Women with systemic lupus erythematosus get pregnant more easily than women with rheumatoid arthritis

Women with systemic lupus erythematosus get pregnant more easily than women with rheumatoid... Abstract Objectives To examine possible differences in the ability to get pregnant and time to pregnancy (TTP) in women with SLE and RA, and to study possible influencing factors. Methods Data from RevNatus, a Norwegian nationwide prospective observational register including women with inflammatory rheumatic diseases when planning pregnancy or after conception, was used. We compared rate of achieved pregnancy, the pregnancy outcomes live birth or pregnancy loss, and TTP between women with SLE (n = 53) and women with RA (n = 180). TTP was compared between the groups using Kaplan-Meier plots, and Cox proportional hazard regression was performed adjusting for maternal age, parity and medication use. RAND-36 was used to assess health-related quality of life (HRQoL) in women achieving and not achieving pregnancy. Results Women with SLE had a pregnancy ratio of 1.91 (95% CI: 1.27, 2.88, P = 0.002) compared with women with RA, and a substantially shorter median TTP (3.0 vs 7.0 months, P = 0.001). Higher maternal age, medication use and low HRQoL in the physical domains may influence the ability to achieve pregnancy and prolong TTP in women with RA. Women with SLE not achieving pregnancy had lower HRQoL scores than SLE-women achieving pregnancy, while women with RA had generally low scores in physical domains whether or not achieving pregnancy, indicating poor HRQoL. Conclusions In the studied cohort, women with SLE got pregnant more easily than women with RA. SLE, RA, fertility, family planning, health-related quality of life Rheumatology key messages Women with SLE more often succeed in achieving pregnancy than women with RA. Women with SLE have a shorter time to pregnancy than women with RA. Health-related quality of life in SLE and RA influence the ability to achieve pregnancy. Introduction Fertility is the capacity to establish a clinical pregnancy, while fecundity is the capacity to have a live birth [1]. Total fertility rate (TFR) is defined as the average number of live births per woman [1]. Female fertility and fecundity may be compromised, resulting in increased time to establish pregnancy (TTP) and reduced TFR [2]. The TFR in Norway has gradually declined from 3 children in 1964 to 1.7 in 2015 [3]. SLE and RA are autoinflammatory, systemic rheumatic diseases affecting fertile women. SLE typically leads to manifestations of skin, joints and internal organs [4], and has a more serious prognosis compared with RA, which classically is more often limited to the musculoskeletal system [5]. Previous studies have shown that women with SLE and RA have lower TFR than the general obstetric population, although there has been an increasing number of children born to mothers with rheumatic diseases during recent decades [6, 7]. Subfertility is defined as TTP >1 year, and has increased in Norwegian women [8]. A higher subfertility occurrence of 36–42% in RA-women [9–11] is perceived to be the main cause of reduced TFR in this group, although lower fecundity may also play a role [12]. In women with SLE, compromised fecundity is considered the main reason for reduced TFR [13], even though severe and active disease as well as medication use are also associated with reduced fertility [14, 15]. Studies comparing fertility, fecundity, TFR and influencing factors between SLE and RA patients are rare, although extended data should be of importance to patients as well as treating physicians. In women with chronic rheumatic diseases the disease itself, the treatment and fear of complications may lower TFR [10, 14, 16–19] due to ovulatory disturbances [9], reduced ovarian reserve [20–23] and impaired sexual function caused by decreased health-related quality of life (HRQoL) [18, 24, 25]. Previous findings indicate lower HRQoL in rheumatic diseases compared with population controls [26, 27], and in RA especially in the physical domains [28]. Acquiring a chronic disease while of reproductive age may influence family planning. Clowse et al. [10] found that women with SLE and RA reported fewer children than wished for, and that personal choice was one of the reasons. The objective of this study was to examine possible differences in the ability to achieve pregnancy and TTP among women with SLE and RA, and to study possible influencing factors including HRQoL. Methods Study population The study population was retrieved from RevNatus, a nationwide Norwegian multicentre, prospective observational register including women with inflammatory rheumatic diseases when planning pregnancy or after conception. The register was established in 2006, and all but two departments of rheumatology contribute with eligible patients. According to national guidelines [29], pregnant women with rheumatic diseases should have follow-up by a specialist in rheumatology. Women ⩾18 years of age are recruited and followed-up in each trimester of pregnancy and at 6 weeks, 6 and 12 months after birth. Disease characteristics, disease activity, HRQoL, use of medications, outcomes and complications in mother and child are recorded. Studied women were included before pregnancy and had follow-up during pregnancy and 6 weeks after birth or pregnancy loss, or at 1 year if not achieving pregnancy (NAP). They were included in the period 2006–16. Ethics The RevNatus register was approved by the regional committee for medical and health research ethics (REC Central) in 2006. Eligible women signed written informed consent before inclusion in the register. The present study has been approved by REC Central (2012/1905). Variables Background variables were obtained from data collected at the preconception visit and included background and disease-specific characteristics, medication use, HRQoL variables and information on earlier pregnancy outcomes. Disease activity was measured using scores validated for the respective disease: lupus activity index (LAI) in SLE [30] and DAS-CRP in RA [31]. The main outcome variables were achieving pregnancy (AP) (yes/no), TTP, live birth or pregnancy loss. These data were collected after birth or pregnancy loss, or at study closure. TTP TTP was defined as the time in months between pregnancy wish and the first day of the last menstrual period before pregnancy, or by subtracting 40 weeks from the expected date of delivery based on an US examination around 18 weeks of pregnancy. Women were censored at the end of the study period if they had been included in the register at least 1 year earlier without becoming pregnant. HRQoL RAND-36 [32] is a composite measure of different aspects of HRQoL. It has eight domains: physical function, role physical, bodily pain, general health, vitality, social function, role emotional and mental health, each including 2–10 items and translating to a score of 0–100. A higher score indicates a better HRQoL. A change in score of ⩾5 points is considered a minimal clinically important difference, with ⩾5 and <10 perceived a marginal change and ⩾10 a clear change [33]. It is a generic measure, useful for comparing HRQoL between diseases [34]. RAND-36 is validated for use in both RA [35] and SLE [36]. Statistics Group comparisons were performed using independent samples t-test for continuous variables and the unconditional z-pooled test [37, 38] or the exact Wilcoxon-Mann–Whitney test for categorical variables. TTP was compared between the groups using Kaplan-Meier plots and the log rank test, and further using Cox proportional hazard regression, unadjusted as well as adjusted for maternal age, parity and use of DMARDs. We use the term pregnancy ratio for hazard ratio in Cox regression. Two-sided P < 0.05 were considered statistically significant, and 95% CIs are reported where relevant. The statistical analyses were performed using IBM SPSS Statistics for Windows, Version 24.0, SPSS24 (IBM Corp., Armonk, NY, USA) and StatXact11 (Cytel, Cambridge, MA, USA) (unconditional z-pooled test). Results Patient characteristics We included 53 women with SLE and 180 women with RA in the study. See supplementary Fig. S1, available at Rheumatology online for the selection process. Background characteristics are shown in Table 1. There were no statistically significant differences between the groups. Table 1 Background characteristics at inclusion among women with SLE and RA Characteristic SLE, n = 53 RA, n = 180 P-value Age, mean (s.d.), years 30.2 (3.92) 31.1 (4.58) 0.22     ≥35 years 8 (15.1) 38 (21.1)     Missing, n 0 0 Parity 0.89a,b     0 28 (54.9) 92 (53.8)     1 17 (33.3) 57 (33.3)     2+ 6 (11.8) 22 (12.9)     Missing, n 2 9 Positive history of smoking 5 (10.6) 12 (7.1) 0.46b     Missing, n 6 11 BMI, mean (s.d.), kg/m2 24.7 (5.6) 25.0 (4.8) 0.72     Underweight (<18.5 kg/m2) 0 8 (5.1)     Normalweight (18.5–24.9 kg/m2) 24 (61.5) 78 (49.7)     Overweight (≥25 kg/m2) 15 (38.5) 71 (45.2)     Missing, n 14 23 Educational level 0.91c     Lowd 4 (7.5) 4 (2.4)     Intermediatee 10 (18.9) 42 (24.7)     Highf 39 (73.6) 124 (72.9)     Missing, n 0 10 Prior pregnancy loss 15 (30.0) 41 (27.9) 0.92b     Missing, n 3 33 Prior preterm birth 1 (4.8) 2 (3.0) 0.83b     Missing, n 2 12 Prior preeclampsia 2 (12.5) 7 (13.5) 1.0b     Missing, n 7 27 Characteristic SLE, n = 53 RA, n = 180 P-value Age, mean (s.d.), years 30.2 (3.92) 31.1 (4.58) 0.22     ≥35 years 8 (15.1) 38 (21.1)     Missing, n 0 0 Parity 0.89a,b     0 28 (54.9) 92 (53.8)     1 17 (33.3) 57 (33.3)     2+ 6 (11.8) 22 (12.9)     Missing, n 2 9 Positive history of smoking 5 (10.6) 12 (7.1) 0.46b     Missing, n 6 11 BMI, mean (s.d.), kg/m2 24.7 (5.6) 25.0 (4.8) 0.72     Underweight (<18.5 kg/m2) 0 8 (5.1)     Normalweight (18.5–24.9 kg/m2) 24 (61.5) 78 (49.7)     Overweight (≥25 kg/m2) 15 (38.5) 71 (45.2)     Missing, n 14 23 Educational level 0.91c     Lowd 4 (7.5) 4 (2.4)     Intermediatee 10 (18.9) 42 (24.7)     Highf 39 (73.6) 124 (72.9)     Missing, n 0 10 Prior pregnancy loss 15 (30.0) 41 (27.9) 0.92b     Missing, n 3 33 Prior preterm birth 1 (4.8) 2 (3.0) 0.83b     Missing, n 2 12 Prior preeclampsia 2 (12.5) 7 (13.5) 1.0b     Missing, n 7 27 Reported as n (%) unless otherwise stated. a No children vs one or more child. b Unconditional z-pooled test. c Exact Wilcoxon-Mann–Whitney. d 10 years. e 12–13 years. f >15 years. Table 1 Background characteristics at inclusion among women with SLE and RA Characteristic SLE, n = 53 RA, n = 180 P-value Age, mean (s.d.), years 30.2 (3.92) 31.1 (4.58) 0.22     ≥35 years 8 (15.1) 38 (21.1)     Missing, n 0 0 Parity 0.89a,b     0 28 (54.9) 92 (53.8)     1 17 (33.3) 57 (33.3)     2+ 6 (11.8) 22 (12.9)     Missing, n 2 9 Positive history of smoking 5 (10.6) 12 (7.1) 0.46b     Missing, n 6 11 BMI, mean (s.d.), kg/m2 24.7 (5.6) 25.0 (4.8) 0.72     Underweight (<18.5 kg/m2) 0 8 (5.1)     Normalweight (18.5–24.9 kg/m2) 24 (61.5) 78 (49.7)     Overweight (≥25 kg/m2) 15 (38.5) 71 (45.2)     Missing, n 14 23 Educational level 0.91c     Lowd 4 (7.5) 4 (2.4)     Intermediatee 10 (18.9) 42 (24.7)     Highf 39 (73.6) 124 (72.9)     Missing, n 0 10 Prior pregnancy loss 15 (30.0) 41 (27.9) 0.92b     Missing, n 3 33 Prior preterm birth 1 (4.8) 2 (3.0) 0.83b     Missing, n 2 12 Prior preeclampsia 2 (12.5) 7 (13.5) 1.0b     Missing, n 7 27 Characteristic SLE, n = 53 RA, n = 180 P-value Age, mean (s.d.), years 30.2 (3.92) 31.1 (4.58) 0.22     ≥35 years 8 (15.1) 38 (21.1)     Missing, n 0 0 Parity 0.89a,b     0 28 (54.9) 92 (53.8)     1 17 (33.3) 57 (33.3)     2+ 6 (11.8) 22 (12.9)     Missing, n 2 9 Positive history of smoking 5 (10.6) 12 (7.1) 0.46b     Missing, n 6 11 BMI, mean (s.d.), kg/m2 24.7 (5.6) 25.0 (4.8) 0.72     Underweight (<18.5 kg/m2) 0 8 (5.1)     Normalweight (18.5–24.9 kg/m2) 24 (61.5) 78 (49.7)     Overweight (≥25 kg/m2) 15 (38.5) 71 (45.2)     Missing, n 14 23 Educational level 0.91c     Lowd 4 (7.5) 4 (2.4)     Intermediatee 10 (18.9) 42 (24.7)     Highf 39 (73.6) 124 (72.9)     Missing, n 0 10 Prior pregnancy loss 15 (30.0) 41 (27.9) 0.92b     Missing, n 3 33 Prior preterm birth 1 (4.8) 2 (3.0) 0.83b     Missing, n 2 12 Prior preeclampsia 2 (12.5) 7 (13.5) 1.0b     Missing, n 7 27 Reported as n (%) unless otherwise stated. a No children vs one or more child. b Unconditional z-pooled test. c Exact Wilcoxon-Mann–Whitney. d 10 years. e 12–13 years. f >15 years. Among women with SLE, 12 (24.5%) had been pregnant before being diagnosed with rheumatic disease. This applied to 55 (35.9%) women with RA. Data was not available in 4 SLE-women and 27 RA-women. After diagnosis but before the current follow-up, 24 (48.0%) SLE-women and 61 (39.4%) RA-women had achieved pregnancy. No data were available in 3 and 25 women, respectively. The mean number of prior pregnancies per woman at inclusion was 1.3 for both disease groups. Table 2 describes and compares disease-related characteristics among women with SLE and RA. Women with SLE were younger at diagnosis, had longer disease duration, a higher percentage had active disease and the majority used one or more DMARD. Table 2 Disease-related characteristics at inclusion among women with SLE and RA Characteristic SLE, n = 53 RA, n = 180 P-value Age at diagnosis, mean (s.d.), years 21.6 (6.1) 25.3 (5.9) <0.001     Missing, n 4 12 ACR criteria fulfilled 34 (91.9) 119 (84.4) 0.25a     Missing, n 16 39 Disease duration, mean (s.d.), years 8.6 (6.1) 5.7 (4.8) 0.001     Missing, n 4 12 Active disease 24 (66.0) 59 (38.8) 0.002a     Missing, n 17 28 NSAID use 4 (7.7) 21 (12.0) 0.41a     Missing, n 1 5 Prednisolone-use 22 (42.3) 55 (31.4) 0.15a     Missing, n 1 5 ≥1 DMARD 40 (90.9) 77 (44.0) <0.001     Missing, n 9 5 Characteristic SLE, n = 53 RA, n = 180 P-value Age at diagnosis, mean (s.d.), years 21.6 (6.1) 25.3 (5.9) <0.001     Missing, n 4 12 ACR criteria fulfilled 34 (91.9) 119 (84.4) 0.25a     Missing, n 16 39 Disease duration, mean (s.d.), years 8.6 (6.1) 5.7 (4.8) 0.001     Missing, n 4 12 Active disease 24 (66.0) 59 (38.8) 0.002a     Missing, n 17 28 NSAID use 4 (7.7) 21 (12.0) 0.41a     Missing, n 1 5 Prednisolone-use 22 (42.3) 55 (31.4) 0.15a     Missing, n 1 5 ≥1 DMARD 40 (90.9) 77 (44.0) <0.001     Missing, n 9 5 Reported as n (%) unless otherwise stated. a Unconditional z-pooled test. Table 2 Disease-related characteristics at inclusion among women with SLE and RA Characteristic SLE, n = 53 RA, n = 180 P-value Age at diagnosis, mean (s.d.), years 21.6 (6.1) 25.3 (5.9) <0.001     Missing, n 4 12 ACR criteria fulfilled 34 (91.9) 119 (84.4) 0.25a     Missing, n 16 39 Disease duration, mean (s.d.), years 8.6 (6.1) 5.7 (4.8) 0.001     Missing, n 4 12 Active disease 24 (66.0) 59 (38.8) 0.002a     Missing, n 17 28 NSAID use 4 (7.7) 21 (12.0) 0.41a     Missing, n 1 5 Prednisolone-use 22 (42.3) 55 (31.4) 0.15a     Missing, n 1 5 ≥1 DMARD 40 (90.9) 77 (44.0) <0.001     Missing, n 9 5 Characteristic SLE, n = 53 RA, n = 180 P-value Age at diagnosis, mean (s.d.), years 21.6 (6.1) 25.3 (5.9) <0.001     Missing, n 4 12 ACR criteria fulfilled 34 (91.9) 119 (84.4) 0.25a     Missing, n 16 39 Disease duration, mean (s.d.), years 8.6 (6.1) 5.7 (4.8) 0.001     Missing, n 4 12 Active disease 24 (66.0) 59 (38.8) 0.002a     Missing, n 17 28 NSAID use 4 (7.7) 21 (12.0) 0.41a     Missing, n 1 5 Prednisolone-use 22 (42.3) 55 (31.4) 0.15a     Missing, n 1 5 ≥1 DMARD 40 (90.9) 77 (44.0) <0.001     Missing, n 9 5 Reported as n (%) unless otherwise stated. a Unconditional z-pooled test. During follow-up, 47 (88.7%) SLE-women and 130 (72.2%) RA-women conceived. The Kaplan-Meier plot in Fig. 1 illustrates the higher success rate in AP among women with SLE compared with women with RA, as well as a shorter TTP with median 3.0 months (95% CI: 1.36, 4.64) in SLE and median 7.0 months (95% CI: 5.29, 8.71) in RA. The differences were statistically significant (log rank test with χ2 11.45, P = 0.001). Eight (15.1%) of 53 women with SLE and 65 (36.1%) of 180 women with RA had TTP exceeding 1 year (P = 0.005), indicating subfertility. Cox regression showed a pregnancy ratio of 1.72 (95% CI: 1.23, 2.41, P = 0.002) for women with SLE compared with women with RA. The pregnancy ratio increased to 1.91 (95% CI: 1.27, 2.88, P = 0.002) after adjusting for maternal age, parity and DMARDs use. Fig. 1 View largeDownload slide Kaplan-Meier plot for time to pregnancy, comparing women with SLE and RA Fig. 1 View largeDownload slide Kaplan-Meier plot for time to pregnancy, comparing women with SLE and RA The main outcomes are outlined in Table 3. In women AP during follow-up, assisted reproduction only occurred in women with RA and mean TTP was shorter in women with SLE than women with RA. Table 3 Pregnancy-related outcomes among women with SLE and RA Outcome SLE, n = 53 RA, n = 180 P-value Achieved pregnancy 47 (88.7) 130 (72.2) 0.014a     Missing, n 0 0 Outcome 0.031b     Live birth 38 (71.7) 104 (57.8)     Pregnancy loss 9 (17.0) 26 (14.4)     Not pregnant 6 (11.3) 50 (27.8)     Missing, n 0 0 Assisted reproductionc 0 12 (11.1) 0.02a     Missing, n 7 22 Months to pregnancy, mean (s.d.)c 3.9 (4.7) 6.2 (7.7) 0.017     Missing, n 0 0 TTP >1 yearc 2 (4.3) 18 (13.8) 0.11a     Missing, n 0 0 Outcome SLE, n = 53 RA, n = 180 P-value Achieved pregnancy 47 (88.7) 130 (72.2) 0.014a     Missing, n 0 0 Outcome 0.031b     Live birth 38 (71.7) 104 (57.8)     Pregnancy loss 9 (17.0) 26 (14.4)     Not pregnant 6 (11.3) 50 (27.8)     Missing, n 0 0 Assisted reproductionc 0 12 (11.1) 0.02a     Missing, n 7 22 Months to pregnancy, mean (s.d.)c 3.9 (4.7) 6.2 (7.7) 0.017     Missing, n 0 0 TTP >1 yearc 2 (4.3) 18 (13.8) 0.11a     Missing, n 0 0 Reported as n (%) unless otherwise stated. a Unconditional z-pooled test. b Exact Wilcoxon-Mann–Whitney. c Outcomes in women achieving pregnancy during follow-up. Table 3 Pregnancy-related outcomes among women with SLE and RA Outcome SLE, n = 53 RA, n = 180 P-value Achieved pregnancy 47 (88.7) 130 (72.2) 0.014a     Missing, n 0 0 Outcome 0.031b     Live birth 38 (71.7) 104 (57.8)     Pregnancy loss 9 (17.0) 26 (14.4)     Not pregnant 6 (11.3) 50 (27.8)     Missing, n 0 0 Assisted reproductionc 0 12 (11.1) 0.02a     Missing, n 7 22 Months to pregnancy, mean (s.d.)c 3.9 (4.7) 6.2 (7.7) 0.017     Missing, n 0 0 TTP >1 yearc 2 (4.3) 18 (13.8) 0.11a     Missing, n 0 0 Outcome SLE, n = 53 RA, n = 180 P-value Achieved pregnancy 47 (88.7) 130 (72.2) 0.014a     Missing, n 0 0 Outcome 0.031b     Live birth 38 (71.7) 104 (57.8)     Pregnancy loss 9 (17.0) 26 (14.4)     Not pregnant 6 (11.3) 50 (27.8)     Missing, n 0 0 Assisted reproductionc 0 12 (11.1) 0.02a     Missing, n 7 22 Months to pregnancy, mean (s.d.)c 3.9 (4.7) 6.2 (7.7) 0.017     Missing, n 0 0 TTP >1 yearc 2 (4.3) 18 (13.8) 0.11a     Missing, n 0 0 Reported as n (%) unless otherwise stated. a Unconditional z-pooled test. b Exact Wilcoxon-Mann–Whitney. c Outcomes in women achieving pregnancy during follow-up. Four of six women with SLE NAP were nulliparous, and a higher frequency smoked, had active disease or were overweight compared with SLE-women AP. Women with RA NAP were older and had a history of preeclampsia more frequently than women with RA AP (Table 4). Table 4 Background and clinical characteristics in women with SLE and RA AP and NAP Characteristic SLE SLE P-value RA RA P-value AP, n = 47 NAP, n = 6 AP, n = 130 NAP, n = 50 Maternal age, mean (s.d.), years 30.2 (4.0) 30.7 (3.8) 0.76 30.4 (4.4) 32.9 (4.7) 0.001     Missing, n 0 0 0 0 Parity 0.29a,b 0.28a,b     0 24 (52.2) 4 (80.0) 63 (51.2) 29 (60.4)     1 17 (37.0) 0 44 (35.8) 13 (27.1)     2+ 5 (10.8) 1 (20.0) 16 (13.0) 6 (12.5)     Missing, n 1 1 7 2 Positive history of smoking 4 (9.8) 1 (16.7) 0.84b 9 (7.6) 3 (6.0) 0.75b     Missing, n 6 0 11 0 BMI, mean (s.d.) 24.5 (5.4) 28.0 (6.5) 0.16 24.9 (4.6) 25.5 (5.2) 0.64     Missing, n 13 1 23 0 Educational level 0.61c 0.60c     Lowd 3 (6.4) 1 (16.7) 3 (2.5) 1 (2.0)     Intermediatee 9 (19.1) 1 (16.7) 28 (23.3) 14 (28.0)     Highf 35 (74.5) 4 (66.7) 89 (74.2) 35 (70.0)     Missing, n 0 0 10 0 Age at diagnosis, mean (s.d.), years 21.4 (6.1) 23.3 (5.8) 0.47 25.1 (6.0) 26.0 (5.5) 0.35     Missing, n 4 0 9 3 ACR criteria fulfilledg 31 (91.2) 3 (100.0) 0.86b 87 (84.5) 32 (84.2) 0.99b     Missing, n 13 3 27 12 Disease duration, mean (s.d.), years 8.8 (6.2) 7.3 (5.8) 0.60 5.3 (4.9) 6.7 (4.7) 0.088     Missing, n 4 0 9 3 Active disease 21 (63.6) 3 (100.0) 0.27b 45 (41.7) 14 (31.8) 0.27b     Missing, n 14 3 22 6 Prior pregnancy loss 14 (31.1) 1 (20.0) 0.81b 30 (28.3) 11 (26.8) 0.95b     Missing, n 2 1 24 9 Prior preterm birth 1 (5.0) 0 1.0b 2 (3.9) 0 0.82b     Missing, n 2 0 9 3 Prior preeclampsia 2 (13.3) 0 1.0b 3 (7.3) 4 (36.4) 0.018b     Missing, n 7 0 19 8 Characteristic SLE SLE P-value RA RA P-value AP, n = 47 NAP, n = 6 AP, n = 130 NAP, n = 50 Maternal age, mean (s.d.), years 30.2 (4.0) 30.7 (3.8) 0.76 30.4 (4.4) 32.9 (4.7) 0.001     Missing, n 0 0 0 0 Parity 0.29a,b 0.28a,b     0 24 (52.2) 4 (80.0) 63 (51.2) 29 (60.4)     1 17 (37.0) 0 44 (35.8) 13 (27.1)     2+ 5 (10.8) 1 (20.0) 16 (13.0) 6 (12.5)     Missing, n 1 1 7 2 Positive history of smoking 4 (9.8) 1 (16.7) 0.84b 9 (7.6) 3 (6.0) 0.75b     Missing, n 6 0 11 0 BMI, mean (s.d.) 24.5 (5.4) 28.0 (6.5) 0.16 24.9 (4.6) 25.5 (5.2) 0.64     Missing, n 13 1 23 0 Educational level 0.61c 0.60c     Lowd 3 (6.4) 1 (16.7) 3 (2.5) 1 (2.0)     Intermediatee 9 (19.1) 1 (16.7) 28 (23.3) 14 (28.0)     Highf 35 (74.5) 4 (66.7) 89 (74.2) 35 (70.0)     Missing, n 0 0 10 0 Age at diagnosis, mean (s.d.), years 21.4 (6.1) 23.3 (5.8) 0.47 25.1 (6.0) 26.0 (5.5) 0.35     Missing, n 4 0 9 3 ACR criteria fulfilledg 31 (91.2) 3 (100.0) 0.86b 87 (84.5) 32 (84.2) 0.99b     Missing, n 13 3 27 12 Disease duration, mean (s.d.), years 8.8 (6.2) 7.3 (5.8) 0.60 5.3 (4.9) 6.7 (4.7) 0.088     Missing, n 4 0 9 3 Active disease 21 (63.6) 3 (100.0) 0.27b 45 (41.7) 14 (31.8) 0.27b     Missing, n 14 3 22 6 Prior pregnancy loss 14 (31.1) 1 (20.0) 0.81b 30 (28.3) 11 (26.8) 0.95b     Missing, n 2 1 24 9 Prior preterm birth 1 (5.0) 0 1.0b 2 (3.9) 0 0.82b     Missing, n 2 0 9 3 Prior preeclampsia 2 (13.3) 0 1.0b 3 (7.3) 4 (36.4) 0.018b     Missing, n 7 0 19 8 Reported as n (%) unless otherwise stated. a No children vs one or more child. b The unconditional z-pooled test. c Exact Wilcoxon-Mann–Whitney. d 10 years. e 12–13 years. f >15 years. g According to diagnosis. AP: achieving pregnancy; NAP: not achieving pregnancy. Table 4 Background and clinical characteristics in women with SLE and RA AP and NAP Characteristic SLE SLE P-value RA RA P-value AP, n = 47 NAP, n = 6 AP, n = 130 NAP, n = 50 Maternal age, mean (s.d.), years 30.2 (4.0) 30.7 (3.8) 0.76 30.4 (4.4) 32.9 (4.7) 0.001     Missing, n 0 0 0 0 Parity 0.29a,b 0.28a,b     0 24 (52.2) 4 (80.0) 63 (51.2) 29 (60.4)     1 17 (37.0) 0 44 (35.8) 13 (27.1)     2+ 5 (10.8) 1 (20.0) 16 (13.0) 6 (12.5)     Missing, n 1 1 7 2 Positive history of smoking 4 (9.8) 1 (16.7) 0.84b 9 (7.6) 3 (6.0) 0.75b     Missing, n 6 0 11 0 BMI, mean (s.d.) 24.5 (5.4) 28.0 (6.5) 0.16 24.9 (4.6) 25.5 (5.2) 0.64     Missing, n 13 1 23 0 Educational level 0.61c 0.60c     Lowd 3 (6.4) 1 (16.7) 3 (2.5) 1 (2.0)     Intermediatee 9 (19.1) 1 (16.7) 28 (23.3) 14 (28.0)     Highf 35 (74.5) 4 (66.7) 89 (74.2) 35 (70.0)     Missing, n 0 0 10 0 Age at diagnosis, mean (s.d.), years 21.4 (6.1) 23.3 (5.8) 0.47 25.1 (6.0) 26.0 (5.5) 0.35     Missing, n 4 0 9 3 ACR criteria fulfilledg 31 (91.2) 3 (100.0) 0.86b 87 (84.5) 32 (84.2) 0.99b     Missing, n 13 3 27 12 Disease duration, mean (s.d.), years 8.8 (6.2) 7.3 (5.8) 0.60 5.3 (4.9) 6.7 (4.7) 0.088     Missing, n 4 0 9 3 Active disease 21 (63.6) 3 (100.0) 0.27b 45 (41.7) 14 (31.8) 0.27b     Missing, n 14 3 22 6 Prior pregnancy loss 14 (31.1) 1 (20.0) 0.81b 30 (28.3) 11 (26.8) 0.95b     Missing, n 2 1 24 9 Prior preterm birth 1 (5.0) 0 1.0b 2 (3.9) 0 0.82b     Missing, n 2 0 9 3 Prior preeclampsia 2 (13.3) 0 1.0b 3 (7.3) 4 (36.4) 0.018b     Missing, n 7 0 19 8 Characteristic SLE SLE P-value RA RA P-value AP, n = 47 NAP, n = 6 AP, n = 130 NAP, n = 50 Maternal age, mean (s.d.), years 30.2 (4.0) 30.7 (3.8) 0.76 30.4 (4.4) 32.9 (4.7) 0.001     Missing, n 0 0 0 0 Parity 0.29a,b 0.28a,b     0 24 (52.2) 4 (80.0) 63 (51.2) 29 (60.4)     1 17 (37.0) 0 44 (35.8) 13 (27.1)     2+ 5 (10.8) 1 (20.0) 16 (13.0) 6 (12.5)     Missing, n 1 1 7 2 Positive history of smoking 4 (9.8) 1 (16.7) 0.84b 9 (7.6) 3 (6.0) 0.75b     Missing, n 6 0 11 0 BMI, mean (s.d.) 24.5 (5.4) 28.0 (6.5) 0.16 24.9 (4.6) 25.5 (5.2) 0.64     Missing, n 13 1 23 0 Educational level 0.61c 0.60c     Lowd 3 (6.4) 1 (16.7) 3 (2.5) 1 (2.0)     Intermediatee 9 (19.1) 1 (16.7) 28 (23.3) 14 (28.0)     Highf 35 (74.5) 4 (66.7) 89 (74.2) 35 (70.0)     Missing, n 0 0 10 0 Age at diagnosis, mean (s.d.), years 21.4 (6.1) 23.3 (5.8) 0.47 25.1 (6.0) 26.0 (5.5) 0.35     Missing, n 4 0 9 3 ACR criteria fulfilledg 31 (91.2) 3 (100.0) 0.86b 87 (84.5) 32 (84.2) 0.99b     Missing, n 13 3 27 12 Disease duration, mean (s.d.), years 8.8 (6.2) 7.3 (5.8) 0.60 5.3 (4.9) 6.7 (4.7) 0.088     Missing, n 4 0 9 3 Active disease 21 (63.6) 3 (100.0) 0.27b 45 (41.7) 14 (31.8) 0.27b     Missing, n 14 3 22 6 Prior pregnancy loss 14 (31.1) 1 (20.0) 0.81b 30 (28.3) 11 (26.8) 0.95b     Missing, n 2 1 24 9 Prior preterm birth 1 (5.0) 0 1.0b 2 (3.9) 0 0.82b     Missing, n 2 0 9 3 Prior preeclampsia 2 (13.3) 0 1.0b 3 (7.3) 4 (36.4) 0.018b     Missing, n 7 0 19 8 Reported as n (%) unless otherwise stated. a No children vs one or more child. b The unconditional z-pooled test. c Exact Wilcoxon-Mann–Whitney. d 10 years. e 12–13 years. f >15 years. g According to diagnosis. AP: achieving pregnancy; NAP: not achieving pregnancy. Medication at inclusion Traditional NSAIDs were used more often in women with RA and prednisolone more often in women with SLE (Table 2) before pregnancy. The most commonly used DMARD was HCQ in SLE (80.8%) and SSZ in RA (28.6%). One (1.9%) SLE-woman and 20 (11.4%) RA-women used MTX, while 3 (5.8%) SLE-women used MMF preconceptionally. Fifty-one (29.1%) RA-women used TNF-α inhibitors at inclusion (see supplementary Table S1, available at Rheumatology online). HRQoL There were no statistically significant differences comparing HRQoL in women AP and NAP in the two groups. However, women with SLE NAP had lower mean scores than women with SLE AP, exceeding the minimal clinically important difference in several domains (Diff score ⩾5) (Table 5). Table 5 HRQoL in women with SLE and RA AP and NAP Domain SLE SLE P-value Diff score RA RA P-value Diff score AP, n = 47 NAP, n = 6 AP, n = 130 NAP, n = 50 Physical function 90.2 (13.5) 80.8 (21.1) 0.33 −9.4 80.1 (19.8) 78.9 (22.1) 0.74 −1.2     Missing, n 5 0 19 6 Physical role 65.2 (40.7) 45.8 (40.1) 0.28 −19.4 58.9 (40.4) 57.4 (45.0) 0.85 −1.5     Missing, n 5 0 19 6 Bodily pain 72.5 (23.6) 79.0 (31.6) 0.55 +6.5 61.8 (24.0) 65.4 (25.4) 0.42 +3.6     Missing, n 5 0 19 6 General health 60.3 (26.1) 56.0 (13.9) 0.55 −4.3 57.5 (21.9) 57.0 (24.1) 0.90 −0.5     Missing, n 5 0 20 6 Vitality 50.7 (22.4) 42.5 (27.2) 0.42 −8.2 48.0 (19.9) 50.1 (21.0) 0.56 +2.1     Missing, n 5 0 19 7 Social function 75.0 (24.4) 64.6 (27.9) 0.34 −10.4 80.6 (22.8) 80.4 (21.3) 0.95 −0.2     Missing, n 5 0 19 6 Role emotional 79.4 (36.8) 50.0 (46.0) 0.082 −29.4 81.7 (32.3) 77.3 (35.1) 0.46 −4.4     Missing, n 5 0 19 6 Mental health 74.9 (14.7) 68.7 (12.8) 0.53 −6.2 77.7 (13.7) 80.2 (15.4) 0.33 +2.5     Missing, n 5 0 19 7 Domain SLE SLE P-value Diff score RA RA P-value Diff score AP, n = 47 NAP, n = 6 AP, n = 130 NAP, n = 50 Physical function 90.2 (13.5) 80.8 (21.1) 0.33 −9.4 80.1 (19.8) 78.9 (22.1) 0.74 −1.2     Missing, n 5 0 19 6 Physical role 65.2 (40.7) 45.8 (40.1) 0.28 −19.4 58.9 (40.4) 57.4 (45.0) 0.85 −1.5     Missing, n 5 0 19 6 Bodily pain 72.5 (23.6) 79.0 (31.6) 0.55 +6.5 61.8 (24.0) 65.4 (25.4) 0.42 +3.6     Missing, n 5 0 19 6 General health 60.3 (26.1) 56.0 (13.9) 0.55 −4.3 57.5 (21.9) 57.0 (24.1) 0.90 −0.5     Missing, n 5 0 20 6 Vitality 50.7 (22.4) 42.5 (27.2) 0.42 −8.2 48.0 (19.9) 50.1 (21.0) 0.56 +2.1     Missing, n 5 0 19 7 Social function 75.0 (24.4) 64.6 (27.9) 0.34 −10.4 80.6 (22.8) 80.4 (21.3) 0.95 −0.2     Missing, n 5 0 19 6 Role emotional 79.4 (36.8) 50.0 (46.0) 0.082 −29.4 81.7 (32.3) 77.3 (35.1) 0.46 −4.4     Missing, n 5 0 19 6 Mental health 74.9 (14.7) 68.7 (12.8) 0.53 −6.2 77.7 (13.7) 80.2 (15.4) 0.33 +2.5     Missing, n 5 0 19 7 Reported as mean (s.d.) unless otherwise stated. AP: achieving pregnancy; NAP: not achieving pregnancy; HRQoL: health-related quality of life. Table 5 HRQoL in women with SLE and RA AP and NAP Domain SLE SLE P-value Diff score RA RA P-value Diff score AP, n = 47 NAP, n = 6 AP, n = 130 NAP, n = 50 Physical function 90.2 (13.5) 80.8 (21.1) 0.33 −9.4 80.1 (19.8) 78.9 (22.1) 0.74 −1.2     Missing, n 5 0 19 6 Physical role 65.2 (40.7) 45.8 (40.1) 0.28 −19.4 58.9 (40.4) 57.4 (45.0) 0.85 −1.5     Missing, n 5 0 19 6 Bodily pain 72.5 (23.6) 79.0 (31.6) 0.55 +6.5 61.8 (24.0) 65.4 (25.4) 0.42 +3.6     Missing, n 5 0 19 6 General health 60.3 (26.1) 56.0 (13.9) 0.55 −4.3 57.5 (21.9) 57.0 (24.1) 0.90 −0.5     Missing, n 5 0 20 6 Vitality 50.7 (22.4) 42.5 (27.2) 0.42 −8.2 48.0 (19.9) 50.1 (21.0) 0.56 +2.1     Missing, n 5 0 19 7 Social function 75.0 (24.4) 64.6 (27.9) 0.34 −10.4 80.6 (22.8) 80.4 (21.3) 0.95 −0.2     Missing, n 5 0 19 6 Role emotional 79.4 (36.8) 50.0 (46.0) 0.082 −29.4 81.7 (32.3) 77.3 (35.1) 0.46 −4.4     Missing, n 5 0 19 6 Mental health 74.9 (14.7) 68.7 (12.8) 0.53 −6.2 77.7 (13.7) 80.2 (15.4) 0.33 +2.5     Missing, n 5 0 19 7 Domain SLE SLE P-value Diff score RA RA P-value Diff score AP, n = 47 NAP, n = 6 AP, n = 130 NAP, n = 50 Physical function 90.2 (13.5) 80.8 (21.1) 0.33 −9.4 80.1 (19.8) 78.9 (22.1) 0.74 −1.2     Missing, n 5 0 19 6 Physical role 65.2 (40.7) 45.8 (40.1) 0.28 −19.4 58.9 (40.4) 57.4 (45.0) 0.85 −1.5     Missing, n 5 0 19 6 Bodily pain 72.5 (23.6) 79.0 (31.6) 0.55 +6.5 61.8 (24.0) 65.4 (25.4) 0.42 +3.6     Missing, n 5 0 19 6 General health 60.3 (26.1) 56.0 (13.9) 0.55 −4.3 57.5 (21.9) 57.0 (24.1) 0.90 −0.5     Missing, n 5 0 20 6 Vitality 50.7 (22.4) 42.5 (27.2) 0.42 −8.2 48.0 (19.9) 50.1 (21.0) 0.56 +2.1     Missing, n 5 0 19 7 Social function 75.0 (24.4) 64.6 (27.9) 0.34 −10.4 80.6 (22.8) 80.4 (21.3) 0.95 −0.2     Missing, n 5 0 19 6 Role emotional 79.4 (36.8) 50.0 (46.0) 0.082 −29.4 81.7 (32.3) 77.3 (35.1) 0.46 −4.4     Missing, n 5 0 19 6 Mental health 74.9 (14.7) 68.7 (12.8) 0.53 −6.2 77.7 (13.7) 80.2 (15.4) 0.33 +2.5     Missing, n 5 0 19 7 Reported as mean (s.d.) unless otherwise stated. AP: achieving pregnancy; NAP: not achieving pregnancy; HRQoL: health-related quality of life. Discussion In our study, women with SLE had higher pregnancy ratio and shorter TTP compared with women with RA. We found no differences in background characteristics to explain this finding, but there are differences in disease-related characteristics that may be of relevance. Women with SLE were younger at diagnosis and had longer disease duration at inclusion. It may be of advantage to have time to accept and adjust to a chronic disease before family planning is relevant, as opposed to acquiring a disease when the wish for and expectations about having children have already been expressed. This is in accordance with earlier findings comparing women with juvenile arthritis and RA [39]. Previous studies have found that both disease groups have increased subfertility and reduced TFRs compared with population controls [8, 10, 14, 15, 39, 40]. Generally, age is one of the main factors determining subfertility [41]. In our study, women with SLE had a mean age similar to the general obstetric population in Norway [42], with no significant difference between women AP and NAP. Accordingly, age does not seem to influence fertility in women with SLE, besides the general increase in maternal age at first birth [8]. In contrast, women with RA had a substantially higher mean age, found to be statistically significantly higher in women NAP compared with women AP. Previous studies showed that women who were childless at diagnosis had lower parity than matched references [39]. In both women with SLE and RA NAP, we found higher frequencies of nulliparity compared with in women AP, even though the small SLE group demands caution in interpreting the results. During follow-up, 19.1% (9/47) of women with SLE and 20.0% (26/130) with RA AP had pregnancy loss, respectively, indicating no difference in fecundity. This is in contrast to earlier findings reporting a higher frequency of pregnancy loss in women with SLE than women with RA [10]. In the general population the pregnancy loss rate is commonly reported to be lower, around 15% [43, 44]. It is possible that early miscarriages were acknowledged and reported more often due to the tight follow-up in the RevNatus register. However, higher occurrence of miscarriages in SLE after diagnosis compared with before diagnosis [45] are reported. Similarly, women with RA had a higher relative risk of miscarriage compared with reference women without inflammatory rheumatic disease in a recent Norwegian study [12]. Positive aPL is associated with pregnancy loss, and this is well documented in SLE [46, 47]. The SLE-women in our population that had a pregnancy loss did not have any positive aPL (missing data in two of nine women). The biological and clinical meaning of aPL concerning fertility remains to be clarified [48]. Due to the high level of missing data in the registration of these antibodies, we can not assess their impact in our population of women with SLE and RA. In our study, only one miscarriage was reported associated with medication with teratogenic potential (MTX) used <3 months before pregnancy or during pregnancy. No other associations between medication and pregnancy loss were found. Diminished ovarian reserve due to SLE and RA itself is discussed as a reason for lower TFR, although it is controversial [20–23]. Unfortunately, neither Anti-Müllerian hormone (AMH) levels nor antral follicle count to assess this were registered in RevNatus. Prior CYC administration is a proven risk factor for ovarian failure and decreasing AMH levels [49]. In our study, two women with SLE (with live births) had been treated with CYC >5 years earlier, but none of the women NAP in either diagnosis group was treated with CYC in the past or at inclusion. Accordingly, CYC does not affect the ability to achieve pregnancy in our cohort. NSAID use may cause ovulatory disturbances and transiently reduce fertility [49]. None of the SLE-women NAP used NSAIDs, while 18.4% of RA-women NAP did, potentially extending TTP and amplifying the age factor. Moreover, we found a substantially higher (although not statistically significant) use of NSAIDs in women with RA NAP than AP, possibly strengthening this effect. A lower frequency of women with SLE (7.7%) used DMARDs incompatible with pregnancy at inclusion compared with women with RA (11.4%). In SLE-women NAP, MMF was used in one woman at inclusion, while in RA-women NAP, MTX was used in 14.3% at inclusion. Accordingly, the need to adjust medication and ensure a clinically acceptable disease-modifying effect before conception may be required more often in women with RA, resulting in extended TTP and higher maternal age. Nevertheless, in 13 women with RA AP there were 12 live births and one miscarriage. They were all exposed to MTX <3 months before pregnancy or in early pregnancy, illustrating that medication use does not always delay conception. There were no statistically significant differences concerning use of MTX in RA-women AP and NAP, supporting recent studies demonstrating that MTX use does not reduce ovarian function [9, 22]. Women with SLE more frequently had active disease, a known risk factor for reduced fertility and fecundity [14, 47], and in the small group of SLE-women NAP this was even more apparent. However, women with active SLE had mainly low disease activity (LAI <0.5) with mean LAI 0.28 (0.063–0.79), while women with active RA had moderate disease activity (DAS-CRP >3.2) with mean DAS-CRP 3.62 (2.80–6.39). We believe this can explain why disease activity does not interfere more with fertility and fecundity in the women with SLE in our cohort. Women with SLE failing to conceive had poorer HRQoL than SLE-women AP. In the domains physical role, social function and role emotional we found a clear change (deterioration), and in the domains physical function, vitality and mental health a marginal change compared with the SLE-women AP. In this group, reduced HRQoL in the domains social function, role emotional and mental health may impair sexual function, in line with earlier findings [10, 25]. The low HRQoL scores in both disease groups concerning vitality and general health may impact TTP and the choice or ability to achieve pregnancy. Women with RA had similar but generally low scores whether AP or NAP concerning physical role and bodily pain, implicating physical hindrance to sexual activity, while social functioning, role emotional and mental health domains were higher. Our results indicate that women with RA have a generally lower HRQoL than women with SLE, and that this is a probable risk factor for prolonged TTP and lower TFR in these women. A strength of this study is the prospective follow-up design, securing more accurate and unbiased registration of disease activity, medication use and HRQoL domains. A possible weakness is that some of the women may not have a pregnancy wish at the time of inclusion in the register, but plan pregnancy in the future. Not excluding a patient when a pregnancy wish is no longer present is another potential bias. However, we excluded 22 women because pregnancy was no longer relevant due to changing social status or other life events, reducing this source of error. A selection bias may be that SLE is a potentially more serious disease than RA, and that women with severe SLE do not try to conceive, while this is rarely the case in women with RA. Another selection bias might be that women with mild disease, especially RA, are not recruited into RevNatus, biasing our population towards more severe disease. However, pregnant women with rheumatic diseases should have preconception counselling and specialized health care follow-up [2, 19, 29, 46, 47], which should mean recruitment in RevNatus. In our prospective study, women with SLE had fewer problems in AP than women with RA. There was a similar occurrence of pregnancy loss, indicating reduced fecundity in both groups compared with references without rheumatic disease. In women with RA, higher maternal age, more use of NSAIDs and medication not compatible with pregnancy together with a lower HRQoL compared with women with SLE are factors impacting negatively on TTP and TFR. These findings may be helpful in counselling women with rheumatic diseases who plan pregnancy. Focus on disease activity and medication needs continued attention, and maternal age must be acknowledged as an important risk factor for reduced fertility. Moreover, assessing HRQoL may identify factors contributing to NAP. Acknowledgements The authors would like to thank the participating departments of rheumatology at the following hospitals for including patients in RevNatus: Betanien Hospital, Skien; Diakonhjemmet Hospital, Oslo; Haugesund Sanitetsforenings Rheumatism Hospital, Haugesund; Haukeland University Hospital, Bergen; Helse Førde, Førde Hospital, Førde; Helse Møre og Romsdal, Ålesund Hospital, Ålesund; Lillehammer Hospital for Rheumatic Diseases, Lillehammer; Nordland Hospital, Bodø; Oslo University Hospital Rikshospitalet, Oslo; Private practice Anne N. 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Nat Rev Rheumatol 2017 ; 13 : 485 – 93 . 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) http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Rheumatology Oxford University Press

Women with systemic lupus erythematosus get pregnant more easily than women with rheumatoid arthritis

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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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10.1093/rheumatology/key049
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Abstract

Abstract Objectives To examine possible differences in the ability to get pregnant and time to pregnancy (TTP) in women with SLE and RA, and to study possible influencing factors. Methods Data from RevNatus, a Norwegian nationwide prospective observational register including women with inflammatory rheumatic diseases when planning pregnancy or after conception, was used. We compared rate of achieved pregnancy, the pregnancy outcomes live birth or pregnancy loss, and TTP between women with SLE (n = 53) and women with RA (n = 180). TTP was compared between the groups using Kaplan-Meier plots, and Cox proportional hazard regression was performed adjusting for maternal age, parity and medication use. RAND-36 was used to assess health-related quality of life (HRQoL) in women achieving and not achieving pregnancy. Results Women with SLE had a pregnancy ratio of 1.91 (95% CI: 1.27, 2.88, P = 0.002) compared with women with RA, and a substantially shorter median TTP (3.0 vs 7.0 months, P = 0.001). Higher maternal age, medication use and low HRQoL in the physical domains may influence the ability to achieve pregnancy and prolong TTP in women with RA. Women with SLE not achieving pregnancy had lower HRQoL scores than SLE-women achieving pregnancy, while women with RA had generally low scores in physical domains whether or not achieving pregnancy, indicating poor HRQoL. Conclusions In the studied cohort, women with SLE got pregnant more easily than women with RA. SLE, RA, fertility, family planning, health-related quality of life Rheumatology key messages Women with SLE more often succeed in achieving pregnancy than women with RA. Women with SLE have a shorter time to pregnancy than women with RA. Health-related quality of life in SLE and RA influence the ability to achieve pregnancy. Introduction Fertility is the capacity to establish a clinical pregnancy, while fecundity is the capacity to have a live birth [1]. Total fertility rate (TFR) is defined as the average number of live births per woman [1]. Female fertility and fecundity may be compromised, resulting in increased time to establish pregnancy (TTP) and reduced TFR [2]. The TFR in Norway has gradually declined from 3 children in 1964 to 1.7 in 2015 [3]. SLE and RA are autoinflammatory, systemic rheumatic diseases affecting fertile women. SLE typically leads to manifestations of skin, joints and internal organs [4], and has a more serious prognosis compared with RA, which classically is more often limited to the musculoskeletal system [5]. Previous studies have shown that women with SLE and RA have lower TFR than the general obstetric population, although there has been an increasing number of children born to mothers with rheumatic diseases during recent decades [6, 7]. Subfertility is defined as TTP >1 year, and has increased in Norwegian women [8]. A higher subfertility occurrence of 36–42% in RA-women [9–11] is perceived to be the main cause of reduced TFR in this group, although lower fecundity may also play a role [12]. In women with SLE, compromised fecundity is considered the main reason for reduced TFR [13], even though severe and active disease as well as medication use are also associated with reduced fertility [14, 15]. Studies comparing fertility, fecundity, TFR and influencing factors between SLE and RA patients are rare, although extended data should be of importance to patients as well as treating physicians. In women with chronic rheumatic diseases the disease itself, the treatment and fear of complications may lower TFR [10, 14, 16–19] due to ovulatory disturbances [9], reduced ovarian reserve [20–23] and impaired sexual function caused by decreased health-related quality of life (HRQoL) [18, 24, 25]. Previous findings indicate lower HRQoL in rheumatic diseases compared with population controls [26, 27], and in RA especially in the physical domains [28]. Acquiring a chronic disease while of reproductive age may influence family planning. Clowse et al. [10] found that women with SLE and RA reported fewer children than wished for, and that personal choice was one of the reasons. The objective of this study was to examine possible differences in the ability to achieve pregnancy and TTP among women with SLE and RA, and to study possible influencing factors including HRQoL. Methods Study population The study population was retrieved from RevNatus, a nationwide Norwegian multicentre, prospective observational register including women with inflammatory rheumatic diseases when planning pregnancy or after conception. The register was established in 2006, and all but two departments of rheumatology contribute with eligible patients. According to national guidelines [29], pregnant women with rheumatic diseases should have follow-up by a specialist in rheumatology. Women ⩾18 years of age are recruited and followed-up in each trimester of pregnancy and at 6 weeks, 6 and 12 months after birth. Disease characteristics, disease activity, HRQoL, use of medications, outcomes and complications in mother and child are recorded. Studied women were included before pregnancy and had follow-up during pregnancy and 6 weeks after birth or pregnancy loss, or at 1 year if not achieving pregnancy (NAP). They were included in the period 2006–16. Ethics The RevNatus register was approved by the regional committee for medical and health research ethics (REC Central) in 2006. Eligible women signed written informed consent before inclusion in the register. The present study has been approved by REC Central (2012/1905). Variables Background variables were obtained from data collected at the preconception visit and included background and disease-specific characteristics, medication use, HRQoL variables and information on earlier pregnancy outcomes. Disease activity was measured using scores validated for the respective disease: lupus activity index (LAI) in SLE [30] and DAS-CRP in RA [31]. The main outcome variables were achieving pregnancy (AP) (yes/no), TTP, live birth or pregnancy loss. These data were collected after birth or pregnancy loss, or at study closure. TTP TTP was defined as the time in months between pregnancy wish and the first day of the last menstrual period before pregnancy, or by subtracting 40 weeks from the expected date of delivery based on an US examination around 18 weeks of pregnancy. Women were censored at the end of the study period if they had been included in the register at least 1 year earlier without becoming pregnant. HRQoL RAND-36 [32] is a composite measure of different aspects of HRQoL. It has eight domains: physical function, role physical, bodily pain, general health, vitality, social function, role emotional and mental health, each including 2–10 items and translating to a score of 0–100. A higher score indicates a better HRQoL. A change in score of ⩾5 points is considered a minimal clinically important difference, with ⩾5 and <10 perceived a marginal change and ⩾10 a clear change [33]. It is a generic measure, useful for comparing HRQoL between diseases [34]. RAND-36 is validated for use in both RA [35] and SLE [36]. Statistics Group comparisons were performed using independent samples t-test for continuous variables and the unconditional z-pooled test [37, 38] or the exact Wilcoxon-Mann–Whitney test for categorical variables. TTP was compared between the groups using Kaplan-Meier plots and the log rank test, and further using Cox proportional hazard regression, unadjusted as well as adjusted for maternal age, parity and use of DMARDs. We use the term pregnancy ratio for hazard ratio in Cox regression. Two-sided P < 0.05 were considered statistically significant, and 95% CIs are reported where relevant. The statistical analyses were performed using IBM SPSS Statistics for Windows, Version 24.0, SPSS24 (IBM Corp., Armonk, NY, USA) and StatXact11 (Cytel, Cambridge, MA, USA) (unconditional z-pooled test). Results Patient characteristics We included 53 women with SLE and 180 women with RA in the study. See supplementary Fig. S1, available at Rheumatology online for the selection process. Background characteristics are shown in Table 1. There were no statistically significant differences between the groups. Table 1 Background characteristics at inclusion among women with SLE and RA Characteristic SLE, n = 53 RA, n = 180 P-value Age, mean (s.d.), years 30.2 (3.92) 31.1 (4.58) 0.22     ≥35 years 8 (15.1) 38 (21.1)     Missing, n 0 0 Parity 0.89a,b     0 28 (54.9) 92 (53.8)     1 17 (33.3) 57 (33.3)     2+ 6 (11.8) 22 (12.9)     Missing, n 2 9 Positive history of smoking 5 (10.6) 12 (7.1) 0.46b     Missing, n 6 11 BMI, mean (s.d.), kg/m2 24.7 (5.6) 25.0 (4.8) 0.72     Underweight (<18.5 kg/m2) 0 8 (5.1)     Normalweight (18.5–24.9 kg/m2) 24 (61.5) 78 (49.7)     Overweight (≥25 kg/m2) 15 (38.5) 71 (45.2)     Missing, n 14 23 Educational level 0.91c     Lowd 4 (7.5) 4 (2.4)     Intermediatee 10 (18.9) 42 (24.7)     Highf 39 (73.6) 124 (72.9)     Missing, n 0 10 Prior pregnancy loss 15 (30.0) 41 (27.9) 0.92b     Missing, n 3 33 Prior preterm birth 1 (4.8) 2 (3.0) 0.83b     Missing, n 2 12 Prior preeclampsia 2 (12.5) 7 (13.5) 1.0b     Missing, n 7 27 Characteristic SLE, n = 53 RA, n = 180 P-value Age, mean (s.d.), years 30.2 (3.92) 31.1 (4.58) 0.22     ≥35 years 8 (15.1) 38 (21.1)     Missing, n 0 0 Parity 0.89a,b     0 28 (54.9) 92 (53.8)     1 17 (33.3) 57 (33.3)     2+ 6 (11.8) 22 (12.9)     Missing, n 2 9 Positive history of smoking 5 (10.6) 12 (7.1) 0.46b     Missing, n 6 11 BMI, mean (s.d.), kg/m2 24.7 (5.6) 25.0 (4.8) 0.72     Underweight (<18.5 kg/m2) 0 8 (5.1)     Normalweight (18.5–24.9 kg/m2) 24 (61.5) 78 (49.7)     Overweight (≥25 kg/m2) 15 (38.5) 71 (45.2)     Missing, n 14 23 Educational level 0.91c     Lowd 4 (7.5) 4 (2.4)     Intermediatee 10 (18.9) 42 (24.7)     Highf 39 (73.6) 124 (72.9)     Missing, n 0 10 Prior pregnancy loss 15 (30.0) 41 (27.9) 0.92b     Missing, n 3 33 Prior preterm birth 1 (4.8) 2 (3.0) 0.83b     Missing, n 2 12 Prior preeclampsia 2 (12.5) 7 (13.5) 1.0b     Missing, n 7 27 Reported as n (%) unless otherwise stated. a No children vs one or more child. b Unconditional z-pooled test. c Exact Wilcoxon-Mann–Whitney. d 10 years. e 12–13 years. f >15 years. Table 1 Background characteristics at inclusion among women with SLE and RA Characteristic SLE, n = 53 RA, n = 180 P-value Age, mean (s.d.), years 30.2 (3.92) 31.1 (4.58) 0.22     ≥35 years 8 (15.1) 38 (21.1)     Missing, n 0 0 Parity 0.89a,b     0 28 (54.9) 92 (53.8)     1 17 (33.3) 57 (33.3)     2+ 6 (11.8) 22 (12.9)     Missing, n 2 9 Positive history of smoking 5 (10.6) 12 (7.1) 0.46b     Missing, n 6 11 BMI, mean (s.d.), kg/m2 24.7 (5.6) 25.0 (4.8) 0.72     Underweight (<18.5 kg/m2) 0 8 (5.1)     Normalweight (18.5–24.9 kg/m2) 24 (61.5) 78 (49.7)     Overweight (≥25 kg/m2) 15 (38.5) 71 (45.2)     Missing, n 14 23 Educational level 0.91c     Lowd 4 (7.5) 4 (2.4)     Intermediatee 10 (18.9) 42 (24.7)     Highf 39 (73.6) 124 (72.9)     Missing, n 0 10 Prior pregnancy loss 15 (30.0) 41 (27.9) 0.92b     Missing, n 3 33 Prior preterm birth 1 (4.8) 2 (3.0) 0.83b     Missing, n 2 12 Prior preeclampsia 2 (12.5) 7 (13.5) 1.0b     Missing, n 7 27 Characteristic SLE, n = 53 RA, n = 180 P-value Age, mean (s.d.), years 30.2 (3.92) 31.1 (4.58) 0.22     ≥35 years 8 (15.1) 38 (21.1)     Missing, n 0 0 Parity 0.89a,b     0 28 (54.9) 92 (53.8)     1 17 (33.3) 57 (33.3)     2+ 6 (11.8) 22 (12.9)     Missing, n 2 9 Positive history of smoking 5 (10.6) 12 (7.1) 0.46b     Missing, n 6 11 BMI, mean (s.d.), kg/m2 24.7 (5.6) 25.0 (4.8) 0.72     Underweight (<18.5 kg/m2) 0 8 (5.1)     Normalweight (18.5–24.9 kg/m2) 24 (61.5) 78 (49.7)     Overweight (≥25 kg/m2) 15 (38.5) 71 (45.2)     Missing, n 14 23 Educational level 0.91c     Lowd 4 (7.5) 4 (2.4)     Intermediatee 10 (18.9) 42 (24.7)     Highf 39 (73.6) 124 (72.9)     Missing, n 0 10 Prior pregnancy loss 15 (30.0) 41 (27.9) 0.92b     Missing, n 3 33 Prior preterm birth 1 (4.8) 2 (3.0) 0.83b     Missing, n 2 12 Prior preeclampsia 2 (12.5) 7 (13.5) 1.0b     Missing, n 7 27 Reported as n (%) unless otherwise stated. a No children vs one or more child. b Unconditional z-pooled test. c Exact Wilcoxon-Mann–Whitney. d 10 years. e 12–13 years. f >15 years. Among women with SLE, 12 (24.5%) had been pregnant before being diagnosed with rheumatic disease. This applied to 55 (35.9%) women with RA. Data was not available in 4 SLE-women and 27 RA-women. After diagnosis but before the current follow-up, 24 (48.0%) SLE-women and 61 (39.4%) RA-women had achieved pregnancy. No data were available in 3 and 25 women, respectively. The mean number of prior pregnancies per woman at inclusion was 1.3 for both disease groups. Table 2 describes and compares disease-related characteristics among women with SLE and RA. Women with SLE were younger at diagnosis, had longer disease duration, a higher percentage had active disease and the majority used one or more DMARD. Table 2 Disease-related characteristics at inclusion among women with SLE and RA Characteristic SLE, n = 53 RA, n = 180 P-value Age at diagnosis, mean (s.d.), years 21.6 (6.1) 25.3 (5.9) <0.001     Missing, n 4 12 ACR criteria fulfilled 34 (91.9) 119 (84.4) 0.25a     Missing, n 16 39 Disease duration, mean (s.d.), years 8.6 (6.1) 5.7 (4.8) 0.001     Missing, n 4 12 Active disease 24 (66.0) 59 (38.8) 0.002a     Missing, n 17 28 NSAID use 4 (7.7) 21 (12.0) 0.41a     Missing, n 1 5 Prednisolone-use 22 (42.3) 55 (31.4) 0.15a     Missing, n 1 5 ≥1 DMARD 40 (90.9) 77 (44.0) <0.001     Missing, n 9 5 Characteristic SLE, n = 53 RA, n = 180 P-value Age at diagnosis, mean (s.d.), years 21.6 (6.1) 25.3 (5.9) <0.001     Missing, n 4 12 ACR criteria fulfilled 34 (91.9) 119 (84.4) 0.25a     Missing, n 16 39 Disease duration, mean (s.d.), years 8.6 (6.1) 5.7 (4.8) 0.001     Missing, n 4 12 Active disease 24 (66.0) 59 (38.8) 0.002a     Missing, n 17 28 NSAID use 4 (7.7) 21 (12.0) 0.41a     Missing, n 1 5 Prednisolone-use 22 (42.3) 55 (31.4) 0.15a     Missing, n 1 5 ≥1 DMARD 40 (90.9) 77 (44.0) <0.001     Missing, n 9 5 Reported as n (%) unless otherwise stated. a Unconditional z-pooled test. Table 2 Disease-related characteristics at inclusion among women with SLE and RA Characteristic SLE, n = 53 RA, n = 180 P-value Age at diagnosis, mean (s.d.), years 21.6 (6.1) 25.3 (5.9) <0.001     Missing, n 4 12 ACR criteria fulfilled 34 (91.9) 119 (84.4) 0.25a     Missing, n 16 39 Disease duration, mean (s.d.), years 8.6 (6.1) 5.7 (4.8) 0.001     Missing, n 4 12 Active disease 24 (66.0) 59 (38.8) 0.002a     Missing, n 17 28 NSAID use 4 (7.7) 21 (12.0) 0.41a     Missing, n 1 5 Prednisolone-use 22 (42.3) 55 (31.4) 0.15a     Missing, n 1 5 ≥1 DMARD 40 (90.9) 77 (44.0) <0.001     Missing, n 9 5 Characteristic SLE, n = 53 RA, n = 180 P-value Age at diagnosis, mean (s.d.), years 21.6 (6.1) 25.3 (5.9) <0.001     Missing, n 4 12 ACR criteria fulfilled 34 (91.9) 119 (84.4) 0.25a     Missing, n 16 39 Disease duration, mean (s.d.), years 8.6 (6.1) 5.7 (4.8) 0.001     Missing, n 4 12 Active disease 24 (66.0) 59 (38.8) 0.002a     Missing, n 17 28 NSAID use 4 (7.7) 21 (12.0) 0.41a     Missing, n 1 5 Prednisolone-use 22 (42.3) 55 (31.4) 0.15a     Missing, n 1 5 ≥1 DMARD 40 (90.9) 77 (44.0) <0.001     Missing, n 9 5 Reported as n (%) unless otherwise stated. a Unconditional z-pooled test. During follow-up, 47 (88.7%) SLE-women and 130 (72.2%) RA-women conceived. The Kaplan-Meier plot in Fig. 1 illustrates the higher success rate in AP among women with SLE compared with women with RA, as well as a shorter TTP with median 3.0 months (95% CI: 1.36, 4.64) in SLE and median 7.0 months (95% CI: 5.29, 8.71) in RA. The differences were statistically significant (log rank test with χ2 11.45, P = 0.001). Eight (15.1%) of 53 women with SLE and 65 (36.1%) of 180 women with RA had TTP exceeding 1 year (P = 0.005), indicating subfertility. Cox regression showed a pregnancy ratio of 1.72 (95% CI: 1.23, 2.41, P = 0.002) for women with SLE compared with women with RA. The pregnancy ratio increased to 1.91 (95% CI: 1.27, 2.88, P = 0.002) after adjusting for maternal age, parity and DMARDs use. Fig. 1 View largeDownload slide Kaplan-Meier plot for time to pregnancy, comparing women with SLE and RA Fig. 1 View largeDownload slide Kaplan-Meier plot for time to pregnancy, comparing women with SLE and RA The main outcomes are outlined in Table 3. In women AP during follow-up, assisted reproduction only occurred in women with RA and mean TTP was shorter in women with SLE than women with RA. Table 3 Pregnancy-related outcomes among women with SLE and RA Outcome SLE, n = 53 RA, n = 180 P-value Achieved pregnancy 47 (88.7) 130 (72.2) 0.014a     Missing, n 0 0 Outcome 0.031b     Live birth 38 (71.7) 104 (57.8)     Pregnancy loss 9 (17.0) 26 (14.4)     Not pregnant 6 (11.3) 50 (27.8)     Missing, n 0 0 Assisted reproductionc 0 12 (11.1) 0.02a     Missing, n 7 22 Months to pregnancy, mean (s.d.)c 3.9 (4.7) 6.2 (7.7) 0.017     Missing, n 0 0 TTP >1 yearc 2 (4.3) 18 (13.8) 0.11a     Missing, n 0 0 Outcome SLE, n = 53 RA, n = 180 P-value Achieved pregnancy 47 (88.7) 130 (72.2) 0.014a     Missing, n 0 0 Outcome 0.031b     Live birth 38 (71.7) 104 (57.8)     Pregnancy loss 9 (17.0) 26 (14.4)     Not pregnant 6 (11.3) 50 (27.8)     Missing, n 0 0 Assisted reproductionc 0 12 (11.1) 0.02a     Missing, n 7 22 Months to pregnancy, mean (s.d.)c 3.9 (4.7) 6.2 (7.7) 0.017     Missing, n 0 0 TTP >1 yearc 2 (4.3) 18 (13.8) 0.11a     Missing, n 0 0 Reported as n (%) unless otherwise stated. a Unconditional z-pooled test. b Exact Wilcoxon-Mann–Whitney. c Outcomes in women achieving pregnancy during follow-up. Table 3 Pregnancy-related outcomes among women with SLE and RA Outcome SLE, n = 53 RA, n = 180 P-value Achieved pregnancy 47 (88.7) 130 (72.2) 0.014a     Missing, n 0 0 Outcome 0.031b     Live birth 38 (71.7) 104 (57.8)     Pregnancy loss 9 (17.0) 26 (14.4)     Not pregnant 6 (11.3) 50 (27.8)     Missing, n 0 0 Assisted reproductionc 0 12 (11.1) 0.02a     Missing, n 7 22 Months to pregnancy, mean (s.d.)c 3.9 (4.7) 6.2 (7.7) 0.017     Missing, n 0 0 TTP >1 yearc 2 (4.3) 18 (13.8) 0.11a     Missing, n 0 0 Outcome SLE, n = 53 RA, n = 180 P-value Achieved pregnancy 47 (88.7) 130 (72.2) 0.014a     Missing, n 0 0 Outcome 0.031b     Live birth 38 (71.7) 104 (57.8)     Pregnancy loss 9 (17.0) 26 (14.4)     Not pregnant 6 (11.3) 50 (27.8)     Missing, n 0 0 Assisted reproductionc 0 12 (11.1) 0.02a     Missing, n 7 22 Months to pregnancy, mean (s.d.)c 3.9 (4.7) 6.2 (7.7) 0.017     Missing, n 0 0 TTP >1 yearc 2 (4.3) 18 (13.8) 0.11a     Missing, n 0 0 Reported as n (%) unless otherwise stated. a Unconditional z-pooled test. b Exact Wilcoxon-Mann–Whitney. c Outcomes in women achieving pregnancy during follow-up. Four of six women with SLE NAP were nulliparous, and a higher frequency smoked, had active disease or were overweight compared with SLE-women AP. Women with RA NAP were older and had a history of preeclampsia more frequently than women with RA AP (Table 4). Table 4 Background and clinical characteristics in women with SLE and RA AP and NAP Characteristic SLE SLE P-value RA RA P-value AP, n = 47 NAP, n = 6 AP, n = 130 NAP, n = 50 Maternal age, mean (s.d.), years 30.2 (4.0) 30.7 (3.8) 0.76 30.4 (4.4) 32.9 (4.7) 0.001     Missing, n 0 0 0 0 Parity 0.29a,b 0.28a,b     0 24 (52.2) 4 (80.0) 63 (51.2) 29 (60.4)     1 17 (37.0) 0 44 (35.8) 13 (27.1)     2+ 5 (10.8) 1 (20.0) 16 (13.0) 6 (12.5)     Missing, n 1 1 7 2 Positive history of smoking 4 (9.8) 1 (16.7) 0.84b 9 (7.6) 3 (6.0) 0.75b     Missing, n 6 0 11 0 BMI, mean (s.d.) 24.5 (5.4) 28.0 (6.5) 0.16 24.9 (4.6) 25.5 (5.2) 0.64     Missing, n 13 1 23 0 Educational level 0.61c 0.60c     Lowd 3 (6.4) 1 (16.7) 3 (2.5) 1 (2.0)     Intermediatee 9 (19.1) 1 (16.7) 28 (23.3) 14 (28.0)     Highf 35 (74.5) 4 (66.7) 89 (74.2) 35 (70.0)     Missing, n 0 0 10 0 Age at diagnosis, mean (s.d.), years 21.4 (6.1) 23.3 (5.8) 0.47 25.1 (6.0) 26.0 (5.5) 0.35     Missing, n 4 0 9 3 ACR criteria fulfilledg 31 (91.2) 3 (100.0) 0.86b 87 (84.5) 32 (84.2) 0.99b     Missing, n 13 3 27 12 Disease duration, mean (s.d.), years 8.8 (6.2) 7.3 (5.8) 0.60 5.3 (4.9) 6.7 (4.7) 0.088     Missing, n 4 0 9 3 Active disease 21 (63.6) 3 (100.0) 0.27b 45 (41.7) 14 (31.8) 0.27b     Missing, n 14 3 22 6 Prior pregnancy loss 14 (31.1) 1 (20.0) 0.81b 30 (28.3) 11 (26.8) 0.95b     Missing, n 2 1 24 9 Prior preterm birth 1 (5.0) 0 1.0b 2 (3.9) 0 0.82b     Missing, n 2 0 9 3 Prior preeclampsia 2 (13.3) 0 1.0b 3 (7.3) 4 (36.4) 0.018b     Missing, n 7 0 19 8 Characteristic SLE SLE P-value RA RA P-value AP, n = 47 NAP, n = 6 AP, n = 130 NAP, n = 50 Maternal age, mean (s.d.), years 30.2 (4.0) 30.7 (3.8) 0.76 30.4 (4.4) 32.9 (4.7) 0.001     Missing, n 0 0 0 0 Parity 0.29a,b 0.28a,b     0 24 (52.2) 4 (80.0) 63 (51.2) 29 (60.4)     1 17 (37.0) 0 44 (35.8) 13 (27.1)     2+ 5 (10.8) 1 (20.0) 16 (13.0) 6 (12.5)     Missing, n 1 1 7 2 Positive history of smoking 4 (9.8) 1 (16.7) 0.84b 9 (7.6) 3 (6.0) 0.75b     Missing, n 6 0 11 0 BMI, mean (s.d.) 24.5 (5.4) 28.0 (6.5) 0.16 24.9 (4.6) 25.5 (5.2) 0.64     Missing, n 13 1 23 0 Educational level 0.61c 0.60c     Lowd 3 (6.4) 1 (16.7) 3 (2.5) 1 (2.0)     Intermediatee 9 (19.1) 1 (16.7) 28 (23.3) 14 (28.0)     Highf 35 (74.5) 4 (66.7) 89 (74.2) 35 (70.0)     Missing, n 0 0 10 0 Age at diagnosis, mean (s.d.), years 21.4 (6.1) 23.3 (5.8) 0.47 25.1 (6.0) 26.0 (5.5) 0.35     Missing, n 4 0 9 3 ACR criteria fulfilledg 31 (91.2) 3 (100.0) 0.86b 87 (84.5) 32 (84.2) 0.99b     Missing, n 13 3 27 12 Disease duration, mean (s.d.), years 8.8 (6.2) 7.3 (5.8) 0.60 5.3 (4.9) 6.7 (4.7) 0.088     Missing, n 4 0 9 3 Active disease 21 (63.6) 3 (100.0) 0.27b 45 (41.7) 14 (31.8) 0.27b     Missing, n 14 3 22 6 Prior pregnancy loss 14 (31.1) 1 (20.0) 0.81b 30 (28.3) 11 (26.8) 0.95b     Missing, n 2 1 24 9 Prior preterm birth 1 (5.0) 0 1.0b 2 (3.9) 0 0.82b     Missing, n 2 0 9 3 Prior preeclampsia 2 (13.3) 0 1.0b 3 (7.3) 4 (36.4) 0.018b     Missing, n 7 0 19 8 Reported as n (%) unless otherwise stated. a No children vs one or more child. b The unconditional z-pooled test. c Exact Wilcoxon-Mann–Whitney. d 10 years. e 12–13 years. f >15 years. g According to diagnosis. AP: achieving pregnancy; NAP: not achieving pregnancy. Table 4 Background and clinical characteristics in women with SLE and RA AP and NAP Characteristic SLE SLE P-value RA RA P-value AP, n = 47 NAP, n = 6 AP, n = 130 NAP, n = 50 Maternal age, mean (s.d.), years 30.2 (4.0) 30.7 (3.8) 0.76 30.4 (4.4) 32.9 (4.7) 0.001     Missing, n 0 0 0 0 Parity 0.29a,b 0.28a,b     0 24 (52.2) 4 (80.0) 63 (51.2) 29 (60.4)     1 17 (37.0) 0 44 (35.8) 13 (27.1)     2+ 5 (10.8) 1 (20.0) 16 (13.0) 6 (12.5)     Missing, n 1 1 7 2 Positive history of smoking 4 (9.8) 1 (16.7) 0.84b 9 (7.6) 3 (6.0) 0.75b     Missing, n 6 0 11 0 BMI, mean (s.d.) 24.5 (5.4) 28.0 (6.5) 0.16 24.9 (4.6) 25.5 (5.2) 0.64     Missing, n 13 1 23 0 Educational level 0.61c 0.60c     Lowd 3 (6.4) 1 (16.7) 3 (2.5) 1 (2.0)     Intermediatee 9 (19.1) 1 (16.7) 28 (23.3) 14 (28.0)     Highf 35 (74.5) 4 (66.7) 89 (74.2) 35 (70.0)     Missing, n 0 0 10 0 Age at diagnosis, mean (s.d.), years 21.4 (6.1) 23.3 (5.8) 0.47 25.1 (6.0) 26.0 (5.5) 0.35     Missing, n 4 0 9 3 ACR criteria fulfilledg 31 (91.2) 3 (100.0) 0.86b 87 (84.5) 32 (84.2) 0.99b     Missing, n 13 3 27 12 Disease duration, mean (s.d.), years 8.8 (6.2) 7.3 (5.8) 0.60 5.3 (4.9) 6.7 (4.7) 0.088     Missing, n 4 0 9 3 Active disease 21 (63.6) 3 (100.0) 0.27b 45 (41.7) 14 (31.8) 0.27b     Missing, n 14 3 22 6 Prior pregnancy loss 14 (31.1) 1 (20.0) 0.81b 30 (28.3) 11 (26.8) 0.95b     Missing, n 2 1 24 9 Prior preterm birth 1 (5.0) 0 1.0b 2 (3.9) 0 0.82b     Missing, n 2 0 9 3 Prior preeclampsia 2 (13.3) 0 1.0b 3 (7.3) 4 (36.4) 0.018b     Missing, n 7 0 19 8 Characteristic SLE SLE P-value RA RA P-value AP, n = 47 NAP, n = 6 AP, n = 130 NAP, n = 50 Maternal age, mean (s.d.), years 30.2 (4.0) 30.7 (3.8) 0.76 30.4 (4.4) 32.9 (4.7) 0.001     Missing, n 0 0 0 0 Parity 0.29a,b 0.28a,b     0 24 (52.2) 4 (80.0) 63 (51.2) 29 (60.4)     1 17 (37.0) 0 44 (35.8) 13 (27.1)     2+ 5 (10.8) 1 (20.0) 16 (13.0) 6 (12.5)     Missing, n 1 1 7 2 Positive history of smoking 4 (9.8) 1 (16.7) 0.84b 9 (7.6) 3 (6.0) 0.75b     Missing, n 6 0 11 0 BMI, mean (s.d.) 24.5 (5.4) 28.0 (6.5) 0.16 24.9 (4.6) 25.5 (5.2) 0.64     Missing, n 13 1 23 0 Educational level 0.61c 0.60c     Lowd 3 (6.4) 1 (16.7) 3 (2.5) 1 (2.0)     Intermediatee 9 (19.1) 1 (16.7) 28 (23.3) 14 (28.0)     Highf 35 (74.5) 4 (66.7) 89 (74.2) 35 (70.0)     Missing, n 0 0 10 0 Age at diagnosis, mean (s.d.), years 21.4 (6.1) 23.3 (5.8) 0.47 25.1 (6.0) 26.0 (5.5) 0.35     Missing, n 4 0 9 3 ACR criteria fulfilledg 31 (91.2) 3 (100.0) 0.86b 87 (84.5) 32 (84.2) 0.99b     Missing, n 13 3 27 12 Disease duration, mean (s.d.), years 8.8 (6.2) 7.3 (5.8) 0.60 5.3 (4.9) 6.7 (4.7) 0.088     Missing, n 4 0 9 3 Active disease 21 (63.6) 3 (100.0) 0.27b 45 (41.7) 14 (31.8) 0.27b     Missing, n 14 3 22 6 Prior pregnancy loss 14 (31.1) 1 (20.0) 0.81b 30 (28.3) 11 (26.8) 0.95b     Missing, n 2 1 24 9 Prior preterm birth 1 (5.0) 0 1.0b 2 (3.9) 0 0.82b     Missing, n 2 0 9 3 Prior preeclampsia 2 (13.3) 0 1.0b 3 (7.3) 4 (36.4) 0.018b     Missing, n 7 0 19 8 Reported as n (%) unless otherwise stated. a No children vs one or more child. b The unconditional z-pooled test. c Exact Wilcoxon-Mann–Whitney. d 10 years. e 12–13 years. f >15 years. g According to diagnosis. AP: achieving pregnancy; NAP: not achieving pregnancy. Medication at inclusion Traditional NSAIDs were used more often in women with RA and prednisolone more often in women with SLE (Table 2) before pregnancy. The most commonly used DMARD was HCQ in SLE (80.8%) and SSZ in RA (28.6%). One (1.9%) SLE-woman and 20 (11.4%) RA-women used MTX, while 3 (5.8%) SLE-women used MMF preconceptionally. Fifty-one (29.1%) RA-women used TNF-α inhibitors at inclusion (see supplementary Table S1, available at Rheumatology online). HRQoL There were no statistically significant differences comparing HRQoL in women AP and NAP in the two groups. However, women with SLE NAP had lower mean scores than women with SLE AP, exceeding the minimal clinically important difference in several domains (Diff score ⩾5) (Table 5). Table 5 HRQoL in women with SLE and RA AP and NAP Domain SLE SLE P-value Diff score RA RA P-value Diff score AP, n = 47 NAP, n = 6 AP, n = 130 NAP, n = 50 Physical function 90.2 (13.5) 80.8 (21.1) 0.33 −9.4 80.1 (19.8) 78.9 (22.1) 0.74 −1.2     Missing, n 5 0 19 6 Physical role 65.2 (40.7) 45.8 (40.1) 0.28 −19.4 58.9 (40.4) 57.4 (45.0) 0.85 −1.5     Missing, n 5 0 19 6 Bodily pain 72.5 (23.6) 79.0 (31.6) 0.55 +6.5 61.8 (24.0) 65.4 (25.4) 0.42 +3.6     Missing, n 5 0 19 6 General health 60.3 (26.1) 56.0 (13.9) 0.55 −4.3 57.5 (21.9) 57.0 (24.1) 0.90 −0.5     Missing, n 5 0 20 6 Vitality 50.7 (22.4) 42.5 (27.2) 0.42 −8.2 48.0 (19.9) 50.1 (21.0) 0.56 +2.1     Missing, n 5 0 19 7 Social function 75.0 (24.4) 64.6 (27.9) 0.34 −10.4 80.6 (22.8) 80.4 (21.3) 0.95 −0.2     Missing, n 5 0 19 6 Role emotional 79.4 (36.8) 50.0 (46.0) 0.082 −29.4 81.7 (32.3) 77.3 (35.1) 0.46 −4.4     Missing, n 5 0 19 6 Mental health 74.9 (14.7) 68.7 (12.8) 0.53 −6.2 77.7 (13.7) 80.2 (15.4) 0.33 +2.5     Missing, n 5 0 19 7 Domain SLE SLE P-value Diff score RA RA P-value Diff score AP, n = 47 NAP, n = 6 AP, n = 130 NAP, n = 50 Physical function 90.2 (13.5) 80.8 (21.1) 0.33 −9.4 80.1 (19.8) 78.9 (22.1) 0.74 −1.2     Missing, n 5 0 19 6 Physical role 65.2 (40.7) 45.8 (40.1) 0.28 −19.4 58.9 (40.4) 57.4 (45.0) 0.85 −1.5     Missing, n 5 0 19 6 Bodily pain 72.5 (23.6) 79.0 (31.6) 0.55 +6.5 61.8 (24.0) 65.4 (25.4) 0.42 +3.6     Missing, n 5 0 19 6 General health 60.3 (26.1) 56.0 (13.9) 0.55 −4.3 57.5 (21.9) 57.0 (24.1) 0.90 −0.5     Missing, n 5 0 20 6 Vitality 50.7 (22.4) 42.5 (27.2) 0.42 −8.2 48.0 (19.9) 50.1 (21.0) 0.56 +2.1     Missing, n 5 0 19 7 Social function 75.0 (24.4) 64.6 (27.9) 0.34 −10.4 80.6 (22.8) 80.4 (21.3) 0.95 −0.2     Missing, n 5 0 19 6 Role emotional 79.4 (36.8) 50.0 (46.0) 0.082 −29.4 81.7 (32.3) 77.3 (35.1) 0.46 −4.4     Missing, n 5 0 19 6 Mental health 74.9 (14.7) 68.7 (12.8) 0.53 −6.2 77.7 (13.7) 80.2 (15.4) 0.33 +2.5     Missing, n 5 0 19 7 Reported as mean (s.d.) unless otherwise stated. AP: achieving pregnancy; NAP: not achieving pregnancy; HRQoL: health-related quality of life. Table 5 HRQoL in women with SLE and RA AP and NAP Domain SLE SLE P-value Diff score RA RA P-value Diff score AP, n = 47 NAP, n = 6 AP, n = 130 NAP, n = 50 Physical function 90.2 (13.5) 80.8 (21.1) 0.33 −9.4 80.1 (19.8) 78.9 (22.1) 0.74 −1.2     Missing, n 5 0 19 6 Physical role 65.2 (40.7) 45.8 (40.1) 0.28 −19.4 58.9 (40.4) 57.4 (45.0) 0.85 −1.5     Missing, n 5 0 19 6 Bodily pain 72.5 (23.6) 79.0 (31.6) 0.55 +6.5 61.8 (24.0) 65.4 (25.4) 0.42 +3.6     Missing, n 5 0 19 6 General health 60.3 (26.1) 56.0 (13.9) 0.55 −4.3 57.5 (21.9) 57.0 (24.1) 0.90 −0.5     Missing, n 5 0 20 6 Vitality 50.7 (22.4) 42.5 (27.2) 0.42 −8.2 48.0 (19.9) 50.1 (21.0) 0.56 +2.1     Missing, n 5 0 19 7 Social function 75.0 (24.4) 64.6 (27.9) 0.34 −10.4 80.6 (22.8) 80.4 (21.3) 0.95 −0.2     Missing, n 5 0 19 6 Role emotional 79.4 (36.8) 50.0 (46.0) 0.082 −29.4 81.7 (32.3) 77.3 (35.1) 0.46 −4.4     Missing, n 5 0 19 6 Mental health 74.9 (14.7) 68.7 (12.8) 0.53 −6.2 77.7 (13.7) 80.2 (15.4) 0.33 +2.5     Missing, n 5 0 19 7 Domain SLE SLE P-value Diff score RA RA P-value Diff score AP, n = 47 NAP, n = 6 AP, n = 130 NAP, n = 50 Physical function 90.2 (13.5) 80.8 (21.1) 0.33 −9.4 80.1 (19.8) 78.9 (22.1) 0.74 −1.2     Missing, n 5 0 19 6 Physical role 65.2 (40.7) 45.8 (40.1) 0.28 −19.4 58.9 (40.4) 57.4 (45.0) 0.85 −1.5     Missing, n 5 0 19 6 Bodily pain 72.5 (23.6) 79.0 (31.6) 0.55 +6.5 61.8 (24.0) 65.4 (25.4) 0.42 +3.6     Missing, n 5 0 19 6 General health 60.3 (26.1) 56.0 (13.9) 0.55 −4.3 57.5 (21.9) 57.0 (24.1) 0.90 −0.5     Missing, n 5 0 20 6 Vitality 50.7 (22.4) 42.5 (27.2) 0.42 −8.2 48.0 (19.9) 50.1 (21.0) 0.56 +2.1     Missing, n 5 0 19 7 Social function 75.0 (24.4) 64.6 (27.9) 0.34 −10.4 80.6 (22.8) 80.4 (21.3) 0.95 −0.2     Missing, n 5 0 19 6 Role emotional 79.4 (36.8) 50.0 (46.0) 0.082 −29.4 81.7 (32.3) 77.3 (35.1) 0.46 −4.4     Missing, n 5 0 19 6 Mental health 74.9 (14.7) 68.7 (12.8) 0.53 −6.2 77.7 (13.7) 80.2 (15.4) 0.33 +2.5     Missing, n 5 0 19 7 Reported as mean (s.d.) unless otherwise stated. AP: achieving pregnancy; NAP: not achieving pregnancy; HRQoL: health-related quality of life. Discussion In our study, women with SLE had higher pregnancy ratio and shorter TTP compared with women with RA. We found no differences in background characteristics to explain this finding, but there are differences in disease-related characteristics that may be of relevance. Women with SLE were younger at diagnosis and had longer disease duration at inclusion. It may be of advantage to have time to accept and adjust to a chronic disease before family planning is relevant, as opposed to acquiring a disease when the wish for and expectations about having children have already been expressed. This is in accordance with earlier findings comparing women with juvenile arthritis and RA [39]. Previous studies have found that both disease groups have increased subfertility and reduced TFRs compared with population controls [8, 10, 14, 15, 39, 40]. Generally, age is one of the main factors determining subfertility [41]. In our study, women with SLE had a mean age similar to the general obstetric population in Norway [42], with no significant difference between women AP and NAP. Accordingly, age does not seem to influence fertility in women with SLE, besides the general increase in maternal age at first birth [8]. In contrast, women with RA had a substantially higher mean age, found to be statistically significantly higher in women NAP compared with women AP. Previous studies showed that women who were childless at diagnosis had lower parity than matched references [39]. In both women with SLE and RA NAP, we found higher frequencies of nulliparity compared with in women AP, even though the small SLE group demands caution in interpreting the results. During follow-up, 19.1% (9/47) of women with SLE and 20.0% (26/130) with RA AP had pregnancy loss, respectively, indicating no difference in fecundity. This is in contrast to earlier findings reporting a higher frequency of pregnancy loss in women with SLE than women with RA [10]. In the general population the pregnancy loss rate is commonly reported to be lower, around 15% [43, 44]. It is possible that early miscarriages were acknowledged and reported more often due to the tight follow-up in the RevNatus register. However, higher occurrence of miscarriages in SLE after diagnosis compared with before diagnosis [45] are reported. Similarly, women with RA had a higher relative risk of miscarriage compared with reference women without inflammatory rheumatic disease in a recent Norwegian study [12]. Positive aPL is associated with pregnancy loss, and this is well documented in SLE [46, 47]. The SLE-women in our population that had a pregnancy loss did not have any positive aPL (missing data in two of nine women). The biological and clinical meaning of aPL concerning fertility remains to be clarified [48]. Due to the high level of missing data in the registration of these antibodies, we can not assess their impact in our population of women with SLE and RA. In our study, only one miscarriage was reported associated with medication with teratogenic potential (MTX) used <3 months before pregnancy or during pregnancy. No other associations between medication and pregnancy loss were found. Diminished ovarian reserve due to SLE and RA itself is discussed as a reason for lower TFR, although it is controversial [20–23]. Unfortunately, neither Anti-Müllerian hormone (AMH) levels nor antral follicle count to assess this were registered in RevNatus. Prior CYC administration is a proven risk factor for ovarian failure and decreasing AMH levels [49]. In our study, two women with SLE (with live births) had been treated with CYC >5 years earlier, but none of the women NAP in either diagnosis group was treated with CYC in the past or at inclusion. Accordingly, CYC does not affect the ability to achieve pregnancy in our cohort. NSAID use may cause ovulatory disturbances and transiently reduce fertility [49]. None of the SLE-women NAP used NSAIDs, while 18.4% of RA-women NAP did, potentially extending TTP and amplifying the age factor. Moreover, we found a substantially higher (although not statistically significant) use of NSAIDs in women with RA NAP than AP, possibly strengthening this effect. A lower frequency of women with SLE (7.7%) used DMARDs incompatible with pregnancy at inclusion compared with women with RA (11.4%). In SLE-women NAP, MMF was used in one woman at inclusion, while in RA-women NAP, MTX was used in 14.3% at inclusion. Accordingly, the need to adjust medication and ensure a clinically acceptable disease-modifying effect before conception may be required more often in women with RA, resulting in extended TTP and higher maternal age. Nevertheless, in 13 women with RA AP there were 12 live births and one miscarriage. They were all exposed to MTX <3 months before pregnancy or in early pregnancy, illustrating that medication use does not always delay conception. There were no statistically significant differences concerning use of MTX in RA-women AP and NAP, supporting recent studies demonstrating that MTX use does not reduce ovarian function [9, 22]. Women with SLE more frequently had active disease, a known risk factor for reduced fertility and fecundity [14, 47], and in the small group of SLE-women NAP this was even more apparent. However, women with active SLE had mainly low disease activity (LAI <0.5) with mean LAI 0.28 (0.063–0.79), while women with active RA had moderate disease activity (DAS-CRP >3.2) with mean DAS-CRP 3.62 (2.80–6.39). We believe this can explain why disease activity does not interfere more with fertility and fecundity in the women with SLE in our cohort. Women with SLE failing to conceive had poorer HRQoL than SLE-women AP. In the domains physical role, social function and role emotional we found a clear change (deterioration), and in the domains physical function, vitality and mental health a marginal change compared with the SLE-women AP. In this group, reduced HRQoL in the domains social function, role emotional and mental health may impair sexual function, in line with earlier findings [10, 25]. The low HRQoL scores in both disease groups concerning vitality and general health may impact TTP and the choice or ability to achieve pregnancy. Women with RA had similar but generally low scores whether AP or NAP concerning physical role and bodily pain, implicating physical hindrance to sexual activity, while social functioning, role emotional and mental health domains were higher. Our results indicate that women with RA have a generally lower HRQoL than women with SLE, and that this is a probable risk factor for prolonged TTP and lower TFR in these women. A strength of this study is the prospective follow-up design, securing more accurate and unbiased registration of disease activity, medication use and HRQoL domains. A possible weakness is that some of the women may not have a pregnancy wish at the time of inclusion in the register, but plan pregnancy in the future. Not excluding a patient when a pregnancy wish is no longer present is another potential bias. However, we excluded 22 women because pregnancy was no longer relevant due to changing social status or other life events, reducing this source of error. A selection bias may be that SLE is a potentially more serious disease than RA, and that women with severe SLE do not try to conceive, while this is rarely the case in women with RA. Another selection bias might be that women with mild disease, especially RA, are not recruited into RevNatus, biasing our population towards more severe disease. However, pregnant women with rheumatic diseases should have preconception counselling and specialized health care follow-up [2, 19, 29, 46, 47], which should mean recruitment in RevNatus. In our prospective study, women with SLE had fewer problems in AP than women with RA. There was a similar occurrence of pregnancy loss, indicating reduced fecundity in both groups compared with references without rheumatic disease. In women with RA, higher maternal age, more use of NSAIDs and medication not compatible with pregnancy together with a lower HRQoL compared with women with SLE are factors impacting negatively on TTP and TFR. These findings may be helpful in counselling women with rheumatic diseases who plan pregnancy. Focus on disease activity and medication needs continued attention, and maternal age must be acknowledged as an important risk factor for reduced fertility. Moreover, assessing HRQoL may identify factors contributing to NAP. Acknowledgements The authors would like to thank the participating departments of rheumatology at the following hospitals for including patients in RevNatus: Betanien Hospital, Skien; Diakonhjemmet Hospital, Oslo; Haugesund Sanitetsforenings Rheumatism Hospital, Haugesund; Haukeland University Hospital, Bergen; Helse Førde, Førde Hospital, Førde; Helse Møre og Romsdal, Ålesund Hospital, Ålesund; Lillehammer Hospital for Rheumatic Diseases, Lillehammer; Nordland Hospital, Bodø; Oslo University Hospital Rikshospitalet, Oslo; Private practice Anne N. 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Nat Rev Rheumatol 2017 ; 13 : 485 – 93 . 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 14, 2018

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