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Review
. 2023 Nov;15(22):1179-1193.
doi: 10.2217/epi-2023-0263. Epub 2023 Nov 29.

Maternal caffeine consumption during pregnancy and offspring cord blood DNA methylation: an epigenome-wide association study meta-analysis

Laura Schellhas  1   2   3 , Giulietta S Monasso  4   5 , Janine F Felix  4   5 , Vincent Wv Jaddoe  4   5 , Peiyuan Huang  2 , Sílvia Fernández-Barrés  6   7 , Martine Vrijheid  6   8   9 , Giancarlo Pesce  10 , Isabella Annesi-Maesano  11   12 , Christian M Page  13 , Anne-Lise Brantsæter  14 , Mona Bekkhus  15 , Siri E Håberg  16 , Stephanie J London  17 , Marcus R Munafò  1   2   18 , Luisa Zuccolo  2   19   20 , Gemma C Sharp  2   19   21
Affiliations
Review

Maternal caffeine consumption during pregnancy and offspring cord blood DNA methylation: an epigenome-wide association study meta-analysis

Laura Schellhas et al. Epigenomics. 2023 Nov.

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.

Keywords: DNA methylation; PACE consortium; caffeine; epigenetics; offspring health; pregnancy.

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.

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Conflict of interest statement

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.

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.

Figures

Figure 1.
Figure 1.. Effect size estimates at the top CpG sites found in the probe-level analysis.
Total caff model = total caffeine; Coffee model = caffeine from coffee; Tea model = caffeine from tea; Cola model = caffeine from cola. Error bars represent 95% CIs.
See this image and copyright information in PMC

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