{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T01:49:02Z","timestamp":1789523342085,"version":"build-2803163510"},"reference-count":29,"publisher":"BMJ","issue":"1","license":[{"start":{"date-parts":[[2022,1,6]],"date-time":"2022-01-06T00:00:00Z","timestamp":1641427200000},"content-version":"unspecified","delay-in-days":5,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000069","name":"National Institute of Arthritis and Musculoskeletal and Skin Diseases","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000069","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100006510","name":"Duke","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100006510","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100006260","name":"Rheumatology Research Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100006260","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100016228","name":"Derfner Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100016228","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Thrasher Research Fund, the Derfner Foundation"}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["Lupus Sci Med"],"accepted":{"date-parts":[[2021,12,6]]},"published-print":{"date-parts":[[2022,1]]},"abstract":"<jats:sec>\n                  <jats:title>Objective<\/jats:title>\n                  <jats:p>Evaluate the impact of pregnancy physiology and medication non-adherence on serum hydroxychloroquine (HCQ) pharmacokinetics (PK) and exposure-response in SLE.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>We conducted a PK analysis using data from two observational pregnancy registries. We enrolled pregnant women with SLE taking HCQ at least 3 months prior to, and throughout pregnancy, and excluded those with multiple gestations. Using the PK model, we conducted dosing simulations and imputed 0%\/20%\/40%\/60% non-adherence to evaluate the impact of adherence versus physiological changes on HCQ concentrations. We compared the effect of pregnancy-average non-adherent concentrations (\u2264100\u2009ng\/mL vs &gt;100\u2009ng\/mL) on preterm birth using adjusted logistic regression.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>We enrolled 56 women who had 61 pregnancies. By the third trimester, mean apparent HCQ clearance increased by 59.6%. At a dosage of 400 mg\/day, fully adherent patients are expected to have HCQ concentrations \u2264100\u2009ng\/mL only 0.3% of the time, compared with 24.2% when 60% of doses are missed. Persistently low HCQ concentrations throughout pregnancy were associated with a significantly higher odds of preterm birth, controlling for lupus nephritis and race (OR 11.2; 95% CI 2.3 to 54.2; p=0.003).<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>We observed significant changes in HCQ PK during pregnancy, resulting in a shortening in the drug\u2019s half-life by 10 days; however, medication non-adherence had a more pronounced effect on HCQ exposure compared with physiological changes alone. Moreover, pregnant women with non-adherent HCQ concentrations had significantly higher rates of preterm birth. Accordingly, optimising adherence in pregnancy may be more clinically meaningful than adjusting HCQ dosage to account for physiological changes. PK modelling indicates that serum HCQ concentrations \u2264100\u2009ng\/mL are suggestive of non-adherence regardless of trimester and may help identify pregnancies at risk for poor outcomes.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1136\/lupus-2021-000602","type":"journal-article","created":{"date-parts":[[2022,1,7]],"date-time":"2022-01-07T11:05:47Z","timestamp":1641553547000},"page":"e000602","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":26,"title":["Hydroxychloroquine PK and exposure-response in pregnancies with lupus: the importance of adherence for neonatal outcomes"],"prefix":"10.1136","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4016-1680","authenticated-orcid":false,"given":"Stephen J","family":"Balevic","sequence":"first","affiliation":[{"name":"Department of Pediatrics, Duke University, Durham, North Carolina, USA"},{"name":"Duke Clinical Research Institute, Durham, North Carolina, USA"},{"name":"Department of Internal Medicine, Duke University, Durham, North Carolina, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Weiner","sequence":"additional","affiliation":[{"name":"Division of Pharmacotherapy and Experimental Therapeutics, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8579-3470","authenticated-orcid":false,"given":"Megan E B","family":"Clowse","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Duke University, Durham, North Carolina, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amanda M","family":"Eudy","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Duke University, Durham, North Carolina, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anil R","family":"Maharaj","sequence":"additional","affiliation":[{"name":"Pharmaceutical Sciences, The University of British Columbia, Vancouver, British Columbia, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christoph P","family":"Hornik","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Duke University, Durham, North Carolina, USA"},{"name":"Duke Clinical Research Institute, Durham, North Carolina, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Cohen-Wolkowiez","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Duke University, Durham, North Carolina, USA"},{"name":"Duke Clinical Research Institute, Durham, North Carolina, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Gonzalez","sequence":"additional","affiliation":[{"name":"Division of Pharmacotherapy and Experimental Therapeutics, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"239","published-online":{"date-parts":[[2022,1,7]]},"reference":[{"key":"2025091514483458000_9.1.e000602.1","doi-asserted-by":"crossref","first-page":"441","DOI":"10.1016\/j.rdc.2021.04.008","article-title":"Management of pregnancy in lupus","volume":"47","author":"Moyer","year":"2021","journal-title":"Rheum Dis Clin North Am"},{"key":"2025091514483458000_9.1.e000602.2","doi-asserted-by":"crossref","first-page":"164","DOI":"10.7326\/M19-0120","article-title":"Trends in maternal and fetal outcomes among pregnant women with systemic lupus erythematosus in the United States: a cross-sectional analysis","volume":"171","author":"Mehta","year":"2019","journal-title":"Ann Intern Med"},{"key":"2025091514483458000_9.1.e000602.3","first-page":"annrheumdis-2017-212535","article-title":"E ffect of pregnancy on disease flares in patients with systemic lupus erythematosus","volume":"38","author":"Eudy","year":"2018","journal-title":"Ann Rheum Dis"},{"key":"2025091514483458000_9.1.e000602.4","doi-asserted-by":"publisher","DOI":"10.3899\/jrheum.180158"},{"key":"2025091514483458000_9.1.e000602.5","doi-asserted-by":"publisher","DOI":"10.3899\/jrheum.200802"},{"key":"2025091514483458000_9.1.e000602.6","doi-asserted-by":"publisher","DOI":"10.7326\/M14-2235"},{"key":"2025091514483458000_9.1.e000602.7","doi-asserted-by":"publisher","DOI":"10.1136\/annrheumdis-2017-211641"},{"key":"2025091514483458000_9.1.e000602.8","doi-asserted-by":"publisher","DOI":"10.1191\/096120301678646137"},{"key":"2025091514483458000_9.1.e000602.9","doi-asserted-by":"crossref","first-page":"1163","DOI":"10.1177\/09612033211007199","article-title":"Hydroxychloroquine prophylaxis for preeclampsia, hypertension and prematurity in pregnant patients with systemic lupus erythematosus: a meta-analysis","volume":"30","author":"Duan","year":"2021","journal-title":"Lupus"},{"key":"2025091514483458000_9.1.e000602.10","doi-asserted-by":"crossref","first-page":"529","DOI":"10.1002\/art.41191","article-title":"2020 American College of rheumatology guideline for the management of reproductive health in rheumatic and musculoskeletal diseases","volume":"72","author":"Sammaritano","year":"2020","journal-title":"Arthritis Rheumatol"},{"key":"2025091514483458000_9.1.e000602.11","doi-asserted-by":"publisher","DOI":"10.1136\/annrheumdis-2016-209770"},{"key":"2025091514483458000_9.1.e000602.12","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-pharmtox-011613-140009"},{"key":"2025091514483458000_9.1.e000602.13","doi-asserted-by":"publisher","DOI":"10.2165\/11597440-000000000-00000"},{"key":"2025091514483458000_9.1.e000602.14","doi-asserted-by":"crossref","first-page":"525","DOI":"10.1007\/s40262-018-0712-z","article-title":"Pharmacokinetics of hydroxychloroquine in pregnancies with rheumatic diseases","volume":"58","author":"Balevic","year":"2019","journal-title":"Clin Pharmacokinet"},{"key":"2025091514483458000_9.1.e000602.15","doi-asserted-by":"crossref","first-page":"374","DOI":"10.1002\/cpt.1194","article-title":"A prospective international study on adherence to treatment in 305 patients with flaring SLE: assessment by drug levels and self-administered questionnaires","volume":"106","author":"Costedoat-Chalumeau","year":"2019","journal-title":"Clin Pharmacol Ther"},{"key":"2025091514483458000_9.1.e000602.16","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1186\/s13075-020-02291-z","article-title":"Hydroxychloroquine levels in patients with systemic lupus erythematosus: whole blood is preferable but serum levels also detect non-adherence","volume":"22","author":"Blanchet","year":"2020","journal-title":"Arthritis Res Ther"},{"key":"2025091514483458000_9.1.e000602.17","doi-asserted-by":"crossref","first-page":"1712","DOI":"10.1002\/acr.22636","article-title":"Medication nonadherence is associated with increased subsequent acute care utilization among Medicaid beneficiaries with systemic lupus erythematosus","volume":"67","author":"Feldman","year":"2015","journal-title":"Arthritis Care Res"},{"key":"2025091514483458000_9.1.e000602.18","doi-asserted-by":"publisher","DOI":"10.1177\/0961203312447868"},{"key":"2025091514483458000_9.1.e000602.19","doi-asserted-by":"publisher","DOI":"10.3899\/jrheum.150379"},{"key":"2025091514483458000_9.1.e000602.20","doi-asserted-by":"publisher","DOI":"10.1097\/TP.0b013e318278d367"},{"key":"2025091514483458000_9.1.e000602.21","doi-asserted-by":"publisher","DOI":"10.1002\/art.22898"},{"key":"2025091514483458000_9.1.e000602.22","doi-asserted-by":"publisher","DOI":"10.1007\/s10787-015-0239-y"},{"key":"2025091514483458000_9.1.e000602.23","first-page":"1874","article-title":"Concentration-effect relationship of hydroxychloroquine in rheumatoid arthritis--a cross sectional study","volume":"20","author":"Tett","year":"1993","journal-title":"J Rheumatol"},{"key":"2025091514483458000_9.1.e000602.24","doi-asserted-by":"crossref","unstructured":"Browning DJ . Pharmacology of chloroquine and hydroxychloroquine. hydroxychloroquine and chloroquine retinopathy, 2014: 35\u201363.","DOI":"10.1007\/978-1-4939-0597-3_2"},{"key":"2025091514483458000_9.1.e000602.25","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2020.05.045"},{"key":"2025091514483458000_9.1.e000602.26","doi-asserted-by":"crossref","first-page":"741","DOI":"10.1177\/0961203321989803","article-title":"The importance of pregnancy planning in lupus pregnancies","volume":"30","author":"Rajendran","year":"2021","journal-title":"Lupus"},{"key":"2025091514483458000_9.1.e000602.27","doi-asserted-by":"crossref","first-page":"2176","DOI":"10.1002\/art.39194","article-title":"Determinants of hydroxychloroquine blood concentration variations in systemic lupus erythematosus","volume":"67","author":"Jallouli","year":"2015","journal-title":"Arthritis Rheumatol"},{"key":"2025091514483458000_9.1.e000602.28","doi-asserted-by":"crossref","first-page":"536","DOI":"10.1002\/acr.22962","article-title":"Factors related to blood hydroxychloroquine concentration in patients with systemic lupus erythematosus","volume":"69","author":"Yeon Lee","year":"2017","journal-title":"Arthritis Care Res"},{"key":"2025091514483458000_9.1.e000602.29","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1186\/s13075-020-02211-1","article-title":"Measurement of hydroxychloroquine in blood from SLE patients using LC-HRMS-evaluation of whole blood, plasma, and serum as sample matrices","volume":"22","author":"Carlsson","year":"2020","journal-title":"Arthritis Res Ther"}],"container-title":["Lupus Science &amp; Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1136\/lupus-2021-000602","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,9,15]],"date-time":"2025-09-15T21:48:45Z","timestamp":1757972925000},"score":1,"resource":{"primary":{"URL":"https:\/\/lupus.bmj.com\/lookup\/doi\/10.1136\/lupus-2021-000602"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,1]]},"references-count":29,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2022,1,7]]},"published-print":{"date-parts":[[2022,1]]}},"alternative-id":["10.1136\/lupus-2021-000602"],"URL":"https:\/\/doi.org\/10.1136\/lupus-2021-000602","relation":{},"ISSN":["2053-8790"],"issn-type":[{"value":"2053-8790","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,1]]}}}