{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,14]],"date-time":"2026-07-14T13:23:35Z","timestamp":1784035415404,"version":"3.55.0"},"reference-count":41,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2019,3,3]],"date-time":"2019-03-03T00:00:00Z","timestamp":1551571200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["BE 4500\/3\u20101"],"award-info":[{"award-number":["BE 4500\/3\u20101"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["ME 910\/2\u20101"],"award-info":[{"award-number":["ME 910\/2\u20101"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["SCHA 1749\/3\u20101"],"award-info":[{"award-number":["SCHA 1749\/3\u20101"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Pharmacoepidemiology and Drug"],"published-print":{"date-parts":[[2019,5]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Purpose<\/jats:title><jats:p>Observational cohort studies are essential to evaluate the risk of adverse pregnancy outcomes associated with drug intake. Besides left truncation and competing events, it is crucial to account for the time\u2010dynamic pattern of drug exposure. In fact, potentially harmful medications are often discontinued, which might affect the outcome. Ignoring these challenges may lead to biased estimation of drug\u2010related risks highlighting the need for adequate statistical techniques.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We reanalyze updated data of a recently published study provided by the German Embryotox pharmacovigilance institute. The aim of the study was to quantify the effect of discontinuation of vitamin K antagonist phenprocoumon on the risk of spontaneous abortion.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>We outline multistate methodology as a powerful method removing bias in probability estimation inherent to commonly used crude proportions. We incorporate time\u2010dependent discontinuation and competing pregnancy outcomes as separate states in a multistate model, which enables the formulation of hazard\u2010based Cox proportional hazard models and the application of so\u2010called landmark techniques. Results show that early discontinuation of phenprocoumon substantially reduces the risk of spontaneous abortion, which is of great importance for both pregnant women and treating physicians.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>An adequate handling of discontinuation times is essential when analyzing the risk of spontaneous abortion. The proposed concepts are not restricted to pregnancy outcome studies but have broad usage in other fields of epidemiology. Our nontechnical report may provide guidance for the design and analysis of future studies. Example code is provided.<\/jats:p><\/jats:sec>","DOI":"10.1002\/pds.4710","type":"journal-article","created":{"date-parts":[[2019,3,4]],"date-time":"2019-03-04T01:43:52Z","timestamp":1551663832000},"page":"616-624","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Multistate methodology improves risk assessment under time\u2010varying drug intake\u2014a new view on pregnancy outcomes following coumarin exposure"],"prefix":"10.1002","volume":"28","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2625-4167","authenticated-orcid":false,"given":"Tobias","family":"Bluhmki","sequence":"first","affiliation":[{"name":"Institute of Statistics Ulm University  Ulm Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anne\u2010Katrin","family":"Fietz","sequence":"additional","affiliation":[{"name":"Charit\u00e9 \u2013 Universit\u00e4tsmedizin Berlin, corporate member of Freie Universit\u00e4t Berlin, Humboldt\u2010Universit\u00e4t zu Berlin, and Berlin Institute of Health Pharmakovigilanzzentrum, Embryonaltoxikologie, Institut f\u00fcr Klinische Pharmakologie  Berlin Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Regina","family":"Stegherr","sequence":"additional","affiliation":[{"name":"Institute of Statistics Ulm University  Ulm Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Evelin","family":"Beck","sequence":"additional","affiliation":[{"name":"Charit\u00e9 \u2013 Universit\u00e4tsmedizin Berlin, corporate member of Freie Universit\u00e4t Berlin, Humboldt\u2010Universit\u00e4t zu Berlin, and Berlin Institute of Health Pharmakovigilanzzentrum, Embryonaltoxikologie, Institut f\u00fcr Klinische Pharmakologie  Berlin Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephanie","family":"Padberg","sequence":"additional","affiliation":[{"name":"Charit\u00e9 \u2013 Universit\u00e4tsmedizin Berlin, corporate member of Freie Universit\u00e4t Berlin, Humboldt\u2010Universit\u00e4t zu Berlin, and Berlin Institute of Health Pharmakovigilanzzentrum, Embryonaltoxikologie, Institut f\u00fcr Klinische Pharmakologie  Berlin Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jan","family":"Beyersmann","sequence":"additional","affiliation":[{"name":"Institute of Statistics Ulm University  Ulm Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christof","family":"Schaefer","sequence":"additional","affiliation":[{"name":"Charit\u00e9 \u2013 Universit\u00e4tsmedizin Berlin, corporate member of Freie Universit\u00e4t Berlin, Humboldt\u2010Universit\u00e4t zu Berlin, and Berlin Institute of Health Pharmakovigilanzzentrum, Embryonaltoxikologie, Institut f\u00fcr Klinische Pharmakologie  Berlin Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Reinhard","family":"Meister","sequence":"additional","affiliation":[{"name":"Beuth Hochschule f\u00fcr Technik \u2013 University of Applied Sciences  Berlin Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2019,3,3]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.reprotox.2006.11.005"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.1136\/bmjopen-2013-004365"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00228-017-2351-y"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.reprotox.2012.01.006"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.reprotox.2008.05.064"},{"key":"e_1_2_11_7_1","doi-asserted-by":"publisher","DOI":"10.1093\/aje\/kwt285"},{"key":"e_1_2_11_8_1","volume-title":"Modern Epidemiology","author":"Rothman KJ","year":"2008"},{"key":"e_1_2_11_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.reprotox.2008.06.006"},{"key":"e_1_2_11_10_1","doi-asserted-by":"publisher","DOI":"10.1002\/pds.3731"},{"key":"e_1_2_11_11_1","doi-asserted-by":"publisher","DOI":"10.1002\/bdra.23271"},{"key":"e_1_2_11_12_1","doi-asserted-by":"publisher","DOI":"10.1093\/epirev\/mxt011"},{"key":"e_1_2_11_13_1","doi-asserted-by":"publisher","DOI":"10.1093\/aje\/kwp107"},{"key":"e_1_2_11_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.vaccine.2012.04.081"},{"key":"e_1_2_11_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1473-3099(15)00547-2"},{"key":"e_1_2_11_16_1","doi-asserted-by":"publisher","DOI":"10.1160\/TH16-11-0838"},{"key":"e_1_2_11_17_1","doi-asserted-by":"publisher","DOI":"10.1002\/pds.4277"},{"key":"e_1_2_11_18_1","doi-asserted-by":"publisher","DOI":"10.1007\/978-1-4614-2035-4"},{"key":"e_1_2_11_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jclinepi.2016.11.001"},{"key":"e_1_2_11_20_1","doi-asserted-by":"publisher","DOI":"10.1093\/cid\/ciw191"},{"key":"e_1_2_11_21_1","doi-asserted-by":"publisher","DOI":"10.1017\/ice.2017.107"},{"key":"e_1_2_11_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jamda.2016.08.022"},{"key":"e_1_2_11_23_1","doi-asserted-by":"publisher","DOI":"10.1093\/aje\/kwq384"},{"key":"e_1_2_11_24_1","doi-asserted-by":"publisher","DOI":"10.3109\/17453674.2012.684140"},{"key":"e_1_2_11_25_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.addbeh.2011.09.012"},{"key":"e_1_2_11_26_1","doi-asserted-by":"publisher","DOI":"10.1002\/bimj.200900039"},{"key":"e_1_2_11_27_1","doi-asserted-by":"publisher","DOI":"10.1002\/pst.1739"},{"key":"e_1_2_11_28_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajog.2014.09.028"},{"key":"e_1_2_11_29_1","doi-asserted-by":"publisher","DOI":"10.1201\/b16720-35"},{"key":"e_1_2_11_30_1","doi-asserted-by":"publisher","DOI":"10.1093\/aje\/kwm324"},{"key":"e_1_2_11_31_1","doi-asserted-by":"publisher","DOI":"10.1002\/pds.3301"},{"key":"e_1_2_11_32_1","doi-asserted-by":"publisher","DOI":"10.1017\/S0950268812002178"},{"key":"e_1_2_11_33_1","doi-asserted-by":"publisher","DOI":"10.1093\/ije\/dyr189"},{"key":"e_1_2_11_34_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jclinepi.2012.09.017"},{"key":"e_1_2_11_35_1","doi-asserted-by":"publisher","DOI":"10.1201\/b11311"},{"key":"e_1_2_11_36_1","doi-asserted-by":"publisher","DOI":"10.18637\/jss.v038.i07"},{"key":"e_1_2_11_37_1","doi-asserted-by":"publisher","DOI":"10.1007\/978-1-4757-3294-8"},{"key":"e_1_2_11_38_1","doi-asserted-by":"publisher","DOI":"10.1093\/biomet\/90.1.15"},{"key":"e_1_2_11_39_1","doi-asserted-by":"publisher","DOI":"10.1007\/978-0-387-68560-1"},{"key":"e_1_2_11_40_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijerph110303074"},{"key":"e_1_2_11_41_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12889-015-2408-8"},{"key":"e_1_2_11_42_1","doi-asserted-by":"publisher","DOI":"10.1093\/aje\/kwv163"}],"container-title":["Pharmacoepidemiology and Drug Safety"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fpds.4710","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/pds.4710","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/pds.4710","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/pds.4710","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,9,9]],"date-time":"2023-09-09T18:58:56Z","timestamp":1694285936000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/pds.4710"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,3,3]]},"references-count":41,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2019,5]]}},"alternative-id":["10.1002\/pds.4710"],"URL":"https:\/\/doi.org\/10.1002\/pds.4710","archive":["Portico"],"relation":{},"ISSN":["1053-8569","1099-1557"],"issn-type":[{"value":"1053-8569","type":"print"},{"value":"1099-1557","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,3,3]]},"assertion":[{"value":"2018-03-07","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2018-11-15","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2019-03-03","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}