{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T13:30:04Z","timestamp":1790688604673,"version":"4.1.0"},"reference-count":24,"publisher":"Oxford University Press (OUP)","issue":"6","license":[{"start":{"date-parts":[[2021,1,11]],"date-time":"2021-01-11T00:00:00Z","timestamp":1610323200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2021,6,1]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>The scientific community relies on postmarketing approaches to define the risk of using medications in pregnancy because information available at the time of drug approval is limited. Most studies carried out in pregnancy focus on a single outcome or selected outcomes. However, women must balance the benefit of treatment against all possible adverse effects. We aimed to apply and evaluate a tree-based scan statistic data-mining method (TreeScan; Martin Kulldorff, Harvard Medical School, Boston, Massachusetts) as a safety surveillance approach that allows for simultaneous evaluation of a comprehensive range of adverse pregnancy outcomes, while preserving the overall rate of false-positive alerts. We evaluated TreeScan with a cohort design and adjustment via propensity score techniques, using 2 test cases: 1) opioids and neonatal opioid withdrawal syndrome and 2) valproate and congenital malformations, implemented in pregnancy cohorts nested within the Medicaid Analytic eXtract (January 1, 2000\u2013December 31, 2014) and the IBM MarketScan Research Database (IBM, Armonk, New York) (January 1, 2003\u2013September 30, 2015). In both cases, we identified known safety concerns, with only 1 previously unreported alert at the preset statistical alerting threshold. This evaluation shows the promise of TreeScan-based approaches for systematic drug safety monitoring in pregnancy. A targeted screening approach followed by deeper investigation to refine understanding of potential signals will ensure that pregnant women and their physicians have access to the best available evidence to inform treatment decisions.<\/jats:p>","DOI":"10.1093\/aje\/kwaa288","type":"journal-article","created":{"date-parts":[[2021,1,7]],"date-time":"2021-01-07T22:59:53Z","timestamp":1610060393000},"page":"1159-1168","source":"Crossref","is-referenced-by-count":28,"title":["Active Surveillance of the Safety of Medications Used During Pregnancy"],"prefix":"10.1093","volume":"190","author":[{"given":"Krista F","family":"Huybrechts","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin","family":"Kulldorff","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sonia","family":"Hern\u00e1ndez-D\u00edaz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brian T","family":"Bateman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanmin","family":"Zhu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Helen","family":"Mogun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shirley V","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2021,1,11]]},"reference":[{"issue":"6","key":"2021060111394085600_ref1","doi-asserted-by":"crossref","first-page":"554","DOI":"10.1176\/appi.ajp.2012.12030367","article-title":"The last therapeutic orphan: the pregnant woman","volume":"169","author":"Wisner","year":"2012","journal-title":"Am J Psychiatry"},{"key":"2021060111394085600_ref2","first-page":"146","volume-title":"Environment and Birth Defects","author":"Wilson","year":"1973","edition":"1st"},{"issue":"4 suppl","key":"2021060111394085600_ref3","doi-asserted-by":"crossref","first-page":"984","DOI":"10.1542\/peds.113.S3.984","article-title":"Utilization of animal studies to determine the effects and human risks of environmental toxicants (drugs, chemicals, and physical agents)","volume":"113","author":"Brent","year":"2004","journal-title":"Pediatrics"},{"issue":"7","key":"2021060111394085600_ref4","doi-asserted-by":"crossref","first-page":"906","DOI":"10.1002\/pds.4789","article-title":"Use of real world evidence from healthcare utilization data to evaluate drug safety during pregnancy","volume":"28","author":"Huybrechts","year":"2019","journal-title":"Pharmacoepidemiol Drug Saf."},{"key":"2021060111394085600_ref5","author":"Kulldorff"},{"issue":"5","key":"2021060111394085600_ref6","doi-asserted-by":"crossref","first-page":"517","DOI":"10.1002\/pds.3423","article-title":"Drug safety data mining with a tree-based scan statistic","volume":"22","author":"Kulldorff","year":"2013","journal-title":"Pharmacoepidemiol Drug Saf"},{"issue":"6","key":"2021060111394085600_ref7","doi-asserted-by":"crossref","first-page":"895","DOI":"10.1097\/EDE.0000000000000907","article-title":"Data mining for adverse drug events with a propensity score matched tree-based scan statistic","volume":"29","author":"Wang","year":"2018","journal-title":"Epidemiology"},{"issue":"6","key":"2021060111394085600_ref8","doi-asserted-by":"crossref","first-page":"1269","DOI":"10.1093\/aje\/kwy023","article-title":"Assessment of quadrivalent human papillomavirus vaccine safety using the self-controlled tree-temporal scan statistic signal-detection method in the Sentinel System","volume":"187","author":"Yih","year":"2018","journal-title":"Am J Epidemiol"},{"issue":"2","key":"2021060111394085600_ref9","doi-asserted-by":"crossref","first-page":"323","DOI":"10.1111\/1541-0420.00039","article-title":"A tree-based scan statistic for database disease surveillance","volume":"59","author":"Kulldorff","year":"2003","journal-title":"Biometrics"},{"key":"2021060111394085600_ref10","author":"Healthcare Cost and Utilization Project, Agency for Healthcare Research and Quality"},{"issue":"1","key":"2021060111394085600_ref11","article-title":"Statistical power for postlicensure medical product safety data mining","volume":"5","author":"Maro","year":"2018","journal-title":"eGEMS"},{"issue":"23","key":"2021060111394085600_ref12","doi-asserted-by":"crossref","first-page":"2429","DOI":"10.1001\/jama.2018.18307","article-title":"Association of maternal first-trimester ondansetron use with cardiac malformations and oral clefts in offspring","volume":"320","author":"Huybrechts","year":"2018","journal-title":"JAMA"},{"key":"2021060111394085600_ref13","article-title":"Oral fluconazole use in the first trimester and risk of congenital malformations: population based cohort study","volume":"369","author":"Zhu","year":"2020","journal-title":"BMJ"},{"key":"2021060111394085600_ref14","article-title":"Maternal and fetal outcomes following exposure to duloxetine in pregnancy: cohort study","volume":"368","author":"Huybrechts","year":"2020","journal-title":"BMJ"},{"issue":"2","key":"2021060111394085600_ref15","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1097\/EDE.0000000000000595","article-title":"Propensity-score-based fine stratification approach for confounding adjustment when exposure is infrequent","volume":"28","author":"Desai","year":"2017","journal-title":"Epidemiology"},{"issue":"6","key":"2021060111394085600_ref16","doi-asserted-by":"crossref","first-page":"e67405","DOI":"10.1371\/journal.pone.0067405","article-title":"Harnessing the Medicaid Analytic eXtract (MAX) to evaluate medications in pregnancy: design considerations","volume":"8","author":"Palmsten","year":"2013","journal-title":"PLoS One"},{"key":"2021060111394085600_ref17","doi-asserted-by":"crossref","first-page":"h2102","DOI":"10.1136\/bmj.h2102","article-title":"Exposure to prescription opioid analgesics in utero and risk of neonatal abstinence syndrome: population based cohort study","volume":"350","author":"Desai","year":"2015","journal-title":"BMJ"},{"key":"2021060111394085600_ref18","doi-asserted-by":"crossref","first-page":"j3326","DOI":"10.1136\/bmj.j3326","article-title":"Risk of neonatal drug withdrawal after intrauterine co-exposure to opioids and psychotropic medications: cohort study","volume":"358","author":"Huybrechts","year":"2017","journal-title":"BMJ"},{"issue":"1","key":"2021060111394085600_ref19","doi-asserted-by":"crossref","first-page":"179","DOI":"10.3390\/pharmaceutics5010179","article-title":"Drug adverse event detection in health plan data using the gamma Poisson shrinker and comparison to the tree-based scan statistic","volume":"5","author":"Brown","year":"2013","journal-title":"Pharmaceutics"},{"key":"2021060111394085600_ref20","volume-title":"Sentinel CBER Surveillance Protocol: Evaluation of HPV9 (Gardasil 9) Vaccine Safety Surveillance Using the TreeScan Data Mining Method","author":"Yih","year":"2016"},{"issue":"11","key":"2021060111394085600_ref21","article-title":"Monotherapy treatment of epilepsy in pregnancy: congenital malformation outcomes in the child","volume":"11","author":"Weston","year":"2016","journal-title":"Cochrane Database Syst Rev"},{"issue":"4","key":"2021060111394085600_ref22","doi-asserted-by":"crossref","first-page":"e342","DOI":"10.1212\/WNL.0000000000004857","article-title":"Topiramate use early in pregnancy and the risk of oral clefts: a pregnancy cohort study","volume":"90","author":"Hernandez-Diaz","year":"2018","journal-title":"Neurology"},{"issue":"2","key":"2021060111394085600_ref23","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1289\/ehp.11766","article-title":"Medications as a potential source of exposure to phthalates in the U.S. population","volume":"117","author":"Hern\u00e1ndez-D\u00edaz","year":"2009","journal-title":"Environ Health Perspect"},{"issue":"3","key":"2021060111394085600_ref24","doi-asserted-by":"crossref","first-page":"379","DOI":"10.1289\/ehp.1103998","article-title":"Identification of phthalates in medications and dietary supplement formulations in the United States and Canada","volume":"120","author":"Kelley","year":"2012","journal-title":"Environ Health Perspect"}],"container-title":["American Journal of Epidemiology"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/academic.oup.com\/aje\/advance-article-pdf\/doi\/10.1093\/aje\/kwaa288\/37560260\/kwaa288.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"http:\/\/academic.oup.com\/aje\/article-pdf\/190\/6\/1159\/38391374\/kwaa288.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/academic.oup.com\/aje\/article-pdf\/190\/6\/1159\/38391374\/kwaa288.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,10]],"date-time":"2022-12-10T23:26:38Z","timestamp":1670714798000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/aje\/article\/190\/6\/1159\/6071894"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,1,11]]},"references-count":24,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2021,1,11]]},"published-print":{"date-parts":[[2021,6,1]]}},"URL":"https:\/\/doi.org\/10.1093\/aje\/kwaa288","relation":{},"ISSN":["0002-9262","1476-6256"],"issn-type":[{"value":"0002-9262","type":"print"},{"value":"1476-6256","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2021,6]]},"published":{"date-parts":[[2021,1,11]]}}}