{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,13]],"date-time":"2026-05-13T16:24:22Z","timestamp":1778689462559,"version":"3.51.4"},"reference-count":39,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2024,11,26]],"date-time":"2024-11-26T00:00:00Z","timestamp":1732579200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"German Federal Institute for Drugs and Medical Devices (BfArM)","award":["V-16529\/68605\/2015-2019"],"award-info":[{"award-number":["V-16529\/68605\/2015-2019"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>Background: Paracetamol and non-steroidal anti-inflammatory drugs (NSAIDs) are frequently used during pregnancy. Due to their fetotoxicity, NSAIDs are contraindicated during the third trimester. There is ongoing controversy about the extent to which NSAIDs may cause cardiovascular and renal impairment in the fetus earlier in the second trimester. Paracetamol, used as an effective treatment for closure of patent ductus arteriosus (PDA) after birth, is suspected to cause similar but unwanted effects during the third trimester of pregnancy. Methods: Three major pharmacovigilance databases (VigilanceCentral, EudraVigilance, and VigiBase) were searched for Individual Case Safety Reports (ICSRs; n = 1288) on fetotoxic effects that have been shown to result from NSAID exposure in late pregnancy. Results: In 219\/1288 cases, an NSAID and\/or paracetamol was taken after the first trimester, and the ICSR was not related to other reported risk factors. Out of these 219 ICSRs, 48 were exposed to NSAIDs in the second but not the third trimester or to paracetamol in the third trimester. Causality assessment was \u201cprobable or likely\u201d in four NSAID reports and none of the paracetamol reports. Conclusions: The scarcity of adverse drug reactions (ADRs) in our study and in the literature, despite decades of pharmaceutical marketing and worldwide use of paracetamol as an analgesic of choice in the third trimester and the absence of formal contraindications against NSAIDs in the second trimester, speaks against a substantial cardiovascular and nephrotoxic risk of temporary use of NSAIDs in the second trimester or paracetamol in the third trimester. NSAIDs continue to be contraindicated in the third trimester.<\/jats:p>","DOI":"10.3390\/ph17121592","type":"journal-article","created":{"date-parts":[[2024,11,26]],"date-time":"2024-11-26T07:40:32Z","timestamp":1732606832000},"page":"1592","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Do Major Pharmacovigilance Databases Support Evidence of Second Trimester NSAID and Third Trimester Paracetamol Fetotoxicity?"],"prefix":"10.3390","volume":"17","author":[{"given":"Katarina","family":"Dathe","sequence":"first","affiliation":[{"name":"Charit\u00e9\u2014Universit\u00e4tsmedizin Berlin, Corporate Member of Freie Universit\u00e4t Berlin and Humboldt-Universit\u00e4t zu Berlin, Institute of Clinical Pharmacology and Toxicology, Embryotox Center of Clinical Teratology and Drug Safety in Pregnancy, Augustenburger Platz 1, 13353 Berlin, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Carolin","family":"Benndorf","sequence":"additional","affiliation":[{"name":"Charit\u00e9\u2014Universit\u00e4tsmedizin Berlin, Corporate Member of Freie Universit\u00e4t Berlin and Humboldt-Universit\u00e4t zu Berlin, Institute of Clinical Pharmacology and Toxicology, Embryotox Center of Clinical Teratology and Drug Safety in Pregnancy, Augustenburger Platz 1, 13353 Berlin, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Simone","family":"Bergner","sequence":"additional","affiliation":[{"name":"Federal Institute for Drugs and Medical Devices, Pharmacovigilance Division, Kurt-Georg-Kiesinger-Allee 3, 53175 Bonn, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9001-0525","authenticated-orcid":false,"given":"Christof","family":"Schaefer","sequence":"additional","affiliation":[{"name":"Charit\u00e9\u2014Universit\u00e4tsmedizin Berlin, Corporate Member of Freie Universit\u00e4t Berlin and Humboldt-Universit\u00e4t zu Berlin, Institute of Clinical Pharmacology and Toxicology, Embryotox Center of Clinical Teratology and Drug Safety in Pregnancy, Augustenburger Platz 1, 13353 Berlin, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2024,11,26]]},"reference":[{"key":"ref_1","unstructured":"(2024, November 14). Best Use of Medicines in Pregnancy (Bumps). Available online: https:\/\/www.medicinesinpregnancy.org\/leaflets-a-z\/."},{"key":"ref_2","unstructured":"(2024, October 31). MotherToBaby. Available online: https:\/\/mothertobaby.org\/fact-sheets."},{"key":"ref_3","unstructured":"Centre de R\u00e9f\u00e9rence sur les Agents T\u00e9ratog\u00e8nes (CRAT) (2024, November 14). M\u00e9dicaments et Grossesse. Available online: https:\/\/www.lecrat.fr\/24\/."},{"key":"ref_4","unstructured":"Pharmakovigilanz und Beratungszentrum f\u00fcr Embryonaltoxikologie (Embryotox) (2024, October 31). See Fact-Sheets (Arzneimittelinformationen). Available online: https:\/\/www.embryotox.de\/arzneimittel."},{"key":"ref_5","unstructured":"Schaefer, C., Peters, P., and Miller, R.K. (2015). Drugs During Pregnancy and Lactation: Treatment Options and Risk Assessment, Academic Press. [3rd ed.]."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"993","DOI":"10.1007\/s10654-021-00754-4","article-title":"Prenatal and postnatal exposure to acetaminophen in relation to autism spectrum and attention-deficit and hyperactivity symptoms in childhood: Meta-analysis in six European population-based cohorts","volume":"36","author":"Alemany","year":"2021","journal-title":"Eur. J. Epidemiol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1817","DOI":"10.1093\/aje\/kwy086","article-title":"Prenatal Exposure to Acetaminophen and Risk for Attention Deficit Hyperactivity Disorder and Autistic Spectrum Disorder: A Systematic Review, Meta-Analysis, and Meta-Regression Analysis of Cohort Studies","volume":"187","author":"Masarwa","year":"2018","journal-title":"Am. J. Epidemiol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"757","DOI":"10.1038\/s41574-021-00553-7","article-title":"Paracetamol use during pregnancy\u2014a call for precautionary action","volume":"17","author":"Bauer","year":"2021","journal-title":"Nat. Rev. Endocrinol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1038\/s41574-021-00605-y","article-title":"Handle with care\u2014interpretation, synthesis and dissemination of data on paracetamol in pregnancy","volume":"18","author":"Damkier","year":"2022","journal-title":"Nat. Rev. Endocrinol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1205","DOI":"10.1001\/jama.2024.3172","article-title":"Acetaminophen Use During Pregnancy and Children\u2019s Risk of Autism, ADHD, and Intellectual Disability","volume":"331","author":"Ahlqvist","year":"2024","journal-title":"JAMA"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"e12020","DOI":"10.1002\/jcv2.12020","article-title":"Acetaminophen use during pregnancy and offspring attention deficit hyperactivity disorder\u2014A longitudinal sibling control study","volume":"1","author":"Gustavson","year":"2021","journal-title":"JCPP Adv."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"256","DOI":"10.1016\/S0002-9378(97)70184-4","article-title":"The effect of indomethacin tocolysis on fetal ductus arteriosus constriction with advancing gestational age","volume":"177","author":"Vermillion","year":"1997","journal-title":"Am. J. Obs. Gynecol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1350","DOI":"10.1016\/S0002-9378(11)90763-7","article-title":"Effect of advancing gestational age on the frequency of fetal ductal constriction in association with maternal indomethacin use","volume":"168","author":"Moise","year":"1993","journal-title":"Am. J. Obs. Gynecol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"638","DOI":"10.3109\/14767058.2015.1015413","article-title":"Fetal ductus arteriosus constriction and closure: Analysis of the causes and perinatal outcome related to 45 consecutive cases","volume":"29","author":"Lopes","year":"2016","journal-title":"J. Matern. Fetal Neonatal Med."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"700","DOI":"10.1007\/BF00869093","article-title":"Renal failure in the neonate associated with in utero exposure to non-steroidal anti-inflammatory agents","volume":"8","author":"Kaplan","year":"1994","journal-title":"Pediatr. Nephrol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"617","DOI":"10.1016\/0002-9378(94)90073-6","article-title":"Persistent anuria, neonatal death, and renal microcystic lesions after prenatal exposure to indomethacin","volume":"171","author":"Carlus","year":"1994","journal-title":"Am. J. Obs. Gynecol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1347","DOI":"10.1007\/s00228-019-02712-2","article-title":"Risk estimation of fetal adverse effects after short-term second trimester exposure to non-steroidal anti-inflammatory drugs: A literature review","volume":"75","author":"Dathe","year":"2019","journal-title":"Eur. J. Clin. Pharmacol."},{"key":"ref_18","first-page":"3647","article-title":"Efficacy and safety of oral paracetamol versus oral ibuprofen for closure of patent ductus arteriosus in preterm infants: A randomized controlled trial","volume":"32","author":"Ahmed","year":"2018","journal-title":"J. Matern. Fetal Neonatal Med."},{"key":"ref_19","first-page":"CD010061","article-title":"Paracetamol (acetaminophen) for patent ductus arteriosus in preterm or low birth weight infants","volume":"2018","author":"Ohlsson","year":"2018","journal-title":"Cochrane Database Syst. Rev."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"86","DOI":"10.1055\/s-2007-999349","article-title":"Long-term indomethacin therapy decreases fetal urine output and results in oligohydramnios","volume":"8","author":"Kirshon","year":"1991","journal-title":"Am. J. Perinatol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"312","DOI":"10.1111\/j.1471-0528.1990.tb01807.x","article-title":"Oligohydramnios associated with prostaglandin synthetase inhibitors in preterm labour","volume":"97","author":"Hendricks","year":"1990","journal-title":"Br. J. Obstet. Gynaecol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"469","DOI":"10.2350\/07-11-0368.1","article-title":"Antenatal closure of the ductus arteriosus and hydrops fetalis","volume":"14","year":"2011","journal-title":"Pediatr. Dev. Pathol."},{"key":"ref_23","first-page":"557","article-title":"Premature closure of the ductus arteriosus causing intra-uterine death. A case report","volume":"70","author":"Truter","year":"1986","journal-title":"South. Afr. Med. J. Suid-Afr. Tydskr. Vir. Geneeskd."},{"key":"ref_24","unstructured":"United States Food and Drug Administration (FDA) (2024, November 20). FDA Recommends Avoiding Use of NSAIDs in Pregnancy at 20 Weeks or Later Because They Can Result in Low Amniotic Fluid. FDA Drug Safety Communication, Available online: https:\/\/www.fda.gov\/drugs\/drug-safety-and-availability\/fda-recommends-avoiding-use-nsaids-pregnancy-20-weeks-or-later-because-they-can-result-low-amniotic."},{"key":"ref_25","unstructured":"European Medicines Agency (EMA) (2024, November 20). Report from the CMDh Meeting Held on 19\u201320 July 2022 \u201cNSAID Containing Medicinal Products (for Systemic Use) and Use During Pregnancy\u201d, Available online: https:\/\/sukl.gov.cz\/file\/100016_1_1."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"e20174021","DOI":"10.1542\/peds.2017-4021","article-title":"Paracetamol\/Acetaminophen During Pregnancy Induces Prenatal Ductus Arteriosus Closure","volume":"142","author":"Becquet","year":"2018","journal-title":"Pediatrics"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1111\/bcp.13778","article-title":"Maternal paracetamol intake and fetal ductus arteriosus constriction or closure: A case series analysis","volume":"85","author":"Allegaert","year":"2019","journal-title":"Br. J. Clin. Pharmacol."},{"key":"ref_28","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-trimester paracetamol use: Evaluation of the German Embryotox cohort","volume":"126","author":"Dathe","year":"2019","journal-title":"BJOG"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"100288","DOI":"10.1016\/j.ajogmf.2020.100288","article-title":"Acetaminophen in late pregnancy and potential for in utero closure of the ductus arteriosus-a pharmacokinetic evaluation and critical review of the literature","volume":"3","author":"Hutson","year":"2021","journal-title":"Am. J. Obstet. Gynecol. MFM"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1019","DOI":"10.1007\/s00228-020-03039-z","article-title":"Maternal paracetamol intake and fetal ductus arteriosus constriction\/closure: Comprehensive signal evaluation using the Austin Bradford Hill criteria","volume":"77","author":"Hauben","year":"2021","journal-title":"Eur. J. Clin. Pharmacol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1935","DOI":"10.1007\/s00228-021-03191-0","article-title":"Maternal paracetamol intake and fetal ductus arteriosus closure: Adding pieces to the scenery","volume":"77","author":"Allegaert","year":"2021","journal-title":"Eur. J. Clin. Pharmacol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1002\/uog.2647","article-title":"Reversible contriction of the fetal ductus arteriosus after maternal use of topical diclofenac and methyl salicylate","volume":"27","author":"Torloni","year":"2006","journal-title":"Ultrasound Obs. Gynecol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1055\/s-2007-994128","article-title":"Isolated ductal closure in utero diagnosed by fetal echocardiography","volume":"14","author":"Leal","year":"1997","journal-title":"Am. J. Perinatol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1590\/S0066-782X2003001200007","article-title":"Intrauterine ductus arteriosus constriction: Analysis of a historic cohort of 20 cases","volume":"81","author":"Luchese","year":"2003","journal-title":"Arq. Bras. Cardiol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1285","DOI":"10.7863\/jum.2012.31.8.1285","article-title":"Idiopathic constriction of the fetal ductus arteriosus: Three cases and review of the literature","volume":"31","author":"Enzensberger","year":"2012","journal-title":"J. Ultrasound Med."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"397","DOI":"10.2165\/00002018-200629050-00004","article-title":"Effects of maternally administered drugs on the fetal and neonatal kidney","volume":"29","author":"Boubred","year":"2006","journal-title":"Drug Saf."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"327","DOI":"10.1007\/s00404-015-3648-7","article-title":"Renal oligo- and anhydramnios: Cause, course and outcome--a single-center study","volume":"292","author":"Spiro","year":"2015","journal-title":"Arch. Gynecol. Obs."},{"key":"ref_38","first-page":"71","article-title":"Alteration of the amniotic fluid and neonatal outcome","volume":"75","author":"Volante","year":"2004","journal-title":"Acta Biomed."},{"key":"ref_39","unstructured":"World Health Organisation (WHO) (2024, November 20). The Use of the WHO-UMC System for Standardised Case Causality Assessment. Available online: https:\/\/www.who.int\/publications\/m\/item\/WHO-causality-assessment."}],"container-title":["Pharmaceuticals"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1424-8247\/17\/12\/1592\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T16:39:43Z","timestamp":1760114383000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1424-8247\/17\/12\/1592"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,11,26]]},"references-count":39,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2024,12]]}},"alternative-id":["ph17121592"],"URL":"https:\/\/doi.org\/10.3390\/ph17121592","relation":{},"ISSN":["1424-8247"],"issn-type":[{"value":"1424-8247","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,11,26]]}}}