{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,14]],"date-time":"2026-06-14T09:06:25Z","timestamp":1781427985900,"version":"3.54.1"},"reference-count":42,"publisher":"Oxford University Press (OUP)","issue":"6","license":[{"start":{"date-parts":[[2023,9,28]],"date-time":"2023-09-28T00:00:00Z","timestamp":1695859200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000272","name":"National Institute for Health Research","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000272","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100018956","name":"Cambridge Biomedical Research Centre","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100018956","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Women\u2019s Health theme","award":["BRC-1215\u201320014"],"award-info":[{"award-number":["BRC-1215\u201320014"]}]},{"DOI":"10.13039\/501100000265","name":"Medical Research Council","doi-asserted-by":"publisher","award":["G1100221"],"award-info":[{"award-number":["G1100221"]}],"id":[{"id":"10.13039\/501100000265","id-type":"DOI","asserted-by":"publisher"}]},{"name":"National Health Service"},{"DOI":"10.13039\/501100000276","name":"Department of Health and Social Care","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000276","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100010269","name":"Wellcome Trust","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100010269","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2023,12,25]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>In pregnancy, women are encouraged to cease smoking and limit caffeine intake. We employed objective definitions of smoking and caffeine exposure to assess their association with adverse outcomes.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>We conducted a case cohort study within the Pregnancy Outcome Prediction study to analyse maternal serum metabolomics in samples from 12, 20, 28 and 36\u2009weeks of gestational age. Objective smoking status was defined based on detectable cotinine levels at each time point and objective caffeine exposure was based on tertiles of paraxanthine levels at each time point. We used logistic and linear regression to examine the association between cotinine, paraxanthine and the risk of pre-eclampsia, spontaneous pre-term birth (sPTB), fetal growth restriction (FGR), gestational diabetes mellitus and birthweight.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>There were 914 and 915 women in the smoking and caffeine analyses, respectively. Compared with no exposure to smoking, consistent exposure to smoking was associated with an increased risk of sPTB [adjusted odds ratio (aOR)\u2009=\u20092.58, 95% CI: 1.14 to 5.85)] and FGR (aOR\u2009=\u20094.07, 95% CI: 2.14 to 7.74) and lower birthweight (\u03b2\u2009=\u2009\u2013387\u2009g, 95% CI: \u2013622\u2009g to \u2013153\u2009g). On univariate analysis, consistently high levels of paraxanthine were associated with an increased risk of FGR but that association attenuated when adjusting for maternal characteristics and objective\u2014but not self-reported\u2014smoking status.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>Based on objective data, consistent exposure to smoking throughout pregnancy was strongly associated with sPTB and FGR. High levels of paraxanthine were not independently associated with any of the studied outcomes and were confounded by smoking.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1093\/ije\/dyad123","type":"journal-article","created":{"date-parts":[[2023,9,28]],"date-time":"2023-09-28T03:08:04Z","timestamp":1695870484000},"page":"1756-1765","source":"Crossref","is-referenced-by-count":15,"title":["Objective measures of smoking and caffeine intake and the risk of adverse pregnancy outcomes"],"prefix":"10.1093","volume":"52","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4240-5594","authenticated-orcid":false,"given":"Roshan J","family":"Selvaratnam","sequence":"first","affiliation":[{"name":"The Ritchie Centre, Department of Obstetrics and Gynaecology, Monash University , VIC, Melbourne, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0799-1105","authenticated-orcid":false,"given":"Ulla","family":"Sovio","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynaecology, University of Cambridge , Cambridge, UK"},{"name":"Centre for Trophoblast Research, Department of Physiology, Development and Neuroscience, University of Cambridge , Cambridge, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6142-4443","authenticated-orcid":false,"given":"Emma","family":"Cook","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynaecology, University of Cambridge , Cambridge, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7178-8921","authenticated-orcid":false,"given":"Francesca","family":"Gaccioli","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynaecology, University of Cambridge , Cambridge, UK"},{"name":"Centre for Trophoblast Research, Department of Physiology, Development and Neuroscience, University of Cambridge , Cambridge, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2936-4890","authenticated-orcid":false,"given":"D Stephen","family":"Charnock-Jones","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynaecology, University of Cambridge , Cambridge, UK"},{"name":"Centre for Trophoblast Research, Department of Physiology, Development and Neuroscience, University of Cambridge , Cambridge, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gordon C S","family":"Smith","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynaecology, University of Cambridge , Cambridge, UK"},{"name":"Centre for Trophoblast Research, Department of Physiology, Development and Neuroscience, University of Cambridge , Cambridge, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2023,9,28]]},"reference":[{"key":"2023122523574235500_dyad123-B1","doi-asserted-by":"crossref","first-page":"1737","DOI":"10.1007\/s43032-021-00756-3","article-title":"Maternal factors for intrauterine growth retardation: systematic review and meta-analysis of observational studies","volume":"30","author":"Yang","year":"2023","journal-title":"Reprod Sci"},{"key":"2023122523574235500_dyad123-B2","doi-asserted-by":"crossref","first-page":"465","DOI":"10.1016\/S0002-9378(00)70240-7","article-title":"A systematic review and meta-analysis of prospective studies on the association between maternal cigarette smoking and preterm delivery","volume":"182","author":"Shah","year":"2000","journal-title":"Am J Obstet Gynecol"},{"key":"2023122523574235500_dyad123-B3","doi-asserted-by":"crossref","first-page":"176","DOI":"10.1007\/s12519-021-00501-5","article-title":"Maternal smoking status during pregnancy and low birth weight in offspring: systematic review and meta-analysis of 55 cohort studies published from 1986 to 2020","volume":"18","author":"Di","year":"2022","journal-title":"World J Pediatr"},{"key":"2023122523574235500_dyad123-B4","doi-asserted-by":"crossref","first-page":"e0132334","DOI":"10.1371\/journal.pone.0132334","article-title":"Maternal caffeine consumption during pregnancy and risk of low birth weight: a dose-response meta-analysis of observational studies","volume":"10","author":"Rhee","year":"2015","journal-title":"PLoS One"},{"key":"2023122523574235500_dyad123-B5","doi-asserted-by":"crossref","first-page":"43667","DOI":"10.18632\/oncotarget.6190","article-title":"Cigarette smoking during pregnancy and preeclampsia risk: a systematic review and meta-analysis of prospective studies","volume":"6","author":"Wei","year":"2015","journal-title":"Oncotarget"},{"key":"2023122523574235500_dyad123-B6","doi-asserted-by":"crossref","first-page":"1100","DOI":"10.1161\/HYPERTENSIONAHA.109.148973","article-title":"How does smoking reduce the risk of preeclampsia?","volume":"55","author":"Karumanchi","year":"2010","journal-title":"Hypertension"},{"key":"2023122523574235500_dyad123-B7","doi-asserted-by":"crossref","first-page":"279","DOI":"10.1038\/s41366-020-0617-4","article-title":"Association of maternal caffeine intake during pregnancy with low birth weight, childhood overweight, and obesity: a meta-analysis of cohort studies","volume":"45","author":"Jin","year":"2021","journal-title":"Int J Obes (Lond)"},{"key":"2023122523574235500_dyad123-B8","doi-asserted-by":"crossref","first-page":"174","DOI":"10.1186\/s12916-014-0174-6","article-title":"Maternal caffeine intake during pregnancy is associated with risk of low birth weight: a systematic review and dose-response meta-analysis","volume":"12","author":"Chen","year":"2014","journal-title":"BMC Med"},{"key":"2023122523574235500_dyad123-B9","doi-asserted-by":"crossref","first-page":"e213238","DOI":"10.1001\/jamanetworkopen.2021.3238","article-title":"Association between maternal caffeine consumption and metabolism and neonatal anthropometry: a secondary analysis of the NICHD fetal growth studies\u2013singletons","volume":"4","author":"Gleason","year":"2021","journal-title":"JAMA Netw Open"},{"key":"2023122523574235500_dyad123-B10","doi-asserted-by":"crossref","first-page":"a2332","DOI":"10.1136\/bmj.a2332","article-title":"Maternal caffeine intake during pregnancy and risk of fetal growth restriction: a large prospective observational study","volume":"337","author":"Group","year":"2008","journal-title":"BMJ"},{"key":"2023122523574235500_dyad123-B11","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1093\/aje\/155.1.32","article-title":"Maternal serum caffeine metabolites and small-for-gestational age birth","volume":"155","author":"Klebanoff","year":"2002","journal-title":"Am J Epidemiol"},{"key":"2023122523574235500_dyad123-B12","doi-asserted-by":"crossref","first-page":"b4347","DOI":"10.1136\/bmj.b4347","article-title":"Reliability of self reported smoking status by pregnant women for estimating smoking prevalence: a retrospective, cross sectional study","volume":"339","author":"Shipton","year":"2009","journal-title":"BMJ"},{"key":"2023122523574235500_dyad123-B13","doi-asserted-by":"crossref","first-page":"571","DOI":"10.1007\/s00213-008-1403-5","article-title":"Methodological considerations for the quantification of self-reported caffeine use","volume":"203","author":"Addicott","year":"2009","journal-title":"Psychopharmacology (Berl)"},{"key":"2023122523574235500_dyad123-B14","doi-asserted-by":"crossref","first-page":"164","DOI":"10.1136\/tobaccocontrol-2011-050298","article-title":"Assessing secondhand smoke using biological markers","volume":"22","author":"Avila-Tang","year":"2013","journal-title":"Tob Control"},{"key":"2023122523574235500_dyad123-B15","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1016\/S1047-2797(97)00125-7","article-title":"Serum caffeine and paraxanthine as markers for reported caffeine intake in pregnancy","volume":"8","author":"Klebanoff","year":"1998","journal-title":"Ann Epidemiol"},{"key":"2023122523574235500_dyad123-B16","doi-asserted-by":"crossref","first-page":"54","DOI":"10.1038\/clpt.1986.10","article-title":"Assessment of caffeine exposure: Caffeine content of beverages, caffeine intake, and plasma concentrations of methylxanthines","volume":"39","author":"Lelo","year":"1986","journal-title":"Clin Pharmacol Ther"},{"key":"2023122523574235500_dyad123-B17","doi-asserted-by":"crossref","first-page":"S17","DOI":"10.1016\/j.placenta.2016.10.011","article-title":"The pregnancy outcome prediction (POP) study: investigating the relationship between serial prenatal ultrasonography, biomarkers, placental phenotype and adverse pregnancy outcomes","volume":"59","author":"Gaccioli","year":"2017","journal-title":"Placenta"},{"key":"2023122523574235500_dyad123-B18","doi-asserted-by":"crossref","first-page":"301","DOI":"10.1093\/ije\/dyz098","article-title":"4-Hydroxyglutamate is a novel predictor of pre-eclampsia","volume":"49","author":"Sovio","year":"2020","journal-title":"Int J Epidemiol"},{"key":"2023122523574235500_dyad123-B19","doi-asserted-by":"crossref","first-page":"1122","DOI":"10.1097\/01.AOG.0000437382.03963.88","article-title":"The American College of Obstetricians and Gynecologists. Hypertension in pregnancy: executive summary","volume":"122","year":"2013","journal-title":"Obstet Gynecol"},{"key":"2023122523574235500_dyad123-B20","doi-asserted-by":"crossref","first-page":"168","DOI":"10.1046\/j.1469-0705.1995.06030168.x","article-title":"An adjustable fetal weight standard","volume":"6","author":"Gardosi","year":"1995","journal-title":"Ultrasound Obstet Gynecol"},{"key":"2023122523574235500_dyad123-B21","doi-asserted-by":"crossref","first-page":"348","DOI":"10.1038\/s41591-020-0804-9","article-title":"A maternal serum metabolite ratio predicts fetal growth restriction at term","volume":"26","author":"Sovio","year":"2020","journal-title":"Nat Med"},{"key":"2023122523574235500_dyad123-B22","doi-asserted-by":"crossref","first-page":"2089","DOI":"10.1016\/S0140-6736(15)00131-2","article-title":"Screening for fetal growth restriction with universal third trimester ultrasonography in nulliparous women in the Pregnancy Outcome Prediction (POP) study: a prospective cohort study","volume":"386","author":"Sovio","year":"2015","journal-title":"Lancet"},{"key":"2023122523574235500_dyad123-B23","doi-asserted-by":"crossref","first-page":"982","DOI":"10.2337\/dc16-0160","article-title":"Accelerated fetal growth prior to diagnosis of gestational diabetes mellitus: a prospective cohort study of nulliparous women","volume":"39","author":"Sovio","year":"2016","journal-title":"Diabetes Care"},{"key":"2023122523574235500_dyad123-B24","doi-asserted-by":"crossref","first-page":"731","DOI":"10.1161\/HYPERTENSIONAHA.116.08620","article-title":"Prediction of preeclampsia using the soluble fms-like tyrosine kinase 1 to placental growth factor ratio","volume":"69","author":"Sovio","year":"2017","journal-title":"Hypertension"},{"key":"2023122523574235500_dyad123-B25","volume-title":"The English Indices of Deprivation 2007","author":"Noble","year":"2008"},{"key":"2023122523574235500_dyad123-B26","doi-asserted-by":"crossref","first-page":"456","DOI":"10.1093\/aje\/kwf220","article-title":"Association of maternal caffeine consumption with decrements in fetal growth","volume":"157","author":"Bracken","year":"2003","journal-title":"Am J Epidemiol"},{"key":"2023122523574235500_dyad123-B27","doi-asserted-by":"crossref","first-page":"S37","DOI":"10.1016\/j.ajog.2006.10.100","article-title":"Circulating angiogenic factors in smokers and non-smokers during normotensive pregnancy","volume":"195","author":"Levine","year":"2006","journal-title":"Am J Obstet Gynecol"},{"key":"2023122523574235500_dyad123-B28","doi-asserted-by":"crossref","first-page":"943","DOI":"10.1038\/ajh.2008.219","article-title":"Cigarette smoke exposure and angiogenic factors in pregnancy and preeclampsia","volume":"21","author":"Jeyabalan","year":"2008","journal-title":"Am J Hypertens"},{"key":"2023122523574235500_dyad123-B29","doi-asserted-by":"crossref","first-page":"246","DOI":"10.1136\/jech.51.3.246","article-title":"Smoking during pregnancy: how reliable are maternal self reports in New Zealand?","volume":"51","author":"Ford","year":"1997","journal-title":"J Epidemiol Community Health"},{"key":"2023122523574235500_dyad123-B30","doi-asserted-by":"crossref","first-page":"2471","DOI":"10.2741\/2248","article-title":"Smoking and risk of preeclampsia: a systematic review","volume":"12","author":"England","year":"2007","journal-title":"Front Biosci"},{"key":"2023122523574235500_dyad123-B31","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1002\/ijgo.13709","article-title":"The association between smoking during pregnancy and hypertensive disorders of pregnancy: a systematic review and meta-analysis","volume":"157","author":"Wang","year":"2022","journal-title":"Int J Gynaecol Obstet"},{"key":"2023122523574235500_dyad123-B32","doi-asserted-by":"crossref","first-page":"208","DOI":"10.1016\/S0749-3797(98)00089-0","article-title":"Effects of smoking during pregnancy: five meta-analyses","volume":"16","author":"Castles","year":"1999","journal-title":"Am J Prev Med"},{"key":"2023122523574235500_dyad123-B33","doi-asserted-by":"crossref","first-page":"1254","DOI":"10.1161\/HYPERTENSIONAHA.109.147082","article-title":"Tobacco use during pregnancy and preeclampsia risk","volume":"55","author":"Wikstr\u00f6m","year":"2010","journal-title":"Hypertension"},{"key":"2023122523574235500_dyad123-B34","author":"The Fetal Medicine Foundation"},{"key":"2023122523574235500_dyad123-B35","doi-asserted-by":"crossref","first-page":"1120","DOI":"10.3945\/ajcn.2010.29789","article-title":"Caffeine consumption during pregnancy and risk of preterm birth: a meta-analysis","volume":"92","author":"Maslova","year":"2010","journal-title":"Am J Clin Nutr"},{"key":"2023122523574235500_dyad123-B36","doi-asserted-by":"crossref","first-page":"3045","DOI":"10.1111\/jog.15445","article-title":"The association between caffeine exposure during pregnancy and risk of gestational hypertension\/preeclampsia: a meta-analysis and systematical review","volume":"48","author":"Chen","year":"2022","journal-title":"J Obstet Gynaecol Res"},{"key":"2023122523574235500_dyad123-B37","doi-asserted-by":"crossref","first-page":"e2133401","DOI":"10.1001\/jamanetworkopen.2021.33401","article-title":"Assessment of caffeine consumption and maternal cardiometabolic pregnancy complications","volume":"4","author":"Hinkle","year":"2021","journal-title":"JAMA Netw Open"},{"key":"2023122523574235500_dyad123-B38","doi-asserted-by":"crossref","first-page":"420","DOI":"10.1111\/1471-0528.12930","article-title":"First trimester coffee and tea intake and risk of gestational diabetes mellitus: a study within a national birth cohort","volume":"122","author":"Hinkle","year":"2015","journal-title":"BJOG"},{"key":"2023122523574235500_dyad123-B39","doi-asserted-by":"crossref","first-page":"1358","DOI":"10.1136\/bmj.313.7069.1358","article-title":"Relation of caffeine intake and blood caffeine concentrations during pregnancy to fetal growth: prospective population based study","volume":"313","author":"Cook","year":"1996","journal-title":"BMJ"},{"key":"2023122523574235500_dyad123-B40","doi-asserted-by":"crossref","first-page":"1958","DOI":"10.1093\/ije\/dyx147","article-title":"Heavier smoking increases coffee consumption: findings from a Mendelian randomization analysis","volume":"46","author":"Bj\u00f8rngaard","year":"2017","journal-title":"Int J Epidemiol"},{"key":"2023122523574235500_dyad123-B41","doi-asserted-by":"crossref","first-page":"481","DOI":"10.1208\/s12248-009-9127-y","article-title":"Insights into the substrate specificity, inhibitors, regulation, and polymorphisms and the clinical impact of human cytochrome P450 1A2","volume":"11","author":"Zhou","year":"2009","journal-title":"Aaps J"},{"key":"2023122523574235500_dyad123-B42","doi-asserted-by":"crossref","first-page":"172","DOI":"10.1016\/j.annepidem.2007.11.005","article-title":"Prenatal caffeine assessment: fetal and maternal biomarkers or self-reported intake?","volume":"18","author":"Grosso","year":"2008","journal-title":"Ann Epidemiol"}],"container-title":["International Journal of Epidemiology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/ije\/article-pdf\/52\/6\/1756\/54850491\/dyad123.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/ije\/article-pdf\/52\/6\/1756\/54850491\/dyad123.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,12,25]],"date-time":"2023-12-25T23:58:23Z","timestamp":1703548703000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/ije\/article\/52\/6\/1756\/7283200"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,9,28]]},"references-count":42,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2023,9,28]]},"published-print":{"date-parts":[[2023,12,25]]}},"URL":"https:\/\/doi.org\/10.1093\/ije\/dyad123","relation":{},"ISSN":["0300-5771","1464-3685"],"issn-type":[{"value":"0300-5771","type":"print"},{"value":"1464-3685","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2023,12,1]]},"published":{"date-parts":[[2023,9,28]]}}}