INSERM UMR-S 1136, Team of Epidemiology of Allergic and Respiratory Diseases (EPAR), Institute Pierre Louis of Epidemiology and Public Health (IPLESP), Sorbonne University, Paris, 75005, France

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Isabella Annesi-Maesano

https://orcid.org/0000-0002-6340-9300

Institute Desbrest of Epidemiology and Public Health, INSERM and Montpellier University, Montpellier, 34090, France

Department of Allergic and Respiratory Diseases, Montpellier University Hospital, Montpellier, 34295, France

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Christian M Page

https://orcid.org/0000-0002-1897-3666

Department of Physical Health and Aging, Division for Mental and Physical Health, Norwegian Institute of Public Health, Oslo, 0456, Norway

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Anne-Lise Brantsæter

https://orcid.org/0000-0001-6315-7134

Department of Food Safety, Division of Climate and Environmental Health, Norwegian Institute of Public Health, Oslo, 0456, Norway

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Mona Bekkhus

https://orcid.org/0000-0002-4447-8909

PROMENTA Research Centre, Department of Psychology, University of Oslo, Oslo, 0373, Norway

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Siri E Håberg

https://orcid.org/0000-0002-2199-5225

Centre for Fertility and Health, Norwegian Institute of Public Health, Oslo, 0456, Norway

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Stephanie J London

https://orcid.org/0000-0003-4911-5290

Epidemiology Branch, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, NC 27709, USA

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Marcus R Munafò

https://orcid.org/0000-0002-4049-993X

School of Psychological Science, University of Bristol, Bristol, BS8 1QU, UK

MRC Integrative Epidemiology Unit at the University of Bristol, Bristol, BS8 2BN, UK

NIHR Biomedical Research Centre at the University Hospitals Bristol NHS Foundation Trust and the University of Bristol, Bristol, BS2 8DX, UK

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Luisa Zuccolo

https://orcid.org/0000-0002-7049-3037

MRC Integrative Epidemiology Unit at the University of Bristol, Bristol, BS8 2BN, UK

Department of Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, BS8 2PN, UK

Health Data Science Centre, Human Technopole, Milan, 20157, Italy

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Gemma C Sharp

https://orcid.org/0000-0003-2906-4035

MRC Integrative Epidemiology Unit at the University of Bristol, Bristol, BS8 2BN, UK

Department of Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, BS8 2PN, UK

School of Psychology, University of Exeter, Exeter, EX4 4PY, UK

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Published Online:29 Nov 2023https://doi.org/10.2217/epi-2023-0263

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Abstract

Background: Prenatal caffeine exposure may influence offspring health via DNA methylation, but no large studies have tested this. Materials & methods: Epigenome-wide association studies and differentially methylated regions in cord blood (450k or EPIC Illumina arrays) were meta-analyzed across six European cohorts (n = 3725). Differential methylation related to self-reported caffeine intake (mg/day) from coffee, tea and cola was compared with assess whether caffeine is driving effects. Results: One CpG site (cg19370043, PRRX1) was associated with caffeine and another (cg14591243, STAG1) with cola intake. A total of 12–22 differentially methylated regions were detected with limited overlap across caffeinated beverages. Conclusion: We found little evidence to support an intrauterine effect of caffeine on offspring DNA methylation. Statistical power limitations may have impacted our findings.

Plain language summary

Current guidelines recommend pregnant women to limit caffeine intake to less than 200 mg daily, even though there is no clear proof of its effects on human development. A biological explanation for how exposure to caffeine during pregnancy influences development would help clarify if recommended limits are justified. An epigenetic mechanism, called DNA methylation (DNAm), has been suggested as a potential biological explanation for how caffeine intake during pregnancy influences health development. DNAm can switch genes ‘on’ or ‘off’ in response to environmental influences and therefore act as a bridge between genes and the environment. Studies have found that smoking during pregnancy is connected to over 6000 changes in DNAm at birth, with lasting effects into adulthood. To explore the link between caffeine intake during pregnancy and DNAm at birth, we analyzed data from 3725 mother–child pairs living in different European countries. We looked at effects from coffee, tea and cola intake during pregnancy on children's DNAm at birth. We found one change in DNAm to be connected to total caffeine and another to cola consumption during pregnancy. These few connections do not provide convincing evidence that caffeine intake during pregnancy impacts children's DNAm at birth. However, because mothers in our study consumed little caffeine, it is possible that results would be different in studies with participants consuming high amounts of caffeine during pregnancy. Potentially, our study did not include enough people to find very small changes in DNAm that are connected to caffeine consumption during pregnancy.

Tweetable abstract

EWAS meta-analysis of six European cohorts finds no support for an intrauterine effect of caffeine on DNA methylation at birth. Associations are likely driven by diverse confounding structures of caffeinated drinks, not caffeine itself.

Keywords:

Papers of special note have been highlighted as: • of interest; •• of considerable interest

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Received 20 July 2023

Accepted 2 November 2023

Published online 29 November 2023

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Supplementary data

To view the supplementary data that accompany this paper please visit the journal website at: www.futuremedicine.com/doi/suppl/10.2217/epi-2023-0263

Author contributions

L Schellhas and GC Sharp contributed to the study conceptualization and design of the study. L Schellhas conducted the cohort analyses in ALSPAC and BiB, conducted the meta-analysis and quality control analysis under supervision of GC Sharp, and wrote the manuscript. GC Sharp, MR Munafò and L Zuccolo were substantially involved in the interpretation of data for the study and contributed to critically revise the work for important intellectual content. GS Monasso conducted the cohort analysis using Generation R data under supervision of JF Felix. VWV Jaddoe contributed with data acquisition for Generation R. P Huang conducted the shadow meta-analysis. S Fernández-Barrés conducted the analysis in INMA under the supervision of M Vrijheid. G Pesce conducted the analysis in EDEN under the supervision of I Annesi-Maesano. C Page conducted the cohort analysis using data of MoBa. SE Håberg contributed with data acquisition for MoBa. AL Brantsæter generated the caffeine variables in MoBa. M Bekkhus contributed to the study design and generated the outcome measures (psychometric variables) using MoBa data. SJ London contributed with data generation for MoBa and also initiated the Pregnancy and Childhood Epigenetics consortium, of which this study is part. All coauthors reviewed/edited the manuscript and approved the final version.

Acknowledgments

ALSPAC: We are extremely grateful to all the families who took part in this study, the midwives for their help in recruiting them and the whole ALSPAC team, which includes interviewers, computer and laboratory technicians, clerical workers, research scientists, volunteers, managers, receptionists and nurses. Informed consent for the use of data collected via questionnaires and clinics was obtained from participants following the recommendations of the ALSPAC Ethics and Law Committee at the time.

BiB: BiB is only possible because of the enthusiasm and commitment of the children and parents in BiB. We are grateful to all the participants, practitioners and researchers who have made BiB happen. 450K DNAm and genotype array data was generated in the Bristol Bioresource Laboratory Illumina Facility, University of Bristol. Ethical approval for the data collection was granted by Bradford Research Ethics Committee (ref. 07/H1302/112). On registration with the study, pregnant mothers gave written informed consent for themselves and on behalf of their child.

Generation R: The Generation R Study is conducted by Erasmus Medical Center, University Medical Center Rotterdam, in close collaboration with the School of Law and Faculty of Social Sciences of the Erasmus University Rotterdam, the Municipal Health Service Rotterdam area, Rotterdam, the Rotterdam Homecare Foundation, Rotterdam and the Stichting Trombosedienst and Artsenlaboratorium Rijnmond (STAR-MDC), Rotterdam. We gratefully acknowledge the contribution of children and parents, general practitioners, hospitals, midwives and pharmacies in Rotterdam. The study protocol was approved by the Medical Ethical Committee of the Erasmus Medical Centre, Rotterdam. Written informed consent was obtained for all participants. The generation and management of the Illumina 450K methylation array data (epigenome-wide association study [EWAS] data) for the Generation R Study was executed by the Human Genotyping Facility of the Genetic Laboratory of the Department of Internal Medicine, Erasmus MC, The Netherlands. We thank M Verbiest, M Jhamai, S Higgins, M Verkerk and L Stolk for their help in creating the EWAS database. We thank A Teumer for his work on the quality control and normalization scripts.

MoBa: We are grateful to all the participating families in Norway who take part in this ongoing cohort study. MoBa mothers provided written informed consent. The establishment of MoBa and initial data collection was based on a license from the Norwegian Data Protection Agency and approval from The Regional Committees for Medical and Health Research Ethics. MoBa is currently regulated by the Norwegian Health Registry Act. The study was approved by the Regional Committee for Ethics in Medical Research, Norway (no. 2017/1362). In addition, MoBa1 was approved by the Institutional Review Board of the National Institute of Environmental Health Sciences, USA. The consent given by the participants does not allow for storage of data on an individual level in repositories or journals.

INMA: INMA researchers would like to thank all the participants for their generous collaboration. A full roster of the INMA Project Investigators can be found at www.proyectoinma.org/proyecto-inma/investigadores/. Informed consent was obtained from all participants and the study was approved by the Hospital Ethics Committees in each participating region.

EDEN: We are indebted to the EDEN participating families and the midwife research assistants (L Douhaud, S Bedel, B Lortholary, S Gabriel, M Rogeon, M Malinbaum) for data collection. We thank the EDEN mother–child cohort study group (I Annesi-Maesano, JY Bernard, J Botton, MA Charles, P Dargent-Molina, B de Lauzon-Guillain, P Ducimetière, M de Agostini, B Foliguet, A Forhan, X Fritel, A Germa, V Goua, R Hankard, B Heude, M Kaminski, B Larroque, N Lelong, J Lepeule, G Magnin, L Marchand, C Nabet, F Pierre, R Slama, MJ Saurel-Cubizolles, M Schweitzer, O Thiebaugeorges). Ethics approval for data collection was granted by the ethics committee of Kremlin Bicêtre and the Commission Nationale Informatique et Liberté.

Financial disclosure

ALSPAC: The UK Medical Research Council (MRC) and Wellcome (grant no. 217065/Z/19/Z) and the University of Bristol provide core support for ALSPAC. This publication is the work of the authors and L Schellhas will serve as guarantor for the contents of this paper. A comprehensive list of grants funding is available on the ALSPAC website (www.bristol.ac.uk/alspac/external/documents/grant-acknowledgements.pdf). This research was performed in the UK Medical Research Council Integrative Epidemiology Unit (grant no. MC_UU_00011/7 and MC_UU_00011/5) and also supported by the National Institute for Health Research Bristol Biomedical Research Centre at University Hospitals Bristol National Health Service Foundation Trust and the University of Bristol. The views expressed in this publication are those of the authors and not necessarily those of the National Health Service, the National Institute for Health Research or the Department of Health and Social Care.

This research was also conducted as part of the Childhood and Adolescence Psychopathology: Unravelling the Complex Etiology by a Large Interdisciplinary Collaboration in Europe) project, funded by the EU's Horizon 2020 research and innovation program, Marie Sklodowska Curie Actions – MSCA-ITN-2016 – Innovative Training Networks under grant agreement no. 721567.

GC Sharp is financially supported by an MRC New Investigator Research (grant code MR/S009310/1), an MRC project grant (MR/W020297/1) and the European Joint Programming Initiative ‘A Healthy Diet for a Healthy Life’ (JPI HDHL, NutriPROGRAM project, UK MRC MR/S036520/1).

BiB: BiB receives core funding from the Wellcome Trust (WT101597MA), the British Heart Foundation (CS/16/4/32482), a joint grant from the UK MRC and UK Economic and Social Science Research Council (MR/N024397/1) and the National Institute for Health Research under its Collaboration for Applied Health Research and Care for Yorkshire and Humber. The research presented in this paper, including obtaining genome-wide and epigenome-wide DNA methylation data is supported by the US NIH (R01 DK10324) and European Research Council (ERC) under the EU's Seventh Framework Programme (FP7/2007-2013) ERC grant agreement no. 669545.

Generation R: The general design of the Generation R Study is made possible by financial support from the Erasmus MC, Erasmus University Rotterdam, The Netherlands Organization for Health Research and Development and the Ministry of Health, Welfare and Sport. The EWAS data were funded by a grant to VW Jaddoe from The Netherlands Genomics Initiative/Netherlands Organisation for Scientific Research Netherlands Consortium for Healthy Aging (project no. 050-060-810), by funds from the Genetic Laboratory of the Department of Internal Medicine, Erasmus MC and by a grant from the National Institute of Child and Human Development (R01HD068437). VW Jaddoe received a Consolidator Grant from the European Research Council (ERC-2014-CoG-648916). This project received funding from the EU's Horizon 2020 research and innovation program (733206, LifeCycle; 874739, LongITools; 874583, ATHLETE; 824989, EUCAN-Connect) and from the European JPI HDHL (NutriPROGRAM project, ZonMw The Netherlands no. 529051022 and PREcisE project ZonMw The Netherlands no. 529051023).

MoBa: The Norwegian Mother, Father and Child Cohort Study is supported by the Norwegian Ministry of Health and Care Services and the Ministry of Education and Research. MoBa 1 and 2 were supported by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences (Z01-ES-49019), NIH/National Institute of Environmental Health Sciences contract no. N01-ES-75558, the Norwegian Research Council/BIOBANK (grant no. 221097). This work was partly supported by the Research Council of Norway through its Centres of Excellence funding scheme, project no. 262700. Where authors are identified as personnel of the International Agency for Research on Cancer/WHO, the authors alone are responsible for the views expressed in this article and they do not necessarily represent the decisions, policy or views of the International Agency for Research on Cancer/WHO.

INMA: This study was funded by grants from Instituto de Salud Carlos III (Red INMA G03/176, CB06/02/0041, PI041436, PI081151 incl. FEDER funds), Generalitat de Catalunya-CIRIT 1999SGR 00241, Fundació La marató de TV3 (090430), EU Commission (261357-MeDALL: Mechanisms of the Development of Allergy), European Research Council (268479-BREATHE: Brain Development and Air Pollution Ultrafine Particles in School Children) and the European JPI HDHL (and Instituto de Salud Carlos III) under the grant agreement no. AC18/00006 (NutriPROGRAM project). We acknowledge support from the Spanish Ministry of Science and Innovation and the State Research Agency through the Centro de Excelencia Severo Ochoa 2019–2023 Program (CEX2018-000806-S), and support from the Generalitat de Catalunya through the Research Centres of Catalonia Program.

EDEN: Foundation for Medical Research (FRM), National Agency for Research (ANR), National Institute for Research in Public health (IRESP: TGIR cohorte santé 2008 program), French Ministry of Health (DGS), French Ministry of Research, INSERM Bone and Joint Diseases National Research (PRO-A) and Human Nutrition National Research Programs, Paris-Sud University, Nestlé, French National Institute for Population Health Surveillance (InVS), French National Institute for Health Education (INPES), the EU FP7 programs (FP7/2007-2013, HELIX, ESCAPE, ENRIECO, Medall projects), Diabetes National Research Program (in collaboration with the French Association of Diabetic Patients [AFD]), French Agency for Environmental Health Safety (now ANSES), Mutuelle Générale de l'Education Nationale complementary health insurance, French National Agency for Food Security, French Speaking Association for the Study of Diabetes and Metabolism (ALFEDIAM), Sao Paulo Research Foundation (FAPESP) grant no. 2012/51290-6, and EU-funded MeDALL project.

The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Competing interests disclosure

The authors have no competing interests or relevant affiliations with any organization or entity with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

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Ethical conduct of research

The authors state that they have obtained appropriate institutional review board approval or have followed the principles outlined in the Declaration of Helsinki for all human or animal experimental investigations.

In addition, for investigations involving human subjects, informed consent has been obtained from the participants involved.

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