{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,3]],"date-time":"2026-03-03T01:44:40Z","timestamp":1772502280691,"version":"3.50.1"},"reference-count":40,"publisher":"Public Library of Science (PLoS)","issue":"1","license":[{"start":{"date-parts":[[2025,1,16]],"date-time":"2025-01-16T00:00:00Z","timestamp":1736985600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100005743","name":"Universit\u00e0 Cattolica del Sacro Cuore","doi-asserted-by":"publisher","award":["line D3.2"],"award-info":[{"award-number":["line D3.2"]}],"id":[{"id":"10.13039\/501100005743","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003196","name":"Ministero della Salute","doi-asserted-by":"publisher","award":["PREV-A-2022-12377025"],"award-info":[{"award-number":["PREV-A-2022-12377025"]}],"id":[{"id":"10.13039\/501100003196","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:sec id=\"sec001\">\n<jats:title>Background<\/jats:title>\n<jats:p>The study of women exposures and child outcomes occurring in the first 1,000 days of life since conception enhances understanding of the relationships between environmental factors, epigenetic changes, and disease development, extending beyond childhood and spanning the entire lifespan. Generation Gemelli is a recently launched case-control study that enrolls mother-newborns pairs in one of the largest university hospitals in Italy, in order to examine the association between maternal environmental exposures and intrauterine growth restriction (IUGR) and the risk of premature birth. The study will also evaluate the association of maternal exposures and the health and growth of infants and children up to 24 months of age.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec002\">\n<jats:title>Methods<\/jats:title>\n<jats:p>The study entails the set-up of a case-control study within a birth cohort. With approximately 4,000 annual deliveries, we aim to enroll 140 cases (newborns with IUGR and premature birth) and 280 controls per year, from September 2022. A comprehensive questionnaire will be used to gather information about various types of maternal environmental exposures before and during pregnancy. We will collect biological samples from both mothers and newborns (including vaginal swab, placenta sample, blood, saliva, meconium, and bronchoalveolar lavage fluid) at birth and within the early hours of the newborn\u2019s life. We will perform laboratory examinations including dosage of heavy metals and essential elements, investigation of placental distress and fetal brain damage of biomarkers, analysis of microbiota and of DNA methylation profile. We will conduct clinical follow-up assessments in both cases and controls at months 12 and 24 and we will collect anthropometric data, feeding types with particular reference to breastfeeding and its duration, pediatric emergency room visits, hospitalizations, medication usage, known allergies, and neuropsychological development.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec003\">\n<jats:title>Discussion<\/jats:title>\n<jats:p>The Generation Gemelli case-control study holds the promise of significantly enhancing our comprehension of how maternal environmental exposures relate to the health of children and the broader population. The study of the exposome will provide insights into the relationships between environmental exposures, epigenetic changes and health outcomes during the first 1000 days of life and onward.<\/jats:p>\n<\/jats:sec>","DOI":"10.1371\/journal.pone.0317458","type":"journal-article","created":{"date-parts":[[2025,1,16]],"date-time":"2025-01-16T18:32:19Z","timestamp":1737052339000},"page":"e0317458","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":1,"title":["Environmental maternal exposures and the risk of premature birth and intrauterine growth restriction: The Generation Gemelli study protocol of newborn exposome"],"prefix":"10.1371","volume":"20","author":[{"given":"Leonardo","family":"Villani","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Angelo Maria","family":"Pezzullo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5013-0733","authenticated-orcid":true,"given":"Roberta","family":"Pastorino","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-4663-2619","authenticated-orcid":true,"given":"Alessandra","family":"Maio","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Francesca","family":"Stollagli","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chiara","family":"Tirone","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marta","family":"Barba","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Angela Maria","family":"Cozzolino","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Denise","family":"Pires Marafon","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Martina","family":"Porcelli","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Annamaria","family":"Sbordone","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maria Letizia","family":"Patti","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anthea","family":"Bottoni","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Angela","family":"Paladini","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Simona","family":"Fattore","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Domenico Marco","family":"Romeo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ornella","family":"Parolini","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wanda","family":"Lattanzi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Guido","family":"Rindi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Luca","family":"Tamagnone","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marco","family":"Marazza","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maurizio","family":"Genuardi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4707-2242","authenticated-orcid":true,"given":"Elisabetta","family":"Tabolacci","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eugenio Maria","family":"Mercuri","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Antonio","family":"Chiaretti","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2959-8571","authenticated-orcid":true,"given":"Tina","family":"Pasciuto","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maurizio","family":"Sanguinetti","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Vincenzo","family":"Valentini","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Giovanni","family":"Scambia","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Walter","family":"Ricciardi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Giovanni","family":"Vento","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Antonio","family":"Lanzone","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stefania","family":"Boccia","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"340","published-online":{"date-parts":[[2025,1,16]]},"reference":[{"key":"pone.0317458.ref001","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1146\/annurev.publhealth.26.021304.144505","article-title":"A life course approach to chronic disease epidemiology","author":"J Lynch","year":"2005","journal-title":"Annual Review of Public Health"},{"key":"pone.0317458.ref002","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1056\/NEJMra0708473","article-title":"Effect of In Utero and Early-Life Conditions on Adult Health and Disease","volume":"359","author":"PD Gluckman","year":"2008","journal-title":"New England Journal of Medicine"},{"key":"pone.0317458.ref003","article-title":"The origins of health and disease: The influence of maternal diseases and lifestyle during gestation","author":"L Capra","year":"2013","journal-title":"Italian Journal of Pediatrics"},{"key":"pone.0317458.ref004","doi-asserted-by":"crossref","first-page":"437","DOI":"10.3945\/jn.109.116327","article-title":"Maternal micronutrient deficiency, fetal development, and the risk of chronic disease","author":"P Christian","year":"2010","journal-title":"Journal of Nutrition"},{"key":"pone.0317458.ref005","first-page":"186","article-title":"Mercury Exposure and Children\u2019s Health","volume":"40","author":"S Bose-O\u2019Reilly","year":"2010","journal-title":"Curr Probl Pediatr Adolesc Health Care"},{"key":"pone.0317458.ref006","doi-asserted-by":"crossref","first-page":"1243","DOI":"10.1111\/j.1471-0528.2008.01822.x","article-title":"Transgenerational effects of prenatal exposure to the Dutch famine on neonatal adiposity and health in later life","volume":"115","author":"RC Painter","year":"2008","journal-title":"BJOG"},{"key":"pone.0317458.ref007","first-page":"16","article-title":"The Role of Nutrition in Brain Development: The Golden Opportunity of the \u201cFirst 1000 Days.\u201d","volume":"175","author":"SE Cusick","year":"2016","journal-title":"Journal of Pediatrics"},{"key":"pone.0317458.ref008","first-page":"443","article-title":"Epigenetic programming\u2014The important first 1000 days","volume-title":"Acta Paediatrica, International Journal of Paediatrics","author":"A Linn\u00e9r","year":"2020"},{"key":"pone.0317458.ref009","doi-asserted-by":"crossref","first-page":"419","DOI":"10.1016\/j.siny.2004.03.001","article-title":"Maternal constraint of fetal growth and its consequences","author":"PD Gluckman","year":"2004","journal-title":"Seminars in Fetal and Neonatal Medicine"},{"key":"pone.0317458.ref010","first-page":"101","article-title":"A life course approach to cardiovascular aging","volume-title":"Future Cardiology","author":"R Hardy","year":"2015"},{"key":"pone.0317458.ref011","first-page":"591","article-title":"Preventive strategies for mental health","volume-title":"The Lancet Psychiatry","author":"C Arango","year":"2018"},{"key":"pone.0317458.ref012","doi-asserted-by":"crossref","first-page":"309","DOI":"10.1146\/annurev-publhealth-040617-014629","article-title":"Environmental Influences on the Epigenome: Exposure-Associated DNA Methylation in Human Populations","volume":"39","author":"EM Martin","year":"2018","journal-title":"Annu Rev Public Health"},{"key":"pone.0317458.ref013","doi-asserted-by":"crossref","first-page":"359","DOI":"10.1002\/bies.201300113","article-title":"A paternal environmental legacy: Evidence for epigenetic inheritance through the male germ line","volume":"36","author":"A Soubry","year":"2014","journal-title":"BioEssays"},{"key":"pone.0317458.ref014","doi-asserted-by":"crossref","DOI":"10.1016\/j.coesh.2023.100455","article-title":"The exposome approach to study children\u2019s health","volume-title":"Current Opinion in Environmental Science and Health","author":"E Handakas","year":"2023"},{"key":"pone.0317458.ref015","first-page":"385","article-title":"The Children\u2019s Health Exposure Analysis Resource: Enabling research into the environmental influences on children\u2019s health outcomes","volume-title":"Current Opinion in Pediatrics","author":"DM Balshaw","year":"2017"},{"key":"pone.0317458.ref016","doi-asserted-by":"crossref","first-page":"1847","DOI":"10.1158\/1055-9965.EPI-05-0456","article-title":"Complementing the genome with an \u201cexposome\u201d: The outstanding challenge of environmental exposure measurement in molecular epidemiology","author":"CP Wild","year":"2005","journal-title":"Cancer Epidemiology Biomarkers and Prevention"},{"key":"pone.0317458.ref017","doi-asserted-by":"crossref","DOI":"10.1038\/s41467-022-34422-2","article-title":"Multi-omics signatures of the human early life exposome","volume":"13","author":"L Maitre","year":"2022","journal-title":"Nat Commun"},{"key":"pone.0317458.ref018","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1146\/annurev-pharmtox-010818-021315","article-title":"The Exposome: Molecules to Populations","volume":"59","author":"MM Niedzwiecki","year":"2019","journal-title":"Annual Review of Pharmacology and Toxicology Annu Rev Pharmacol Toxicol"},{"key":"pone.0317458.ref019","doi-asserted-by":"crossref","first-page":"876","DOI":"10.1136\/thoraxjnl-2013-204949","article-title":"The exposome: a new paradigm to study the impact of environment on health","volume":"69","author":"M. Vrijheid","year":"2014","journal-title":"Thorax"},{"key":"pone.0317458.ref020","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1093\/ije\/dyr236","article-title":"The exposome: From concept to utility","author":"CP Wild","year":"2012","journal-title":"International Journal of Epidemiology"},{"key":"pone.0317458.ref021","doi-asserted-by":"crossref","first-page":"333","DOI":"10.1002\/uog.15884","article-title":"Consensus definition of fetal growth restriction: a Delphi procedure","volume":"48","author":"SJ Gordijn","year":"2016","journal-title":"Ultrasound Obstet Gynecol"},{"key":"pone.0317458.ref022","doi-asserted-by":"crossref","first-page":"B2","DOI":"10.1016\/j.ajog.2016.04.017","article-title":"Periviable birth: Interim update","volume":"215","author":"JL Ecker","year":"2016","journal-title":"Am J Obstet Gynecol"},{"key":"pone.0317458.ref023","first-page":"108","volume":"106","author":"C Del Rosario","year":"2021","journal-title":"How to use the Bayley Scales of Infant and Toddler Development. Archives of Disease in Childhood\u2014Education and Practice"},{"key":"pone.0317458.ref024","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1111\/1471-0528.12430","article-title":"A rapid questionnaire assessment of environmental exposures to pregnant women in the INTERGROWTH-21st Project","volume":"120","author":"B Eskenazi","year":"2013","journal-title":"BJOG"},{"key":"pone.0317458.ref025","doi-asserted-by":"crossref","DOI":"10.1186\/s12199-018-0733-0","article-title":"Questionnaire results on exposure characteristics of pregnant women participating in the Japan Environment and Children Study (JECS)","volume":"23","author":"M Iwai-Shimada","year":"2018","journal-title":"Environ Health Prev Med"},{"key":"pone.0317458.ref026","doi-asserted-by":"crossref","first-page":"377","DOI":"10.1016\/j.jbi.2008.08.010","article-title":"Research electronic data capture (REDCap)-A metadata-driven methodology and workflow process for providing translational research informatics support","volume":"42","author":"PA Harris","year":"2009","journal-title":"J Biomed Inform"},{"key":"pone.0317458.ref027","unstructured":"Data Integrity and Compliance With Drug CGMP: Questions and Answers | FDA. [cited 4 Nov 2024]. Available: https:\/\/www.fda.gov\/regulatory-information\/search-fda-guidance-documents\/data-integrity-and-compliance-drug-cgmp-questions-and-answers"},{"key":"pone.0317458.ref028","first-page":"331","article-title":"Environmental pollutants and child health-A review of recent concerns","volume-title":"International Journal of Hygiene and Environmental Health","author":"M Vrijheid","year":"2016"},{"key":"pone.0317458.ref029","doi-asserted-by":"crossref","DOI":"10.1016\/j.envpol.2021.117404","article-title":"Early life multiple exposures and child cognitive function: A multi-centric birth cohort study in six European countries","volume":"284","author":"J Julvez","year":"2021","journal-title":"Environmental Pollution"},{"key":"pone.0317458.ref030","article-title":"Programming of weight and obesity across the lifecourse by the maternal metabolic exposome: A systematic review","volume-title":"Molecular Aspects of Medicine","author":"J Strain","year":"2022"},{"key":"pone.0317458.ref031","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1515\/reveh-2016-0032","article-title":"Future of environmental research in the age of epigenomics and exposomics","volume":"32","author":"N. Holland","year":"2017","journal-title":"Rev Environ Health"},{"key":"pone.0317458.ref032","doi-asserted-by":"crossref","DOI":"10.1016\/j.envint.2020.105622","article-title":"Using methylome data to inform exposome-health association studies: An application to the identification of environmental drivers of child body mass index","volume":"138","author":"S Cadiou","year":"2020","journal-title":"Environ Int."},{"key":"pone.0317458.ref033","doi-asserted-by":"crossref","DOI":"10.1093\/exposome\/osad001","article-title":"Epigenetics and the exposome: DNA methylation as a proxy for health impacts of prenatal environmental exposures","volume":"3","author":"ML Colwell","year":"2023","journal-title":"Exposome"},{"key":"pone.0317458.ref034","first-page":"29","article-title":"European birth cohorts for environmental health research","volume-title":"Environmental Health Perspectives","author":"M Vrijheid","year":"2012"},{"key":"pone.0317458.ref035","first-page":"81","article-title":"The impact of social determinants and lifestyles on dietary patterns during pregnancy: Evidence from the \u201cMamma & Bambino\u201d study","volume":"31","author":"A Maugeri","year":"2019","journal-title":"Ann Ig"},{"key":"pone.0317458.ref036","doi-asserted-by":"crossref","DOI":"10.3389\/fpubh.2020.00125","article-title":"Birth Cohorts in Highly Contaminated Sites: A Tool for Monitoring the Relationships Between Environmental Pollutants and Children\u2019s Health","volume":"8","author":"G Drago","year":"2020","journal-title":"Front Public Health"},{"key":"pone.0317458.ref037","doi-asserted-by":"crossref","DOI":"10.1186\/1471-2431-14-36","article-title":"Piccolipi\u00f9, a multicenter birth cohort in Italy: Protocol of the study","volume":"14","author":"S Farchi","year":"2014","journal-title":"BMC Pediatr"},{"key":"pone.0317458.ref038","doi-asserted-by":"crossref","first-page":"190","DOI":"10.1017\/thg.2012.85","article-title":"An update on the Italian Twin Register: Advances in cohort recruitment, project building and network development","volume":"16","author":"S Brescianini","year":"2013","journal-title":"Twin Research and Human Genetics"},{"key":"pone.0317458.ref039","doi-asserted-by":"crossref","first-page":"831","DOI":"10.1007\/s10654-007-9194-2","article-title":"Feasibility of recruiting a birth cohort through the Internet: The experience of the NINFEA cohort","volume":"22","author":"L Richiardi","year":"2007","journal-title":"Eur J Epidemiol"},{"key":"pone.0317458.ref040","doi-asserted-by":"crossref","DOI":"10.3390\/nu15081922","article-title":"The Effect of Maternal Dietary Patterns on Birth Weight for Gestational Age: Findings from the MAMI-MED Cohort","volume":"15","author":"M Barchitta","year":"2023","journal-title":"Nutrients"}],"container-title":["PLOS ONE"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0317458","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,1,16]],"date-time":"2025-01-16T18:32:33Z","timestamp":1737052353000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0317458"}},"subtitle":[],"editor":[{"given":"Ewa","family":"Tomaszewska","sequence":"first","affiliation":[],"role":[{"role":"editor","vocabulary":"crossref"}]}],"short-title":[],"issued":{"date-parts":[[2025,1,16]]},"references-count":40,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2025,1,16]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0317458","relation":{},"ISSN":["1932-6203"],"issn-type":[{"value":"1932-6203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,1,16]]}}}