{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T10:10:29Z","timestamp":1790763029504,"version":"4.1.0"},"reference-count":26,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2022,11,30]],"date-time":"2022-11-30T00:00:00Z","timestamp":1669766400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Pharmacoepidemiology and Drug"],"published-print":{"date-parts":[[2023,2]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Purpose<\/jats:title><jats:p>Large health\u2010care databases are increasingly used for research on drug utilization and safety in pregnancy. For the <jats:italic>German Pharmacoepidemiological Research Database<\/jats:italic> (<jats:italic>GePaRD<\/jats:italic>), covering ~20% of the German population, algorithms have been developed to identify pregnancies, to estimate their date of onset and to link mothers to their babies. Using this methodology, we aimed to conduct a proof\u2010of\u2010concept analysis on the known association between valproate (VPA) exposure in early pregnancy and spina bifida in the exposed child.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We identified all pregnancies in <jats:italic>GePaRD<\/jats:italic> between 2006 and 2016 in women aged 12 to 50\u2009years. To each VPA dispensation of these women, an exposure period was assigned, based on the dispensation date and the number of defined daily doses in the dispensed package. A pregnancy was classified as exposed to VPA in the critical time window if this exposure period overlapped with the first 55\u2009days of pregnancy. Risk ratios were calculated for spina bifida in live births and induced abortions comparing VPA\u2010exposed ones to all pregnancies.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Overall, we identified 1\u2009271\u2009384 pregnancies fulfilling the inclusion criteria. Of these, 668 pregnancies (0.053%) were classified as exposed to VPA in the critical time window regarding spina bifida. An induced abortion accompanied by a diagnosis of spina bifida was observed in one of the VPA\u2010exposed pregnancies (0.15%) and in 154 of all pregnancies (0.012%), yielding a risk ratio of 12.4 (95% confidence interval [CI]: 1.7\u201388.2). Out of 775\u2009875 pregnancies ending in a live birth, 366 (0.047%) were classified as VPA exposed. A diagnosis of spina bifida was coded in 3 of 366 VPA\u2010exposed live births (0.82%) and in 260 of all live births (0.03%), yielding a relative risk of 24.5 (95% CI: 7.9\u201376.0).<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Our proof\u2010of\u2010concept analysis based on <jats:italic>GePaRD<\/jats:italic> showed a strong association between intrauterine exposure to VPA and occurrence of spina bifida. The results are plausible and consistent with the literature, supporting the suitability of <jats:italic>GePaRD<\/jats:italic> and the developed algorithms to conduct studies on drug safety in pregnancy.<\/jats:p><\/jats:sec>","DOI":"10.1002\/pds.5573","type":"journal-article","created":{"date-parts":[[2022,11,19]],"date-time":"2022-11-19T16:08:36Z","timestamp":1668874116000},"page":"148-157","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Investigating drug safety in pregnancy based on the German Pharmacoepidemiological Research Database (GePaRD): A proof\u2010of\u2010concept analysis on the association between valproate and spina bifida"],"prefix":"10.1002","volume":"32","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1886-2923","authenticated-orcid":false,"given":"Ulrike","family":"Haug","sequence":"first","affiliation":[{"name":"Department of Clinical Epidemiology Leibniz Institute for Prevention Research and Epidemiology \u2013 BIPS  Bremen Germany"},{"name":"Faculty of Human and Health Sciences University of Bremen  Bremen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5964-954X","authenticated-orcid":false,"given":"Bianca","family":"Kollhorst","sequence":"additional","affiliation":[{"name":"Department of Biometry and Data Management Leibniz Institute for Prevention Research and Epidemiology \u2013 BIPS  Bremen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0224-1866","authenticated-orcid":false,"given":"Tania","family":"Schink","sequence":"additional","affiliation":[{"name":"Department of Clinical Epidemiology Leibniz Institute for Prevention Research and Epidemiology \u2013 BIPS  Bremen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kathrin","family":"Th\u00f6ne","sequence":"additional","affiliation":[{"name":"Techniker Krankenkasse  Hamburg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8674-5817","authenticated-orcid":false,"given":"Katarina","family":"Dathe","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, Pharmakovigilanz\u2010 und Beratungszentrum f\u00fcr Embryonaltoxikologie Institut f\u00fcr Klinische Pharmakologie und Toxikologie  Berlin 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, Pharmakovigilanz\u2010 und Beratungszentrum f\u00fcr Embryonaltoxikologie Institut f\u00fcr Klinische Pharmakologie und Toxikologie  Berlin Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marlies","family":"Onken","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, Pharmakovigilanz\u2010 und Beratungszentrum f\u00fcr Embryonaltoxikologie Institut f\u00fcr Klinische Pharmakologie und Toxikologie  Berlin Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2022,11,30]]},"reference":[{"key":"e_1_2_13_2_1","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2018.17716"},{"key":"e_1_2_13_3_1","doi-asserted-by":"publisher","DOI":"10.1002\/pds.4789"},{"key":"e_1_2_13_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jclinepi.2004.10.012"},{"key":"e_1_2_13_5_1","doi-asserted-by":"publisher","DOI":"10.1002\/pds.2038"},{"key":"e_1_2_13_6_1","doi-asserted-by":"publisher","DOI":"10.3389\/fpubh.2020.00350"},{"key":"e_1_2_13_7_1","doi-asserted-by":"publisher","DOI":"10.1002\/pds.4588"},{"key":"e_1_2_13_8_1","doi-asserted-by":"publisher","DOI":"10.1212\/wnl.0000000000007696"},{"key":"e_1_2_13_9_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa0907328"},{"key":"e_1_2_13_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/s1474\u20104422(15)00314\u20102"},{"key":"e_1_2_13_11_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrdp.2015.7"},{"key":"e_1_2_13_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/s1474\u20104422(18)30107\u20108"},{"key":"e_1_2_13_13_1","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2013.2270"},{"key":"e_1_2_13_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/s1474\u20104422(12)70323\u2010x"},{"key":"e_1_2_13_15_1","unstructured":"European Medicines Agency. 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Accessed February 15 2022.https:\/\/eu\u2010rd\u2010platform.jrc.ec.europa.eu\/eurocat\/eurocat\u2010data\/prevalence_en"},{"key":"e_1_2_13_27_1","unstructured":"EUROCAT \u2010 European network of population\u2010based registries for the epidemiological surveillance of congenital anomalies. Number of cases prevalence per 10 000 births and proportion of Spina Bifida for all full registries from 2006 \u2010 2016. 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