99.0) 0.193 SGA (<10th percentile), n (%)g 16 (16.2) 9 (11.4) 1 (1.4) 0.002 Preterm delivery, n (%)g 18 (18.2) 9 (11.4) 1 (1.4) 0.001 Congenital anomalies, n (%)e 3 (3.0) 3 (3.8) —     Hirschsprung disease 1 — —     Ventricular septal defect 1 — —     Unilateral kidney — 1 —     Down syndrome 1f 1 —     Di George Syndrome — 1 — a P-values were calculated using the Kruskal–Wallis test for continuous variables and Fisher’s exact test for categorical variables. b Percentage based on number of women in each group. c Median DAS28-CRP in patients with RA, median ASDAS in patients with axSpA. d Percentage based on number of pregnancies. e Percentage based on number of fetuses. f Induced fetal demise because of Down syndrome. g Percentage based on number of live births. Hirschsprung disease: Congenital aganglionic megacolon; PPROM: preterm premature rupture of membranes; SGA: small for gestational age. In patients with RA, the median disease activity scores as measured by the DAS28-CRP were below 3.2 in all trimesters. By contrast, women with axSpA showed persistent active disease throughout pregnancy reflected by median ASDAS-CRP scores higher than 2.1. Among RA patients, 82.3% were on anti-rheumatic drugs at any time point during pregnancy, the most common being DMARDs (42.7% on SSZ, 30.3% on a combination of SSZ and HCQ) and glucocorticoids (50% being on either prednisone or prednisolone). TNF inhibitor (TNFi) treatment at any time during pregnancy was used in 29.2% of all pregnancies of RA patients. Among axSpA patients, 75.6% were on anti-rheumatic drugs at any time point during pregnancy, the most common being TNFi (39.7%) and NSAIDs (46.2%). The percentage of drugs used at each trimester is displayed in Fig. 1. Fig. 1 View largeDownload slide Distribution of treatments during pregnancies Treatment during pregnancy in patients with RA (A) and axSpA (B). Bars show the percentages for each treatment mode by trimester. NSAID were used before gestational week 32; DMARDs were SSZ and HCQ. Fig. 1 View largeDownload slide Distribution of treatments during pregnancies Treatment during pregnancy in patients with RA (A) and axSpA (B). Bars show the percentages for each treatment mode by trimester. NSAID were used before gestational week 32; DMARDs were SSZ and HCQ. Effect of disease on pregnancy outcome Compared with HCs, pregnant women with RA and axSpA had a higher risk for pregnancy complications (gestational diabetes, preeclampsia, infection, preterm premature rupture of membranes), for small for gestational age infants and for preterm deliveries in both the univariate model and the multivariate model (all P < 0.05, Table 2). Table 2 Impact of RA and axSpA on adverse pregnancy outcome and caesarean section Outcome variables RA axSpA Crude OR (95% CI) Adjusted ORa (95% CI) Crude OR (95% CI) Adjusted ORa (95% CI) Prematurity 15.9* (2.07, 122.40) 14.3* (1.84, 111.25) 9.1* (1.13, 74.05) 8.4* (1.03, 69.18) SGA 13.8* (1.78, 106.75) 13.0* (1.67, 100.63) 9.0* (1.11, 72.97) 8.7* (1.07, 70.72) Pregnancy complicationsb 8.9* (1.13, 70.88) 9.5* (1.17, 77.36) 15.1* (1.93, 118.08) 16.4* (2.05, 131.53) C-section, total 2.4* (1.21, 4.59) 2.2* (1.14, 4.37) 1.8 (0.92, 3.72) 1.8 (0.89, 3.63) C-section, elective 2.0 (0.86, 4.70) 1.9 (0.82, 4.55) 1.5 (0.62, 3.80) 1.5 (0.60, 3.72) C-section, emergency 1.9 (0.83, 4.30) 1.8 (0.78, 4.10) 1.7 (0.73, 4.09) 1.7 (0.71, 4.01) Outcome variables RA axSpA Crude OR (95% CI) Adjusted ORa (95% CI) Crude OR (95% CI) Adjusted ORa (95% CI) Prematurity 15.9* (2.07, 122.40) 14.3* (1.84, 111.25) 9.1* (1.13, 74.05) 8.4* (1.03, 69.18) SGA 13.8* (1.78, 106.75) 13.0* (1.67, 100.63) 9.0* (1.11, 72.97) 8.7* (1.07, 70.72) Pregnancy complicationsb 8.9* (1.13, 70.88) 9.5* (1.17, 77.36) 15.1* (1.93, 118.08) 16.4* (2.05, 131.53) C-section, total 2.4* (1.21, 4.59) 2.2* (1.14, 4.37) 1.8 (0.92, 3.72) 1.8 (0.89, 3.63) C-section, elective 2.0 (0.86, 4.70) 1.9 (0.82, 4.55) 1.5 (0.62, 3.80) 1.5 (0.60, 3.72) C-section, emergency 1.9 (0.83, 4.30) 1.8 (0.78, 4.10) 1.7 (0.73, 4.09) 1.7 (0.71, 4.01) Crude and adjusted odds ratio (OR) of adverse pregnancy outcomes and caesarean section (C-section) in RA and axSpA compared with healthy controls. a Adjusted odds ratio for maternal age and gravidity. b Pregnancy complications: preeclampsia, gestational diabetes, infection, preterm premature rupture of membranes. * P < 0.05. SGA, small for gestational age. Table 2 Impact of RA and axSpA on adverse pregnancy outcome and caesarean section Outcome variables RA axSpA Crude OR (95% CI) Adjusted ORa (95% CI) Crude OR (95% CI) Adjusted ORa (95% CI) Prematurity 15.9* (2.07, 122.40) 14.3* (1.84, 111.25) 9.1* (1.13, 74.05) 8.4* (1.03, 69.18) SGA 13.8* (1.78, 106.75) 13.0* (1.67, 100.63) 9.0* (1.11, 72.97) 8.7* (1.07, 70.72) Pregnancy complicationsb 8.9* (1.13, 70.88) 9.5* (1.17, 77.36) 15.1* (1.93, 118.08) 16.4* (2.05, 131.53) C-section, total 2.4* (1.21, 4.59) 2.2* (1.14, 4.37) 1.8 (0.92, 3.72) 1.8 (0.89, 3.63) C-section, elective 2.0 (0.86, 4.70) 1.9 (0.82, 4.55) 1.5 (0.62, 3.80) 1.5 (0.60, 3.72) C-section, emergency 1.9 (0.83, 4.30) 1.8 (0.78, 4.10) 1.7 (0.73, 4.09) 1.7 (0.71, 4.01) Outcome variables RA axSpA Crude OR (95% CI) Adjusted ORa (95% CI) Crude OR (95% CI) Adjusted ORa (95% CI) Prematurity 15.9* (2.07, 122.40) 14.3* (1.84, 111.25) 9.1* (1.13, 74.05) 8.4* (1.03, 69.18) SGA 13.8* (1.78, 106.75) 13.0* (1.67, 100.63) 9.0* (1.11, 72.97) 8.7* (1.07, 70.72) Pregnancy complicationsb 8.9* (1.13, 70.88) 9.5* (1.17, 77.36) 15.1* (1.93, 118.08) 16.4* (2.05, 131.53) C-section, total 2.4* (1.21, 4.59) 2.2* (1.14, 4.37) 1.8 (0.92, 3.72) 1.8 (0.89, 3.63) C-section, elective 2.0 (0.86, 4.70) 1.9 (0.82, 4.55) 1.5 (0.62, 3.80) 1.5 (0.60, 3.72) C-section, emergency 1.9 (0.83, 4.30) 1.8 (0.78, 4.10) 1.7 (0.73, 4.09) 1.7 (0.71, 4.01) Crude and adjusted odds ratio (OR) of adverse pregnancy outcomes and caesarean section (C-section) in RA and axSpA compared with healthy controls. a Adjusted odds ratio for maternal age and gravidity. b Pregnancy complications: preeclampsia, gestational diabetes, infection, preterm premature rupture of membranes. * P < 0.05. SGA, small for gestational age. Compared with neonates born to healthy mothers, those born to women with RA showed a mean reduction in birth weight of 414.4 g (95% CI: −584.2, −244.6 g, P < 0.001) and those born to women with axSpA revealed a mean reduction in birth weight of 254.4 g (95% CI: −433.0, −75.8 g, P < 0.01). Congenital anomalies occurred in three infants of mothers with RA and in three infants of mothers with axSpA as displayed in Table 1. The medication used in these patients was hydroxychloroquine in one patient with RA, a combination of TNFi, glucocorticoids and SSZ in the second patient with RA, a combination of TNFi, glucocorticoids, SSZ and HCQ in the third patient with RA, a combination of TNFi and glucocorticoids in two women with axSpA, and NSAID in the third patient with axSpA. One foetal demise was induced in the case of one foetus of a twin pregnancy because of Down syndrome and multiple malformations. Delivery mode Compared with HCs, patients with RA were more likely to have a delivery by C-section (P = 0.024, Table 2), which was not seen in women with axSpA. Moreover, active disease and DMARD treatment were each predictive for delivery by C-section in patients with RA (P = 0.048 and P = 0.012, Table 3) in the unadjusted comparison, indicating that an insufficient control of disease activity might play a role in this context. After adjustment, only the latter association remained significant (P = 0.011). Table 3 Association of adverse pregnancy outcomes and C-section with RA Outcome and independent variables Crude OR (95% CI) Adjusted OR (95% CI) Preterm delivery     DAS28-CRP > 3.2 during pregnancy 3.6* (1.26, 10.46) 3.9* (1.25, 12.15)     Elevated CRP at 1 T 3.3 (0.53, 19.82) 3.8 (0.58, 25.20)     Elevated CRP at 2 T 2.9 (0.75, 11.12) 3.2 (0.80, 12.75)     Elevated CRP at 3 T 1.1 (0.27, 4.06) 1.0 (0.24, 3.98)     TNFi use during pregnancy 0.6 (0.19, 2.16) 0.7 (0.20, 2.51)     GC use during pregnancy 1.7 (0.61, 4.96) 1.9 (0.62, 5.54)     DMARD use during pregnancy 0.7 (0.26, 2.02) 0.7 (0.23, 2.00)     NSAIDs use during pregnancya 1.7 (0.48, 6.27) 1.8 (0.48, 6.97) Small for gestational age infants     DAS28-CRP > 3.2 during pregnancy 1.4 (0.46, 4.29) 1.3 (0.41, 4.05)     Elevated CRP at 1 T 0.9 (0.22, 3.79) 1.0 (0.23, 4.25)     Elevated CRP at 2 T 1.2 (0.36, 4.17) 1.2 (0.37, 4.61)     Elevated CRP at 3 T 1.1 (0.27, 4.06) 1.0 (0.24, 3.72)     TNFi use during pregnancy 2.2 (0.72, 6.61) 2.6 (0.81, 8.37)     GC use during pregnancy 1.8 (0.61, 5.55) 2.0 (0.63, 6.12)     DMARD use during pregnancy 1.8 (0.58, 5.28) 1.7 (0.56, 5.36)     NSAIDs use during pregnancya 3.2 (0.91, 11.08) 3.4 (0.92, 12.15) Pregnancy complicationsb     DAS28-CRP > 3.2 during pregnancy 0.5 (0.09, 2.24) 0.5 (0.11, 3.07)     Elevated CRP at 1 T 1.5 (0.27, 8.17) 6.3 (0.54, 72.80)     Elevated CRP at 2 T 2.2 (0.34, 14.10) 2.1 (0.31, 14.26)     Elevated CRP at 3 T 0.6 (0.15, 2.68) 0.7 (0.15, 3.10)     TNFi use during pregnancy 0.9 (0.22, 3.67) 1.0 (0.23, 4.51)     GC use during pregnancy 0.8 (0.2, 2.87) 0.9 (0.21, 3.43)     DMARD use during pregnancy 1.2 (0.33, 4.14) 1.1 (0.30, 4.29)     NSAIDs use during pregnancya 1.2 (0.24, 6.36) 1.5 (0.28, 8.20) C-section     DAS28-CRP > 3.2 during pregnancy 2.5* (1.01, 6.14) 2.2 (0.85, 5.90)     Elevated CRP at 1 T 1.6 (0.51, 5.18) 2.1 (0.60, 7.08)     Elevated CRP at 2 T 2.0 (0.72, 5.54) 2.4 (0.81, 7.17)     Elevated CRP at 3 T 2.0 (0.70, 5.52) 1.7 (0.59, 5.07)     TNFi use during pregnancy 0.5 (0.19, 1.28) 0.6 (0.20, 1.50)     GC use during pregnancy 2.2 (0.96, 5.11) 2.3 (0.94, 5.82)     DMARD use during pregnancy 3.0* (1.28, 7.06) 3.2* (1.26, 7.90)     NSAIDs use during pregnancya 2.7 (0.83, 8.55) 3.0 (0.86, 10.54) Outcome and independent variables Crude OR (95% CI) Adjusted OR (95% CI) Preterm delivery     DAS28-CRP > 3.2 during pregnancy 3.6* (1.26, 10.46) 3.9* (1.25, 12.15)     Elevated CRP at 1 T 3.3 (0.53, 19.82) 3.8 (0.58, 25.20)     Elevated CRP at 2 T 2.9 (0.75, 11.12) 3.2 (0.80, 12.75)     Elevated CRP at 3 T 1.1 (0.27, 4.06) 1.0 (0.24, 3.98)     TNFi use during pregnancy 0.6 (0.19, 2.16) 0.7 (0.20, 2.51)     GC use during pregnancy 1.7 (0.61, 4.96) 1.9 (0.62, 5.54)     DMARD use during pregnancy 0.7 (0.26, 2.02) 0.7 (0.23, 2.00)     NSAIDs use during pregnancya 1.7 (0.48, 6.27) 1.8 (0.48, 6.97) Small for gestational age infants     DAS28-CRP > 3.2 during pregnancy 1.4 (0.46, 4.29) 1.3 (0.41, 4.05)     Elevated CRP at 1 T 0.9 (0.22, 3.79) 1.0 (0.23, 4.25)     Elevated CRP at 2 T 1.2 (0.36, 4.17) 1.2 (0.37, 4.61)     Elevated CRP at 3 T 1.1 (0.27, 4.06) 1.0 (0.24, 3.72)     TNFi use during pregnancy 2.2 (0.72, 6.61) 2.6 (0.81, 8.37)     GC use during pregnancy 1.8 (0.61, 5.55) 2.0 (0.63, 6.12)     DMARD use during pregnancy 1.8 (0.58, 5.28) 1.7 (0.56, 5.36)     NSAIDs use during pregnancya 3.2 (0.91, 11.08) 3.4 (0.92, 12.15) Pregnancy complicationsb     DAS28-CRP > 3.2 during pregnancy 0.5 (0.09, 2.24) 0.5 (0.11, 3.07)     Elevated CRP at 1 T 1.5 (0.27, 8.17) 6.3 (0.54, 72.80)     Elevated CRP at 2 T 2.2 (0.34, 14.10) 2.1 (0.31, 14.26)     Elevated CRP at 3 T 0.6 (0.15, 2.68) 0.7 (0.15, 3.10)     TNFi use during pregnancy 0.9 (0.22, 3.67) 1.0 (0.23, 4.51)     GC use during pregnancy 0.8 (0.2, 2.87) 0.9 (0.21, 3.43)     DMARD use during pregnancy 1.2 (0.33, 4.14) 1.1 (0.30, 4.29)     NSAIDs use during pregnancya 1.2 (0.24, 6.36) 1.5 (0.28, 8.20) C-section     DAS28-CRP > 3.2 during pregnancy 2.5* (1.01, 6.14) 2.2 (0.85, 5.90)     Elevated CRP at 1 T 1.6 (0.51, 5.18) 2.1 (0.60, 7.08)     Elevated CRP at 2 T 2.0 (0.72, 5.54) 2.4 (0.81, 7.17)     Elevated CRP at 3 T 2.0 (0.70, 5.52) 1.7 (0.59, 5.07)     TNFi use during pregnancy 0.5 (0.19, 1.28) 0.6 (0.20, 1.50)     GC use during pregnancy 2.2 (0.96, 5.11) 2.3 (0.94, 5.82)     DMARD use during pregnancy 3.0* (1.28, 7.06) 3.2* (1.26, 7.90)     NSAIDs use during pregnancya 2.7 (0.83, 8.55) 3.0 (0.86, 10.54) Adjusted OR: adjusted for maternal age and gravidity. a NSAIDs used before gestational week 32. b Pregnancy complications: preeclampsia, gestational diabetes, infection, preterm premature rupture of membranes. * P < 0.05. T: trimester; TNFi: tumour necrosis factor inhibitor. Table 3 Association of adverse pregnancy outcomes and C-section with RA Outcome and independent variables Crude OR (95% CI) Adjusted OR (95% CI) Preterm delivery     DAS28-CRP > 3.2 during pregnancy 3.6* (1.26, 10.46) 3.9* (1.25, 12.15)     Elevated CRP at 1 T 3.3 (0.53, 19.82) 3.8 (0.58, 25.20)     Elevated CRP at 2 T 2.9 (0.75, 11.12) 3.2 (0.80, 12.75)     Elevated CRP at 3 T 1.1 (0.27, 4.06) 1.0 (0.24, 3.98)     TNFi use during pregnancy 0.6 (0.19, 2.16) 0.7 (0.20, 2.51)     GC use during pregnancy 1.7 (0.61, 4.96) 1.9 (0.62, 5.54)     DMARD use during pregnancy 0.7 (0.26, 2.02) 0.7 (0.23, 2.00)     NSAIDs use during pregnancya 1.7 (0.48, 6.27) 1.8 (0.48, 6.97) Small for gestational age infants     DAS28-CRP > 3.2 during pregnancy 1.4 (0.46, 4.29) 1.3 (0.41, 4.05)     Elevated CRP at 1 T 0.9 (0.22, 3.79) 1.0 (0.23, 4.25)     Elevated CRP at 2 T 1.2 (0.36, 4.17) 1.2 (0.37, 4.61)     Elevated CRP at 3 T 1.1 (0.27, 4.06) 1.0 (0.24, 3.72)     TNFi use during pregnancy 2.2 (0.72, 6.61) 2.6 (0.81, 8.37)     GC use during pregnancy 1.8 (0.61, 5.55) 2.0 (0.63, 6.12)     DMARD use during pregnancy 1.8 (0.58, 5.28) 1.7 (0.56, 5.36)     NSAIDs use during pregnancya 3.2 (0.91, 11.08) 3.4 (0.92, 12.15) Pregnancy complicationsb     DAS28-CRP > 3.2 during pregnancy 0.5 (0.09, 2.24) 0.5 (0.11, 3.07)     Elevated CRP at 1 T 1.5 (0.27, 8.17) 6.3 (0.54, 72.80)     Elevated CRP at 2 T 2.2 (0.34, 14.10) 2.1 (0.31, 14.26)     Elevated CRP at 3 T 0.6 (0.15, 2.68) 0.7 (0.15, 3.10)     TNFi use during pregnancy 0.9 (0.22, 3.67) 1.0 (0.23, 4.51)     GC use during pregnancy 0.8 (0.2, 2.87) 0.9 (0.21, 3.43)     DMARD use during pregnancy 1.2 (0.33, 4.14) 1.1 (0.30, 4.29)     NSAIDs use during pregnancya 1.2 (0.24, 6.36) 1.5 (0.28, 8.20) C-section     DAS28-CRP > 3.2 during pregnancy 2.5* (1.01, 6.14) 2.2 (0.85, 5.90)     Elevated CRP at 1 T 1.6 (0.51, 5.18) 2.1 (0.60, 7.08)     Elevated CRP at 2 T 2.0 (0.72, 5.54) 2.4 (0.81, 7.17)     Elevated CRP at 3 T 2.0 (0.70, 5.52) 1.7 (0.59, 5.07)     TNFi use during pregnancy 0.5 (0.19, 1.28) 0.6 (0.20, 1.50)     GC use during pregnancy 2.2 (0.96, 5.11) 2.3 (0.94, 5.82)     DMARD use during pregnancy 3.0* (1.28, 7.06) 3.2* (1.26, 7.90)     NSAIDs use during pregnancya 2.7 (0.83, 8.55) 3.0 (0.86, 10.54) Outcome and independent variables Crude OR (95% CI) Adjusted OR (95% CI) Preterm delivery     DAS28-CRP > 3.2 during pregnancy 3.6* (1.26, 10.46) 3.9* (1.25, 12.15)     Elevated CRP at 1 T 3.3 (0.53, 19.82) 3.8 (0.58, 25.20)     Elevated CRP at 2 T 2.9 (0.75, 11.12) 3.2 (0.80, 12.75)     Elevated CRP at 3 T 1.1 (0.27, 4.06) 1.0 (0.24, 3.98)     TNFi use during pregnancy 0.6 (0.19, 2.16) 0.7 (0.20, 2.51)     GC use during pregnancy 1.7 (0.61, 4.96) 1.9 (0.62, 5.54)     DMARD use during pregnancy 0.7 (0.26, 2.02) 0.7 (0.23, 2.00)     NSAIDs use during pregnancya 1.7 (0.48, 6.27) 1.8 (0.48, 6.97) Small for gestational age infants     DAS28-CRP > 3.2 during pregnancy 1.4 (0.46, 4.29) 1.3 (0.41, 4.05)     Elevated CRP at 1 T 0.9 (0.22, 3.79) 1.0 (0.23, 4.25)     Elevated CRP at 2 T 1.2 (0.36, 4.17) 1.2 (0.37, 4.61)     Elevated CRP at 3 T 1.1 (0.27, 4.06) 1.0 (0.24, 3.72)     TNFi use during pregnancy 2.2 (0.72, 6.61) 2.6 (0.81, 8.37)     GC use during pregnancy 1.8 (0.61, 5.55) 2.0 (0.63, 6.12)     DMARD use during pregnancy 1.8 (0.58, 5.28) 1.7 (0.56, 5.36)     NSAIDs use during pregnancya 3.2 (0.91, 11.08) 3.4 (0.92, 12.15) Pregnancy complicationsb     DAS28-CRP > 3.2 during pregnancy 0.5 (0.09, 2.24) 0.5 (0.11, 3.07)     Elevated CRP at 1 T 1.5 (0.27, 8.17) 6.3 (0.54, 72.80)     Elevated CRP at 2 T 2.2 (0.34, 14.10) 2.1 (0.31, 14.26)     Elevated CRP at 3 T 0.6 (0.15, 2.68) 0.7 (0.15, 3.10)     TNFi use during pregnancy 0.9 (0.22, 3.67) 1.0 (0.23, 4.51)     GC use during pregnancy 0.8 (0.2, 2.87) 0.9 (0.21, 3.43)     DMARD use during pregnancy 1.2 (0.33, 4.14) 1.1 (0.30, 4.29)     NSAIDs use during pregnancya 1.2 (0.24, 6.36) 1.5 (0.28, 8.20) C-section     DAS28-CRP > 3.2 during pregnancy 2.5* (1.01, 6.14) 2.2 (0.85, 5.90)     Elevated CRP at 1 T 1.6 (0.51, 5.18) 2.1 (0.60, 7.08)     Elevated CRP at 2 T 2.0 (0.72, 5.54) 2.4 (0.81, 7.17)     Elevated CRP at 3 T 2.0 (0.70, 5.52) 1.7 (0.59, 5.07)     TNFi use during pregnancy 0.5 (0.19, 1.28) 0.6 (0.20, 1.50)     GC use during pregnancy 2.2 (0.96, 5.11) 2.3 (0.94, 5.82)     DMARD use during pregnancy 3.0* (1.28, 7.06) 3.2* (1.26, 7.90)     NSAIDs use during pregnancya 2.7 (0.83, 8.55) 3.0 (0.86, 10.54) Adjusted OR: adjusted for maternal age and gravidity. a NSAIDs used before gestational week 32. b Pregnancy complications: preeclampsia, gestational diabetes, infection, preterm premature rupture of membranes. * P < 0.05. T: trimester; TNFi: tumour necrosis factor inhibitor. Effect of disease activity and anti-rheumatic drugs Next the influence of disease-specific aspects and of anti-rheumatic drugs on adverse pregnancy outcome was analysed. The percentage of patients showing active disease any time during pregnancy was 31.3% for women with RA (defined as DAS28-CRP > 3.2). Active RA at any trimester during pregnancy was significantly predictive for preterm delivery (P = 019, Table 3). In axSpA, active disease (defined as ASDAS-CRP > 2.1) occurred in 78.3% of the patients during the course of pregnancy, yet was most prevalent at the second trimester. Among women with axSpA, 44% had elevated CRP levels around gestational week 20, which were related to increased disease activity in all cases. In the regression model, an elevated CRP level at the second trimester was significantly predictive for preterm delivery (P = 0.028; Table 4). Table 4 Association of adverse pregnancy outcome and C-section with axial SpA Outcome and independent variables Crude OR (95% CI) Adjusted OR (95% CI) Preterm delivery     ASDAS > 2.1 during pregnancy 0.8 (0.20, 3.34) 1.0 (0.22, 4.76)     Elevated CRP at 1 T 2.2 (0.32, 15.00) 2.4 (0.30, 20.01)     Elevated CRP at 2 T 10.8* (1.19, 98.36) 13.8* (1.33, 143.94)     Elevated CRP at 3 T 1.3 (0.27, 5.63) 0.9 (0.16, 5.27)     TNFi use during pregnancy 3.4 (0.79, 14.98) 4.5 (0.90¸ 22.51)     GC use during pregnancy 0.9 (0.18, 4.93) 1.8 (0.28, 11.32)     DMARD use during pregnancy 2.5 (0.43, 14.41) 2.4 (0.31, 17.82)     NSAIDs use during pregnancya 0.6 (0.13, 2.44) 0.5 (0.10, 2.82) Small for gestational age infants     ASDAS > 2.1 during pregnancy 0.8 (0.20, 3.26) 0.8 (0.17, 3.53)     Elevated CRP at 1 T 0.3 (0.03, 2.82) 0.4 (0.03, 3.93)     Elevated CRP at 2 T 1.9 (0.37, 9.31) 2.1 (0.38, 11.10)     Elevated CRP at 3 T 1.7 (0.35, 8.64) 1.7 (0.32, 9.04)     TNFi use during pregnancy 1.2 (0.31, 5.05) 1.3 (0.30, 5.60)     GC use during pregnancy 0.9 (0.18, 5.02) 0.9 (0.15, 4.82)     DMARD use during pregnancy NA NA     NSAIDs use during pregnancya 1.5 (0.38, 6.20) 2.4 (0.53, 10.61) Pregnancy complicationsb     ASDAS > 2.1 during pregnancy 0.9 (0.27, 2.76) 1.0 (0.27, 3.66)     Elevated CRP at 1 T 1.0 (0.19, 5.17) 0.6 (0.08, 4.37)     Elevated CRP at 2 T 2.5 (0.52, 11.64) 2.7 (0.45, 15.93)     Elevated CRP at 3 T 0.8 (0.19, 3.11) 0.8 (0.18, 3.19)     TNFi use during pregnancy 3.4* (1.03, 11.51) 3.5 (1.00, 12.12)     GC use during pregnancy 1.4 (0.38, 5.25) 1.8 (0.43, 7.59)     DMARD use during pregnancy 1.4 (0.25, 7.36) 2.6 (0.40, 16.87)     NSAIDs use during pregnancya 1.7 (0.53, 5.51) 1.4 (0.37, 5.33) C-section     ASDAS > 2.1 during pregnancy 0.8 (0.33, 2.14) 1.2 (0.43, 3.43)     Elevated CRP at 1 T 2.0 (0.53, 7.60) 2.0 (0.42, 9.82)     Elevated CRP at 2 T 1.5 (0.50, 4.78) 1.5 (0.44, 5.34)     Elevated CRP at 3 T 1.1 (0.36, 3.35) 1.1 (0.35, 3.75)     TNFi use during pregnancy 0.9 (0.34, 2.20) 0.9 (0.31, 2.40)     GC use during pregnancy 1.2 (0.42, 3.54) 1.7 (0.54, 5.58)     DMARD use during pregnancy 1.5 (0.35, 6.60) 1.2 (0.22¸ 6.39)     NSAIDs use during pregnancya 0.8 (0.30, 1.90) 0.8 (0.27, 2.27) Outcome and independent variables Crude OR (95% CI) Adjusted OR (95% CI) Preterm delivery     ASDAS > 2.1 during pregnancy 0.8 (0.20, 3.34) 1.0 (0.22, 4.76)     Elevated CRP at 1 T 2.2 (0.32, 15.00) 2.4 (0.30, 20.01)     Elevated CRP at 2 T 10.8* (1.19, 98.36) 13.8* (1.33, 143.94)     Elevated CRP at 3 T 1.3 (0.27, 5.63) 0.9 (0.16, 5.27)     TNFi use during pregnancy 3.4 (0.79, 14.98) 4.5 (0.90¸ 22.51)     GC use during pregnancy 0.9 (0.18, 4.93) 1.8 (0.28, 11.32)     DMARD use during pregnancy 2.5 (0.43, 14.41) 2.4 (0.31, 17.82)     NSAIDs use during pregnancya 0.6 (0.13, 2.44) 0.5 (0.10, 2.82) Small for gestational age infants     ASDAS > 2.1 during pregnancy 0.8 (0.20, 3.26) 0.8 (0.17, 3.53)     Elevated CRP at 1 T 0.3 (0.03, 2.82) 0.4 (0.03, 3.93)     Elevated CRP at 2 T 1.9 (0.37, 9.31) 2.1 (0.38, 11.10)     Elevated CRP at 3 T 1.7 (0.35, 8.64) 1.7 (0.32, 9.04)     TNFi use during pregnancy 1.2 (0.31, 5.05) 1.3 (0.30, 5.60)     GC use during pregnancy 0.9 (0.18, 5.02) 0.9 (0.15, 4.82)     DMARD use during pregnancy NA NA     NSAIDs use during pregnancya 1.5 (0.38, 6.20) 2.4 (0.53, 10.61) Pregnancy complicationsb     ASDAS > 2.1 during pregnancy 0.9 (0.27, 2.76) 1.0 (0.27, 3.66)     Elevated CRP at 1 T 1.0 (0.19, 5.17) 0.6 (0.08, 4.37)     Elevated CRP at 2 T 2.5 (0.52, 11.64) 2.7 (0.45, 15.93)     Elevated CRP at 3 T 0.8 (0.19, 3.11) 0.8 (0.18, 3.19)     TNFi use during pregnancy 3.4* (1.03, 11.51) 3.5 (1.00, 12.12)     GC use during pregnancy 1.4 (0.38, 5.25) 1.8 (0.43, 7.59)     DMARD use during pregnancy 1.4 (0.25, 7.36) 2.6 (0.40, 16.87)     NSAIDs use during pregnancya 1.7 (0.53, 5.51) 1.4 (0.37, 5.33) C-section     ASDAS > 2.1 during pregnancy 0.8 (0.33, 2.14) 1.2 (0.43, 3.43)     Elevated CRP at 1 T 2.0 (0.53, 7.60) 2.0 (0.42, 9.82)     Elevated CRP at 2 T 1.5 (0.50, 4.78) 1.5 (0.44, 5.34)     Elevated CRP at 3 T 1.1 (0.36, 3.35) 1.1 (0.35, 3.75)     TNFi use during pregnancy 0.9 (0.34, 2.20) 0.9 (0.31, 2.40)     GC use during pregnancy 1.2 (0.42, 3.54) 1.7 (0.54, 5.58)     DMARD use during pregnancy 1.5 (0.35, 6.60) 1.2 (0.22¸ 6.39)     NSAIDs use during pregnancya 0.8 (0.30, 1.90) 0.8 (0.27, 2.27) Adjusted odds ratio for maternal age and gravidity. a NSAIDs used before gestational week 32. b Pregnancy complications: preeclampsia, gestational diabetes, infection, preterm premature rupture of membranes. * P < 0.05. T: trimester; NA: not applicable. Table 4 Association of adverse pregnancy outcome and C-section with axial SpA Outcome and independent variables Crude OR (95% CI) Adjusted OR (95% CI) Preterm delivery     ASDAS > 2.1 during pregnancy 0.8 (0.20, 3.34) 1.0 (0.22, 4.76)     Elevated CRP at 1 T 2.2 (0.32, 15.00) 2.4 (0.30, 20.01)     Elevated CRP at 2 T 10.8* (1.19, 98.36) 13.8* (1.33, 143.94)     Elevated CRP at 3 T 1.3 (0.27, 5.63) 0.9 (0.16, 5.27)     TNFi use during pregnancy 3.4 (0.79, 14.98) 4.5 (0.90¸ 22.51)     GC use during pregnancy 0.9 (0.18, 4.93) 1.8 (0.28, 11.32)     DMARD use during pregnancy 2.5 (0.43, 14.41) 2.4 (0.31, 17.82)     NSAIDs use during pregnancya 0.6 (0.13, 2.44) 0.5 (0.10, 2.82) Small for gestational age infants     ASDAS > 2.1 during pregnancy 0.8 (0.20, 3.26) 0.8 (0.17, 3.53)     Elevated CRP at 1 T 0.3 (0.03, 2.82) 0.4 (0.03, 3.93)     Elevated CRP at 2 T 1.9 (0.37, 9.31) 2.1 (0.38, 11.10)     Elevated CRP at 3 T 1.7 (0.35, 8.64) 1.7 (0.32, 9.04)     TNFi use during pregnancy 1.2 (0.31, 5.05) 1.3 (0.30, 5.60)     GC use during pregnancy 0.9 (0.18, 5.02) 0.9 (0.15, 4.82)     DMARD use during pregnancy NA NA     NSAIDs use during pregnancya 1.5 (0.38, 6.20) 2.4 (0.53, 10.61) Pregnancy complicationsb     ASDAS > 2.1 during pregnancy 0.9 (0.27, 2.76) 1.0 (0.27, 3.66)     Elevated CRP at 1 T 1.0 (0.19, 5.17) 0.6 (0.08, 4.37)     Elevated CRP at 2 T 2.5 (0.52, 11.64) 2.7 (0.45, 15.93)     Elevated CRP at 3 T 0.8 (0.19, 3.11) 0.8 (0.18, 3.19)     TNFi use during pregnancy 3.4* (1.03, 11.51) 3.5 (1.00, 12.12)     GC use during pregnancy 1.4 (0.38, 5.25) 1.8 (0.43, 7.59)     DMARD use during pregnancy 1.4 (0.25, 7.36) 2.6 (0.40, 16.87)     NSAIDs use during pregnancya 1.7 (0.53, 5.51) 1.4 (0.37, 5.33) C-section     ASDAS > 2.1 during pregnancy 0.8 (0.33, 2.14) 1.2 (0.43, 3.43)     Elevated CRP at 1 T 2.0 (0.53, 7.60) 2.0 (0.42, 9.82)     Elevated CRP at 2 T 1.5 (0.50, 4.78) 1.5 (0.44, 5.34)     Elevated CRP at 3 T 1.1 (0.36, 3.35) 1.1 (0.35, 3.75)     TNFi use during pregnancy 0.9 (0.34, 2.20) 0.9 (0.31, 2.40)     GC use during pregnancy 1.2 (0.42, 3.54) 1.7 (0.54, 5.58)     DMARD use during pregnancy 1.5 (0.35, 6.60) 1.2 (0.22¸ 6.39)     NSAIDs use during pregnancya 0.8 (0.30, 1.90) 0.8 (0.27, 2.27) Outcome and independent variables Crude OR (95% CI) Adjusted OR (95% CI) Preterm delivery     ASDAS > 2.1 during pregnancy 0.8 (0.20, 3.34) 1.0 (0.22, 4.76)     Elevated CRP at 1 T 2.2 (0.32, 15.00) 2.4 (0.30, 20.01)     Elevated CRP at 2 T 10.8* (1.19, 98.36) 13.8* (1.33, 143.94)     Elevated CRP at 3 T 1.3 (0.27, 5.63) 0.9 (0.16, 5.27)     TNFi use during pregnancy 3.4 (0.79, 14.98) 4.5 (0.90¸ 22.51)     GC use during pregnancy 0.9 (0.18, 4.93) 1.8 (0.28, 11.32)     DMARD use during pregnancy 2.5 (0.43, 14.41) 2.4 (0.31, 17.82)     NSAIDs use during pregnancya 0.6 (0.13, 2.44) 0.5 (0.10, 2.82) Small for gestational age infants     ASDAS > 2.1 during pregnancy 0.8 (0.20, 3.26) 0.8 (0.17, 3.53)     Elevated CRP at 1 T 0.3 (0.03, 2.82) 0.4 (0.03, 3.93)     Elevated CRP at 2 T 1.9 (0.37, 9.31) 2.1 (0.38, 11.10)     Elevated CRP at 3 T 1.7 (0.35, 8.64) 1.7 (0.32, 9.04)     TNFi use during pregnancy 1.2 (0.31, 5.05) 1.3 (0.30, 5.60)     GC use during pregnancy 0.9 (0.18, 5.02) 0.9 (0.15, 4.82)     DMARD use during pregnancy NA NA     NSAIDs use during pregnancya 1.5 (0.38, 6.20) 2.4 (0.53, 10.61) Pregnancy complicationsb     ASDAS > 2.1 during pregnancy 0.9 (0.27, 2.76) 1.0 (0.27, 3.66)     Elevated CRP at 1 T 1.0 (0.19, 5.17) 0.6 (0.08, 4.37)     Elevated CRP at 2 T 2.5 (0.52, 11.64) 2.7 (0.45, 15.93)     Elevated CRP at 3 T 0.8 (0.19, 3.11) 0.8 (0.18, 3.19)     TNFi use during pregnancy 3.4* (1.03, 11.51) 3.5 (1.00, 12.12)     GC use during pregnancy 1.4 (0.38, 5.25) 1.8 (0.43, 7.59)     DMARD use during pregnancy 1.4 (0.25, 7.36) 2.6 (0.40, 16.87)     NSAIDs use during pregnancya 1.7 (0.53, 5.51) 1.4 (0.37, 5.33) C-section     ASDAS > 2.1 during pregnancy 0.8 (0.33, 2.14) 1.2 (0.43, 3.43)     Elevated CRP at 1 T 2.0 (0.53, 7.60) 2.0 (0.42, 9.82)     Elevated CRP at 2 T 1.5 (0.50, 4.78) 1.5 (0.44, 5.34)     Elevated CRP at 3 T 1.1 (0.36, 3.35) 1.1 (0.35, 3.75)     TNFi use during pregnancy 0.9 (0.34, 2.20) 0.9 (0.31, 2.40)     GC use during pregnancy 1.2 (0.42, 3.54) 1.7 (0.54, 5.58)     DMARD use during pregnancy 1.5 (0.35, 6.60) 1.2 (0.22¸ 6.39)     NSAIDs use during pregnancya 0.8 (0.30, 1.90) 0.8 (0.27, 2.27) Adjusted odds ratio for maternal age and gravidity. a NSAIDs used before gestational week 32. b Pregnancy complications: preeclampsia, gestational diabetes, infection, preterm premature rupture of membranes. * P < 0.05. T: trimester; NA: not applicable. Regarding anti-rheumatic therapy, the univariate regression analysis revealed that patients with axSpA who were treated with TNFi any time during pregnancy were more likely to experience pregnancy complications than patients without TNFi treatment. The following pregnancy complications were observed in these patients: one had gestational diabetes, two developed preeclampsia, four had infections (two vaginal infections with preterm premature rupture of membranes, two upper respiratory tract infections; none had corticosteroids at the time of infection). The association of TNFi use in women with axSpA and pregnancy complications was attenuated in the multivariate model adjusted for age and gravidity (Tables 3 and 4). Additional analysis We further conducted a sensitivity analysis, limiting the analysis to 92 singleton pregnancies in patients with RA and to 76 singleton pregnancies in patients with axSpA. Most point estimates were similar to in the main analysis when comparing pregnancy outcome and C-section rate in RA and axSpA with those of HCs and when analysing the influence of disease activity on preterm delivery (supplementary Tables S1–S3, available at Rheumatology online). Discussion In this study, we showed that RA and axSpA are associated with adverse pregnancy outcomes. Active disease was a risk factor for preterm delivery not only in RA but also in axSpA. So far, disease activity as a risk factor for preterm delivery has been previously described in women with RA [8], but it has not been identified in prospectively studied patients with axSpA. Of the axSpA patients, 78% experienced active disease during the course of pregnancy as determined by objective and disease-specific measures of disease activity. However, as with all disease activity measures in pregnancy, no validation has been performed in pregnant patients, and so a certain bias by pregnancy itself cannot be fully excluded. Other prospective studies analysing disease activity in pregnant patients with AS using different measures showed active disease during pregnancy in 62–80% of the women [3–5]. In our study population, active disease and elevated CRP levels occurred most often at the second trimester. The second trimester visit was performed at gestational week 20, a known phase of increased inflammatory back pain and morning stiffness in pregnant patients with AS [4]. By contrast, pregnancy-related back pain is usually seen at the third trimester in healthy pregnant women [21, 22]. Remarkably, the subgroup of patients at risk for preterm delivery could not be identified using ASDAS values but could by increased CRP levels. ASDAS is a composite index combining four subjective clinical variables and the natural logarithm of the CRP. An elevated CRP level is a direct sign known to correlate with more severe disease and with active axial joint inflammation in patients with axSpA [23–25]. Our data indicate that elevated CRP levels may also qualify to predict premature delivery in pregnant women with axSpA. In addition, our patients with axSpA were at risk for having pregnancy complications and offspring that are SGA compared with healthy women. This is in line with an increased risk for prematurity and SGA seen in a large Swedish population-based case-control study in women with AS [13]. In this registry study, no disease activity measures were used and information about medication was obtained by drug dispensation 12 months prior to delivery only. The authors presumed a possible association between SGA offspring and maternal disease severity, since the risk for SGA increased with more extensive drug dispensation [13]. A former retrospective study using a standardized questionnaire did not show increased risks of adverse pregnancy outcome [12]. Differences in study design are likely to have contributed to these opposed findings. Among our patients with RA one-third had active disease during pregnancy. This proportion is comparable to that of the prospective Organization of Teratology Information Specialists (OTIS) study [8] whereas in the prospective Pregnancy-induced Amelioration of Rheumatoid Arthritis (PARA) study, half of the patients with RA experienced active disease during pregnancy [26]. Differences in the treatment intensity during pregnancy might account for the discrepant proportion of patients with active disease since TNFi were used in about 30% of our patients and 67% of the OTIS patients but not in those of the PARA study. In our patients with RA, active disease was predictive for preterm delivery. In addition, RA was associated with pregnancy complications and offspring being SGA. Our results are in line with those of the OTIS study showing an association of preterm delivery and SGA with more severe disease [8]. However, in the PARA study, disease activity was associated with lower birthweight but prednisone treatment was related to preterm delivery [7]. In our cohort, no association between any use of prednisone and preterm delivery was found. Dosing could play a role since prednisone use above 10 mg any time during pregnancy was an independent predictor for preterm delivery in the OTIS study, but did not modify the association between disease severity and preterm delivery [8]. Regarding delivery mode, most women with RA and axSpA had vaginal deliveries. However, there was an increased risk of C-section in women with RA compared with HCs. Disease activity and DMARD use were associated with C-section in patients with RA. This implies that an insufficient control of disease activity results in C-section. Accordingly, an increased risk for C-section in patients with RA has been described by others comparing RA versus controls or analysing the subgroup of patients with more severe disease [8, 14, 27]. Interestingly, our patients with axSpA did not show an increased risk of C-section compared with healthy women, despite the fact that most had active disease. This contrasts with previous studies that reported a higher risk for C-section compared with reference subjects [13, 14]. Cases with more extensive anti-rheumatic therapy tended to have a higher risk for elective C-section in the Swedish registry study [13]. Differences in the C-section rates in the absence of foetal problems or pregnancy-related complications might depend on several factors such as disease severity, the wish of the patient and the judgement of the obstetrician. Among our patients, the frequency of TNFi treatment during pregnancy was higher in women with axSpA than in women with RA. In patients with axSpA, TNFi use was associated with pregnancy complications such as infections, gestational diabetes and preeclampsia in the univariate analysis but not in the adjusted model. Prednisone, which has been identified as a risk factor for serious infections in pregnancy, was not used as a co-medication in any of these patients around the time of infection [28]. Data from a recent meta-analysis comparing pregnancy outcome between TNFi users versus non-users confirm that TNFi do not increase the rates of pregnancy-related complications [10]. Our study is limited in the number of patients and in the number of outcome events, which did not allow for a model with more extensive adjustments. A strength of this study was the analysis of pregnancy outcome not only by disease status but also by disease activity. In summary, our results showed that patients with RA and axSpA were at risk of poor pregnancy outcome. The comparison between both diseases revealed that maternal disease activity was an overarching predictor for preterm delivery. Targeting inactive disease in pregnant patients is important to allow for successful pregnancy and to impede disease progression. Based on a risk–benefit analysis and on a process of shared decision-making with the patient, an effective treatment with pregnancy-compatible drugs [9, 29] should be continued beyond conception. Acknowledgements We would like to thank Dr Lukas Bütikofer from the Clinical Trial Unit Bern for his statistical consulting. Funding: No specific funding was received from any bodies in the public, commercial or not-for-profit sectors to carry out the work described in this manuscript. Disclosure statement: F.F. has received an unrestricted grant from UCB Pharma. All other authors have declared no conflicts of interest. Supplementary data Supplementary data are available at Rheumatology online. References 1 de Man YA , Dolhain RJ , van de Geijn FE , Willemsen SP , Hazes JM. Disease activity of rheumatoid arthritis during pregnancy: results from a nationwide prospective study . Arthritis Rheum 2008 ; 59 : 1241 – 8 . 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Risk for adverse pregnancy outcome in axial spondyloarthritis and rheumatoid arthritis: disease activity matters

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Oxford University Press
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© The Author(s) 2018. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oup.com
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1462-0324
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1462-0332
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10.1093/rheumatology/key053
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Abstract

Abstract Objective To analyse pregnancy outcome and delivery mode in patients with RA and axial spondyloarthritis (axSpA) in relation to disease activity and anti-rheumatic drugs. Methods Patients with RA and axSpA were compared with age-matched healthy controls (HCs) with respect to pregnancy outcome and delivery mode. Disease activity (DAS28, ASDAS, CRP) and medication use of patients was assessed once at each trimester. ORs with 95% CI were calculated with univariate and multivariate regression models. Results We analysed 244 pregnancies, of which 96 occurred in patients with RA, 78 in patients with axSpA and 70 in HCs. The adjusted analysis showed that pregnant women with RA and axSpA had a higher risk of pregnancy complications (gestational diabetes, preeclampsia, infection, preterm premature rupture of membranes), small for gestational age infants and preterm deliveries (all P < 0.05). Active disease was a predictor for preterm delivery in both RA [odds ratio (OR) = 3.9, 95% CI: 1.25, 12.15] and axSpA (OR = 13.8, 95% CI: 1.33, 143.94). Regarding delivery mode, most patients had vaginal deliveries. However, women with RA revealed an increased risk of caesarean section compared with HC (P < 0.05), which was not seen in patients with axSpA. Conclusion Our findings show that disease activity of RA and axSpA during pregnancy influences pregnancy outcome. To allow for successful pregnancy a treatment strategy that targets inactive disease beyond conception should be followed. rheumatoid arthritis, axial spondyloarthritis, pregnancy Rheumatology key messages Women with RA and axial SpA are at risk for adverse pregnancy outcomes. Active disease is a predictor for preterm delivery in pregnant women with RA and axial SpA. Introduction Inflammatory rheumatic diseases such as RA and axial spondyloarthritis (axSpA) affect women of childbearing age. The interaction of pregnancy and the inflammatory rheumatic disease may influence maternal and foetal health. Pregnancy-mediated changes of the immune system may exert a positive effect on disease activity in about 48–65% of pregnant women with RA, yet remission is only seen in about 16–27% of these patients [1, 2]. In women with axSpA, pregnancy has no ameliorating effect on disease activity. Symptoms are reported in 60–80% of these women with a worsening of pain and morning stiffness around gestational week 20 [3–5]. In addition, the discontinuation of anti-rheumatic drugs around conception could be a risk factor for disease deterioration in RA and axSpA in the first or second trimester, respectively [6]. Active disease during pregnancy, however, not only poses a risk for future articular damage but could also be associated with pregnancy complications and adverse pregnancy outcome [7, 8]. To control disease symptoms in pregnant patients with RA and axSpA, therapy with pregnancy-compatible anti-rheumatic drugs is often needed [9]. In this context, the increase of reassuring data on the use of TNF inhibitors (TNFi) in pregnancy over time has resulted in a higher proportion of pregnant women with inflammatory rheumatic diseases being treated with TNFi [9, 10]. Both, the rheumatic disease and anti-rheumatic drugs can have an influence on pregnancy course and outcome as well as on delivery mode. In pregnant women with RA, the risk of adverse pregnancy outcome such as preterm delivery, infants being small for gestational age or having a reduced birth weight is elevated [7, 8, 11]. Two studies in RA patients have shown in a prospective way that disease activity contributes to these adverse pregnancy outcomes [7, 8]. In pregnant women with AS, retrospective data from a questionnaire study and two registry studies show inconsistent results ranging from no adverse effect on pregnancy outcome to increased rates of premature and small for gestational age infants [12–14]. Regarding delivery mode, most studies have found an increased rate of caesarean section (C-sections) in women with RA and axSpA versus reference subjects [8, 13, 14]. Prospective data on the outcome of pregnancies in patients with axSpA are lacking. Further studies in RA are necessary that include patients with TNFi use. The aim of this study was to analyse the outcome of pregnancy and the delivery mode in women with RA and axSpA vs healthy women as well as in relation to disease activity and therapy with anti-rheumatic drugs. Methods Patients All patients were prospectively followed at the Centre for Pregnancy in Rheumatic Diseases at the Department of Rheumatology of the University Hospital of Bern between 2000 and 2016. Age-matched healthy women not showing any pre-existing risk factors were included during the same time frame. The group of healthy women was recruited among pregnant employees of the University Hospital of Bern as well as at the Department of Obstetrics and Gynecology of the University Hospital of Bern. Patients with RA had to fulfil the revised 1987 ACR classification criteria for RA [15]. Patients with axSpA fulfilled the ESSG criteria for SpA [16]. All patients with SpA also fulfilled the Assessment of SpondyloArthritis international Society criteria for axSpA; for patients recruited before 2009, the Assessment of SpondyloArthritis international Society criteria were applied in retrospect [17]. The study was approved by the ethics committee of the Canton of Bern, Switzerland. Women were included after they provided written informed consent. Time points, assessments and definitions All patients were seen at each trimester during pregnancy (gestational weeks 10–12, 20–22 and 30–32) and after delivery, 6–8 weeks postpartum. The standard protocol consisted of a routine physical examination, assessment of diseases activity including the measurement of CRP (measured by NycoCard, Alere Technologies AS, Oslo, Norway) and recording of the current medication and complications. At the postpartum visit, information was collected on delivery mode, birth, neonatal health and complications such as preeclampsia, gestational diabetes, infection and preterm premature rupture of membranes. The data from healthy pregnant women were recorded twice: between gestational weeks 30–32 and at 8 weeks postpartum. All healthy women had normal CRP values at inclusion. Disease activity in RA was assessed using the three-variable DAS28-CRP since this score was shown to perform best in pregnancy [18]. Active disease in RA patients was defined as DAS28-CRP scores higher than 3.2. Disease activity in women with axSpA was assessed using the ASDAS-CRP [19]. In our experience, the ASDAS-CRP is able to reflect disease activity in pregnant patients with axSpA since it combines few subjective items with the CRP and is not biased by a fatigue question. Active disease in women with axSpA was defined by ASDAS-CRP scores higher than 2.1. In patients with axSpA recruited prior to the development of the ASDAS-CRP in 2009, the ASDAS-CRP scores were calculated retrospectively using the CRP, the scores of the patient global assessment (0–10) and the scores of the BASDAI questions about back pain, duration of morning stiffness and peripheral pain [20]. Preterm birth was defined as a live birth before gestational week 37. Small for gestational age (SGA) neonates were defined as those with a birth weight below the 10th percentile for gestational age. Statistical analysis Patients with RA and axSpA were compared with those of matched healthy controls (HCs) with respect to pregnancy complications, pregnancy outcome and delivery mode. To compare the two patients’ groups and the HCs, the Kruskal–Wallis test was used for continuous variables and the Fisher’s exact test for categorical variables. To identify risk factors for adverse pregnancy outcomes and delivery modes, univariate and multivariate logistic regression analyses were performed. Differences in birth weight of neonates in patients and references were examined in multivariate linear regression analyses. In the multivariate regression analyses, adjustments were made for age and gravidity. P < 0.05 was regarded as significant. Data were analysed using IBM SPSS Statistics 22 software package (IBM Corp., Armonk, NY, USA). Results Disease course and medication We analysed 244 pregnancies, of which 96 occurred in 86 RA patients, 78 in 70 axSpA patients and 70 in 70 age-matched healthy women (Table 1). Table 1 Descriptive information on mothers, pregnancies, deliveries and infants Characteristics Rheumatoid arthritis, n = 86 Axial spondyloarthritis, n = 70 Healthy controls, n = 70 P-valuea Maternal age at delivery, median (range), years 32 (22–44) 32 (23–41) 32 (20–41) 0.556 RF or ACPA positive, n (%)b 51 (59.3) HLA B-27, n (%)b 48 (68.6) SpA with peripheral arthritis, n (%)b 32 (45.7) Disease activity during pregnancyc     First trimester 2.3 2.5     Second trimester 2.4 2.4     Third trimester 2.3 2.2 Pregnancy 96 78 70     Twin pregnancy, n 4 2 0     Primigravidae, n (%)b 57 (66.3) 45 (64.3) 43 (61.4) 0.919 Pregnancy complications, n (%)d 11 (11.5) 14 (17.9) 1 (1.43) 0.002     Gestational diabetes 2 5 1     Preeclampsia 4 2 —     Infection 1 4 —     PPROM 4 3 — Delivery mode     Vaginal delivery, n (%)d 49 (51.0) 45 (57.8) 51 (72.9) 0.036     Caesarian section         Total, n (%) 43 (44.8) 31 (39.7) 19 (27.1) 0.036         Elective, n 21 14 9 0.267         Emergency, n 22 17 10 0.309         Unknown 4 2 — Infant     Live birth, n (%)e 99 (99.0) 79 (98.8) 70 (100)     Stillbirth/induced fetal demisef 1f 1 — Median birth weight (range), g 3100 (1250–4455) 3245 (1450–4740) 3460 (2620–4500) 0.000 Median birth weight percentile 32.4 (0.4–99.4) 38.2 (2.1–98.8) 72.5 (4.0–99.0) 0.193 SGA (<10th percentile), n (%)g 16 (16.2) 9 (11.4) 1 (1.4) 0.002 Preterm delivery, n (%)g 18 (18.2) 9 (11.4) 1 (1.4) 0.001 Congenital anomalies, n (%)e 3 (3.0) 3 (3.8) —     Hirschsprung disease 1 — —     Ventricular septal defect 1 — —     Unilateral kidney — 1 —     Down syndrome 1f 1 —     Di George Syndrome — 1 — Characteristics Rheumatoid arthritis, n = 86 Axial spondyloarthritis, n = 70 Healthy controls, n = 70 P-valuea Maternal age at delivery, median (range), years 32 (22–44) 32 (23–41) 32 (20–41) 0.556 RF or ACPA positive, n (%)b 51 (59.3) HLA B-27, n (%)b 48 (68.6) SpA with peripheral arthritis, n (%)b 32 (45.7) Disease activity during pregnancyc     First trimester 2.3 2.5     Second trimester 2.4 2.4     Third trimester 2.3 2.2 Pregnancy 96 78 70     Twin pregnancy, n 4 2 0     Primigravidae, n (%)b 57 (66.3) 45 (64.3) 43 (61.4) 0.919 Pregnancy complications, n (%)d 11 (11.5) 14 (17.9) 1 (1.43) 0.002     Gestational diabetes 2 5 1     Preeclampsia 4 2 —     Infection 1 4 —     PPROM 4 3 — Delivery mode     Vaginal delivery, n (%)d 49 (51.0) 45 (57.8) 51 (72.9) 0.036     Caesarian section         Total, n (%) 43 (44.8) 31 (39.7) 19 (27.1) 0.036         Elective, n 21 14 9 0.267         Emergency, n 22 17 10 0.309         Unknown 4 2 — Infant     Live birth, n (%)e 99 (99.0) 79 (98.8) 70 (100)     Stillbirth/induced fetal demisef 1f 1 — Median birth weight (range), g 3100 (1250–4455) 3245 (1450–4740) 3460 (2620–4500) 0.000 Median birth weight percentile 32.4 (0.4–99.4) 38.2 (2.1–98.8) 72.5 (4.0–99.0) 0.193 SGA (<10th percentile), n (%)g 16 (16.2) 9 (11.4) 1 (1.4) 0.002 Preterm delivery, n (%)g 18 (18.2) 9 (11.4) 1 (1.4) 0.001 Congenital anomalies, n (%)e 3 (3.0) 3 (3.8) —     Hirschsprung disease 1 — —     Ventricular septal defect 1 — —     Unilateral kidney — 1 —     Down syndrome 1f 1 —     Di George Syndrome — 1 — a P-values were calculated using the Kruskal–Wallis test for continuous variables and Fisher’s exact test for categorical variables. b Percentage based on number of women in each group. c Median DAS28-CRP in patients with RA, median ASDAS in patients with axSpA. d Percentage based on number of pregnancies. e Percentage based on number of fetuses. f Induced fetal demise because of Down syndrome. g Percentage based on number of live births. Hirschsprung disease: Congenital aganglionic megacolon; PPROM: preterm premature rupture of membranes; SGA: small for gestational age. Table 1 Descriptive information on mothers, pregnancies, deliveries and infants Characteristics Rheumatoid arthritis, n = 86 Axial spondyloarthritis, n = 70 Healthy controls, n = 70 P-valuea Maternal age at delivery, median (range), years 32 (22–44) 32 (23–41) 32 (20–41) 0.556 RF or ACPA positive, n (%)b 51 (59.3) HLA B-27, n (%)b 48 (68.6) SpA with peripheral arthritis, n (%)b 32 (45.7) Disease activity during pregnancyc     First trimester 2.3 2.5     Second trimester 2.4 2.4     Third trimester 2.3 2.2 Pregnancy 96 78 70     Twin pregnancy, n 4 2 0     Primigravidae, n (%)b 57 (66.3) 45 (64.3) 43 (61.4) 0.919 Pregnancy complications, n (%)d 11 (11.5) 14 (17.9) 1 (1.43) 0.002     Gestational diabetes 2 5 1     Preeclampsia 4 2 —     Infection 1 4 —     PPROM 4 3 — Delivery mode     Vaginal delivery, n (%)d 49 (51.0) 45 (57.8) 51 (72.9) 0.036     Caesarian section         Total, n (%) 43 (44.8) 31 (39.7) 19 (27.1) 0.036         Elective, n 21 14 9 0.267         Emergency, n 22 17 10 0.309         Unknown 4 2 — Infant     Live birth, n (%)e 99 (99.0) 79 (98.8) 70 (100)     Stillbirth/induced fetal demisef 1f 1 — Median birth weight (range), g 3100 (1250–4455) 3245 (1450–4740) 3460 (2620–4500) 0.000 Median birth weight percentile 32.4 (0.4–99.4) 38.2 (2.1–98.8) 72.5 (4.0–99.0) 0.193 SGA (<10th percentile), n (%)g 16 (16.2) 9 (11.4) 1 (1.4) 0.002 Preterm delivery, n (%)g 18 (18.2) 9 (11.4) 1 (1.4) 0.001 Congenital anomalies, n (%)e 3 (3.0) 3 (3.8) —     Hirschsprung disease 1 — —     Ventricular septal defect 1 — —     Unilateral kidney — 1 —     Down syndrome 1f 1 —     Di George Syndrome — 1 — Characteristics Rheumatoid arthritis, n = 86 Axial spondyloarthritis, n = 70 Healthy controls, n = 70 P-valuea Maternal age at delivery, median (range), years 32 (22–44) 32 (23–41) 32 (20–41) 0.556 RF or ACPA positive, n (%)b 51 (59.3) HLA B-27, n (%)b 48 (68.6) SpA with peripheral arthritis, n (%)b 32 (45.7) Disease activity during pregnancyc     First trimester 2.3 2.5     Second trimester 2.4 2.4     Third trimester 2.3 2.2 Pregnancy 96 78 70     Twin pregnancy, n 4 2 0     Primigravidae, n (%)b 57 (66.3) 45 (64.3) 43 (61.4) 0.919 Pregnancy complications, n (%)d 11 (11.5) 14 (17.9) 1 (1.43) 0.002     Gestational diabetes 2 5 1     Preeclampsia 4 2 —     Infection 1 4 —     PPROM 4 3 — Delivery mode     Vaginal delivery, n (%)d 49 (51.0) 45 (57.8) 51 (72.9) 0.036     Caesarian section         Total, n (%) 43 (44.8) 31 (39.7) 19 (27.1) 0.036         Elective, n 21 14 9 0.267         Emergency, n 22 17 10 0.309         Unknown 4 2 — Infant     Live birth, n (%)e 99 (99.0) 79 (98.8) 70 (100)     Stillbirth/induced fetal demisef 1f 1 — Median birth weight (range), g 3100 (1250–4455) 3245 (1450–4740) 3460 (2620–4500) 0.000 Median birth weight percentile 32.4 (0.4–99.4) 38.2 (2.1–98.8) 72.5 (4.0–99.0) 0.193 SGA (<10th percentile), n (%)g 16 (16.2) 9 (11.4) 1 (1.4) 0.002 Preterm delivery, n (%)g 18 (18.2) 9 (11.4) 1 (1.4) 0.001 Congenital anomalies, n (%)e 3 (3.0) 3 (3.8) —     Hirschsprung disease 1 — —     Ventricular septal defect 1 — —     Unilateral kidney — 1 —     Down syndrome 1f 1 —     Di George Syndrome — 1 — a P-values were calculated using the Kruskal–Wallis test for continuous variables and Fisher’s exact test for categorical variables. b Percentage based on number of women in each group. c Median DAS28-CRP in patients with RA, median ASDAS in patients with axSpA. d Percentage based on number of pregnancies. e Percentage based on number of fetuses. f Induced fetal demise because of Down syndrome. g Percentage based on number of live births. Hirschsprung disease: Congenital aganglionic megacolon; PPROM: preterm premature rupture of membranes; SGA: small for gestational age. In patients with RA, the median disease activity scores as measured by the DAS28-CRP were below 3.2 in all trimesters. By contrast, women with axSpA showed persistent active disease throughout pregnancy reflected by median ASDAS-CRP scores higher than 2.1. Among RA patients, 82.3% were on anti-rheumatic drugs at any time point during pregnancy, the most common being DMARDs (42.7% on SSZ, 30.3% on a combination of SSZ and HCQ) and glucocorticoids (50% being on either prednisone or prednisolone). TNF inhibitor (TNFi) treatment at any time during pregnancy was used in 29.2% of all pregnancies of RA patients. Among axSpA patients, 75.6% were on anti-rheumatic drugs at any time point during pregnancy, the most common being TNFi (39.7%) and NSAIDs (46.2%). The percentage of drugs used at each trimester is displayed in Fig. 1. Fig. 1 View largeDownload slide Distribution of treatments during pregnancies Treatment during pregnancy in patients with RA (A) and axSpA (B). Bars show the percentages for each treatment mode by trimester. NSAID were used before gestational week 32; DMARDs were SSZ and HCQ. Fig. 1 View largeDownload slide Distribution of treatments during pregnancies Treatment during pregnancy in patients with RA (A) and axSpA (B). Bars show the percentages for each treatment mode by trimester. NSAID were used before gestational week 32; DMARDs were SSZ and HCQ. Effect of disease on pregnancy outcome Compared with HCs, pregnant women with RA and axSpA had a higher risk for pregnancy complications (gestational diabetes, preeclampsia, infection, preterm premature rupture of membranes), for small for gestational age infants and for preterm deliveries in both the univariate model and the multivariate model (all P < 0.05, Table 2). Table 2 Impact of RA and axSpA on adverse pregnancy outcome and caesarean section Outcome variables RA axSpA Crude OR (95% CI) Adjusted ORa (95% CI) Crude OR (95% CI) Adjusted ORa (95% CI) Prematurity 15.9* (2.07, 122.40) 14.3* (1.84, 111.25) 9.1* (1.13, 74.05) 8.4* (1.03, 69.18) SGA 13.8* (1.78, 106.75) 13.0* (1.67, 100.63) 9.0* (1.11, 72.97) 8.7* (1.07, 70.72) Pregnancy complicationsb 8.9* (1.13, 70.88) 9.5* (1.17, 77.36) 15.1* (1.93, 118.08) 16.4* (2.05, 131.53) C-section, total 2.4* (1.21, 4.59) 2.2* (1.14, 4.37) 1.8 (0.92, 3.72) 1.8 (0.89, 3.63) C-section, elective 2.0 (0.86, 4.70) 1.9 (0.82, 4.55) 1.5 (0.62, 3.80) 1.5 (0.60, 3.72) C-section, emergency 1.9 (0.83, 4.30) 1.8 (0.78, 4.10) 1.7 (0.73, 4.09) 1.7 (0.71, 4.01) Outcome variables RA axSpA Crude OR (95% CI) Adjusted ORa (95% CI) Crude OR (95% CI) Adjusted ORa (95% CI) Prematurity 15.9* (2.07, 122.40) 14.3* (1.84, 111.25) 9.1* (1.13, 74.05) 8.4* (1.03, 69.18) SGA 13.8* (1.78, 106.75) 13.0* (1.67, 100.63) 9.0* (1.11, 72.97) 8.7* (1.07, 70.72) Pregnancy complicationsb 8.9* (1.13, 70.88) 9.5* (1.17, 77.36) 15.1* (1.93, 118.08) 16.4* (2.05, 131.53) C-section, total 2.4* (1.21, 4.59) 2.2* (1.14, 4.37) 1.8 (0.92, 3.72) 1.8 (0.89, 3.63) C-section, elective 2.0 (0.86, 4.70) 1.9 (0.82, 4.55) 1.5 (0.62, 3.80) 1.5 (0.60, 3.72) C-section, emergency 1.9 (0.83, 4.30) 1.8 (0.78, 4.10) 1.7 (0.73, 4.09) 1.7 (0.71, 4.01) Crude and adjusted odds ratio (OR) of adverse pregnancy outcomes and caesarean section (C-section) in RA and axSpA compared with healthy controls. a Adjusted odds ratio for maternal age and gravidity. b Pregnancy complications: preeclampsia, gestational diabetes, infection, preterm premature rupture of membranes. * P < 0.05. SGA, small for gestational age. Table 2 Impact of RA and axSpA on adverse pregnancy outcome and caesarean section Outcome variables RA axSpA Crude OR (95% CI) Adjusted ORa (95% CI) Crude OR (95% CI) Adjusted ORa (95% CI) Prematurity 15.9* (2.07, 122.40) 14.3* (1.84, 111.25) 9.1* (1.13, 74.05) 8.4* (1.03, 69.18) SGA 13.8* (1.78, 106.75) 13.0* (1.67, 100.63) 9.0* (1.11, 72.97) 8.7* (1.07, 70.72) Pregnancy complicationsb 8.9* (1.13, 70.88) 9.5* (1.17, 77.36) 15.1* (1.93, 118.08) 16.4* (2.05, 131.53) C-section, total 2.4* (1.21, 4.59) 2.2* (1.14, 4.37) 1.8 (0.92, 3.72) 1.8 (0.89, 3.63) C-section, elective 2.0 (0.86, 4.70) 1.9 (0.82, 4.55) 1.5 (0.62, 3.80) 1.5 (0.60, 3.72) C-section, emergency 1.9 (0.83, 4.30) 1.8 (0.78, 4.10) 1.7 (0.73, 4.09) 1.7 (0.71, 4.01) Outcome variables RA axSpA Crude OR (95% CI) Adjusted ORa (95% CI) Crude OR (95% CI) Adjusted ORa (95% CI) Prematurity 15.9* (2.07, 122.40) 14.3* (1.84, 111.25) 9.1* (1.13, 74.05) 8.4* (1.03, 69.18) SGA 13.8* (1.78, 106.75) 13.0* (1.67, 100.63) 9.0* (1.11, 72.97) 8.7* (1.07, 70.72) Pregnancy complicationsb 8.9* (1.13, 70.88) 9.5* (1.17, 77.36) 15.1* (1.93, 118.08) 16.4* (2.05, 131.53) C-section, total 2.4* (1.21, 4.59) 2.2* (1.14, 4.37) 1.8 (0.92, 3.72) 1.8 (0.89, 3.63) C-section, elective 2.0 (0.86, 4.70) 1.9 (0.82, 4.55) 1.5 (0.62, 3.80) 1.5 (0.60, 3.72) C-section, emergency 1.9 (0.83, 4.30) 1.8 (0.78, 4.10) 1.7 (0.73, 4.09) 1.7 (0.71, 4.01) Crude and adjusted odds ratio (OR) of adverse pregnancy outcomes and caesarean section (C-section) in RA and axSpA compared with healthy controls. a Adjusted odds ratio for maternal age and gravidity. b Pregnancy complications: preeclampsia, gestational diabetes, infection, preterm premature rupture of membranes. * P < 0.05. SGA, small for gestational age. Compared with neonates born to healthy mothers, those born to women with RA showed a mean reduction in birth weight of 414.4 g (95% CI: −584.2, −244.6 g, P < 0.001) and those born to women with axSpA revealed a mean reduction in birth weight of 254.4 g (95% CI: −433.0, −75.8 g, P < 0.01). Congenital anomalies occurred in three infants of mothers with RA and in three infants of mothers with axSpA as displayed in Table 1. The medication used in these patients was hydroxychloroquine in one patient with RA, a combination of TNFi, glucocorticoids and SSZ in the second patient with RA, a combination of TNFi, glucocorticoids, SSZ and HCQ in the third patient with RA, a combination of TNFi and glucocorticoids in two women with axSpA, and NSAID in the third patient with axSpA. One foetal demise was induced in the case of one foetus of a twin pregnancy because of Down syndrome and multiple malformations. Delivery mode Compared with HCs, patients with RA were more likely to have a delivery by C-section (P = 0.024, Table 2), which was not seen in women with axSpA. Moreover, active disease and DMARD treatment were each predictive for delivery by C-section in patients with RA (P = 0.048 and P = 0.012, Table 3) in the unadjusted comparison, indicating that an insufficient control of disease activity might play a role in this context. After adjustment, only the latter association remained significant (P = 0.011). Table 3 Association of adverse pregnancy outcomes and C-section with RA Outcome and independent variables Crude OR (95% CI) Adjusted OR (95% CI) Preterm delivery     DAS28-CRP > 3.2 during pregnancy 3.6* (1.26, 10.46) 3.9* (1.25, 12.15)     Elevated CRP at 1 T 3.3 (0.53, 19.82) 3.8 (0.58, 25.20)     Elevated CRP at 2 T 2.9 (0.75, 11.12) 3.2 (0.80, 12.75)     Elevated CRP at 3 T 1.1 (0.27, 4.06) 1.0 (0.24, 3.98)     TNFi use during pregnancy 0.6 (0.19, 2.16) 0.7 (0.20, 2.51)     GC use during pregnancy 1.7 (0.61, 4.96) 1.9 (0.62, 5.54)     DMARD use during pregnancy 0.7 (0.26, 2.02) 0.7 (0.23, 2.00)     NSAIDs use during pregnancya 1.7 (0.48, 6.27) 1.8 (0.48, 6.97) Small for gestational age infants     DAS28-CRP > 3.2 during pregnancy 1.4 (0.46, 4.29) 1.3 (0.41, 4.05)     Elevated CRP at 1 T 0.9 (0.22, 3.79) 1.0 (0.23, 4.25)     Elevated CRP at 2 T 1.2 (0.36, 4.17) 1.2 (0.37, 4.61)     Elevated CRP at 3 T 1.1 (0.27, 4.06) 1.0 (0.24, 3.72)     TNFi use during pregnancy 2.2 (0.72, 6.61) 2.6 (0.81, 8.37)     GC use during pregnancy 1.8 (0.61, 5.55) 2.0 (0.63, 6.12)     DMARD use during pregnancy 1.8 (0.58, 5.28) 1.7 (0.56, 5.36)     NSAIDs use during pregnancya 3.2 (0.91, 11.08) 3.4 (0.92, 12.15) Pregnancy complicationsb     DAS28-CRP > 3.2 during pregnancy 0.5 (0.09, 2.24) 0.5 (0.11, 3.07)     Elevated CRP at 1 T 1.5 (0.27, 8.17) 6.3 (0.54, 72.80)     Elevated CRP at 2 T 2.2 (0.34, 14.10) 2.1 (0.31, 14.26)     Elevated CRP at 3 T 0.6 (0.15, 2.68) 0.7 (0.15, 3.10)     TNFi use during pregnancy 0.9 (0.22, 3.67) 1.0 (0.23, 4.51)     GC use during pregnancy 0.8 (0.2, 2.87) 0.9 (0.21, 3.43)     DMARD use during pregnancy 1.2 (0.33, 4.14) 1.1 (0.30, 4.29)     NSAIDs use during pregnancya 1.2 (0.24, 6.36) 1.5 (0.28, 8.20) C-section     DAS28-CRP > 3.2 during pregnancy 2.5* (1.01, 6.14) 2.2 (0.85, 5.90)     Elevated CRP at 1 T 1.6 (0.51, 5.18) 2.1 (0.60, 7.08)     Elevated CRP at 2 T 2.0 (0.72, 5.54) 2.4 (0.81, 7.17)     Elevated CRP at 3 T 2.0 (0.70, 5.52) 1.7 (0.59, 5.07)     TNFi use during pregnancy 0.5 (0.19, 1.28) 0.6 (0.20, 1.50)     GC use during pregnancy 2.2 (0.96, 5.11) 2.3 (0.94, 5.82)     DMARD use during pregnancy 3.0* (1.28, 7.06) 3.2* (1.26, 7.90)     NSAIDs use during pregnancya 2.7 (0.83, 8.55) 3.0 (0.86, 10.54) Outcome and independent variables Crude OR (95% CI) Adjusted OR (95% CI) Preterm delivery     DAS28-CRP > 3.2 during pregnancy 3.6* (1.26, 10.46) 3.9* (1.25, 12.15)     Elevated CRP at 1 T 3.3 (0.53, 19.82) 3.8 (0.58, 25.20)     Elevated CRP at 2 T 2.9 (0.75, 11.12) 3.2 (0.80, 12.75)     Elevated CRP at 3 T 1.1 (0.27, 4.06) 1.0 (0.24, 3.98)     TNFi use during pregnancy 0.6 (0.19, 2.16) 0.7 (0.20, 2.51)     GC use during pregnancy 1.7 (0.61, 4.96) 1.9 (0.62, 5.54)     DMARD use during pregnancy 0.7 (0.26, 2.02) 0.7 (0.23, 2.00)     NSAIDs use during pregnancya 1.7 (0.48, 6.27) 1.8 (0.48, 6.97) Small for gestational age infants     DAS28-CRP > 3.2 during pregnancy 1.4 (0.46, 4.29) 1.3 (0.41, 4.05)     Elevated CRP at 1 T 0.9 (0.22, 3.79) 1.0 (0.23, 4.25)     Elevated CRP at 2 T 1.2 (0.36, 4.17) 1.2 (0.37, 4.61)     Elevated CRP at 3 T 1.1 (0.27, 4.06) 1.0 (0.24, 3.72)     TNFi use during pregnancy 2.2 (0.72, 6.61) 2.6 (0.81, 8.37)     GC use during pregnancy 1.8 (0.61, 5.55) 2.0 (0.63, 6.12)     DMARD use during pregnancy 1.8 (0.58, 5.28) 1.7 (0.56, 5.36)     NSAIDs use during pregnancya 3.2 (0.91, 11.08) 3.4 (0.92, 12.15) Pregnancy complicationsb     DAS28-CRP > 3.2 during pregnancy 0.5 (0.09, 2.24) 0.5 (0.11, 3.07)     Elevated CRP at 1 T 1.5 (0.27, 8.17) 6.3 (0.54, 72.80)     Elevated CRP at 2 T 2.2 (0.34, 14.10) 2.1 (0.31, 14.26)     Elevated CRP at 3 T 0.6 (0.15, 2.68) 0.7 (0.15, 3.10)     TNFi use during pregnancy 0.9 (0.22, 3.67) 1.0 (0.23, 4.51)     GC use during pregnancy 0.8 (0.2, 2.87) 0.9 (0.21, 3.43)     DMARD use during pregnancy 1.2 (0.33, 4.14) 1.1 (0.30, 4.29)     NSAIDs use during pregnancya 1.2 (0.24, 6.36) 1.5 (0.28, 8.20) C-section     DAS28-CRP > 3.2 during pregnancy 2.5* (1.01, 6.14) 2.2 (0.85, 5.90)     Elevated CRP at 1 T 1.6 (0.51, 5.18) 2.1 (0.60, 7.08)     Elevated CRP at 2 T 2.0 (0.72, 5.54) 2.4 (0.81, 7.17)     Elevated CRP at 3 T 2.0 (0.70, 5.52) 1.7 (0.59, 5.07)     TNFi use during pregnancy 0.5 (0.19, 1.28) 0.6 (0.20, 1.50)     GC use during pregnancy 2.2 (0.96, 5.11) 2.3 (0.94, 5.82)     DMARD use during pregnancy 3.0* (1.28, 7.06) 3.2* (1.26, 7.90)     NSAIDs use during pregnancya 2.7 (0.83, 8.55) 3.0 (0.86, 10.54) Adjusted OR: adjusted for maternal age and gravidity. a NSAIDs used before gestational week 32. b Pregnancy complications: preeclampsia, gestational diabetes, infection, preterm premature rupture of membranes. * P < 0.05. T: trimester; TNFi: tumour necrosis factor inhibitor. Table 3 Association of adverse pregnancy outcomes and C-section with RA Outcome and independent variables Crude OR (95% CI) Adjusted OR (95% CI) Preterm delivery     DAS28-CRP > 3.2 during pregnancy 3.6* (1.26, 10.46) 3.9* (1.25, 12.15)     Elevated CRP at 1 T 3.3 (0.53, 19.82) 3.8 (0.58, 25.20)     Elevated CRP at 2 T 2.9 (0.75, 11.12) 3.2 (0.80, 12.75)     Elevated CRP at 3 T 1.1 (0.27, 4.06) 1.0 (0.24, 3.98)     TNFi use during pregnancy 0.6 (0.19, 2.16) 0.7 (0.20, 2.51)     GC use during pregnancy 1.7 (0.61, 4.96) 1.9 (0.62, 5.54)     DMARD use during pregnancy 0.7 (0.26, 2.02) 0.7 (0.23, 2.00)     NSAIDs use during pregnancya 1.7 (0.48, 6.27) 1.8 (0.48, 6.97) Small for gestational age infants     DAS28-CRP > 3.2 during pregnancy 1.4 (0.46, 4.29) 1.3 (0.41, 4.05)     Elevated CRP at 1 T 0.9 (0.22, 3.79) 1.0 (0.23, 4.25)     Elevated CRP at 2 T 1.2 (0.36, 4.17) 1.2 (0.37, 4.61)     Elevated CRP at 3 T 1.1 (0.27, 4.06) 1.0 (0.24, 3.72)     TNFi use during pregnancy 2.2 (0.72, 6.61) 2.6 (0.81, 8.37)     GC use during pregnancy 1.8 (0.61, 5.55) 2.0 (0.63, 6.12)     DMARD use during pregnancy 1.8 (0.58, 5.28) 1.7 (0.56, 5.36)     NSAIDs use during pregnancya 3.2 (0.91, 11.08) 3.4 (0.92, 12.15) Pregnancy complicationsb     DAS28-CRP > 3.2 during pregnancy 0.5 (0.09, 2.24) 0.5 (0.11, 3.07)     Elevated CRP at 1 T 1.5 (0.27, 8.17) 6.3 (0.54, 72.80)     Elevated CRP at 2 T 2.2 (0.34, 14.10) 2.1 (0.31, 14.26)     Elevated CRP at 3 T 0.6 (0.15, 2.68) 0.7 (0.15, 3.10)     TNFi use during pregnancy 0.9 (0.22, 3.67) 1.0 (0.23, 4.51)     GC use during pregnancy 0.8 (0.2, 2.87) 0.9 (0.21, 3.43)     DMARD use during pregnancy 1.2 (0.33, 4.14) 1.1 (0.30, 4.29)     NSAIDs use during pregnancya 1.2 (0.24, 6.36) 1.5 (0.28, 8.20) C-section     DAS28-CRP > 3.2 during pregnancy 2.5* (1.01, 6.14) 2.2 (0.85, 5.90)     Elevated CRP at 1 T 1.6 (0.51, 5.18) 2.1 (0.60, 7.08)     Elevated CRP at 2 T 2.0 (0.72, 5.54) 2.4 (0.81, 7.17)     Elevated CRP at 3 T 2.0 (0.70, 5.52) 1.7 (0.59, 5.07)     TNFi use during pregnancy 0.5 (0.19, 1.28) 0.6 (0.20, 1.50)     GC use during pregnancy 2.2 (0.96, 5.11) 2.3 (0.94, 5.82)     DMARD use during pregnancy 3.0* (1.28, 7.06) 3.2* (1.26, 7.90)     NSAIDs use during pregnancya 2.7 (0.83, 8.55) 3.0 (0.86, 10.54) Outcome and independent variables Crude OR (95% CI) Adjusted OR (95% CI) Preterm delivery     DAS28-CRP > 3.2 during pregnancy 3.6* (1.26, 10.46) 3.9* (1.25, 12.15)     Elevated CRP at 1 T 3.3 (0.53, 19.82) 3.8 (0.58, 25.20)     Elevated CRP at 2 T 2.9 (0.75, 11.12) 3.2 (0.80, 12.75)     Elevated CRP at 3 T 1.1 (0.27, 4.06) 1.0 (0.24, 3.98)     TNFi use during pregnancy 0.6 (0.19, 2.16) 0.7 (0.20, 2.51)     GC use during pregnancy 1.7 (0.61, 4.96) 1.9 (0.62, 5.54)     DMARD use during pregnancy 0.7 (0.26, 2.02) 0.7 (0.23, 2.00)     NSAIDs use during pregnancya 1.7 (0.48, 6.27) 1.8 (0.48, 6.97) Small for gestational age infants     DAS28-CRP > 3.2 during pregnancy 1.4 (0.46, 4.29) 1.3 (0.41, 4.05)     Elevated CRP at 1 T 0.9 (0.22, 3.79) 1.0 (0.23, 4.25)     Elevated CRP at 2 T 1.2 (0.36, 4.17) 1.2 (0.37, 4.61)     Elevated CRP at 3 T 1.1 (0.27, 4.06) 1.0 (0.24, 3.72)     TNFi use during pregnancy 2.2 (0.72, 6.61) 2.6 (0.81, 8.37)     GC use during pregnancy 1.8 (0.61, 5.55) 2.0 (0.63, 6.12)     DMARD use during pregnancy 1.8 (0.58, 5.28) 1.7 (0.56, 5.36)     NSAIDs use during pregnancya 3.2 (0.91, 11.08) 3.4 (0.92, 12.15) Pregnancy complicationsb     DAS28-CRP > 3.2 during pregnancy 0.5 (0.09, 2.24) 0.5 (0.11, 3.07)     Elevated CRP at 1 T 1.5 (0.27, 8.17) 6.3 (0.54, 72.80)     Elevated CRP at 2 T 2.2 (0.34, 14.10) 2.1 (0.31, 14.26)     Elevated CRP at 3 T 0.6 (0.15, 2.68) 0.7 (0.15, 3.10)     TNFi use during pregnancy 0.9 (0.22, 3.67) 1.0 (0.23, 4.51)     GC use during pregnancy 0.8 (0.2, 2.87) 0.9 (0.21, 3.43)     DMARD use during pregnancy 1.2 (0.33, 4.14) 1.1 (0.30, 4.29)     NSAIDs use during pregnancya 1.2 (0.24, 6.36) 1.5 (0.28, 8.20) C-section     DAS28-CRP > 3.2 during pregnancy 2.5* (1.01, 6.14) 2.2 (0.85, 5.90)     Elevated CRP at 1 T 1.6 (0.51, 5.18) 2.1 (0.60, 7.08)     Elevated CRP at 2 T 2.0 (0.72, 5.54) 2.4 (0.81, 7.17)     Elevated CRP at 3 T 2.0 (0.70, 5.52) 1.7 (0.59, 5.07)     TNFi use during pregnancy 0.5 (0.19, 1.28) 0.6 (0.20, 1.50)     GC use during pregnancy 2.2 (0.96, 5.11) 2.3 (0.94, 5.82)     DMARD use during pregnancy 3.0* (1.28, 7.06) 3.2* (1.26, 7.90)     NSAIDs use during pregnancya 2.7 (0.83, 8.55) 3.0 (0.86, 10.54) Adjusted OR: adjusted for maternal age and gravidity. a NSAIDs used before gestational week 32. b Pregnancy complications: preeclampsia, gestational diabetes, infection, preterm premature rupture of membranes. * P < 0.05. T: trimester; TNFi: tumour necrosis factor inhibitor. Effect of disease activity and anti-rheumatic drugs Next the influence of disease-specific aspects and of anti-rheumatic drugs on adverse pregnancy outcome was analysed. The percentage of patients showing active disease any time during pregnancy was 31.3% for women with RA (defined as DAS28-CRP > 3.2). Active RA at any trimester during pregnancy was significantly predictive for preterm delivery (P = 019, Table 3). In axSpA, active disease (defined as ASDAS-CRP > 2.1) occurred in 78.3% of the patients during the course of pregnancy, yet was most prevalent at the second trimester. Among women with axSpA, 44% had elevated CRP levels around gestational week 20, which were related to increased disease activity in all cases. In the regression model, an elevated CRP level at the second trimester was significantly predictive for preterm delivery (P = 0.028; Table 4). Table 4 Association of adverse pregnancy outcome and C-section with axial SpA Outcome and independent variables Crude OR (95% CI) Adjusted OR (95% CI) Preterm delivery     ASDAS > 2.1 during pregnancy 0.8 (0.20, 3.34) 1.0 (0.22, 4.76)     Elevated CRP at 1 T 2.2 (0.32, 15.00) 2.4 (0.30, 20.01)     Elevated CRP at 2 T 10.8* (1.19, 98.36) 13.8* (1.33, 143.94)     Elevated CRP at 3 T 1.3 (0.27, 5.63) 0.9 (0.16, 5.27)     TNFi use during pregnancy 3.4 (0.79, 14.98) 4.5 (0.90¸ 22.51)     GC use during pregnancy 0.9 (0.18, 4.93) 1.8 (0.28, 11.32)     DMARD use during pregnancy 2.5 (0.43, 14.41) 2.4 (0.31, 17.82)     NSAIDs use during pregnancya 0.6 (0.13, 2.44) 0.5 (0.10, 2.82) Small for gestational age infants     ASDAS > 2.1 during pregnancy 0.8 (0.20, 3.26) 0.8 (0.17, 3.53)     Elevated CRP at 1 T 0.3 (0.03, 2.82) 0.4 (0.03, 3.93)     Elevated CRP at 2 T 1.9 (0.37, 9.31) 2.1 (0.38, 11.10)     Elevated CRP at 3 T 1.7 (0.35, 8.64) 1.7 (0.32, 9.04)     TNFi use during pregnancy 1.2 (0.31, 5.05) 1.3 (0.30, 5.60)     GC use during pregnancy 0.9 (0.18, 5.02) 0.9 (0.15, 4.82)     DMARD use during pregnancy NA NA     NSAIDs use during pregnancya 1.5 (0.38, 6.20) 2.4 (0.53, 10.61) Pregnancy complicationsb     ASDAS > 2.1 during pregnancy 0.9 (0.27, 2.76) 1.0 (0.27, 3.66)     Elevated CRP at 1 T 1.0 (0.19, 5.17) 0.6 (0.08, 4.37)     Elevated CRP at 2 T 2.5 (0.52, 11.64) 2.7 (0.45, 15.93)     Elevated CRP at 3 T 0.8 (0.19, 3.11) 0.8 (0.18, 3.19)     TNFi use during pregnancy 3.4* (1.03, 11.51) 3.5 (1.00, 12.12)     GC use during pregnancy 1.4 (0.38, 5.25) 1.8 (0.43, 7.59)     DMARD use during pregnancy 1.4 (0.25, 7.36) 2.6 (0.40, 16.87)     NSAIDs use during pregnancya 1.7 (0.53, 5.51) 1.4 (0.37, 5.33) C-section     ASDAS > 2.1 during pregnancy 0.8 (0.33, 2.14) 1.2 (0.43, 3.43)     Elevated CRP at 1 T 2.0 (0.53, 7.60) 2.0 (0.42, 9.82)     Elevated CRP at 2 T 1.5 (0.50, 4.78) 1.5 (0.44, 5.34)     Elevated CRP at 3 T 1.1 (0.36, 3.35) 1.1 (0.35, 3.75)     TNFi use during pregnancy 0.9 (0.34, 2.20) 0.9 (0.31, 2.40)     GC use during pregnancy 1.2 (0.42, 3.54) 1.7 (0.54, 5.58)     DMARD use during pregnancy 1.5 (0.35, 6.60) 1.2 (0.22¸ 6.39)     NSAIDs use during pregnancya 0.8 (0.30, 1.90) 0.8 (0.27, 2.27) Outcome and independent variables Crude OR (95% CI) Adjusted OR (95% CI) Preterm delivery     ASDAS > 2.1 during pregnancy 0.8 (0.20, 3.34) 1.0 (0.22, 4.76)     Elevated CRP at 1 T 2.2 (0.32, 15.00) 2.4 (0.30, 20.01)     Elevated CRP at 2 T 10.8* (1.19, 98.36) 13.8* (1.33, 143.94)     Elevated CRP at 3 T 1.3 (0.27, 5.63) 0.9 (0.16, 5.27)     TNFi use during pregnancy 3.4 (0.79, 14.98) 4.5 (0.90¸ 22.51)     GC use during pregnancy 0.9 (0.18, 4.93) 1.8 (0.28, 11.32)     DMARD use during pregnancy 2.5 (0.43, 14.41) 2.4 (0.31, 17.82)     NSAIDs use during pregnancya 0.6 (0.13, 2.44) 0.5 (0.10, 2.82) Small for gestational age infants     ASDAS > 2.1 during pregnancy 0.8 (0.20, 3.26) 0.8 (0.17, 3.53)     Elevated CRP at 1 T 0.3 (0.03, 2.82) 0.4 (0.03, 3.93)     Elevated CRP at 2 T 1.9 (0.37, 9.31) 2.1 (0.38, 11.10)     Elevated CRP at 3 T 1.7 (0.35, 8.64) 1.7 (0.32, 9.04)     TNFi use during pregnancy 1.2 (0.31, 5.05) 1.3 (0.30, 5.60)     GC use during pregnancy 0.9 (0.18, 5.02) 0.9 (0.15, 4.82)     DMARD use during pregnancy NA NA     NSAIDs use during pregnancya 1.5 (0.38, 6.20) 2.4 (0.53, 10.61) Pregnancy complicationsb     ASDAS > 2.1 during pregnancy 0.9 (0.27, 2.76) 1.0 (0.27, 3.66)     Elevated CRP at 1 T 1.0 (0.19, 5.17) 0.6 (0.08, 4.37)     Elevated CRP at 2 T 2.5 (0.52, 11.64) 2.7 (0.45, 15.93)     Elevated CRP at 3 T 0.8 (0.19, 3.11) 0.8 (0.18, 3.19)     TNFi use during pregnancy 3.4* (1.03, 11.51) 3.5 (1.00, 12.12)     GC use during pregnancy 1.4 (0.38, 5.25) 1.8 (0.43, 7.59)     DMARD use during pregnancy 1.4 (0.25, 7.36) 2.6 (0.40, 16.87)     NSAIDs use during pregnancya 1.7 (0.53, 5.51) 1.4 (0.37, 5.33) C-section     ASDAS > 2.1 during pregnancy 0.8 (0.33, 2.14) 1.2 (0.43, 3.43)     Elevated CRP at 1 T 2.0 (0.53, 7.60) 2.0 (0.42, 9.82)     Elevated CRP at 2 T 1.5 (0.50, 4.78) 1.5 (0.44, 5.34)     Elevated CRP at 3 T 1.1 (0.36, 3.35) 1.1 (0.35, 3.75)     TNFi use during pregnancy 0.9 (0.34, 2.20) 0.9 (0.31, 2.40)     GC use during pregnancy 1.2 (0.42, 3.54) 1.7 (0.54, 5.58)     DMARD use during pregnancy 1.5 (0.35, 6.60) 1.2 (0.22¸ 6.39)     NSAIDs use during pregnancya 0.8 (0.30, 1.90) 0.8 (0.27, 2.27) Adjusted odds ratio for maternal age and gravidity. a NSAIDs used before gestational week 32. b Pregnancy complications: preeclampsia, gestational diabetes, infection, preterm premature rupture of membranes. * P < 0.05. T: trimester; NA: not applicable. Table 4 Association of adverse pregnancy outcome and C-section with axial SpA Outcome and independent variables Crude OR (95% CI) Adjusted OR (95% CI) Preterm delivery     ASDAS > 2.1 during pregnancy 0.8 (0.20, 3.34) 1.0 (0.22, 4.76)     Elevated CRP at 1 T 2.2 (0.32, 15.00) 2.4 (0.30, 20.01)     Elevated CRP at 2 T 10.8* (1.19, 98.36) 13.8* (1.33, 143.94)     Elevated CRP at 3 T 1.3 (0.27, 5.63) 0.9 (0.16, 5.27)     TNFi use during pregnancy 3.4 (0.79, 14.98) 4.5 (0.90¸ 22.51)     GC use during pregnancy 0.9 (0.18, 4.93) 1.8 (0.28, 11.32)     DMARD use during pregnancy 2.5 (0.43, 14.41) 2.4 (0.31, 17.82)     NSAIDs use during pregnancya 0.6 (0.13, 2.44) 0.5 (0.10, 2.82) Small for gestational age infants     ASDAS > 2.1 during pregnancy 0.8 (0.20, 3.26) 0.8 (0.17, 3.53)     Elevated CRP at 1 T 0.3 (0.03, 2.82) 0.4 (0.03, 3.93)     Elevated CRP at 2 T 1.9 (0.37, 9.31) 2.1 (0.38, 11.10)     Elevated CRP at 3 T 1.7 (0.35, 8.64) 1.7 (0.32, 9.04)     TNFi use during pregnancy 1.2 (0.31, 5.05) 1.3 (0.30, 5.60)     GC use during pregnancy 0.9 (0.18, 5.02) 0.9 (0.15, 4.82)     DMARD use during pregnancy NA NA     NSAIDs use during pregnancya 1.5 (0.38, 6.20) 2.4 (0.53, 10.61) Pregnancy complicationsb     ASDAS > 2.1 during pregnancy 0.9 (0.27, 2.76) 1.0 (0.27, 3.66)     Elevated CRP at 1 T 1.0 (0.19, 5.17) 0.6 (0.08, 4.37)     Elevated CRP at 2 T 2.5 (0.52, 11.64) 2.7 (0.45, 15.93)     Elevated CRP at 3 T 0.8 (0.19, 3.11) 0.8 (0.18, 3.19)     TNFi use during pregnancy 3.4* (1.03, 11.51) 3.5 (1.00, 12.12)     GC use during pregnancy 1.4 (0.38, 5.25) 1.8 (0.43, 7.59)     DMARD use during pregnancy 1.4 (0.25, 7.36) 2.6 (0.40, 16.87)     NSAIDs use during pregnancya 1.7 (0.53, 5.51) 1.4 (0.37, 5.33) C-section     ASDAS > 2.1 during pregnancy 0.8 (0.33, 2.14) 1.2 (0.43, 3.43)     Elevated CRP at 1 T 2.0 (0.53, 7.60) 2.0 (0.42, 9.82)     Elevated CRP at 2 T 1.5 (0.50, 4.78) 1.5 (0.44, 5.34)     Elevated CRP at 3 T 1.1 (0.36, 3.35) 1.1 (0.35, 3.75)     TNFi use during pregnancy 0.9 (0.34, 2.20) 0.9 (0.31, 2.40)     GC use during pregnancy 1.2 (0.42, 3.54) 1.7 (0.54, 5.58)     DMARD use during pregnancy 1.5 (0.35, 6.60) 1.2 (0.22¸ 6.39)     NSAIDs use during pregnancya 0.8 (0.30, 1.90) 0.8 (0.27, 2.27) Outcome and independent variables Crude OR (95% CI) Adjusted OR (95% CI) Preterm delivery     ASDAS > 2.1 during pregnancy 0.8 (0.20, 3.34) 1.0 (0.22, 4.76)     Elevated CRP at 1 T 2.2 (0.32, 15.00) 2.4 (0.30, 20.01)     Elevated CRP at 2 T 10.8* (1.19, 98.36) 13.8* (1.33, 143.94)     Elevated CRP at 3 T 1.3 (0.27, 5.63) 0.9 (0.16, 5.27)     TNFi use during pregnancy 3.4 (0.79, 14.98) 4.5 (0.90¸ 22.51)     GC use during pregnancy 0.9 (0.18, 4.93) 1.8 (0.28, 11.32)     DMARD use during pregnancy 2.5 (0.43, 14.41) 2.4 (0.31, 17.82)     NSAIDs use during pregnancya 0.6 (0.13, 2.44) 0.5 (0.10, 2.82) Small for gestational age infants     ASDAS > 2.1 during pregnancy 0.8 (0.20, 3.26) 0.8 (0.17, 3.53)     Elevated CRP at 1 T 0.3 (0.03, 2.82) 0.4 (0.03, 3.93)     Elevated CRP at 2 T 1.9 (0.37, 9.31) 2.1 (0.38, 11.10)     Elevated CRP at 3 T 1.7 (0.35, 8.64) 1.7 (0.32, 9.04)     TNFi use during pregnancy 1.2 (0.31, 5.05) 1.3 (0.30, 5.60)     GC use during pregnancy 0.9 (0.18, 5.02) 0.9 (0.15, 4.82)     DMARD use during pregnancy NA NA     NSAIDs use during pregnancya 1.5 (0.38, 6.20) 2.4 (0.53, 10.61) Pregnancy complicationsb     ASDAS > 2.1 during pregnancy 0.9 (0.27, 2.76) 1.0 (0.27, 3.66)     Elevated CRP at 1 T 1.0 (0.19, 5.17) 0.6 (0.08, 4.37)     Elevated CRP at 2 T 2.5 (0.52, 11.64) 2.7 (0.45, 15.93)     Elevated CRP at 3 T 0.8 (0.19, 3.11) 0.8 (0.18, 3.19)     TNFi use during pregnancy 3.4* (1.03, 11.51) 3.5 (1.00, 12.12)     GC use during pregnancy 1.4 (0.38, 5.25) 1.8 (0.43, 7.59)     DMARD use during pregnancy 1.4 (0.25, 7.36) 2.6 (0.40, 16.87)     NSAIDs use during pregnancya 1.7 (0.53, 5.51) 1.4 (0.37, 5.33) C-section     ASDAS > 2.1 during pregnancy 0.8 (0.33, 2.14) 1.2 (0.43, 3.43)     Elevated CRP at 1 T 2.0 (0.53, 7.60) 2.0 (0.42, 9.82)     Elevated CRP at 2 T 1.5 (0.50, 4.78) 1.5 (0.44, 5.34)     Elevated CRP at 3 T 1.1 (0.36, 3.35) 1.1 (0.35, 3.75)     TNFi use during pregnancy 0.9 (0.34, 2.20) 0.9 (0.31, 2.40)     GC use during pregnancy 1.2 (0.42, 3.54) 1.7 (0.54, 5.58)     DMARD use during pregnancy 1.5 (0.35, 6.60) 1.2 (0.22¸ 6.39)     NSAIDs use during pregnancya 0.8 (0.30, 1.90) 0.8 (0.27, 2.27) Adjusted odds ratio for maternal age and gravidity. a NSAIDs used before gestational week 32. b Pregnancy complications: preeclampsia, gestational diabetes, infection, preterm premature rupture of membranes. * P < 0.05. T: trimester; NA: not applicable. Regarding anti-rheumatic therapy, the univariate regression analysis revealed that patients with axSpA who were treated with TNFi any time during pregnancy were more likely to experience pregnancy complications than patients without TNFi treatment. The following pregnancy complications were observed in these patients: one had gestational diabetes, two developed preeclampsia, four had infections (two vaginal infections with preterm premature rupture of membranes, two upper respiratory tract infections; none had corticosteroids at the time of infection). The association of TNFi use in women with axSpA and pregnancy complications was attenuated in the multivariate model adjusted for age and gravidity (Tables 3 and 4). Additional analysis We further conducted a sensitivity analysis, limiting the analysis to 92 singleton pregnancies in patients with RA and to 76 singleton pregnancies in patients with axSpA. Most point estimates were similar to in the main analysis when comparing pregnancy outcome and C-section rate in RA and axSpA with those of HCs and when analysing the influence of disease activity on preterm delivery (supplementary Tables S1–S3, available at Rheumatology online). Discussion In this study, we showed that RA and axSpA are associated with adverse pregnancy outcomes. Active disease was a risk factor for preterm delivery not only in RA but also in axSpA. So far, disease activity as a risk factor for preterm delivery has been previously described in women with RA [8], but it has not been identified in prospectively studied patients with axSpA. Of the axSpA patients, 78% experienced active disease during the course of pregnancy as determined by objective and disease-specific measures of disease activity. However, as with all disease activity measures in pregnancy, no validation has been performed in pregnant patients, and so a certain bias by pregnancy itself cannot be fully excluded. Other prospective studies analysing disease activity in pregnant patients with AS using different measures showed active disease during pregnancy in 62–80% of the women [3–5]. In our study population, active disease and elevated CRP levels occurred most often at the second trimester. The second trimester visit was performed at gestational week 20, a known phase of increased inflammatory back pain and morning stiffness in pregnant patients with AS [4]. By contrast, pregnancy-related back pain is usually seen at the third trimester in healthy pregnant women [21, 22]. Remarkably, the subgroup of patients at risk for preterm delivery could not be identified using ASDAS values but could by increased CRP levels. ASDAS is a composite index combining four subjective clinical variables and the natural logarithm of the CRP. An elevated CRP level is a direct sign known to correlate with more severe disease and with active axial joint inflammation in patients with axSpA [23–25]. Our data indicate that elevated CRP levels may also qualify to predict premature delivery in pregnant women with axSpA. In addition, our patients with axSpA were at risk for having pregnancy complications and offspring that are SGA compared with healthy women. This is in line with an increased risk for prematurity and SGA seen in a large Swedish population-based case-control study in women with AS [13]. In this registry study, no disease activity measures were used and information about medication was obtained by drug dispensation 12 months prior to delivery only. The authors presumed a possible association between SGA offspring and maternal disease severity, since the risk for SGA increased with more extensive drug dispensation [13]. A former retrospective study using a standardized questionnaire did not show increased risks of adverse pregnancy outcome [12]. Differences in study design are likely to have contributed to these opposed findings. Among our patients with RA one-third had active disease during pregnancy. This proportion is comparable to that of the prospective Organization of Teratology Information Specialists (OTIS) study [8] whereas in the prospective Pregnancy-induced Amelioration of Rheumatoid Arthritis (PARA) study, half of the patients with RA experienced active disease during pregnancy [26]. Differences in the treatment intensity during pregnancy might account for the discrepant proportion of patients with active disease since TNFi were used in about 30% of our patients and 67% of the OTIS patients but not in those of the PARA study. In our patients with RA, active disease was predictive for preterm delivery. In addition, RA was associated with pregnancy complications and offspring being SGA. Our results are in line with those of the OTIS study showing an association of preterm delivery and SGA with more severe disease [8]. However, in the PARA study, disease activity was associated with lower birthweight but prednisone treatment was related to preterm delivery [7]. In our cohort, no association between any use of prednisone and preterm delivery was found. Dosing could play a role since prednisone use above 10 mg any time during pregnancy was an independent predictor for preterm delivery in the OTIS study, but did not modify the association between disease severity and preterm delivery [8]. Regarding delivery mode, most women with RA and axSpA had vaginal deliveries. However, there was an increased risk of C-section in women with RA compared with HCs. Disease activity and DMARD use were associated with C-section in patients with RA. This implies that an insufficient control of disease activity results in C-section. Accordingly, an increased risk for C-section in patients with RA has been described by others comparing RA versus controls or analysing the subgroup of patients with more severe disease [8, 14, 27]. Interestingly, our patients with axSpA did not show an increased risk of C-section compared with healthy women, despite the fact that most had active disease. This contrasts with previous studies that reported a higher risk for C-section compared with reference subjects [13, 14]. Cases with more extensive anti-rheumatic therapy tended to have a higher risk for elective C-section in the Swedish registry study [13]. Differences in the C-section rates in the absence of foetal problems or pregnancy-related complications might depend on several factors such as disease severity, the wish of the patient and the judgement of the obstetrician. Among our patients, the frequency of TNFi treatment during pregnancy was higher in women with axSpA than in women with RA. In patients with axSpA, TNFi use was associated with pregnancy complications such as infections, gestational diabetes and preeclampsia in the univariate analysis but not in the adjusted model. Prednisone, which has been identified as a risk factor for serious infections in pregnancy, was not used as a co-medication in any of these patients around the time of infection [28]. Data from a recent meta-analysis comparing pregnancy outcome between TNFi users versus non-users confirm that TNFi do not increase the rates of pregnancy-related complications [10]. Our study is limited in the number of patients and in the number of outcome events, which did not allow for a model with more extensive adjustments. A strength of this study was the analysis of pregnancy outcome not only by disease status but also by disease activity. In summary, our results showed that patients with RA and axSpA were at risk of poor pregnancy outcome. The comparison between both diseases revealed that maternal disease activity was an overarching predictor for preterm delivery. Targeting inactive disease in pregnant patients is important to allow for successful pregnancy and to impede disease progression. Based on a risk–benefit analysis and on a process of shared decision-making with the patient, an effective treatment with pregnancy-compatible drugs [9, 29] should be continued beyond conception. Acknowledgements We would like to thank Dr Lukas Bütikofer from the Clinical Trial Unit Bern for his statistical consulting. Funding: No specific funding was received from any bodies in the public, commercial or not-for-profit sectors to carry out the work described in this manuscript. Disclosure statement: F.F. has received an unrestricted grant from UCB Pharma. All other authors have declared no conflicts of interest. Supplementary data Supplementary data are available at Rheumatology online. References 1 de Man YA , Dolhain RJ , van de Geijn FE , Willemsen SP , Hazes JM. Disease activity of rheumatoid arthritis during pregnancy: results from a nationwide prospective study . Arthritis Rheum 2008 ; 59 : 1241 – 8 . 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BMJ 2017 ; 356 : j895 . Google Scholar CrossRef Search ADS PubMed 29 Forger F , Villiger PM. Treatment of rheumatoid arthritis during pregnancy: present and future . Expert Rev Clin Immunol 2016 ; 12 : 937 – 44 . Google Scholar CrossRef Search ADS PubMed © The Author(s) 2018. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oup.com This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices)

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RheumatologyOxford University Press

Published: Mar 30, 2018

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