{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,27]],"date-time":"2026-08-27T19:56:20Z","timestamp":1787860580045,"version":"build-2784847793"},"reference-count":53,"publisher":"Public Library of Science (PLoS)","issue":"5","license":[{"start":{"date-parts":[[2026,5,14]],"date-time":"2026-05-14T00:00:00Z","timestamp":1778716800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["www.plosmedicine.org"],"crossmark-restriction":false},"short-container-title":["PLoS Med"],"abstract":"<jats:sec id=\"sec001\">\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Pain and fever are common in early pregnancy, yet their management poses a major clinical dilemma. Although not confirmed, recent studies have raised safety concerns regarding acetaminophen. Evidence on the use of nonsteroidal anti-inflammatory drugs (NSAID) in the first trimester remains inconclusive. This uncertainty has left clinicians with limited evidence to guide treatment decisions. This study evaluated the association between first-trimester NSAID exposure and the risk of major congenital malformations (MCMs) in a large, population-based cohort of pregnancies.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"sec002\">\n                    <jats:title>Methods and findings<\/jats:title>\n                    <jats:p>We conducted a population-based retrospective cohort study within the Southern Israeli Pregnancy Registry (siPREG) project, including all singleton pregnancies of women aged 15\u201345 years resulting in live births, stillbirths, or elective terminations for fetal malformations at a Soroka University Medical Center between 1998 and 2018. Pregnancies exposed to established teratogens, multiple gestations, and those with documented genetic or chromosomal anomalies were excluded. First-trimester NSAID exposure was defined by pharmacy dispensations (overall and by specific agents). MCMs were identified from linked clinical, hospitalization, and termination records through the first postnatal year.<\/jats:p>\n                    <jats:p>Propensity scores were estimated using covariates selected via a directed acyclic graph, including maternal age, ethnicity, diabetes, medical indication for NSAID use, exposure to other antipyretics, obesity, smoking, folic-acid use, gravidity, perinatal care, and year of pregnancy. Generalized full matching was used to balance covariates. Adjusted risk ratios were derived using weighted Poisson regression with G-computation, and two-way cluster-robust standard errors, jointly clustering by maternal identifier and matching subclass. Sensitivity analyses included a dose\u2013response assessment across defined-daily-dose (DDD) categories and a tipping-point analysis evaluating the impact of potential misclassification from unrecorded over-the-counter NSAID use.<\/jats:p>\n                    <jats:p>A total of 264,858 singleton pregnancies were included in the final cohort; 20,202 (7.6%) were exposed to NSAID, most commonly ibuprofen (5.1%), diclofenac (1.6%), and naproxen (1.2%). NSAID exposure, in total and as individual agents, was not associated with MCMs overall (8.2% versus 7.0%; matched-adjusted-Relative Risk (aRR) = 0.99 (95% CI [0.90,1.10])) or with organ-system-specific MCMs, including cardiovascular (matched-aRR\u2009=\u20091.05 (95% CI [0.92,1.20]), musculoskeletal (matched-aRR\u2009=\u20091.03 (95% CI [0.77,1.39])), central nervous system (matched-aRR\u2009=\u20090.77 (95% CI [0.53,1.11])), cleft palate (matched-aRR\u2009=\u20090.95 (95% CI [0.47\u20131.91])), gastrointestinal (matched-aRR\u2009=\u20091.03 (95% CI [0.64\u20131.63])), and genitourinary (matched-aRR\u2009=\u20090.99 (95% CI [0.72,1.35])) malformations. Dose\u2013response analyses showed no significant association with MCMs across cumulative NSAID exposure: short-term (1\u20137 DDD, matched-aRR\u2009=\u20091.06 (95% CI [0.97,1.15]), medium-term (8\u201321 DDD, matched-aRR\u2009=\u20091.10 (95% CI [0.99,1.22]), and long-term (&gt;21 DDD, matched-aRR\u2009=\u20091.24 (95% CI [0.94,1.63])). The main limitation was the potential for minor exposure misclassification due to over-the-counter availability of ibuprofen, although sensitivity analyses simulating such misclassification suggested minimal impact on the risk estimates.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"sec003\">\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>In this large, population-based cohort, we found no evidence supporting an association between first-trimester exposure to NSAID and MCMs, providing reassuring evidence regarding their fetal safety in early pregnancy.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1371\/journal.pmed.1005063","type":"journal-article","created":{"date-parts":[[2026,5,14]],"date-time":"2026-05-14T17:21:56Z","timestamp":1778779316000},"page":"e1005063","update-policy":"https:\/\/doi.org\/10.1371\/journal.pmed.corrections_policy","source":"Crossref","is-referenced-by-count":3,"title":["First-trimester nonsteroidal anti-inflammatory drugs exposure and risk of major congenital malformations: A retrospective register-based cohort study"],"prefix":"10.1371","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1785-0952","authenticated-orcid":true,"given":"Ariel Avraham","family":"Hasidim","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-7093-8953","authenticated-orcid":true,"given":"Itamar","family":"Ben Shitrit","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-8218-5476","authenticated-orcid":true,"given":"Daphna","family":"Idan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0328-055X","authenticated-orcid":true,"given":"Tal","family":"Michael","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2355-8854","authenticated-orcid":true,"given":"Amalia","family":"Levy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6484-3769","authenticated-orcid":true,"given":"Gali","family":"Pariente","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2260-9530","authenticated-orcid":true,"given":"Eitan","family":"Lunenfeld","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1820-9278","authenticated-orcid":true,"given":"Sharon","family":"Daniel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2026,5,14]]},"reference":[{"key":"pmed.1005063.ref001"},{"issue":"4","key":"pmed.1005063.ref002","doi-asserted-by":"crossref","first-page":"968","DOI":"10.1007\/s11096-016-0322-5","article-title":"Women\u2019s beliefs about medication use during their pregnancy: a UK perspective","volume":"38","author":"MJ Twigg","year":"2016","journal-title":"Int J Clin Pharm"},{"issue":"8","key":"pmed.1005063.ref003","doi-asserted-by":"crossref","first-page":"875","DOI":"10.1111\/papr.12814","article-title":"Medication use and pain management in pregnancy: a critical review","volume":"19","author":"E Black","year":"2019","journal-title":"Pain Pract"},{"issue":"3","key":"pmed.1005063.ref004","doi-asserted-by":"crossref","DOI":"10.1542\/peds.2013-3205","article-title":"Systematic review and meta-analyses: fever in pregnancy and health impacts in the offspring","volume":"133","author":"JW Dreier","year":"2014","journal-title":"Pediatrics"},{"issue":"1","key":"pmed.1005063.ref005","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1186\/s13229-021-00464-4","article-title":"Fever during pregnancy as a risk factor for neurodevelopmental disorders: results from a systematic review and meta-analysis","volume":"12","author":"S Antoun","year":"2021","journal-title":"Mol Autism"},{"issue":"6","key":"pmed.1005063.ref006","doi-asserted-by":"crossref","first-page":"990","DOI":"10.1016\/j.jpeds.2010.11.058","article-title":"Associations between maternal fever and influenza and congenital heart defects","volume":"158","author":"ME Oster","year":"2011","journal-title":"J Pediatr"},{"issue":"1","key":"pmed.1005063.ref007","doi-asserted-by":"crossref","first-page":"413","DOI":"10.1186\/s12884-017-1585-0","article-title":"Fever in pregnancy and the risk of congenital malformations: a cohort study","volume":"17","author":"L Sass","year":"2017","journal-title":"BMC Pregnancy Childbirth"},{"issue":"10","key":"pmed.1005063.ref008","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pntd.0011721","article-title":"Causes and consequences of fever in Amazonian pregnant women: a large retrospective study from French Guiana","volume":"17","author":"N Hcini","year":"2023","journal-title":"PLoS Negl Trop Dis"},{"issue":"3","key":"pmed.1005063.ref009","doi-asserted-by":"crossref","DOI":"10.1016\/j.ajog.2011.11.019","article-title":"Nonsteroidal antiinflammatory drug use among women and the risk of birth defects","volume":"206","author":"RK Hernandez","year":"2012","journal-title":"Am J Obstet Gynecol"},{"issue":"10","key":"pmed.1005063.ref010","doi-asserted-by":"crossref","first-page":"1575","DOI":"10.1111\/1471-0528.16670","article-title":"Early exposure of pregnant women to non-steroidal anti-inflammatory drugs delivered outside hospitals and preterm birth risk: nationwide cohort study","volume":"128","author":"C Quantin","year":"2021","journal-title":"BJOG"},{"issue":"11","key":"pmed.1005063.ref011","doi-asserted-by":"crossref","first-page":"2163","DOI":"10.3899\/jrheum.120453","article-title":"Major malformations following exposure to nonsteroidal antiinflammatory drugs during the first trimester of pregnancy","volume":"39","author":"S Daniel","year":"2012","journal-title":"J Rheumatol"},{"issue":"4","key":"pmed.1005063.ref012","doi-asserted-by":"crossref","first-page":"268","DOI":"10.1002\/bdrb.20085","article-title":"Risk of congenital anomalies in pregnant users of non-steroidal anti-inflammatory drugs: a nested case-control study","volume":"77","author":"B Ofori","year":"2006","journal-title":"Birth Defects Res B Dev Reprod Toxicol"},{"issue":"7","key":"pmed.1005063.ref013","article-title":"Exposure to non-steroidal anti-inflammatory drugs during pregnancy and the risk of selected birth defects: a prospective cohort study","volume":"6","author":"MMHJ van Gelder","year":"2011","journal-title":"PLoS One"},{"issue":"4","key":"pmed.1005063.ref014","doi-asserted-by":"crossref","DOI":"10.1016\/j.ajog.2014.03.054","article-title":"Case-control analysis of maternal prenatal analgesic use and cardiovascular malformations: Baltimore-Washington Infant Study","volume":"211","author":"CA Marsh","year":"2014","journal-title":"Am J Obstet Gynecol"},{"key":"pmed.1005063.ref015","doi-asserted-by":"crossref","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":"JD Interrante","year":"2017","journal-title":"Ann Epidemiol"},{"issue":"8","key":"pmed.1005063.ref016","doi-asserted-by":"crossref","first-page":"948","DOI":"10.1111\/1471-0528.12192","article-title":"Effects of ibuprofen, diclofenac, naproxen, and piroxicam on the course of pregnancy and pregnancy outcome: a prospective cohort study","volume":"120","author":"K Nezvalov\u00e1-Henriksen","year":"2013","journal-title":"BJOG"},{"issue":"3","key":"pmed.1005063.ref017","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1002\/bdra.20005","article-title":"Maternal use of acetaminophen and nonsteroidal anti-inflammatory drugs (NSAIDs), and muscular ventricular septal defects","volume":"70","author":"MA Cleves","year":"2004","journal-title":"Birth Defects Res A Clin Mol Teratol"},{"issue":"9","key":"pmed.1005063.ref018","doi-asserted-by":"crossref","first-page":"635","DOI":"10.1007\/s00228-004-0829-x","article-title":"A case control study to examine the pharmacological factors underlying ventricular septal defects in the North of England","volume":"60","author":"DN Bateman","year":"2004","journal-title":"Eur J Clin Pharmacol"},{"key":"pmed.1005063.ref019","doi-asserted-by":"crossref","first-page":"122","DOI":"10.1016\/j.reprotox.2018.02.007","article-title":"Safety of diclofenac use during early pregnancy: a prospective observational cohort study","volume":"77","author":"S Padberg","year":"2018","journal-title":"Reprod Toxicol"},{"issue":"6","key":"pmed.1005063.ref020","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":"JP Vandenbroucke","year":"2007","journal-title":"Epidemiology"},{"key":"pmed.1005063.ref021","author":"D Angel","year":"2007"},{"key":"pmed.1005063.ref022","unstructured":"https:\/\/www.btl.gov.il\/Publications\/survey\/Documents\/skira2023.pdf#page=1.00&gsr=0"},{"key":"pmed.1005063.ref023","author":"WHO Collaborating Centre for Drug Statistics Methodology","year":"2025"},{"key":"pmed.1005063.ref024","volume-title":"R: a language and environment for statistical computing","author":"R Core Team","year":"2025"},{"key":"pmed.1005063.ref025","doi-asserted-by":"crossref","first-page":"305","DOI":"10.1016\/0304-4076(85)90158-7","article-title":"Some heteroskedasticity-consistent covariance matrix estimators with improved finite sample properties","volume":"29","author":"CW Sun","year":"1985","journal-title":"J Econom"},{"key":"pmed.1005063.ref026","doi-asserted-by":"crossref","first-page":"1","DOI":"10.18637\/jss.v095.i01","article-title":"Various versatile variances: an object-oriented implementation of clustered covariances in R","volume":"95","author":"A Zeileis","year":"2020","journal-title":"J Stat Softw"},{"key":"pmed.1005063.ref027","doi-asserted-by":"crossref","first-page":"1","DOI":"10.18637\/jss.v016.i09","article-title":"Object-oriented computation of sandwich estimators","volume":"16","author":"A Zeileis","year":"2006","journal-title":"J Stat Softw"},{"key":"pmed.1005063.ref028","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":"A Zeileis","year":"2004","journal-title":"J Stat Softw"},{"key":"pmed.1005063.ref029","doi-asserted-by":"crossref","first-page":"1","DOI":"10.18637\/jss.v111.i09","article-title":"How to interpret statistical models using marginal effects for R and Python","volume":"111","author":"V Arel-Bundock","year":"2024","journal-title":"J Stat Softw"},{"key":"pmed.1005063.ref030","doi-asserted-by":"crossref","first-page":"423","DOI":"10.1017\/pan.2020.32","article-title":"Generalized full matching","volume":"29","author":"F S\u00e4vje","year":"2021","journal-title":"Polit Anal"},{"key":"pmed.1005063.ref031","first-page":"1","article-title":"MatchIt: nonparametric preprocessing for parametric causal inference","volume":"42","author":"DE Ho","year":"2011","journal-title":"J Stat Softw"},{"key":"pmed.1005063.ref032","article-title":"Risk of major congenital malformations in relation to maternal overweight and obesity severity: cohort study of 1.2 million singletons","volume":"357","author":"M Persson","year":"2017","journal-title":"BMJ"},{"issue":"1","key":"pmed.1005063.ref033","doi-asserted-by":"crossref","DOI":"10.4088\/JCP.24f15318","article-title":"Exposure of pregnancy to pregestational diabetes, gestational diabetes, and antidiabetic medications with especial focus on major congenital and cardiac malformations in offspring","volume":"85","author":"C Andrade","year":"2024","journal-title":"J Clin Psychiatry"},{"issue":"12","key":"pmed.1005063.ref034","doi-asserted-by":"crossref","first-page":"2816","DOI":"10.1093\/humrep\/deae233","article-title":"Maternal periconception hyperglycemia, preconception diabetes, and risk of major congenital malformations in offspring","volume":"39","author":"RS Rotem","year":"2024","journal-title":"Hum Reprod"},{"issue":"1","key":"pmed.1005063.ref035","doi-asserted-by":"crossref","first-page":"2947","DOI":"10.1186\/s12889-025-24005-3","article-title":"A study of demographic and clinical characteristics of consumers of non-steroidal anti-inflammatory drugs: a large population-based study utilizing enrollment phase data from the tabari cohort","volume":"25","author":"A Hessami","year":"2025","journal-title":"BMC Public Health"},{"issue":"1","key":"pmed.1005063.ref036","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1186\/s12882-016-0411-7","article-title":"High prevalence of non-steroidal anti-inflammatory drug use among acute kidney injury survivors in the southern community cohort study","volume":"17","author":"L Lipworth","year":"2016","journal-title":"BMC Nephrol"},{"issue":"17","key":"pmed.1005063.ref037","doi-asserted-by":"crossref","first-page":"1257","DOI":"10.1002\/bdr2.1944","article-title":"Periconceptional nonsteroidal anti-inflammatory drug use, folic acid intake, and the risk of spina bifida","volume":"113","author":"DB Esposito","year":"2021","journal-title":"Birth Defects Res"},{"issue":"7591","key":"pmed.1005063.ref038","doi-asserted-by":"crossref","first-page":"433","DOI":"10.1136\/bmj.39133.386296.BE","article-title":"Folic acid and birth malformations","volume":"334","author":"C Bille","year":"2007","journal-title":"BMJ"},{"issue":"1","key":"pmed.1005063.ref039","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1007\/s12687-019-00433-8","article-title":"Consanguinity and genetic diseases among the Bedouin population in the Negev","volume":"11","author":"S Singer","year":"2020","journal-title":"J Community Genet"},{"key":"pmed.1005063.ref040","doi-asserted-by":"crossref","first-page":"342","DOI":"10.1002\/bdr2.1147","article-title":"Maternal report of fever from cold or flu during early pregnancy and the risk for noncardiac birth defects, National Birth Defects Prevention Study, 1997\u20132011","volume":"110","author":"DK Waller","year":"2017","journal-title":"Birth Defects Research"},{"issue":"12","key":"pmed.1005063.ref041","article-title":"Periconceptional maternal fever, folic acid intake, and the risk for neural tube defects","volume":"27","author":"SM Kerr","year":"2017","journal-title":"Ann Epidemiol"},{"issue":"5","key":"pmed.1005063.ref042","doi-asserted-by":"crossref","DOI":"10.1503\/cmaj.130605","article-title":"Fetal exposure to nonsteroidal anti-inflammatory drugs and spontaneous abortions","volume":"186","author":"S Daniel","year":"2014","journal-title":"CMAJ"},{"issue":"1","key":"pmed.1005063.ref043","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1007\/s12687-019-00433-8","article-title":"Consanguinity and genetic diseases among the Bedouin population in the Negev","volume":"11","author":"S Singer","year":"2020","journal-title":"J Community Genet"},{"issue":"2","key":"pmed.1005063.ref044","article-title":"Neonatal and maternal adverse outcomes and exposure to nonsteroidal anti-inflammatory drugs during early pregnancy in South Korea: a nationwide cohort study","volume":"20","author":"E-Y Choi","year":"2023","journal-title":"PLoS Med"},{"issue":"1","key":"pmed.1005063.ref045","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":"A Levy","year":"2012","journal-title":"J Clin Pharmacol"},{"issue":"1","key":"pmed.1005063.ref046","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1111\/apa.16953","article-title":"Detection of severe congenital heart defects in live-born infants in Norway 2017-2020","volume":"113","author":"G Wik","year":"2024","journal-title":"Acta Paediatr"},{"issue":"10","key":"pmed.1005063.ref047","doi-asserted-by":"crossref","first-page":"1103","DOI":"10.1093\/oxfordjournals.aje.a117563","article-title":"Recall accuracy for prescription medications: self-report compared with database information","volume":"142","author":"SL West","year":"1995","journal-title":"Am J Epidemiol"},{"issue":"11","key":"pmed.1005063.ref048","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":"RE Johnson","year":"1991","journal-title":"J Am Geriatr Soc"},{"issue":"4","key":"pmed.1005063.ref049","doi-asserted-by":"crossref","first-page":"837","DOI":"10.1093\/oxfordjournals.aje.a115198","article-title":"Use of Medicaid data for pharmacoepidemiology","volume":"129","author":"WA Ray","year":"1989","journal-title":"Am J Epidemiol"},{"issue":"8","key":"pmed.1005063.ref050","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-sectional study using data from a population-based congenital anomaly registry","volume":"38","author":"L de Jonge","year":"2015","journal-title":"Drug Saf"},{"key":"pmed.1005063.ref051","article-title":"Improvement of drug exposure data in a registration of congenital anomalies: pilot-study: pharmacist and mother as sources for drug exposure data during pregnancy","author":"NFHTSMCC","year":"1999","journal-title":"Teratology"},{"key":"pmed.1005063.ref052","author":"R Balak","year":"2024"},{"key":"pmed.1005063.ref053","doi-asserted-by":"crossref","unstructured":"Daniel S, Koren G, Lunenfeld E, Mha MD, Bilenko N, Ratzon R, et al. Fetal exposure to nonsteroidal anti-inflammatory drugs and spontaneous abortions. 2014. https:\/\/doi.org\/10.1503\/cmaj.130605","DOI":"10.1503\/cmaj.130605"}],"container-title":["PLOS Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pmed.1005063","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,14]],"date-time":"2026-05-14T17:22:05Z","timestamp":1778779325000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pmed.1005063"}},"subtitle":[],"editor":[{"given":"Lars \u00c5ke","family":"Persson","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2026,5,14]]},"references-count":53,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2026,5,14]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pmed.1005063","relation":{},"ISSN":["1549-1676"],"issn-type":[{"value":"1549-1676","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,5,14]]}}}