{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,19]],"date-time":"2026-10-19T02:56:42Z","timestamp":1792378602637,"version":"4.4.0"},"reference-count":36,"publisher":"American Medical Association (AMA)","issue":"6","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JAMA Intern Med"],"published-print":{"date-parts":[[2025,6,1]]},"abstract":"<jats:sec id=\"ab-ioi250009-4\"><jats:title>Importance<\/jats:title><jats:p>Nicotine replacement therapy (NRT), varenicline, and bupropion are effective smoking cessation pharmacotherapies, but evidence on fetal safety is limited.<\/jats:p><\/jats:sec><jats:sec id=\"ab-ioi250009-5\"><jats:title>Objective<\/jats:title><jats:p>To assess whether prenatal use of smoking cessation pharmacotherapies was associated with increased risks of major congenital malformations (MCMs).<\/jats:p><\/jats:sec><jats:sec id=\"ab-ioi250009-6\"><jats:title>Design, Setting, and Participants<\/jats:title><jats:p>This retrospective cohort study was conducted across 4 countries, and results were pooled via meta-analyses. Records of all births (2001-2020) in New South Wales (NSW; Australia), New Zealand (NZ), Norway, and Sweden were linked to prescribed medicine dispensings, hospital admission, outpatient, and death data. Follow-up ended December 31, 2021, and the data were analyzed between August and October 2023. The base cohort comprised 391\u202f474 infants among 267\u202f522 women who smoked during the first trimester or were dispensed a smoking cessation pharmacotherapy 90 days before conception or during the first trimester.<\/jats:p><\/jats:sec><jats:sec id=\"ab-ioi250009-7\"><jats:title>Exposures<\/jats:title><jats:p>Supply of NRT, varenicline, and bupropion overlapping the first trimester. Unexposed infants were born to women who smoked but were not dispensed a pharmacotherapy 90 days preconception and the first trimester. Propensity score matching (1:10) was used.<\/jats:p><\/jats:sec><jats:sec id=\"ab-ioi250009-8\"><jats:title>Main Outcomes and Measures<\/jats:title><jats:p>MCM overall and subgroups.<\/jats:p><\/jats:sec><jats:sec id=\"ab-ioi250009-9\"><jats:title>Results<\/jats:title><jats:p>The mean (SD) maternal age at childbirth was 27.2 (6.0) years. Analyses included 9325 infants exposed to NRT (NSW, NZ), 3031 to varenicline (NSW, NZ, Norway, and Sweden), and 1042 to bupropion (NSW, NZ). Compared with unexposed infants, there were no differences in prevalence of MCMs overall following NRT exposure (37.6 vs 34.4 per 1000 live births; adjusted relative risk [aRR], 1.10; 95% CI, 0.98-1.22), varenicline (32.7 vs 36.6; aRR, 0.90; 95% CI, 0.73-1.10), or bupropion (35.5 vs 38.8; aRR, 0.93; 95% CI, 0.67-1.29). NRT analyses showed no difference in the risk of MCMs of the heart, limbs, genital organs, kidney\/urinary tract, respiratory system, and orofacial clefts but a higher risk of digestive organ MCMs (3.8 vs 2.5 per 1000 live births; aRR, 1.53; 95% CI, 1.05-2.23; <jats:italic>P<\/jats:italic>\u2009=\u2009.41 after multiple comparison adjustment). Varenicline analyses revealed no difference in the risk of heart, limb, and genital MCMs but a higher risk of kidney\/urinary tract MCMs (11.5 vs 4.2 per 1000 live births; aRR, 2.75; 95% CI, 1.42-5.34; <jats:italic>P<\/jats:italic>\u2009=\u2009.09 after multiple comparison adjustment), with findings for other MCMs being too imprecise. For bupropion, data were too sparse to estimate the risk of MCM subgroups.<\/jats:p><\/jats:sec><jats:sec id=\"ab-ioi250009-10\"><jats:title>Conclusions and Relevance<\/jats:title><jats:p>The results of this cohort study suggest that there is no clear increased risk of MCMs associated with prenatal use of NRT and varenicline compared with smoking during the first trimester.<\/jats:p><\/jats:sec>","DOI":"10.1001\/jamainternmed.2025.0290","type":"journal-article","created":{"date-parts":[[2025,3,31]],"date-time":"2025-03-31T16:00:56Z","timestamp":1743436856000},"page":"656","source":"Crossref","is-referenced-by-count":13,"title":["Risk of Major Congenital Malformations Following Prenatal Exposure to Smoking Cessation Medicines"],"prefix":"10.1001","volume":"185","author":[{"given":"Duong T.","family":"Tran","sequence":"first","affiliation":[{"name":"National Drug and Alcohol Research Centre, Faculty of Medicine and Health, University of New South Wales, Sydney, New South Wales, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jacqueline M.","family":"Cohen","sequence":"additional","affiliation":[{"name":"Department of Chronic Diseases, Norwegian Institute of Public Health, Oslo, Norway"},{"name":"Centre for Fertility and Health, Norwegian Institute of Public Health, Oslo, Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah","family":"Donald","sequence":"additional","affiliation":[{"name":"Department of Preventive and Social Medicine, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carolyn E.","family":"Cesta","sequence":"additional","affiliation":[{"name":"Centre for Pharmacoepidemiology, Department of Medicine Solna, Karolinska Institute, Stockholm, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kari","family":"Furu","sequence":"additional","affiliation":[{"name":"Department of Chronic Diseases, Norwegian Institute of Public Health, Oslo, Norway"},{"name":"Centre for Fertility and Health, Norwegian Institute of Public Health, Oslo, Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lianne","family":"Parkin","sequence":"additional","affiliation":[{"name":"Department of Preventive and Social Medicine, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sallie-Anne","family":"Pearson","sequence":"additional","affiliation":[{"name":"Medicines Intelligence Research Program, School of Population Health, Faculty of Medicine and Health, University of New South Wales, Sydney, New South Wales, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johan","family":"Reutfors","sequence":"additional","affiliation":[{"name":"Centre for Pharmacoepidemiology, Department of Medicine Solna, Karolinska Institute, Stockholm, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annelies L.","family":"Robijn","sequence":"additional","affiliation":[{"name":"National Drug and Alcohol Research Centre, Faculty of Medicine and Health, University of New South Wales, Sydney, New South Wales, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Helga","family":"Zoega","sequence":"additional","affiliation":[{"name":"Centre of Public Health Sciences, Faculty of Medicine, University of Iceland, Reykjavik, Iceland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicholas","family":"Zwar","sequence":"additional","affiliation":[{"name":"Faculty of Health Sciences & Medicine, Bond University, Gold Coast, Queensland, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alys","family":"Havard","sequence":"additional","affiliation":[{"name":"National Drug and Alcohol Research Centre, Faculty of Medicine and Health, University of New South Wales, Sydney, New South Wales, Australia"},{"name":"Medicines Intelligence Research Program, School of Population Health, Faculty of Medicine and Health, University of New South Wales, Sydney, New South Wales, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"10","reference":[{"issue":"3","key":"ioi250009r3","doi-asserted-by":"publisher","DOI":"10.1002\/14651858.CD010078.pub3","article-title":"Pharmacological interventions for promoting smoking cessation during pregnancy.","volume":"3","author":"Claire","year":"2020","journal-title":"Cochrane Database Syst Rev"},{"issue":"1","key":"ioi250009r4","doi-asserted-by":"publisher","first-page":"51","DOI":"10.1097\/01.AOG.0000194079.66834.d5","article-title":"Smoking habits, nicotine use, and congenital malformations.","volume":"107","author":"Morales-Su\u00e1rez-Varela","year":"2006","journal-title":"Obstet Gynecol"},{"issue":"5","key":"ioi250009r5","doi-asserted-by":"publisher","first-page":"859","DOI":"10.1542\/peds.2014-2560","article-title":"Nicotine replacement therapy in pregnancy and major congenital anomalies in offspring.","volume":"135","author":"Dhalwani","year":"2015","journal-title":"Pediatrics"},{"issue":"5","key":"ioi250009r6","doi-asserted-by":"publisher","first-page":"e221","DOI":"10.1097\/AOG.0000000000003822","article-title":"Tobacco and nicotine cessation during pregnancy: ACOG committee opinion No. 807.","volume":"135","author":"American College of Obstetricians and Gynecologists","year":"2020","journal-title":"Obstet Gynecol"},{"issue":"6","key":"ioi250009r7","doi-asserted-by":"publisher","DOI":"10.1001\/jamanetworkopen.2024.19245","article-title":"Smoking cessation pharmacotherapy use in pregnancy.","volume":"7","author":"Robijn","year":"2024","journal-title":"JAMA Netw Open"},{"key":"ioi250009r8","doi-asserted-by":"publisher","DOI":"10.1155\/2014\/263981","article-title":"Pregnancy outcome after varenicline exposure in the first trimester.","volume":"2014","author":"Kaplan","year":"2014","journal-title":"Case Rep Obstet Gynecol"},{"issue":"10","key":"ioi250009r9","doi-asserted-by":"publisher","first-page":"1086","DOI":"10.1002\/pds.3489","article-title":"Exposure to the smoking cessation medicine varenicline during pregnancy: a prospective nationwide cohort study.","volume":"22","author":"Harrison-Woolrych","year":"2013","journal-title":"Pharmacoepidemiol Drug Saf"},{"key":"ioi250009r10","doi-asserted-by":"publisher","first-page":"26","DOI":"10.1016\/j.reprotox.2016.11.010","article-title":"Pregnancy outcomes after maternal varenicline use; analysis of surveillance data collected by the European Network of Teratology Information Services.","volume":"67","author":"Richardson","year":"2017","journal-title":"Reprod Toxicol"},{"issue":"1","key":"ioi250009r11","doi-asserted-by":"publisher","first-page":"94","DOI":"10.1002\/pds.4894","article-title":"Risk of adverse birth outcomes after maternal varenicline use: a population-based observational study in Denmark and Sweden.","volume":"29","author":"Pedersen","year":"2020","journal-title":"Pharmacoepidemiol Drug Saf"},{"issue":"1","key":"ioi250009r12","doi-asserted-by":"publisher","first-page":"15","DOI":"10.1186\/s12916-019-1472-9","article-title":"Use of smoking cessation pharmacotherapies during pregnancy is not associated with increased risk of adverse pregnancy outcomes: a population-based cohort study.","volume":"18","author":"Tran","year":"2020","journal-title":"BMC Med"},{"issue":"5","key":"ioi250009r13","doi-asserted-by":"publisher","DOI":"10.4088\/PCC.17r02160","article-title":"Bupropion use during pregnancy: a systematic review.","volume":"19","author":"Hendrick","year":"2017","journal-title":"Prim Care Companion CNS Disord"},{"issue":"8","key":"ioi250009r14","doi-asserted-by":"publisher","first-page":"1001","DOI":"10.1093\/ntr\/nty055","article-title":"Systematic review and meta-analysis to assess the safety of bupropion and varenicline in pregnancy.","volume":"21","author":"Turner","year":"2019","journal-title":"Nicotine Tob Res"},{"issue":"1-2","key":"ioi250009r17","doi-asserted-by":"publisher","first-page":"117","DOI":"10.5324\/nje.v29i1-2.4053","article-title":"A common data model for harmonization in the Nordic Pregnancy Drug Safety Studies (NorPreSS).","volume":"29","author":"Cohen","year":"2021","journal-title":"Nor Epidemiol"},{"issue":"6","key":"ioi250009r18","doi-asserted-by":"publisher","DOI":"10.1080\/03610910902859574","article-title":"Using the standardized difference to compare the prevalence of a binary variable between two groups in observational research.","volume":"38","author":"Austin","year":"2009","journal-title":"Commun Stat Simul Comput"},{"issue":"2","key":"ioi250009r19","doi-asserted-by":"crossref","first-page":"290","DOI":"10.1177\/1536867X1101100208","article-title":"Estimating adjusted risk ratios for matched and unmatched data: an update.","volume":"11","author":"Cummings","year":"2011","journal-title":"Stata J"},{"key":"ioi250009r20","doi-asserted-by":"publisher","first-page":"43","DOI":"10.1093\/epirev\/mxg002","article-title":"Matched cohort methods for injury research.","volume":"25","author":"Cummings","year":"2003","journal-title":"Epidemiol Rev"},{"issue":"5","key":"ioi250009r22","doi-asserted-by":"publisher","first-page":"469","DOI":"10.1093\/oxfordjournals.aje.a010035","article-title":"Random-effects meta-analyses are not always conservative.","volume":"150","author":"Poole","year":"1999","journal-title":"Am J Epidemiol"},{"issue":"7","key":"ioi250009r23","doi-asserted-by":"publisher","first-page":"1624","DOI":"10.1177\/21925682221110527","article-title":"Fixed-effect vs random-effects models for meta-analysis: 3 points to consider.","volume":"12","author":"Dettori","year":"2022","journal-title":"Global Spine J"},{"issue":"3","key":"ioi250009r24","doi-asserted-by":"publisher","first-page":"1","DOI":"10.18637\/jss.v036.i03","article-title":"Conducting meta-analyses in R with the metafor package.","volume":"36","author":"Viechtbauer","year":"2010","journal-title":"J Stat Softw"},{"issue":"25","key":"ioi250009r25","doi-asserted-by":"publisher","first-page":"2397","DOI":"10.1056\/NEJMoa1312828","article-title":"Antidepressant use in pregnancy and the risk of cardiac defects.","volume":"370","author":"Huybrechts","year":"2014","journal-title":"N Engl J Med"},{"issue":"4","key":"ioi250009r26","doi-asserted-by":"publisher","first-page":"268","DOI":"10.7326\/M16-2607","article-title":"Sensitivity analysis in observational research: introducing the E-Value.","volume":"167","author":"VanderWeele","year":"2017","journal-title":"Ann Intern Med"},{"issue":"1","key":"ioi250009r27","doi-asserted-by":"publisher","DOI":"10.1136\/bmjmed-2022-000366","article-title":"Quantifying the impact of unmeasured confounding in observational studies with the E value.","volume":"2","author":"Gaster","year":"2023","journal-title":"BMJ Med"},{"issue":"4","key":"ioi250009r28","doi-asserted-by":"publisher","DOI":"10.1111\/apha.13631","article-title":"Nicotine and vascular dysfunction.","volume":"231","author":"Whitehead","year":"2021","journal-title":"Acta Physiol (Oxf)"},{"issue":"1","key":"ioi250009r29","doi-asserted-by":"publisher","first-page":"8","DOI":"10.1177\/1093526619892351","article-title":"Diagnosis of Hirschsprung disease.","volume":"23","author":"Ambartsumyan","year":"2020","journal-title":"Pediatr Dev Pathol"},{"key":"ioi250009r30","doi-asserted-by":"publisher","first-page":"S79","DOI":"10.1097\/MPG.0b013e3181a15b5e","article-title":"Congenital anorectal malformations: anything new?","volume":"48","author":"Rintala","year":"2009","journal-title":"J Pediatr Gastroenterol Nutr"},{"issue":"12","key":"ioi250009r32","doi-asserted-by":"publisher","first-page":"1246","DOI":"10.1001\/jamapsychiatry.2020.2453","article-title":"Maternal use of specific antidepressant medications during early pregnancy and the risk of selected birth defects.","volume":"77","author":"Anderson","year":"2020","journal-title":"JAMA Psychiatry"},{"issue":"4","key":"ioi250009r33","doi-asserted-by":"publisher","first-page":"715","DOI":"10.1007\/s10995-016-2155-1","article-title":"Trends in timing of pregnancy awareness among US women.","volume":"21","author":"Branum","year":"2017","journal-title":"Matern Child Health J"},{"issue":"6","key":"ioi250009r36","doi-asserted-by":"publisher","first-page":"521","DOI":"10.1111\/ppe.13011","article-title":"Detection of major congenital malformations depends on length of follow-up in Swedish National Health Register Data: implications for pharmacoepidemiological research on medication safety in pregnancy.","volume":"38","author":"Chac\u00f3n","year":"2024","journal-title":"Paediatr Perinat Epidemiol"},{"key":"ioi250009r1","volume-title":"Tobacco in Australia: Facts and Issues","author":"Jenkins","year":"2023"},{"key":"ioi250009r2","volume-title":"Supporting Smoking Cessation: A Guide for Health Professionals","author":"Royal Australian College of General Practitioners","year":"2019","edition":"2nd ed"},{"key":"ioi250009r31","volume-title":"Neonatology","author":"Fanos","year":"2017"},{"key":"ioi250009r34","doi-asserted-by":"crossref","DOI":"10.5772\/intechopen.83128","volume-title":"Congenital Anomalies in Newborn Infants\u2014Clinical and Etiopathological Perspectives","author":"Verma","year":"2021"},{"key":"ioi250009r15","unstructured":"European Surveillance of Congenital Anomalies. EUROCAT guide 1.4 and reference documents (version 28\/12\/2018): section 3.3: EUROCAT subgroups of congenital anomalies. Accessed June 11, 2023. https:\/\/eu-rd-platform.jrc.ec.europa.eu\/sites\/default\/files\/Full_Guide_1_4_version_28_DEC2018.pdf"},{"key":"ioi250009r16","unstructured":"European Surveillance of Congenital Anomalies. EUROCAT prevalence data tables: cases and prevalence (per 10,000 births) of all congenital anomaly subgroups for all registries, from 2011-2021. 2022. https:\/\/eu-rd-platform.jrc.ec.europa.eu\/eurocat\/eurocat-data\/prevalence\/export_en"},{"key":"ioi250009r21","unstructured":"Jann? B. kmatch: Stata module for multivariate-distance and propensity-score matching, including entropy balancing, inverse probability weighting, (coarsened) exact matching, and regression adjustment. Accessed February 23, 2024. https:\/\/ideas.repec.org\/c\/boc\/bocode\/s458346.html"},{"key":"ioi250009r35","unstructured":"Centre for Epidemiology and Evidence. Quality and coverage of the NSW Register of Congenital Conditions using admitted patient data: a record linkage study. https:\/\/www.health.nsw.gov.au\/hsnsw\/Publications\/rocc-apd-linkage-study.pdf"}],"container-title":["JAMA Internal Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/jamanetwork.com\/journals\/jamainternalmedicine\/articlepdf\/2831910\/jamainternal_tran_2025_oi_250009_1748025380.89679.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,6,2]],"date-time":"2025-06-02T15:01:35Z","timestamp":1748876495000},"score":1,"resource":{"primary":{"URL":"https:\/\/jamanetwork.com\/journals\/jamainternalmedicine\/fullarticle\/2831910"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,6,1]]},"references-count":36,"journal-issue":{"issue":"6","published-print":{"date-parts":[[2025,6,1]]}},"URL":"https:\/\/doi.org\/10.1001\/jamainternmed.2025.0290","relation":{},"ISSN":["2168-6106"],"issn-type":[{"value":"2168-6106","type":"print"}],"subject":[],"published":{"date-parts":[[2025,6,1]]}}}