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Zusman E, Sayre EC, Aviña-Zubieta JA, De Vera MA. Patterns of Medication Use Before, During, and After Pregnancy in Women with Systemic Lupus Erythematosus: A Population-Based Cohort Study. Lupus. 2019 Jul 16:961203319863111.
University of British Columbia. Collaboration for Outcomes Research and Evaluation
Zusman, Enav Zipora
Sayre, E. C.
Aviña-Zubieta, J. Antonio
De Vera, Mary
Objectives: This study aimed to characterize the patterns of medication use before, during and after pregnancy in a population-based cohort of women with systemic lupus erythematosus (SLE). Methods: Using population-based administrative data in British Columbia, Canada with valid information on start date of pregnancy, we identified women with SLE who had singleton pregnancies ending in deliveries between January 1st, 2002 and December 31st, 2012. We assessed the proportion of SLE pregnancies exposed to SLE medications – namely antimalarials and immunosuppressants – as well as glucocorticosteroids, and nonsteroidal anti-inflammatory drugs (NSAIDs) 24 months before pregnancy, each trimester of pregnancy, and 12 months post-pregnancy. We also assessed discontinuation of antimalarials and immunosuppressants, defined as no prescriptions in a given window following a prescription in a preceding window. Results: Of 376 pregnancies (284 women) with SLE, 24.2% had one or more dispensing for antimalarials, 8.2% for azathioprine, 19.7% for glucocorticosteroids and 4.8% for NSAIDs during pregnancy. We observed 16.7% discontinuation of antimalarials in the year prior to pregnancy, 29.8% in the first trimester, 9.7% in the second trimester, and 26% in the third trimester. We also observed 29.2% discontinuation of azathioprine in the first trimester, 8% in the second trimester, and 9% in the third trimester. Conclusions: These population-based data show frequent discontinuation of medications, particularly antimalarials, in SLE pregnancies. Findings suggest the importance of educating women with SLE who are pregnant or planning to become pregnant on the benefits and risks of medications during pregnancy.
1 Patterns of Medication Use Before, During, and After Pregnancy in Women with Systemic Lupus Erythematosus: A Population-Based Cohort Study Authors: Enav Z. Zusman, MSc1,2,3; Eric C. Sayre, PhD3; J. Antonio Aviña-Zubieta, MD, PhD3,4; Mary A. De Vera, PhD1,2,3 Author affiliations: 1University of British Columbia Faculty of Pharmaceutical Sciences, Vancouver, Canada; 2Collaboration for Outcomes Research and Evaluation, Vancouver, Canada; 3Arthritis Research Canada, Richmond, BC, Canada; 4University of British Columbia Faculty of Medicine, Department of Medicine, Division of Rheumatology, Vancouver, Canada Key words: systemic lupus erythematosus, pregnancy, reproduction, medications Manuscript word count: 3297 Titles, funding, and grant support: Dr. De Vera holds a Canada Research Chair in Medication Adherence, Utilization, and Outcomes and is a Michael Smith Foundation for Health Research Scholar. Dr. Aviña-Zubieta is a Michael Smith Foundation for Health Research Scholar and the BC Lupus Society Scholar. 2 Ms. Zusman received financial support from Bong Pang Yee Endowment Fund for her work on this project. This research was funded by an operating grant from The Arthritis Society (YIO-13-07). Corresponding author: Mary A. De Vera, PhD University of British Columbia Faculty of Pharmaceutical Sciences 2405 Wesbrook Mall Vancouver, BC, V6T 1Z3 Tel: 604-221-8767; Email: mdevera@mail.ubc.ca ABSTRACT Objectives: This study aimed to characterize the patterns of medication use before, during and after pregnancy in a population-based cohort of women with systemic lupus erythematosus (SLE). Methods: Using population-based administrative data in British Columbia, Canada with valid information on start date of pregnancy, we identified women with SLE who had singleton pregnancies ending in deliveries between January 1st, 2002 and December 31st, 2012. We assessed the proportion of SLE pregnancies exposed to SLE medications – namely antimalarials and immunosuppressants – as well as glucocorticosteroids, and nonsteroidal anti-inflammatory drugs 3 (NSAIDs) 24 months before pregnancy, each trimester of pregnancy, and 12 months post-pregnancy. We also assessed discontinuation of antimalarials and immunosuppressants, defined as no prescriptions in a given window following a prescription in a preceding window. Results: Of 376 pregnancies (284 women) with SLE, 24.2% had one or more dispensing for antimalarials, 8.2% for azathioprine, 19.7% for glucocorticosteroids and 4.8% for NSAIDs during pregnancy. We observed 16.7% discontinuation of antimalarials in the year prior to pregnancy, 29.8% in the first trimester, 9.7% in the second trimester, and 26% in the third trimester. We also observed 29.2% discontinuation of azathioprine in the first trimester, 8% in the second trimester, and 9% in the third trimester. Conclusions: These population-based data show frequent discontinuation of medications, particularly antimalarials, in SLE pregnancies. Findings suggest the importance of educating women with SLE who are pregnant or planning to become pregnant on the benefits and risks of medications during pregnancy. 4 INTRODUCTION Systemic lupus erythematosus (SLE) is a systemic and chronic inflammatory connective tissue disease that is classified as an autoimmune disease. It primarily affects women, often during reproductive years (1). SLE pregnancies are considered high risk (2), as pregnant women with SLE have a greater risk of pregnancy-related complications such as miscarriage, stillbirth, preeclampsia, eclampsia, preterm labor and fetal growth restriction (3–6). Between 25 and 50% of pregnant women with SLE experience flares either during pregnancy or after giving birth, usually during the second and third trimester or in the months following the birth (7,8). High disease activity and flares before and during pregnancy are associated with poor pregnancy prognosis, while low disease activity is associated with normal or close to normal pregnancy outcomes in most women with SLE (2,9,10). In order to manage active disease and reduce the risk of adverse pregnancy, fetal and neonatal outcomes, it is important to keep managing the disease for the duration of the pregnancy (2,9,11). Advances in medicine and medical research over the last few decades, a better understanding of the course of the disease and its progression, and the availability of medications considered effective and safe during pregnancy have led to better outcomes for both the mother and child (9,12). The most commonly used medications for SLE are antimalarials (chloroquine and hydroxychloroquine), immunosuppressants (azathioprine, cyclosporine, cyclophosphamide, leflunomide, methotrexate, and mycophenolate mofetil), which are taken chronically for disease control, and glucocorticosteroids, which are used in flares. With the importance of disease control during SLE pregnancies and increasing evidence on safety, the 4th International Conference on Sex Hormones, Pregnancy and the Rheumatic Diseases in 2006 led to a recommendation stating that when indicated, treatment with hydroxychloroquine should continue during pregnancy and lactation 5 for women with SLE (13). Knowing medication use in pregnant women with SLE is key to understanding how to support patients with family planning and pregnancy decisions. Few prior studies have examined medication use in pregnant women with SLE and showed varying frequencies of use prior to conception, during pregnancy, and post-partum (11,14). To add more nuanced information on patterns of medication use in SLE pregnancies, our objectives were: 1) to characterize the frequency of use of antimalarials, immunosuppressants as well as other medications, before, during, and after pregnancy; and 2) assess discontinuation of antimalarials and immunosuppressants during pregnancy. METHODS Data Sources Population Data British Columbia (Population Data BC) is an extensive data repository that holds individual-level, de-identified, longitudinal data on all health services covering the entire population of BC (estimated 4.7 million residents, May 2018 (15)). Data captured include provincially funded healthcare professionals visits, medically required (fee for service) services, laboratory and diagnostic procedures (16), hospital admissions and discharges (17), and demographics (18) and vital statistics (19,20), since 1990. Population Data BC also encompasses PharmaNet, a comprehensive database of prescription medications dispensed in community pharmacies since 1995 (21). Data used in this study were linked to the BC Perinatal Database Registry (22), which include antenatal, intrapartum, and postpartum maternal and infant data from medical records for almost all BC births, allowing us to assess date of conception. Data also include demographics information, date of conception, delivery and post-delivery information, obstetrics history, and lifestyle behaviors (e.g. smoking status and alcohol and recreational drug use). Indeed, the availability of information on date of conception 6 – based on gestational age using first trimester dating ultrasound or start date of last menstrual period – is a unique feature of this registry. Study Cohort The source population included women (n=305,351) with pregnancies (n=449,098) ending in births between January 1st, 2002 and December 31st, 2012 and covered by BC’s provincial health plan in the period of 24 months prior to and 12 months post-delivery. From the source population, we created a cohort of women with SLE which was defined using the following criteria: 1) having two International Classification of Diseases 9th Revision Codes (ICD-9) for SLE (710.0) from two separate physician visits that were at least 60 days apart and within two years, any time prior to the date of conception; or 2) having at least one hospitalization with an ICD-9 (710.0) or an ICD-10 code for SLE (M32.1, M32.8, M32.9), at any time prior to the date of conception (23). Given that the unit of analysis was individual pregnancy, each pregnancy had to satisfy the above criteria in order to be included in the analyses. Medication Use We used Canadian Drug Identity Codes in the BC PharmaNet to identify use of the SLE medications – namely, antimalarials (hydroxychloroquine, chloroquine) and immunosuppresants (azathioprine, cyclosporine, cyclophosphamide, leflunomide, methotrexate, and mycophenolate mofetil), as well as all prescribed glucocorticosteroids, and NSAIDs in the period between 24 months prior to conception and 12 months post-delivery. As shown in Figure 1, we divided this period into six windows: 1) 24 to 12 months before pregnancy (BC1); 2) 12 months before pregnancy (BC2); 3) first trimester, calculated from the date of conception to 13 weeks (T1); 4) second trimester, calculated from 13 weeks to 26 weeks from the date of conception (T2); 5) third 7 trimester, calculated from 26 weeks to date of delivery; and 6) 12 months after delivery or post-partum (PP). Statistical Analysis We calculated summary statistics of demographic information to describe the study cohort. We determined the proportion of SLE pregnancies exposed to aforementioned medications for each window and also looked at overall medication use during pregnancy per year for antimalarials, azathioprine, glucocorticosteroids and NSAIDs. We then assessed patterns of use of antimalarials and immunosuppresants during pregnancy in terms of discontinuation, defined as no prescription in a given window following at least one prescription in a preceding window. To further examine medication discontinuation, we assessed determinants with multivariable logistic regression models, using generalized estimating equations (GEE) to account for data clusters (e.g. multiple pregnancies clustered by one woman). Covariance structures were selected for the most appropriate model fit (according to lowest quasi information criterion) and computed standard errors of parameter estimates using robust sandwich estimators. We considered as potential determinants, factors that could affect medication use pattern and discontinuation, as indicated in the literature (24,25). These included: prior obstetrical history (prior premature delivery, spontaneous abortions, neonatal death, stillbirth, low birth weight, and congenital anomalies), comorbidities, maternal age at delivery, socioeconomic status based on neighborhood income quintile, and health care utilization (number of antenatal visits, hospitalization). Finally, we compared discontinuation of antimalarials in the periods 2001 to 2006 and 2007 to 2012 to determine potential changes in pattern of use following aforementioned recommendations from the Fourth International Conference on Sex Hormones, Pregnancy and the 8 Rheumatic Diseases in 2006. Finally, all reporting adhered to data sharing agreements, including suppression of cell sizes (e.g., counts) less 6. All analyses were performed using SAS v9.4 (SAS Institute, Cary, North Carolina). Study Conduct We obtained ethics approval from the University of British Columbia Behavioural Research Ethics Board. All data were de-identified and no personal information was available at any point of the study; we followed BC’s Freedom of Information and Privacy Protection Act for all study procedures. This study was funded by The Arthritis Society. The funder played no role in the design or conduct of the study, or in writing this manuscript. All inferences, opinions, and conclusions drawn in this manuscript are those of the authors, and do not reflect the opinions or policies of the Data Steward(s). RESULTS We identified 376 pregnancies from 284 women who were diagnosed with SLE prior to conception. Maternal and pregnancy characteristics are summarized in Table 1. The mean (standard deviation [SD]) age at delivery for our cohort was 31.6 (5.1) and the mean (SD) BMI was 24.8 (5.0) with about fifth of pregnancies being in women who were either overweight or obese. Forty-two pregnancies (11.2%) were in women with SLE nephritis and the mean (SD) gestational age at delivery was 37.5 (2.6) weeks with 38.0% of pregnancies being the first pregnancy for the women and 37.8% of pregnancies ended in a Caesarean section. From 2002 to 2012, considering the entire period of interest before, during, and after pregnancy, overall proportions of SLE pregnancies exposed to antimalarials were 33.2% and azathioprine 9 11.4%. With respect to other medications used during the entire period, 26.3% of SLE pregnancies were exposed to glucocorticosteroids and 23.7% to NSAIDs. Assessment of perinatal medication use by year illustrated in Figure 2 shows wide variation of use of antimalarials ranging from a high of 35.3% in 2005 to a low of 8.3% in 2012. Table 2 summarizes the proportion of SLE pregnancies exposed to medications during specific windows. With respect to antimalarials, 36.2% of SLE pregnancies were exposed before pregnancy. This was followed by lower proportions during pregnancy with 19.1% in the first trimester, 16.7% in the second trimester, and 17.0% in the third trimester, and resumption after pregnancy with 31.1%. Assessment of immunosuppresants show that azathioprine is the most commonly used, with similar patterns of higher proportions of exposed pregnancies before pregnancy (11.7%), lower during pregnancy with 6.6% in the first trimester, 6.4% in the second trimester, and 6.9% in the third trimester and resumption after pregnancy (10.4%). We observed low proportions of exposure before pregnancy to methotrexate (3.5%), mycophenolate (3.2%), and minocycline (2.9%). Finally, with respect to other medications, we observed 33.2% exposure to glucocorticosteroids before pregnancy, 14.9% in the first trimester, 13.3% in the second trimester, 19.7% in the third trimester and 25.3% after pregnancy. As for NSAIDs, 34.8% were exposed before pregnancy and 19.1% after pregnancy. As shown in Figure 3, there was 16.67% discontinuation of antimalarials between the two windows before pregnancy and 28.9% discontinuation from the 12 months before to the start date of pregnancy. During pregnancy, there was 9.7% discontinuation from the first trimester to the second trimester and 26% from the second trimester to the third trimester. When we assessed potential determinants of discontinuation, we found multi-parity to be associated with higher odds of 10 discontinuing antimalarials from the 12 months before to the start date of pregnancy (odds ratio, 3.80, 95% confidence interval, 1.48 to 9.75), and time since SLE diagnosis to be associated with higher odds of discontinuing antimalarials during pregnancy (odds ratio, 1.50, 95% confidence interval, 1.07 to 2.09) In addition, Figure 3 is comparing the discontinuation of antimalarials for the periods, 2001 to 2006 and 2007 to 2012 shows that despite aforementioned recommendations in 2006 declaring antimalarials safe to use during pregnancy, no change in antimalarial discontinuation was seen in the latter period. Given small cell sizes, we were only able to additionally assess discontinuation for azathioprine. Figure 4 shows similar patterns of discontinuation of azathioprine between the two windows before pregnancy (11.5%), before the start date of pregnancy (29.2%), and during trimesters of pregnancy, 8% between second and first trimester, and 9.1% between third and second trimester. DISCUSSION Our objective was to assess patterns of medication use in SLE pregnancies before, during, and after pregnancy using a population-based cohort of women who were diagnosed with SLE before conception. A potentially novel contribution of our study is delineating patterns of use, particularly discontinuation of SLE medications in relevant windows. Indeed among women with chronic disease, pregnancy is often a well-planned event for which preparation can begin months prior to pregnancy (26). In our study, we found discontinuation of antimalarials leading up to pregnancy with 16.7% from 24 months to 12 months before pregnancy and 28.9% from the 12 months to the start of pregnancy. We also found discontinuation in 9.7% from the first trimester to the second trimester and 26% from the second trimester to the third trimester. As these findings conflict with aforementioned recommendations regarding the continued use of antimalarials during SLE 11 pregnancies, they suggest the importance of educating women with SLE who are pregnant or planning to become pregnant on the benefits and risks of medications during pregnancy. We compare our findings with prior studies assessing medication use in SLE pregnancies in other countries, in terms of proportions of pregnancies exposed to antimalarials before and during pregnancy. While 36.2% of our cohort took antimalarials within the two years prior to conception and 24.2% of our cohort took antimalarials during pregnancy, higher use of antimalarials was reported in a US study using administrative data of 712 women with SLE (11) with 60.9% using antimalarials in the 3 month period prior to conception and 34.0% during pregnancy. Using administrative data for 391 women in Sweden, the proportion of use of antimalarials in the 3 month period prior to conception was 23.4% and during pregnancy 36.4% (14). Our study expands on these prior studies in that we assessed medication use over a longer pre-conception period (up to two years) and additionally assessed the post-partum period, showing that 31.1% took antimalarials after delivery. Furthermore, although these prior studies reported declines in utilization of antimalarials with advancing trimesters of pregnancy, neither explicitly defined and assessed discontinuation, as with our study. We also considered our findings on utilization of medications, specifically before pregnancy, in context with medication use among patients with SLE in general. Particularly, we found lower antimalarial use in the one- and two-year period before pregnancy as compared to a multi-center cohort of Canadians living with SLE, with 66% taking antimalarials over their study period from 2005 to 2007, as reported by Bernatsky et al. (27). However, in addition to including both women (90.2%) and men (9.8%), their cohort was older than our cohort (mean age 44.3 vs. 31.6 years), which suggests that women in their study may not be in their fertile years (27). Furthermore, this 12 study was based on 10 clinical adult SLE cohort registries in Canada, which may reflect better care and subsequent medication use of participants as compared to our study, which was based on real-world, administrative data. Although we were primarily interested in antimalarial utilization and discontinuation, findings on perinatal utilization of other relevant medications bear discussion. The first of these is azathioprine. Approximately 60% of SLE patients are diagnosed with lupus nephritis at 5 years post-SLE diagnosis (28), yet, only 11.2% of our cohort was diagnosed with lupus nephritis, and they accounted for half of observed azathioprine use. Of SLE nephritis pregnancies who took azathioprine prior to pregnancy, all continued to take azathioprine in the two years prior to pregnancy, ⩽6 discontinued azathioprine during pregnancy and ⩽6 initiated azathioprine during pregnancy. The low proportion of lupus nephritis in our cohort compared to the general SLE population could account for our cohort’s reported lower azathioprine use. Another relevant medication is low-dose aspirin which is recommended by the European League Against Rheumatism and American College of Obstetricians and Gynecologists for prevention of preeclampsia among women with SLE who are pregnant (29,30). Yet, ⩽6 of our cohort’s pregnancies were prescribed low-dose aspirin. However, our results only captured prescription medications, and women could have taken over the counter low-dose aspirin, which could account for our findings of limited use. Indeed, managing SLE is particularly important in the perinatal period, as disease activity and flares before and during pregnancy were found to be associated with poor pregnancy prognosis and outcomes, such as fetal losses, preterm births, preeclampsia, and intrauterine growth retardation (2,9,10). This can potentially be reduced or avoided if the disease is kept under control during pregnancy and in the period of 6-12 months prior to conception (2,9,11). The risk of flare-up was 13 found to be higher in women who discontinued useful medications (in particular hydroxychloroquine) (31) The observed medication discontinuation of antimalarials during the first, second and third trimester (29.8%, 9.7% and 26%, respectively) could potentially be in part due to concerns and misinformation about medication teratogenicity and fetal risk. Considering that antimalarials (32) are reported to be safe during pregnancy and were not found to be associated with congenital malformation or teratogeneiety (33–35), the relatively high discontinuation rates prior and during pregnancy (16.7% and 53.1%, respectively) are alarming; they may indicate a care gap that may addressed by health care providers and an information gap for women with SLE. As exploratory analyses, we attempted to identify potential determinants of medication discontinuation during pregnancy among women with SLE. The only factors we identified were multi-parity, which was associated with higher odds of discontinuation of antimalarials from the 12 months before to the first trimester (odds ratio, 3.80, 95% confidence interval, 1.48 to 9.75), and time since SLE diagnosis, which was associated with higher odds of discontinuation of antimalarials during pregnancy (odds ratio, 1.50, 95% confidence interval, 1.07 to 2.09). Strengths and limitations of our study deserve comment. Strengths of our data sources including valid information on the date of conception in the BC Perinatal Database Registry linked to capture of all dispensed prescriptions in the PharmaNet database (15,22) allowed for accurate assessment of medication use patterns before, during, and after pregnancy. One of the limitations of using administrative data in observational studies is diagnostic uncertainty. Our case definition for SLE was based on a previously described and validated algorithm for identifying SLE in Canadian administrative data, which was shown to have sensitivity of 98.2% and specificity of 72.5% (36). Also a limitation is that we do not have information on the reasons for discontinuing medications during pregnancy, which may be patient or provider initiated. Finally, Pharmanet only captures 14 prescription medications that were dispensed at a community pharmacy and does not capture medications dispensed during hospital admission, over the counter medications, or samples provided by healthcare providers. This could potentially affect our results. Overall, despite recommendations for their continued use during SLE pregnancy, findings of discontinuation of antimalarials before pregnancy and during pregnancy from our population-based study of pregnant women with SLE may suggest a potential care and information gap. Considering the patterns of medication use seen in this study, it appears that expecting mothers with SLE would benefit from having a discussion with their care providers about how to manage their disease during their pregnancy, which medications are safe to take, and which should be avoided. The importance of disease management during pregnancy should be stressed. This study sheds a light on medication use profile and trajectory in this patient population, adds to the body of knowledge, provides us with a better understanding of what medication counselling is needed for women with SLE who are considering a pregnancy or are currently pregnant/postpartum, and emphasises how we can better educate our health professionals, who are working closely with this population to better address their medical needs and concerns. AUTHORSHIP AND CONTRIBUTIONS Contributions of authors to this study are as follows, for concept and design: De Vera, Sayre, Zusman; acquisition, analysis, and interpretation of data: De Vera, Sayre, Zusman; drafting of manuscript: De Vera, Zusman; critical revision of manuscript for important intellectual content: Aviña-Zubieta, De Vera, Sayre, Zusman; statistical analysis: Sayre; obtained funding: De Vera. All other authors have declared no support from any organisation for the submitted work; no financial 15 relationships with any organisations that might have an interest in the submitted work in the previous three years, no other relationships or activities that could appear to have influenced the submitted work. COPYRIGHT STATEMENT The Corresponding Author has the right to grant on behalf of all authors and does grant on behalf of all authors, a worldwide licence to the Publishers and its licensees in perpetuity, in all forms, formats and media (whether known now or created in the future), to i) publish, reproduce, distribute, display and store the Contribution, ii) translate the Contribution into other languages, create adaptations, reprints, include within collections and create summaries, extracts and/or, abstracts of the Contribution, iii) create any other derivative work(s) based on the Contribution, iv) to exploit all subsidiary rights in the Contribution, v) the inclusion of electronic links from the Contribution to third party material where-ever it may be located; and, vi) licence any third party to do any or all of the above. REFERENCES 1. Petri M. Epidemiology of systemic lupus erythematosus. Best Pract Res Clin Rheumatol. 2002 Dec;16(5):847–58. 2. 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The Accuracy of Administrative Data Diagnoses of Systemic Autoimmune Rheumatic Diseases. The Journal of Rheumatology. 2011;38(8):1612-1616. 1 Patterns of Medication Use Before, During, and After Pregnancy in Women with Systemic Lupus Erythematosus: A Population-Based Cohort Study Authors: Enav Z. Zusman, MSc1,2,3; Eric C. Sayre, PhD3; J. Antonio Aviña-Zubieta, MD, PhD3,4; Mary A. De Vera, PhD1,2,3 Author affiliations: 1University of British Columbia Faculty of Pharmaceutical Sciences, Vancouver, Canada; 2Collaboration for Outcomes Research and Evaluation, Vancouver, Canada; 3Arthritis Research Canada, Richmond, BC, Canada; 4University of British Columbia Faculty of Medicine, Department of Medicine, Division of Rheumatology, Vancouver, Canada Key words: systemic lupus erythematosus, pregnancy, reproduction, medications Manuscript word count: 3297 Titles, funding, and grant support: Dr. De Vera holds a Canada Research Chair in Medication Adherence, Utilization, and Outcomes and is a Michael Smith Foundation for Health Research Scholar. Dr. Aviña-Zubieta is a Michael Smith Foundation for Health Research Scholar and the BC Lupus Society Scholar. 2 Ms. Zusman received financial support from Bong Pang Yee Endowment Fund for her work on this project. This research was funded by an operating grant from The Arthritis Society (YIO-13-07). Corresponding author: Mary A. De Vera, PhD University of British Columbia Faculty of Pharmaceutical Sciences 2405 Wesbrook Mall Vancouver, BC, V6T 1Z3 Tel: 604-221-8767; Email: mdevera@mail.ubc.ca ABSTRACT Objectives: This study aimed to characterize the patterns of medication use before, during and after pregnancy in a population-based cohort of women with systemic lupus erythematosus (SLE). Methods: Using population-based administrative data in British Columbia, Canada with valid information on start date of pregnancy, we identified women with SLE who had singleton pregnancies ending in deliveries between January 1st, 2002 and December 31st, 2012. We assessed the proportion of SLE pregnancies exposed to SLE medications – namely antimalarials and immunosuppressants – as well as glucocorticosteroids, and nonsteroidal anti-inflammatory drugs 3 (NSAIDs) 24 months before pregnancy, each trimester of pregnancy, and 12 months post-pregnancy. We also assessed discontinuation of antimalarials and immunosuppressants, defined as no prescriptions in a given window following a prescription in a preceding window. Results: Of 376 pregnancies (284 women) with SLE, 24.2% had one or more dispensing for antimalarials, 8.2% for azathioprine, 19.7% for glucocorticosteroids and 4.8% for NSAIDs during pregnancy. We observed 16.7% discontinuation of antimalarials in the year prior to pregnancy, 29.8% in the first trimester, 9.7% in the second trimester, and 26% in the third trimester. We also observed 29.2% discontinuation of azathioprine in the first trimester, 8% in the second trimester, and 9% in the third trimester. Conclusions: These population-based data show frequent discontinuation of medications, particularly antimalarials, in SLE pregnancies. Findings suggest the importance of educating women with SLE who are pregnant or planning to become pregnant on the benefits and risks of medications during pregnancy. 4 INTRODUCTION Systemic lupus erythematosus (SLE) is a systemic and chronic inflammatory connective tissue disease that is classified as an autoimmune disease. It primarily affects women, often during reproductive years (1). SLE pregnancies are considered high risk (2), as pregnant women with SLE have a greater risk of pregnancy-related complications such as miscarriage, stillbirth, preeclampsia, eclampsia, preterm labor and fetal growth restriction (3–6). Between 25 and 50% of pregnant women with SLE experience flares either during pregnancy or after giving birth, usually during the second and third trimester or in the months following the birth (7,8). High disease activity and flares before and during pregnancy are associated with poor pregnancy prognosis, while low disease activity is associated with normal or close to normal pregnancy outcomes in most women with SLE (2,9,10). In order to manage active disease and reduce the risk of adverse pregnancy, fetal and neonatal outcomes, it is important to keep managing the disease for the duration of the pregnancy (2,9,11). Advances in medicine and medical research over the last few decades, a better understanding of the course of the disease and its progression, and the availability of medications considered effective and safe during pregnancy have led to better outcomes for both the mother and child (9,12). The most commonly used medications for SLE are antimalarials (chloroquine and hydroxychloroquine), immunosuppressants (azathioprine, cyclosporine, cyclophosphamide, leflunomide, methotrexate, and mycophenolate mofetil), which are taken chronically for disease control, and glucocorticosteroids, which are used in flares. With the importance of disease control during SLE pregnancies and increasing evidence on safety, the 4th International Conference on Sex Hormones, Pregnancy and the Rheumatic Diseases in 2006 led to a recommendation stating that when indicated, treatment with hydroxychloroquine should continue during pregnancy and lactation 5 for women with SLE (13). Knowing medication use in pregnant women with SLE is key to understanding how to support patients with family planning and pregnancy decisions. Few prior studies have examined medication use in pregnant women with SLE and showed varying frequencies of use prior to conception, during pregnancy, and post-partum (11,14). To add more nuanced information on patterns of medication use in SLE pregnancies, our objectives were: 1) to characterize the frequency of use of antimalarials, immunosuppressants as well as other medications, before, during, and after pregnancy; and 2) assess discontinuation of antimalarials and immunosuppressants during pregnancy. METHODS Data Sources Population Data British Columbia (Population Data BC) is an extensive data repository that holds individual-level, de-identified, longitudinal data on all health services covering the entire population of BC (estimated 4.7 million residents, May 2018 (15)). Data captured include provincially funded healthcare professionals visits, medically required (fee for service) services, laboratory and diagnostic procedures (16), hospital admissions and discharges (17), and demographics (18) and vital statistics (19,20), since 1990. Population Data BC also encompasses PharmaNet, a comprehensive database of prescription medications dispensed in community pharmacies since 1995 (21). Data used in this study were linked to the BC Perinatal Database Registry (22), which include antenatal, intrapartum, and postpartum maternal and infant data from medical records for almost all BC births, allowing us to assess date of conception. Data also include demographics information, date of conception, delivery and post-delivery information, obstetrics history, and lifestyle behaviors (e.g. smoking status and alcohol and recreational drug use). Indeed, the availability of information on date of conception 6 – based on gestational age using first trimester dating ultrasound or start date of last menstrual period – is a unique feature of this registry. Study Cohort The source population included women (n=305,351) with pregnancies (n=449,098) ending in births between January 1st, 2002 and December 31st, 2012 and covered by BC’s provincial health plan in the period of 24 months prior to and 12 months post-delivery. From the source population, we created a cohort of women with SLE which was defined using the following criteria: 1) having two International Classification of Diseases 9th Revision Codes (ICD-9) for SLE (710.0) from two separate physician visits that were at least 60 days apart and within two years, any time prior to the date of conception; or 2) having at least one hospitalization with an ICD-9 (710.0) or an ICD-10 code for SLE (M32.1, M32.8, M32.9), at any time prior to the date of conception (23). Given that the unit of analysis was individual pregnancy, each pregnancy had to satisfy the above criteria in order to be included in the analyses. Medication Use We used Canadian Drug Identity Codes in the BC PharmaNet to identify use of the SLE medications – namely, antimalarials (hydroxychloroquine, chloroquine) and immunosuppresants (azathioprine, cyclosporine, cyclophosphamide, leflunomide, methotrexate, and mycophenolate mofetil), as well as all prescribed glucocorticosteroids, and NSAIDs in the period between 24 months prior to conception and 12 months post-delivery. As shown in Figure 1, we divided this period into six windows: 1) 24 to 12 months before pregnancy (BC1); 2) 12 months before pregnancy (BC2); 3) first trimester, calculated from the date of conception to 13 weeks (T1); 4) second trimester, calculated from 13 weeks to 26 weeks from the date of conception (T2); 5) third 7 trimester, calculated from 26 weeks to date of delivery; and 6) 12 months after delivery or post-partum (PP). Statistical Analysis We calculated summary statistics of demographic information to describe the study cohort. We determined the proportion of SLE pregnancies exposed to aforementioned medications for each window and also looked at overall medication use during pregnancy per year for antimalarials, azathioprine, glucocorticosteroids and NSAIDs. We then assessed patterns of use of antimalarials and immunosuppresants during pregnancy in terms of discontinuation, defined as no prescription in a given window following at least one prescription in a preceding window. To further examine medication discontinuation, we assessed determinants with multivariable logistic regression models, using generalized estimating equations (GEE) to account for data clusters (e.g. multiple pregnancies clustered by one woman). Covariance structures were selected for the most appropriate model fit (according to lowest quasi information criterion) and computed standard errors of parameter estimates using robust sandwich estimators. We considered as potential determinants, factors that could affect medication use pattern and discontinuation, as indicated in the literature (24,25). These included: prior obstetrical history (prior premature delivery, spontaneous abortions, neonatal death, stillbirth, low birth weight, and congenital anomalies), comorbidities, maternal age at delivery, socioeconomic status based on neighborhood income quintile, and health care utilization (number of antenatal visits, hospitalization). Finally, we compared discontinuation of antimalarials in the periods 2001 to 2006 and 2007 to 2012 to determine potential changes in pattern of use following aforementioned recommendations from the Fourth International Conference on Sex Hormones, Pregnancy and the 8 Rheumatic Diseases in 2006. Finally, all reporting adhered to data sharing agreements, including suppression of cell sizes (e.g., counts) less 6. All analyses were performed using SAS v9.4 (SAS Institute, Cary, North Carolina). Study Conduct We obtained ethics approval from the University of British Columbia Behavioural Research Ethics Board. All data were de-identified and no personal information was available at any point of the study; we followed BC’s Freedom of Information and Privacy Protection Act for all study procedures. This study was funded by The Arthritis Society. The funder played no role in the design or conduct of the study, or in writing this manuscript. All inferences, opinions, and conclusions drawn in this manuscript are those of the authors, and do not reflect the opinions or policies of the Data Steward(s). RESULTS We identified 376 pregnancies from 284 women who were diagnosed with SLE prior to conception. Maternal and pregnancy characteristics are summarized in Table 1. The mean (standard deviation [SD]) age at delivery for our cohort was 31.6 (5.1) and the mean (SD) BMI was 24.8 (5.0) with about fifth of pregnancies being in women who were either overweight or obese. Forty-two pregnancies (11.2%) were in women with SLE nephritis and the mean (SD) gestational age at delivery was 37.5 (2.6) weeks with 38.0% of pregnancies being the first pregnancy for the women and 37.8% of pregnancies ended in a Caesarean section. From 2002 to 2012, considering the entire period of interest before, during, and after pregnancy, overall proportions of SLE pregnancies exposed to antimalarials were 33.2% and azathioprine 9 11.4%. With respect to other medications used during the entire period, 26.3% of SLE pregnancies were exposed to glucocorticosteroids and 23.7% to NSAIDs. Assessment of perinatal medication use by year illustrated in Figure 2 shows wide variation of use of antimalarials ranging from a high of 35.3% in 2005 to a low of 8.3% in 2012. Table 2 summarizes the proportion of SLE pregnancies exposed to medications during specific windows. With respect to antimalarials, 36.2% of SLE pregnancies were exposed before pregnancy. This was followed by lower proportions during pregnancy with 19.1% in the first trimester, 16.7% in the second trimester, and 17.0% in the third trimester, and resumption after pregnancy with 31.1%. Assessment of immunosuppresants show that azathioprine is the most commonly used, with similar patterns of higher proportions of exposed pregnancies before pregnancy (11.7%), lower during pregnancy with 6.6% in the first trimester, 6.4% in the second trimester, and 6.9% in the third trimester and resumption after pregnancy (10.4%). We observed low proportions of exposure before pregnancy to methotrexate (3.5%), mycophenolate (3.2%), and minocycline (2.9%). Finally, with respect to other medications, we observed 33.2% exposure to glucocorticosteroids before pregnancy, 14.9% in the first trimester, 13.3% in the second trimester, 19.7% in the third trimester and 25.3% after pregnancy. As for NSAIDs, 34.8% were exposed before pregnancy and 19.1% after pregnancy. As shown in Figure 3, there was 16.67% discontinuation of antimalarials between the two windows before pregnancy and 28.9% discontinuation from the 12 months before to the start date of pregnancy. During pregnancy, there was 9.7% discontinuation from the first trimester to the second trimester and 26% from the second trimester to the third trimester. When we assessed potential determinants of discontinuation, we found multi-parity to be associated with higher odds of 10 discontinuing antimalarials from the 12 months before to the start date of pregnancy (odds ratio, 3.80, 95% confidence interval, 1.48 to 9.75), and time since SLE diagnosis to be associated with higher odds of discontinuing antimalarials during pregnancy (odds ratio, 1.50, 95% confidence interval, 1.07 to 2.09) In addition, Figure 3 is comparing the discontinuation of antimalarials for the periods, 2001 to 2006 and 2007 to 2012 shows that despite aforementioned recommendations in 2006 declaring antimalarials safe to use during pregnancy, no change in antimalarial discontinuation was seen in the latter period. Given small cell sizes, we were only able to additionally assess discontinuation for azathioprine. Figure 4 shows similar patterns of discontinuation of azathioprine between the two windows before pregnancy (11.5%), before the start date of pregnancy (29.2%), and during trimesters of pregnancy, 8% between second and first trimester, and 9.1% between third and second trimester. DISCUSSION Our objective was to assess patterns of medication use in SLE pregnancies before, during, and after pregnancy using a population-based cohort of women who were diagnosed with SLE before conception. A potentially novel contribution of our study is delineating patterns of use, particularly discontinuation of SLE medications in relevant windows. Indeed among women with chronic disease, pregnancy is often a well-planned event for which preparation can begin months prior to pregnancy (26). In our study, we found discontinuation of antimalarials leading up to pregnancy with 16.7% from 24 months to 12 months before pregnancy and 28.9% from the 12 months to the start of pregnancy. We also found discontinuation in 9.7% from the first trimester to the second trimester and 26% from the second trimester to the third trimester. As these findings conflict with aforementioned recommendations regarding the continued use of antimalarials during SLE 11 pregnancies, they suggest the importance of educating women with SLE who are pregnant or planning to become pregnant on the benefits and risks of medications during pregnancy. We compare our findings with prior studies assessing medication use in SLE pregnancies in other countries, in terms of proportions of pregnancies exposed to antimalarials before and during pregnancy. While 36.2% of our cohort took antimalarials within the two years prior to conception and 24.2% of our cohort took antimalarials during pregnancy, higher use of antimalarials was reported in a US study using administrative data of 712 women with SLE (11) with 60.9% using antimalarials in the 3 month period prior to conception and 34.0% during pregnancy. Using administrative data for 391 women in Sweden, the proportion of use of antimalarials in the 3 month period prior to conception was 23.4% and during pregnancy 36.4% (14). Our study expands on these prior studies in that we assessed medication use over a longer pre-conception period (up to two years) and additionally assessed the post-partum period, showing that 31.1% took antimalarials after delivery. Furthermore, although these prior studies reported declines in utilization of antimalarials with advancing trimesters of pregnancy, neither explicitly defined and assessed discontinuation, as with our study. We also considered our findings on utilization of medications, specifically before pregnancy, in context with medication use among patients with SLE in general. Particularly, we found lower antimalarial use in the one- and two-year period before pregnancy as compared to a multi-center cohort of Canadians living with SLE, with 66% taking antimalarials over their study period from 2005 to 2007, as reported by Bernatsky et al. (27). However, in addition to including both women (90.2%) and men (9.8%), their cohort was older than our cohort (mean age 44.3 vs. 31.6 years), which suggests that women in their study may not be in their fertile years (27). Furthermore, this 12 study was based on 10 clinical adult SLE cohort registries in Canada, which may reflect better care and subsequent medication use of participants as compared to our study, which was based on real-world, administrative data. Although we were primarily interested in antimalarial utilization and discontinuation, findings on perinatal utilization of other relevant medications bear discussion. The first of these is azathioprine. Approximately 60% of SLE patients are diagnosed with lupus nephritis at 5 years post-SLE diagnosis (28), yet, only 11.2% of our cohort was diagnosed with lupus nephritis, and they accounted for half of observed azathioprine use. Of SLE nephritis pregnancies who took azathioprine prior to pregnancy, all continued to take azathioprine in the two years prior to pregnancy, ⩽6 discontinued azathioprine during pregnancy and ⩽6 initiated azathioprine during pregnancy. The low proportion of lupus nephritis in our cohort compared to the general SLE population could account for our cohort’s reported lower azathioprine use. Another relevant medication is low-dose aspirin which is recommended by the European League Against Rheumatism and American College of Obstetricians and Gynecologists for prevention of preeclampsia among women with SLE who are pregnant (29,30). Yet, ⩽6 of our cohort’s pregnancies were prescribed low-dose aspirin. However, our results only captured prescription medications, and women could have taken over the counter low-dose aspirin, which could account for our findings of limited use. Indeed, managing SLE is particularly important in the perinatal period, as disease activity and flares before and during pregnancy were found to be associated with poor pregnancy prognosis and outcomes, such as fetal losses, preterm births, preeclampsia, and intrauterine growth retardation (2,9,10). This can potentially be reduced or avoided if the disease is kept under control during pregnancy and in the period of 6-12 months prior to conception (2,9,11). The risk of flare-up was 13 found to be higher in women who discontinued useful medications (in particular hydroxychloroquine) (31) The observed medication discontinuation of antimalarials during the first, second and third trimester (29.8%, 9.7% and 26%, respectively) could potentially be in part due to concerns and misinformation about medication teratogenicity and fetal risk. Considering that antimalarials (32) are reported to be safe during pregnancy and were not found to be associated with congenital malformation or teratogeneiety (33–35), the relatively high discontinuation rates prior and during pregnancy (16.7% and 53.1%, respectively) are alarming; they may indicate a care gap that may addressed by health care providers and an information gap for women with SLE. As exploratory analyses, we attempted to identify potential determinants of medication discontinuation during pregnancy among women with SLE. The only factors we identified were multi-parity, which was associated with higher odds of discontinuation of antimalarials from the 12 months before to the first trimester (odds ratio, 3.80, 95% confidence interval, 1.48 to 9.75), and time since SLE diagnosis, which was associated with higher odds of discontinuation of antimalarials during pregnancy (odds ratio, 1.50, 95% confidence interval, 1.07 to 2.09). Strengths and limitations of our study deserve comment. Strengths of our data sources including valid information on the date of conception in the BC Perinatal Database Registry linked to capture of all dispensed prescriptions in the PharmaNet database (15,22) allowed for accurate assessment of medication use patterns before, during, and after pregnancy. One of the limitations of using administrative data in observational studies is diagnostic uncertainty. Our case definition for SLE was based on a previously described and validated algorithm for identifying SLE in Canadian administrative data, which was shown to have sensitivity of 98.2% and specificity of 72.5% (36). Also a limitation is that we do not have information on the reasons for discontinuing medications during pregnancy, which may be patient or provider initiated. Finally, Pharmanet only captures 14 prescription medications that were dispensed at a community pharmacy and does not capture medications dispensed during hospital admission, over the counter medications, or samples provided by healthcare providers. This could potentially affect our results. Overall, despite recommendations for their continued use during SLE pregnancy, findings of discontinuation of antimalarials before pregnancy and during pregnancy from our population-based study of pregnant women with SLE may suggest a potential care and information gap. Considering the patterns of medication use seen in this study, it appears that expecting mothers with SLE would benefit from having a discussion with their care providers about how to manage their disease during their pregnancy, which medications are safe to take, and which should be avoided. The importance of disease management during pregnancy should be stressed. This study sheds a light on medication use profile and trajectory in this patient population, adds to the body of knowledge, provides us with a better understanding of what medication counselling is needed for women with SLE who are considering a pregnancy or are currently pregnant/postpartum, and emphasises how we can better educate our health professionals, who are working closely with this population to better address their medical needs and concerns. AUTHORSHIP AND CONTRIBUTIONS Contributions of authors to this study are as follows, for concept and design: De Vera, Sayre, Zusman; acquisition, analysis, and interpretation of data: De Vera, Sayre, Zusman; drafting of manuscript: De Vera, Zusman; critical revision of manuscript for important intellectual content: Aviña-Zubieta, De Vera, Sayre, Zusman; statistical analysis: Sayre; obtained funding: De Vera. All other authors have declared no support from any organisation for the submitted work; no financial 15 relationships with any organisations that might have an interest in the submitted work in the previous three years, no other relationships or activities that could appear to have influenced the submitted work. COPYRIGHT STATEMENT The Corresponding Author has the right to grant on behalf of all authors and does grant on behalf of all authors, a worldwide licence to the Publishers and its licensees in perpetuity, in all forms, formats and media (whether known now or created in the future), to i) publish, reproduce, distribute, display and store the Contribution, ii) translate the Contribution into other languages, create adaptations, reprints, include within collections and create summaries, extracts and/or, abstracts of the Contribution, iii) create any other derivative work(s) based on the Contribution, iv) to exploit all subsidiary rights in the Contribution, v) the inclusion of electronic links from the Contribution to third party material where-ever it may be located; and, vi) licence any third party to do any or all of the above. REFERENCES 1. Petri M. Epidemiology of systemic lupus erythematosus. Best Pract Res Clin Rheumatol. 2002 Dec;16(5):847–58. 2. 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The Accuracy of Administrative Data Diagnoses of Systemic Autoimmune Rheumatic Diseases. The Journal of Rheumatology. 2011;38(8):1612-1616. Table 1. Maternal and pregnancy characteristics of cohort of pregnant women with SLE Maternal and pregnancy characteristics Age at delivery, mean (s.d.), years SLE duration, median (IQR), years 31.6 (5.1) 3.7 (1.8, 6.6) SLE nephritis, n (%) BMI, mean (s.d.), kg/m2 42 (11.2%) 24.8 (5.0) Neighbourhood income quintle 20th percentile 89 (23.7%) 40th percentile 74 (19.7%) 60th percentile 82 (21.8%) 80th percentile 80 (21.3%) 80-100th percentile 49 (13.0%) Gestational weeks at delivery, mean (s.d.) 37.5 (2.6) Number of antenatal visits, mean (s.d.) 8.9 (4.6) Caesarean section delivery 142 (37.8%) Parity Nulliparous 143 (38.0%) Multiparous 233 (62.0%) Obstetric history Prior premature birth 44 (11.7%) Prior spontaneous abortion 118 (31.4%) Prior congenital anomalies 7 (1.9%) Prior stillbirth 14 (3.7%) Prior low birthweight 25 (6.7%) Depression 21 (5.6%) Anxiety 47 (12.5%) *Abbreviations: s.d. – standard deviation 1 Patterns of Medication Use Before, During, and After Pregnancy in Women with Systemic Lupus Erythematosus: A Population-Based Cohort Study Authors: Enav Z. Zusman, MSc1,2,3; Eric C. Sayre, PhD3; J. Antonio Aviña-Zubieta, MD, PhD3,4; Mary A. De Vera, PhD1,2,3 Author affiliations: 1University of British Columbia Faculty of Pharmaceutical Sciences, Vancouver, Canada; 2Collaboration for Outcomes Research and Evaluation, Vancouver, Canada; 3Arthritis Research Canada, Richmond, BC, Canada; 4University of British Columbia Faculty of Medicine, Department of Medicine, Division of Rheumatology, Vancouver, Canada Key words: systemic lupus erythematosus, pregnancy, reproduction, medications Manuscript word count: 3297 Titles, funding, and grant support: Dr. De Vera holds a Canada Research Chair in Medication Adherence, Utilization, and Outcomes and is a Michael Smith Foundation for Health Research Scholar. Dr. Aviña-Zubieta is a Michael Smith Foundation for Health Research Scholar and the BC Lupus Society Scholar. 2 Ms. Zusman received financial support from Bong Pang Yee Endowment Fund for her work on this project. This research was funded by an operating grant from The Arthritis Society (YIO-13-07). Corresponding author: Mary A. De Vera, PhD University of British Columbia Faculty of Pharmaceutical Sciences 2405 Wesbrook Mall Vancouver, BC, V6T 1Z3 Tel: 604-221-8767; Email: mdevera@mail.ubc.ca ABSTRACT Objectives: This study aimed to characterize the patterns of medication use before, during and after pregnancy in a population-based cohort of women with systemic lupus erythematosus (SLE). Methods: Using population-based administrative data in British Columbia, Canada with valid information on start date of pregnancy, we identified women with SLE who had singleton pregnancies ending in deliveries between January 1st, 2002 and December 31st, 2012. We assessed the proportion of SLE pregnancies exposed to SLE medications – namely antimalarials and immunosuppressants – as well as glucocorticosteroids, and nonsteroidal anti-inflammatory drugs 3 (NSAIDs) 24 months before pregnancy, each trimester of pregnancy, and 12 months post-pregnancy. We also assessed discontinuation of antimalarials and immunosuppressants, defined as no prescriptions in a given window following a prescription in a preceding window. Results: Of 376 pregnancies (284 women) with SLE, 24.2% had one or more dispensing for antimalarials, 8.2% for azathioprine, 19.7% for glucocorticosteroids and 4.8% for NSAIDs during pregnancy. We observed 16.7% discontinuation of antimalarials in the year prior to pregnancy, 29.8% in the first trimester, 9.7% in the second trimester, and 26% in the third trimester. We also observed 29.2% discontinuation of azathioprine in the first trimester, 8% in the second trimester, and 9% in the third trimester. Conclusions: These population-based data show frequent discontinuation of medications, particularly antimalarials, in SLE pregnancies. Findings suggest the importance of educating women with SLE who are pregnant or planning to become pregnant on the benefits and risks of medications during pregnancy. 4 INTRODUCTION Systemic lupus erythematosus (SLE) is a systemic and chronic inflammatory connective tissue disease that is classified as an autoimmune disease. It primarily affects women, often during reproductive years (1). SLE pregnancies are considered high risk (2), as pregnant women with SLE have a greater risk of pregnancy-related complications such as miscarriage, stillbirth, preeclampsia, eclampsia, preterm labor and fetal growth restriction (3–6). Between 25 and 50% of pregnant women with SLE experience flares either during pregnancy or after giving birth, usually during the second and third trimester or in the months following the birth (7,8). High disease activity and flares before and during pregnancy are associated with poor pregnancy prognosis, while low disease activity is associated with normal or close to normal pregnancy outcomes in most women with SLE (2,9,10). In order to manage active disease and reduce the risk of adverse pregnancy, fetal and neonatal outcomes, it is important to keep managing the disease for the duration of the pregnancy (2,9,11). Advances in medicine and medical research over the last few decades, a better understanding of the course of the disease and its progression, and the availability of medications considered effective and safe during pregnancy have led to better outcomes for both the mother and child (9,12). The most commonly used medications for SLE are antimalarials (chloroquine and hydroxychloroquine), immunosuppressants (azathioprine, cyclosporine, cyclophosphamide, leflunomide, methotrexate, and mycophenolate mofetil), which are taken chronically for disease control, and glucocorticosteroids, which are used in flares. With the importance of disease control during SLE pregnancies and increasing evidence on safety, the 4th International Conference on Sex Hormones, Pregnancy and the Rheumatic Diseases in 2006 led to a recommendation stating that when indicated, treatment with hydroxychloroquine should continue during pregnancy and lactation 5 for women with SLE (13). Knowing medication use in pregnant women with SLE is key to understanding how to support patients with family planning and pregnancy decisions. Few prior studies have examined medication use in pregnant women with SLE and showed varying frequencies of use prior to conception, during pregnancy, and post-partum (11,14). To add more nuanced information on patterns of medication use in SLE pregnancies, our objectives were: 1) to characterize the frequency of use of antimalarials, immunosuppressants as well as other medications, before, during, and after pregnancy; and 2) assess discontinuation of antimalarials and immunosuppressants during pregnancy. METHODS Data Sources Population Data British Columbia (Population Data BC) is an extensive data repository that holds individual-level, de-identified, longitudinal data on all health services covering the entire population of BC (estimated 4.7 million residents, May 2018 (15)). Data captured include provincially funded healthcare professionals visits, medically required (fee for service) services, laboratory and diagnostic procedures (16), hospital admissions and discharges (17), and demographics (18) and vital statistics (19,20), since 1990. Population Data BC also encompasses PharmaNet, a comprehensive database of prescription medications dispensed in community pharmacies since 1995 (21). Data used in this study were linked to the BC Perinatal Database Registry (22), which include antenatal, intrapartum, and postpartum maternal and infant data from medical records for almost all BC births, allowing us to assess date of conception. Data also include demographics information, date of conception, delivery and post-delivery information, obstetrics history, and lifestyle behaviors (e.g. smoking status and alcohol and recreational drug use). Indeed, the availability of information on date of conception 6 – based on gestational age using first trimester dating ultrasound or start date of last menstrual period – is a unique feature of this registry. Study Cohort The source population included women (n=305,351) with pregnancies (n=449,098) ending in births between January 1st, 2002 and December 31st, 2012 and covered by BC’s provincial health plan in the period of 24 months prior to and 12 months post-delivery. From the source population, we created a cohort of women with SLE which was defined using the following criteria: 1) having two International Classification of Diseases 9th Revision Codes (ICD-9) for SLE (710.0) from two separate physician visits that were at least 60 days apart and within two years, any time prior to the date of conception; or 2) having at least one hospitalization with an ICD-9 (710.0) or an ICD-10 code for SLE (M32.1, M32.8, M32.9), at any time prior to the date of conception (23). Given that the unit of analysis was individual pregnancy, each pregnancy had to satisfy the above criteria in order to be included in the analyses. Medication Use We used Canadian Drug Identity Codes in the BC PharmaNet to identify use of the SLE medications – namely, antimalarials (hydroxychloroquine, chloroquine) and immunosuppresants (azathioprine, cyclosporine, cyclophosphamide, leflunomide, methotrexate, and mycophenolate mofetil), as well as all prescribed glucocorticosteroids, and NSAIDs in the period between 24 months prior to conception and 12 months post-delivery. As shown in Figure 1, we divided this period into six windows: 1) 24 to 12 months before pregnancy (BC1); 2) 12 months before pregnancy (BC2); 3) first trimester, calculated from the date of conception to 13 weeks (T1); 4) second trimester, calculated from 13 weeks to 26 weeks from the date of conception (T2); 5) third 7 trimester, calculated from 26 weeks to date of delivery; and 6) 12 months after delivery or post-partum (PP). Statistical Analysis We calculated summary statistics of demographic information to describe the study cohort. We determined the proportion of SLE pregnancies exposed to aforementioned medications for each window and also looked at overall medication use during pregnancy per year for antimalarials, azathioprine, glucocorticosteroids and NSAIDs. We then assessed patterns of use of antimalarials and immunosuppresants during pregnancy in terms of discontinuation, defined as no prescription in a given window following at least one prescription in a preceding window. To further examine medication discontinuation, we assessed determinants with multivariable logistic regression models, using generalized estimating equations (GEE) to account for data clusters (e.g. multiple pregnancies clustered by one woman). Covariance structures were selected for the most appropriate model fit (according to lowest quasi information criterion) and computed standard errors of parameter estimates using robust sandwich estimators. We considered as potential determinants, factors that could affect medication use pattern and discontinuation, as indicated in the literature (24,25). These included: prior obstetrical history (prior premature delivery, spontaneous abortions, neonatal death, stillbirth, low birth weight, and congenital anomalies), comorbidities, maternal age at delivery, socioeconomic status based on neighborhood income quintile, and health care utilization (number of antenatal visits, hospitalization). Finally, we compared discontinuation of antimalarials in the periods 2001 to 2006 and 2007 to 2012 to determine potential changes in pattern of use following aforementioned recommendations from the Fourth International Conference on Sex Hormones, Pregnancy and the 8 Rheumatic Diseases in 2006. Finally, all reporting adhered to data sharing agreements, including suppression of cell sizes (e.g., counts) less 6. All analyses were performed using SAS v9.4 (SAS Institute, Cary, North Carolina). Study Conduct We obtained ethics approval from the University of British Columbia Behavioural Research Ethics Board. All data were de-identified and no personal information was available at any point of the study; we followed BC’s Freedom of Information and Privacy Protection Act for all study procedures. This study was funded by The Arthritis Society. The funder played no role in the design or conduct of the study, or in writing this manuscript. All inferences, opinions, and conclusions drawn in this manuscript are those of the authors, and do not reflect the opinions or policies of the Data Steward(s). RESULTS We identified 376 pregnancies from 284 women who were diagnosed with SLE prior to conception. Maternal and pregnancy characteristics are summarized in Table 1. The mean (standard deviation [SD]) age at delivery for our cohort was 31.6 (5.1) and the mean (SD) BMI was 24.8 (5.0) with about fifth of pregnancies being in women who were either overweight or obese. Forty-two pregnancies (11.2%) were in women with SLE nephritis and the mean (SD) gestational age at delivery was 37.5 (2.6) weeks with 38.0% of pregnancies being the first pregnancy for the women and 37.8% of pregnancies ended in a Caesarean section. From 2002 to 2012, considering the entire period of interest before, during, and after pregnancy, overall proportions of SLE pregnancies exposed to antimalarials were 33.2% and azathioprine 9 11.4%. With respect to other medications used during the entire period, 26.3% of SLE pregnancies were exposed to glucocorticosteroids and 23.7% to NSAIDs. Assessment of perinatal medication use by year illustrated in Figure 2 shows wide variation of use of antimalarials ranging from a high of 35.3% in 2005 to a low of 8.3% in 2012. Table 2 summarizes the proportion of SLE pregnancies exposed to medications during specific windows. With respect to antimalarials, 36.2% of SLE pregnancies were exposed before pregnancy. This was followed by lower proportions during pregnancy with 19.1% in the first trimester, 16.7% in the second trimester, and 17.0% in the third trimester, and resumption after pregnancy with 31.1%. Assessment of immunosuppresants show that azathioprine is the most commonly used, with similar patterns of higher proportions of exposed pregnancies before pregnancy (11.7%), lower during pregnancy with 6.6% in the first trimester, 6.4% in the second trimester, and 6.9% in the third trimester and resumption after pregnancy (10.4%). We observed low proportions of exposure before pregnancy to methotrexate (3.5%), mycophenolate (3.2%), and minocycline (2.9%). Finally, with respect to other medications, we observed 33.2% exposure to glucocorticosteroids before pregnancy, 14.9% in the first trimester, 13.3% in the second trimester, 19.7% in the third trimester and 25.3% after pregnancy. As for NSAIDs, 34.8% were exposed before pregnancy and 19.1% after pregnancy. As shown in Figure 3, there was 16.67% discontinuation of antimalarials between the two windows before pregnancy and 28.9% discontinuation from the 12 months before to the start date of pregnancy. During pregnancy, there was 9.7% discontinuation from the first trimester to the second trimester and 26% from the second trimester to the third trimester. When we assessed potential determinants of discontinuation, we found multi-parity to be associated with higher odds of 10 discontinuing antimalarials from the 12 months before to the start date of pregnancy (odds ratio, 3.80, 95% confidence interval, 1.48 to 9.75), and time since SLE diagnosis to be associated with higher odds of discontinuing antimalarials during pregnancy (odds ratio, 1.50, 95% confidence interval, 1.07 to 2.09) In addition, Figure 3 is comparing the discontinuation of antimalarials for the periods, 2001 to 2006 and 2007 to 2012 shows that despite aforementioned recommendations in 2006 declaring antimalarials safe to use during pregnancy, no change in antimalarial discontinuation was seen in the latter period. Given small cell sizes, we were only able to additionally assess discontinuation for azathioprine. Figure 4 shows similar patterns of discontinuation of azathioprine between the two windows before pregnancy (11.5%), before the start date of pregnancy (29.2%), and during trimesters of pregnancy, 8% between second and first trimester, and 9.1% between third and second trimester. DISCUSSION Our objective was to assess patterns of medication use in SLE pregnancies before, during, and after pregnancy using a population-based cohort of women who were diagnosed with SLE before conception. A potentially novel contribution of our study is delineating patterns of use, particularly discontinuation of SLE medications in relevant windows. Indeed among women with chronic disease, pregnancy is often a well-planned event for which preparation can begin months prior to pregnancy (26). In our study, we found discontinuation of antimalarials leading up to pregnancy with 16.7% from 24 months to 12 months before pregnancy and 28.9% from the 12 months to the start of pregnancy. We also found discontinuation in 9.7% from the first trimester to the second trimester and 26% from the second trimester to the third trimester. As these findings conflict with aforementioned recommendations regarding the continued use of antimalarials during SLE 11 pregnancies, they suggest the importance of educating women with SLE who are pregnant or planning to become pregnant on the benefits and risks of medications during pregnancy. We compare our findings with prior studies assessing medication use in SLE pregnancies in other countries, in terms of proportions of pregnancies exposed to antimalarials before and during pregnancy. While 36.2% of our cohort took antimalarials within the two years prior to conception and 24.2% of our cohort took antimalarials during pregnancy, higher use of antimalarials was reported in a US study using administrative data of 712 women with SLE (11) with 60.9% using antimalarials in the 3 month period prior to conception and 34.0% during pregnancy. Using administrative data for 391 women in Sweden, the proportion of use of antimalarials in the 3 month period prior to conception was 23.4% and during pregnancy 36.4% (14). Our study expands on these prior studies in that we assessed medication use over a longer pre-conception period (up to two years) and additionally assessed the post-partum period, showing that 31.1% took antimalarials after delivery. Furthermore, although these prior studies reported declines in utilization of antimalarials with advancing trimesters of pregnancy, neither explicitly defined and assessed discontinuation, as with our study. We also considered our findings on utilization of medications, specifically before pregnancy, in context with medication use among patients with SLE in general. Particularly, we found lower antimalarial use in the one- and two-year period before pregnancy as compared to a multi-center cohort of Canadians living with SLE, with 66% taking antimalarials over their study period from 2005 to 2007, as reported by Bernatsky et al. (27). However, in addition to including both women (90.2%) and men (9.8%), their cohort was older than our cohort (mean age 44.3 vs. 31.6 years), which suggests that women in their study may not be in their fertile years (27). Furthermore, this 12 study was based on 10 clinical adult SLE cohort registries in Canada, which may reflect better care and subsequent medication use of participants as compared to our study, which was based on real-world, administrative data. Although we were primarily interested in antimalarial utilization and discontinuation, findings on perinatal utilization of other relevant medications bear discussion. The first of these is azathioprine. Approximately 60% of SLE patients are diagnosed with lupus nephritis at 5 years post-SLE diagnosis (28), yet, only 11.2% of our cohort was diagnosed with lupus nephritis, and they accounted for half of observed azathioprine use. Of SLE nephritis pregnancies who took azathioprine prior to pregnancy, all continued to take azathioprine in the two years prior to pregnancy, ⩽6 discontinued azathioprine during pregnancy and ⩽6 initiated azathioprine during pregnancy. The low proportion of lupus nephritis in our cohort compared to the general SLE population could account for our cohort’s reported lower azathioprine use. Another relevant medication is low-dose aspirin which is recommended by the European League Against Rheumatism and American College of Obstetricians and Gynecologists for prevention of preeclampsia among women with SLE who are pregnant (29,30). Yet, ⩽6 of our cohort’s pregnancies were prescribed low-dose aspirin. However, our results only captured prescription medications, and women could have taken over the counter low-dose aspirin, which could account for our findings of limited use. Indeed, managing SLE is particularly important in the perinatal period, as disease activity and flares before and during pregnancy were found to be associated with poor pregnancy prognosis and outcomes, such as fetal losses, preterm births, preeclampsia, and intrauterine growth retardation (2,9,10). This can potentially be reduced or avoided if the disease is kept under control during pregnancy and in the period of 6-12 months prior to conception (2,9,11). The risk of flare-up was 13 found to be higher in women who discontinued useful medications (in particular hydroxychloroquine) (31) The observed medication discontinuation of antimalarials during the first, second and third trimester (29.8%, 9.7% and 26%, respectively) could potentially be in part due to concerns and misinformation about medication teratogenicity and fetal risk. Considering that antimalarials (32) are reported to be safe during pregnancy and were not found to be associated with congenital malformation or teratogeneiety (33–35), the relatively high discontinuation rates prior and during pregnancy (16.7% and 53.1%, respectively) are alarming; they may indicate a care gap that may addressed by health care providers and an information gap for women with SLE. As exploratory analyses, we attempted to identify potential determinants of medication discontinuation during pregnancy among women with SLE. The only factors we identified were multi-parity, which was associated with higher odds of discontinuation of antimalarials from the 12 months before to the first trimester (odds ratio, 3.80, 95% confidence interval, 1.48 to 9.75), and time since SLE diagnosis, which was associated with higher odds of discontinuation of antimalarials during pregnancy (odds ratio, 1.50, 95% confidence interval, 1.07 to 2.09). Strengths and limitations of our study deserve comment. Strengths of our data sources including valid information on the date of conception in the BC Perinatal Database Registry linked to capture of all dispensed prescriptions in the PharmaNet database (15,22) allowed for accurate assessment of medication use patterns before, during, and after pregnancy. One of the limitations of using administrative data in observational studies is diagnostic uncertainty. Our case definition for SLE was based on a previously described and validated algorithm for identifying SLE in Canadian administrative data, which was shown to have sensitivity of 98.2% and specificity of 72.5% (36). Also a limitation is that we do not have information on the reasons for discontinuing medications during pregnancy, which may be patient or provider initiated. Finally, Pharmanet only captures 14 prescription medications that were dispensed at a community pharmacy and does not capture medications dispensed during hospital admission, over the counter medications, or samples provided by healthcare providers. This could potentially affect our results. Overall, despite recommendations for their continued use during SLE pregnancy, findings of discontinuation of antimalarials before pregnancy and during pregnancy from our population-based study of pregnant women with SLE may suggest a potential care and information gap. Considering the patterns of medication use seen in this study, it appears that expecting mothers with SLE would benefit from having a discussion with their care providers about how to manage their disease during their pregnancy, which medications are safe to take, and which should be avoided. The importance of disease management during pregnancy should be stressed. This study sheds a light on medication use profile and trajectory in this patient population, adds to the body of knowledge, provides us with a better understanding of what medication counselling is needed for women with SLE who are considering a pregnancy or are currently pregnant/postpartum, and emphasises how we can better educate our health professionals, who are working closely with this population to better address their medical needs and concerns. AUTHORSHIP AND CONTRIBUTIONS Contributions of authors to this study are as follows, for concept and design: De Vera, Sayre, Zusman; acquisition, analysis, and interpretation of data: De Vera, Sayre, Zusman; drafting of manuscript: De Vera, Zusman; critical revision of manuscript for important intellectual content: Aviña-Zubieta, De Vera, Sayre, Zusman; statistical analysis: Sayre; obtained funding: De Vera. All other authors have declared no support from any organisation for the submitted work; no financial 15 relationships with any organisations that might have an interest in the submitted work in the previous three years, no other relationships or activities that could appear to have influenced the submitted work. COPYRIGHT STATEMENT The Corresponding Author has the right to grant on behalf of all authors and does grant on behalf of all authors, a worldwide licence to the Publishers and its licensees in perpetuity, in all forms, formats and media (whether known now or created in the future), to i) publish, reproduce, distribute, display and store the Contribution, ii) translate the Contribution into other languages, create adaptations, reprints, include within collections and create summaries, extracts and/or, abstracts of the Contribution, iii) create any other derivative work(s) based on the Contribution, iv) to exploit all subsidiary rights in the Contribution, v) the inclusion of electronic links from the Contribution to third party material where-ever it may be located; and, vi) licence any third party to do any or all of the above. REFERENCES 1. Petri M. Epidemiology of systemic lupus erythematosus. Best Pract Res Clin Rheumatol. 2002 Dec;16(5):847–58. 2. 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The Accuracy of Administrative Data Diagnoses of Systemic Autoimmune Rheumatic Diseases. The Journal of Rheumatology. 2011;38(8):1612-1616. Table 1. Maternal and pregnancy characteristics of cohort of pregnant women with SLE Maternal and pregnancy characteristics Age at delivery, mean (s.d.), years SLE duration, median (IQR), years 31.6 (5.1) 3.7 (1.8, 6.6) SLE nephritis, n (%) BMI, mean (s.d.), kg/m2 42 (11.2%) 24.8 (5.0) Neighbourhood income quintle 20th percentile 89 (23.7%) 40th percentile 74 (19.7%) 60th percentile 82 (21.8%) 80th percentile 80 (21.3%) 80-100th percentile 49 (13.0%) Gestational weeks at delivery, mean (s.d.) 37.5 (2.6) Number of antenatal visits, mean (s.d.) 8.9 (4.6) Caesarean section delivery 142 (37.8%) Parity Nulliparous 143 (38.0%) Multiparous 233 (62.0%) Obstetric history Prior premature birth 44 (11.7%) Prior spontaneous abortion 118 (31.4%) Prior congenital anomalies 7 (1.9%) Prior stillbirth 14 (3.7%) Prior low birthweight 25 (6.7%) Depression 21 (5.6%) Anxiety 47 (12.5%) *Abbreviations: s.d. – standard deviation Table 2: Proportion of SLE pregnancies exposed to medications during specific windows before, during, and after pregnancy Medication Before pregnancy During pregnancy After pregnancy BC1 BC2 Combined T1 T2 T3 Combined PP Antimalarials 114 (30.3%) 114 (30.3%) 136 (36.2%) 72 (19.1%) 63 (16.7%) 64 (17.0%) 91 (24.3) 117 (31.1%) Immunosuppresants Azathioprine 26 (6.9%) 41 (10.9%) 44 (11.7%) 25 (6.6%) 24 (6.4%) 26 (6.9%) 31 (8.2%) 39 (10.4%) Methotrexate 10 (2.7%) 7 (1.9%) 13 (3.5%) * 0 0 * 10 (2.7%) Mycophenolate 11 (2.9%) 8 (2.1%) 12 (3.2%) 0 0 0 0 * Minocycline 7 (1.9%) * 11 (2.9%) 0 0 0 0 * Cyclosporine * * * * * * * * Cyclophosphamide * 0 * 0 0 0 0 0 Leflunomide * 0 * 0 0 0 0 0 Sulfasalazine * * * * * * * * Other medications Glucocorticosteroids 101 (26.9%) 89 (23.7%) 125 (33.2%) 50 (13.3%) 56 (14.9%) 50 (13.3%) 74 (19.7%) 95 (25.3%) NSAIDs 91 (24.2%) 84 (22.3) 131 (34.8%) 16 (4.3%) * * 18 (4.8%) 72 (19.1%) Low dose aspirin * * * * * * * * * Cell counts ⩽6, suppressed as per data use agreement with Popdata BC Abbreviations: BC1 – 24-12 months before conception BC2 – 12 months before conception T1 – first pregnancy trimester T2- second pregnancy trimester T3- third pregnancy trimester PP- first year post partum NSAID- Nonsteroidal anti-inflammatory drug
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Systemic lupus erythematosus
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Patterns of Medication Use Before, During, and After Pregnancy in Women with Systemic Lupus Erythematosus : A Population-Based Cohort Study
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