{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,7]],"date-time":"2026-08-07T16:49:06Z","timestamp":1786121346407,"version":"build-2736575974"},"reference-count":45,"publisher":"Wiley","license":[{"start":{"date-parts":[[2026,8,6]],"date-time":"2026-08-06T00:00:00Z","timestamp":1785974400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"},{"start":{"date-parts":[[2026,8,6]],"date-time":"2026-08-06T00:00:00Z","timestamp":1785974400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["ascpt.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Clin Pharma and Therapeutics"],"abstract":"\n Pain and fever are common in pregnancy. Dipyrone is widely used in Europe, Latin America, and parts of Asia, but is banned in other countries due to concerns about agranulocytosis. Evidence on its safety in pregnancy remains limited and inconsistent. This study aimed to evaluate whether maternal dipyrone use during the first\u2010 and third\u2010trimesters is associated with major congenital malformations (MCMs) and adverse perinatal or early neonatal outcomes. A population\u2010based cohort of all pregnancies that delivered or underwent elective termination at Soroka University Medical Center from 1998 to 2018, linking maternal, neonatal, and termination records with pharmacy dispensations. Generalized full matching and Poisson regression were used to study the association of first\u2010and third\u2010trimester dipyrone exposure and risks of MCMs, perinatal outcomes, and early neonatal complications, including preterm ductal closure and renal injury. Among 264,858 singleton pregnancies analyzed for first\u2010trimester exposure, 8,987 (3.4%) were exposed to Dipyrone. MCMs occurred in 8.0% of exposed vs. 7.0% of unexposed; however, no association was found after matching (adjusted risk ratio (RR) 1.04, 95% CI: 0.88\u20131.22). No associations were observed with malformation in other organ systems. In third\u2010trimester analyses (\n n<\/jats:italic>\n \u2009=\u2009257,285; 6,362 (2.5%) exposed), dipyrone was not associated with preterm birth, low birthweight, perinatal death, low Apgar scores, or evidence of renal toxicity or premature ductus arteriosus constriction. No dose\u2013response was observed. Sensitivity Analysis for over\u2010the\u2010counter use indicated minimal possible misclassification bias. This study provides evidence supporting maternal dipyrone use in early or late pregnancy is not associated with MCMs, adverse perinatal outcomes, or early neonatal complications.\n <\/jats:p>","DOI":"10.1002\/cpt.70431","type":"journal-article","created":{"date-parts":[[2026,8,7]],"date-time":"2026-08-07T03:45:22Z","timestamp":1786074322000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Maternal Dipyrone Exposure and Risk of Major Congenital Malformations, Adverse Perinatal and Postnatal Outcomes: A Population\u2010Based Cohort Study"],"prefix":"10.1002","author":[{"ORCID":"https:\/\/orcid.org\/0009-0002-7093-8953","authenticated-orcid":false,"given":"Itamar Ben","family":"Shitrit","sequence":"first","affiliation":[{"name":"Department of Epidemiology, Biostatistics, and Community Health Sciences School of Public Health, Faculty of Health Sciences, University of the Negev Beer\u2010Sheva Israel"},{"name":"Joyce and Irving Goldman Medical School, Faculty of Health Sciences, Ben\u2010Gurion University of the Negev Beer\u2010Sheva Israel"},{"name":"Clinical Research Center, Faculty of Health Sciences, Soroka University Medical Center, Ben\u2010Gurion University of the Negev Beer\u2010Sheva Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-8218-5476","authenticated-orcid":false,"given":"Daphna","family":"Idan","sequence":"additional","affiliation":[{"name":"Department of Epidemiology, Biostatistics, and Community Health Sciences School of Public Health, Faculty of Health Sciences, University of the Negev Beer\u2010Sheva Israel"},{"name":"Joyce and Irving Goldman Medical School, Faculty of Health Sciences, Ben\u2010Gurion University of the Negev Beer\u2010Sheva Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1785-0952","authenticated-orcid":false,"given":"Ariel Avraham","family":"Hasidim","sequence":"additional","affiliation":[{"name":"Department of Pediatrics A Schneider Children's Medical Center of Israel Petah Tikva Israel"},{"name":"Gray Faculty of Medicine, Tel Aviv University Tel Aviv Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0328-055X","authenticated-orcid":false,"given":"Tal","family":"Michael","sequence":"additional","affiliation":[{"name":"Department of Epidemiology, Biostatistics, and Community Health Sciences School of Public Health, Faculty of Health Sciences, University of the Negev Beer\u2010Sheva Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2355-8854","authenticated-orcid":false,"given":"Amalia","family":"Levy","sequence":"additional","affiliation":[{"name":"Department of Epidemiology, Biostatistics, and Community Health Sciences School of Public Health, Faculty of Health Sciences, University of the Negev Beer\u2010Sheva Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6484-3769","authenticated-orcid":false,"given":"Gali","family":"Pariente","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology Faculty of Health Sciences Ben\u2010Gurion University of the Negev and Soroka University Medical Center Beer\u2010Sheva Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2260-9530","authenticated-orcid":false,"given":"Eitan","family":"Lunenfeld","sequence":"additional","affiliation":[{"name":"Adelson School of Medicine, Ariel University Ariel Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1820-9278","authenticated-orcid":false,"given":"Sharon","family":"Daniel","sequence":"additional","affiliation":[{"name":"Department of Epidemiology, Biostatistics, and Community Health Sciences School of Public Health, Faculty of Health Sciences, University of the Negev Beer\u2010Sheva Israel"},{"name":"Department of Pediatrics Faculty of Health Sciences, Ben\u2010Gurion University of the Negev Beer\u2010Sheva Israel"},{"name":"Clalit Health Services, Southern District Beer\u2010Sheva Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,8,6]]},"reference":[{"key":"e_1_2_12_1_1","doi-asserted-by":"crossref","first-page":"1131","DOI":"10.1007\/s00404-018-4684-x","article-title":"Emergency department use during pregnancy: a prospective observational study in a single center institution","volume":"297","author":"Thangarajah F.","year":"2018","journal-title":"Arch. Gynecol. Obstet."},{"key":"e_1_2_12_2_1","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1007\/s10995-018-2651-6","article-title":"Emergency care utilization among pregnant Medicaid recipients in North Carolina: an analysis using linked claims and birth records","volume":"23","author":"Vladutiu C.J.","year":"2019","journal-title":"Matern. Child Health J."},{"key":"e_1_2_12_3_1","doi-asserted-by":"crossref","first-page":"645","DOI":"10.1016\/j.annepidem.2017.09.003","article-title":"Risk comparison for prenatal use of analgesics and selected birth defects, National Birth Defects Prevention Study 1997\u20132011","volume":"27","author":"Interrante J.D.","year":"2017","journal-title":"Ann. Epidemiol."},{"key":"e_1_2_12_4_1","doi-asserted-by":"crossref","first-page":"6098","DOI":"10.2174\/1381612823666170825123754","article-title":"Analgesics in pregnancy: an update on use, safety and pharmacokinetic changes in drug disposition","volume":"23","author":"Price H.R.","year":"2017","journal-title":"Curr. Pharm. Des."},{"key":"e_1_2_12_5_1","doi-asserted-by":"crossref","DOI":"10.1016\/j.semperi.2025.152074","article-title":"Pain medication use during pregnancy","volume":"49","author":"Nunge R.A.","year":"2025","journal-title":"Semin. Perinatol."},{"key":"e_1_2_12_6_1","article-title":"Pain Management in Pregnancy: multimodal approaches","volume":"2015","author":"Shah S.","year":"2015","journal-title":"Pain Res. Treat."},{"key":"e_1_2_12_7_1","unstructured":"Metamizole [Dipyrone]. LiverTox: Clinical and Research Information on Drug\u2010Induced Liver Injury(2025)."},{"key":"e_1_2_12_8_1","doi-asserted-by":"crossref","DOI":"10.31744\/einstein_journal\/2022AO6353","article-title":"Real world evidence of the use of metamizole (dipyrone) by the Brazilian population. A retrospective cohort with over 380,000 patients","volume":"20","author":"Sznejder H.","year":"2022","journal-title":"Einstein (S\u00e3o Paulo)"},{"key":"e_1_2_12_9_1","doi-asserted-by":"crossref","DOI":"10.57187\/s.3535","article-title":"Use of metamizole and other non\u2010opioid analgesics in Switzerland between 2014 and 2019: an observational study using a large health insurance claims database","volume":"154","author":"Gut S.","year":"2024","journal-title":"Swiss Med. Wkly."},{"key":"e_1_2_12_10_1","doi-asserted-by":"crossref","DOI":"10.3390\/ijerph17113892","article-title":"Regional differences in prescribing patterns of metamizole in Germany based on data from 70 million persons","volume":"17","author":"Hoffmann F.","year":"2020","journal-title":"Int. J. Environ. Res. Public Health"},{"key":"e_1_2_12_11_1","doi-asserted-by":"crossref","first-page":"760","DOI":"10.1186\/s12884-025-07872-x","article-title":"Adverse effects of dipyrone (metamizole) use during pregnancy on offspring health: a systematic review and meta\u2010analysis","volume":"25","author":"Lino G.M.","year":"2025","journal-title":"BMC Pregnancy Childbirth"},{"key":"e_1_2_12_12_1","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1111\/jcpt.12261","article-title":"Who gets dipyrone (metamizole) in Germany? Prescribing by age, sex and region","volume":"40","author":"Hoffmann F.","year":"2015","journal-title":"J. Clin. Pharm. Ther."},{"key":"e_1_2_12_13_1","doi-asserted-by":"crossref","DOI":"10.1590\/0102-311xen093125","article-title":"Dipyrone use in Brazil: clinical conditions, sociodemographic characteristics, population attitudes and perceptions","volume":"42","author":"Medeiros E.F.F.","year":"2026","journal-title":"Cad. Saude Publica"},{"key":"e_1_2_12_14_1","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1111\/jcpt.12768","article-title":"Metamizole (dipyrone)\u2010induced agranulocytosis: does the risk vary according to ethnicity?","volume":"44","author":"Shah R.R.","year":"2019","journal-title":"J. Clin. Pharm. Ther."},{"key":"e_1_2_12_15_1","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0122918","article-title":"Metamizole\u2010associated adverse events: a systematic review and meta\u2010analysis","volume":"10","author":"K\u00f6tter T.","year":"2015","journal-title":"PLoS One"},{"key":"e_1_2_12_16_1","unstructured":"Review of painkiller metamizole started|European Medicines Agency (EMA)[Internet] Accessed June 18 2026."},{"key":"e_1_2_12_17_1","unstructured":"EMA recommends measures to minimise serious outcomes of known side effect with painkiller metamizole|European Medicines Agency (EMA)[Internet] Accessed June 18 2026."},{"key":"e_1_2_12_18_1","unstructured":"Meeting highlights from the Pharmacovigilance Risk Assessment Committee (PRAC) 2\u20105 September 2024|European Medicines Agency (EMA)[Internet] Accessed June 18 2026."},{"key":"e_1_2_12_19_1","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1007\/s00228-024-03769-4","article-title":"Use of dipyrone during pregnancy and risk of congenital anomalies: a systematic review","volume":"81","author":"Curvello K.D.","year":"2024","journal-title":"Eur. J. Clin. Pharmacol."},{"key":"e_1_2_12_20_1","doi-asserted-by":"crossref","first-page":"805","DOI":"10.1097\/EDE.0b013e3181577511","article-title":"Strengthening the reporting of observational studies in epidemiology (STROBE): explanation and elaboration","volume":"18","author":"Vandenbroucke J.P.","year":"2007","journal-title":"Epidemiology"},{"key":"e_1_2_12_21_1","unstructured":"Angel D.Patterns of fertility in 2006 [Article in Hebrew]. Central Bureau of Statistics: Jerusalem (Israel); (2007). Accessed October 6 2025."},{"key":"e_1_2_12_22_1","unstructured":"."},{"key":"e_1_2_12_23_1","unstructured":"ATCDDD\u2010ATC\/DDD index. [Internet] Accessed November 1 2025."},{"key":"e_1_2_12_24_1","doi-asserted-by":"crossref","first-page":"E177","DOI":"10.1503\/cmaj.130605","article-title":"Fetal exposure to nonsteroidal anti\u2010inflammatory drugs and spontaneous abortions","volume":"186","author":"Daniel S.","year":"2014","journal-title":"CMAJ"},{"key":"e_1_2_12_25_1","unstructured":"Balak R. Levi S.&Knesset Research and Information Center.Prisat batei ha\u2010merkahat be\u2010Yisrael ve\u2010negishutam le\u2010mvutakhei kupot ha\u2010holim [Dispersion of Pharmacies in Israel and Their Accessibility to Health Fund Insurees] (2024). Accessed October 18 2025."},{"key":"e_1_2_12_26_1","doi-asserted-by":"crossref","first-page":"1560","DOI":"10.1111\/1471-0528.15872","article-title":"Negligible risk of prenatal ductus arteriosus closure or fetal renal impairment after third\u2010trimester paracetamol use: evaluation of the German Embryotox cohort","volume":"126","author":"Dathe K.","year":"2019","journal-title":"BJOG"},{"key":"e_1_2_12_27_1","volume-title":"R: A Language and Environment for Statistical Computing","author":"R Core Team","year":"2025"},{"key":"e_1_2_12_28_1","doi-asserted-by":"crossref","first-page":"305","DOI":"10.1016\/0304-4076(85)90158-7","article-title":"Some heteroskedasticity\u2010consistent covariance matrix estimators with improved finite sample properties","volume":"29","author":"Sun C.W.","year":"1985","journal-title":"J. Econom."},{"key":"e_1_2_12_29_1","doi-asserted-by":"crossref","first-page":"1","DOI":"10.18637\/jss.v095.i01","article-title":"Various versatile variances: an object\u2010oriented implementation of clustered covariances in R","volume":"95","author":"Zeileis A.","year":"2020","journal-title":"J. Stat. Softw."},{"key":"e_1_2_12_30_1","doi-asserted-by":"crossref","first-page":"1","DOI":"10.18637\/jss.v016.i09","article-title":"Object\u2010oriented computation of Sandwich estimators","volume":"16","author":"Zeileis A.","year":"2006","journal-title":"J. Stat. Softw."},{"key":"e_1_2_12_31_1","doi-asserted-by":"crossref","first-page":"1","DOI":"10.18637\/jss.v011.i10","article-title":"Econometric computing with HC and HAC covariance matrix estimators","volume":"11","author":"Zeileis A.","year":"2004","journal-title":"J. Stat. Softw."},{"key":"e_1_2_12_32_1","doi-asserted-by":"crossref","first-page":"1","DOI":"10.18637\/jss.v111.i09","article-title":"How to interpret statistical models using marginaleffects for R and python","volume":"111","author":"Arel\u2010Bundock V.","year":"2024","journal-title":"J. Stat. Softw."},{"key":"e_1_2_12_33_1","doi-asserted-by":"crossref","first-page":"423","DOI":"10.1017\/pan.2020.32","article-title":"Generalized full matching","volume":"29","author":"S\u00e4vje F.","year":"2021","journal-title":"Polit. Anal."},{"key":"e_1_2_12_34_1","first-page":"1","article-title":"MatchIt: nonparametric preprocessing for parametric causal inference","volume":"42","author":"Ho D.E.","year":"2011","journal-title":"J. Stat. Softw."},{"key":"e_1_2_12_35_1","doi-asserted-by":"crossref","first-page":"E177","DOI":"10.1503\/cmaj.130605","article-title":"Fetal exposure to nonsteroidal anti\u2010inflammatory drugs and spontaneous abortions","volume":"186","author":"Daniel S.","year":"2014","journal-title":"CMAJ"},{"key":"e_1_2_12_36_1","doi-asserted-by":"crossref","first-page":"176","DOI":"10.1016\/j.ejogrb.2004.07.004","article-title":"Metamizol (dipyrone, optalgin) in pregnancy, is it safe? A prospective comparative study","volume":"119","author":"Bar\u2010Oz B.","year":"2005","journal-title":"Eur. J. Obstet. Gynecol. Reprod. Biol."},{"key":"e_1_2_12_37_1","doi-asserted-by":"crossref","first-page":"1197","DOI":"10.1002\/pds.4277","article-title":"Metamizole use during first trimester\u2010a prospective observational cohort study on pregnancy outcome","volume":"26","author":"Dathe K.","year":"2017","journal-title":"Pharmacoepidemiol. Drug Saf."},{"key":"e_1_2_12_38_1","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s12884-022-04986-4","article-title":"Fetal adverse effects following NSAID or metamizole exposure in the 2nd and 3rd trimester: an evaluation of the German Embryotox cohort","volume":"22","author":"Dathe K.","year":"2022","journal-title":"BMC Pregnancy Childbirth"},{"key":"e_1_2_12_39_1","doi-asserted-by":"crossref","first-page":"78","DOI":"10.1177\/0091270010390806","article-title":"Bias toward the null hypothesis in pregnancy drug studies that do not include data on medical terminations of pregnancy: the folic acid antagonists","volume":"52","author":"Levy A.","year":"2012","journal-title":"J. Clin. Pharmacol."},{"key":"e_1_2_12_40_1","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1111\/apa.16953","article-title":"Detection of severe congenital heart defects in live\u2010born infants in Norway 2017\u20132020","volume":"113","author":"Wik G.","year":"2024","journal-title":"Acta Paediatr."},{"key":"e_1_2_12_41_1","doi-asserted-by":"crossref","first-page":"1103","DOI":"10.1093\/oxfordjournals.aje.a117563","article-title":"Recall accuracy for prescription medications: self\u2010report compared with database information","volume":"142","author":"West S.L.","year":"1995","journal-title":"Am. J. Epidemiol."},{"key":"e_1_2_12_42_1","doi-asserted-by":"crossref","first-page":"1079","DOI":"10.1111\/j.1532-5415.1991.tb02872.x","article-title":"Comparing sources of drug data about the elderly","volume":"39","author":"Johnson R.E.","year":"1991","journal-title":"J. Am. Geriatr. Soc."},{"key":"e_1_2_12_43_1","doi-asserted-by":"crossref","first-page":"837","DOI":"10.1093\/oxfordjournals.aje.a115198","article-title":"Use of Medicaid data for pharmacoepidemiology","volume":"129","author":"Ray W.A.","year":"1989","journal-title":"Am. J. Epidemiol."},{"key":"e_1_2_12_44_1","doi-asserted-by":"crossref","first-page":"737","DOI":"10.1007\/s40264-015-0302-z","article-title":"Actual use of medications prescribed during pregnancy: a cross\u2010sectional study using data from a population\u2010based congenital anomaly registry","volume":"38","author":"Jonge L.","year":"2015","journal-title":"Drug Saf."},{"key":"e_1_2_12_45_1","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1002\/(SICI)1096-9926(199907)60:1<33::AID-TERA9>3.0.CO;2-X","article-title":"Improvement of drug exposure data in a registration of congenital anomalies. Pilot\u2010study: pharmacist and mother as sources for drug exposure data during pregnancy","volume":"60","author":"De Jong van den Berg L.T.","year":"1999","journal-title":"Teratology"}],"container-title":["Clinical Pharmacology & Therapeutics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/cpt.70431","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/cpt.70431","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/cpt.70431","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,7]],"date-time":"2026-08-07T03:45:30Z","timestamp":1786074330000},"score":1,"resource":{"primary":{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/10.1002\/cpt.70431"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,6]]},"references-count":45,"alternative-id":["10.1002\/cpt.70431"],"URL":"https:\/\/doi.org\/10.1002\/cpt.70431","archive":["Portico"],"relation":{},"ISSN":["0009-9236","1532-6535"],"issn-type":[{"value":"0009-9236","type":"print"},{"value":"1532-6535","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,6]]},"assertion":[{"value":"2026-04-20","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-07-27","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-08-06","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"cpt.70431"}}