Cesarean delivery and blood DNA methylation at birth and childhood: Meta-analysis in the Pregnancy and Childhood Epigenetics Consortium

Siwen Wang; Emma Casey; Joanne Sordillo; Sofía Aguilar-Lacasaña; Fernanda Morales Berstein; Richard J. Biedrzycki; Sonia Brescianini; Su Chen; Amy Hough; Elena Isaevska; Woo Jin Kim; Marion Lecorguillé; Sebastian Shaobo Li; Christian M. Page; Jaehyun Park; Stefan Röder; Kristina Salontaji; Gillian Santorelli; Yidan Sun; Sungho Won; Eric Zillich; Lea Zillich; Isabella Annesi-Maesano; S. Hasan Arshad; Mariona Bustamante; Charlotte A.M. Cecil; Hannah R. Elliott; Susan Ewart; Janine F. Felix; Luigi Gagliardi; Siri E. Håberg; Gunda Herberth; Barbara Heude; John W. Holloway; Anke Huels; Wilfried Karmaus; Gerard H. Koppelman; Stephanie J. London; Sunni L. Mumford; Lorenza Nisticò; Maja Popovic; Franca Rusconi; Enrique F. Schisterman; Dan J. Stein; Tabea Send; Henning Tiemeier; Judith M. Vonk; Martine Vrijheid; Joseph Leo Wiemels; Stephanie H. Witt; John Wright; Edwina H. Yeung; Heather J. Zar; Ana C. Zenclussen; Hongmei Zhang; Jorge E. Chavarro; Marie France Hivert

doi:10.1126/sciadv.adr2084

Cesarean delivery and blood DNA methylation at birth and childhood: Meta-analysis in the Pregnancy and Childhood Epigenetics Consortium

Siwen Wang
, Emma Casey
, Joanne Sordillo
, Sofía Aguilar-Lacasaña
, Fernanda Morales Berstein
, Richard J. Biedrzycki
, Sonia Brescianini
, Su Chen
, Amy Hough
, Elena Isaevska
, Woo Jin Kim
, Marion Lecorguillé
, Sebastian Shaobo Li
, Christian M. Page
, Jaehyun Park
, Stefan Röder
, Kristina Salontaji
, Gillian Santorelli
, Yidan Sun
, Sungho Won

Eric Zillich, Lea Zillich, Isabella Annesi-Maesano, S. Hasan Arshad, Mariona Bustamante, Charlotte A.M. Cecil, Hannah R. Elliott, Susan Ewart, Janine F. Felix, Luigi Gagliardi, Siri E. Håberg, Gunda Herberth, Barbara Heude, John W. Holloway, Anke Huels, Wilfried Karmaus, Gerard H. Koppelman, Stephanie J. London, Sunni L. Mumford, Lorenza Nisticò, Maja Popovic, Franca Rusconi, Enrique F. Schisterman, Dan J. Stein, Tabea Send, Henning Tiemeier, Judith M. Vonk, Martine Vrijheid, Joseph Leo Wiemels, Stephanie H. Witt, John Wright, Edwina H. Yeung, Heather J. Zar, Ana C. Zenclussen, Hongmei Zhang, Jorge E. Chavarro^*, Marie France Hivert

^*Corresponding author for this work

Harvard T.H. Chan School of Public Health
Emory University
Harvard Pilgrim Health Care Institute
Barcelona Institute for Global Health (ISGlobal)
Pompeu Fabra University
Spanish Consortium for Research on Epidemiology and Public Health (CIBERESP)
MRC Integrative Epidemiology Unit at the University of Bristol
University of Bristol
National Institutes of Health
Istituto Superiore di Sanita
University of Nebraska Medical Center
Bradford Institute for Health Research
University of Turin
Kangwon National University
Université Paris Cité
University of Southern California
Norwegian Institute of Public Health
Seoul National University
Helmholtz Centre for Environmental Research
University of Groningen
University Medical Centre Groningen
Heidelberg University
Université de Montpellier
CHU Montpellier
University of Southampton
Michigan State University
Azienda USL Toscana Nord Ovest
University of Bergen
University of Memphis
National Institute of Environmental Health Sciences (NIEHS)
UPenn School of Medicine
University of Cape Town
Massachusetts General Hospital

Research output: Contribution to journal › Article › Academic › peer-review

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Abstract

Children born via cesarean delivery have a higher risk of metabolic, immunological, and neurodevelopmental disorders compared to those born via vaginal delivery, although mechanisms remain unclear. We conducted a meta-analysis of epigenome-wide association studies to examine the associations between delivery mode and blood DNA methylation at birth and its persistence in early childhood. Participants were from 19 pregnancy cohorts (9833 term newborns) and 6 pediatric cohorts (2429 children aged 6 to 10 years). We identified six CpGs in cord blood associated with cesarean delivery (effect size range: 0.4 to 0.7%, P < 1.0 × 10^-7): MAP2K2 (cg19423175), LIM2 (cg01500140), CNP (cg13917614), BLM (cg18247172), RASA3 (cg22348356), and RUNX3 (cg20674490), independent of cell proportions and other confounders. In childhood, none of these CpGs were associated with cesarean delivery, and no additional CpGs were identified. Delivery mode was associated with cell proportions at birth but not in childhood. Further research is needed to elucidate cesarean delivery’s molecular influence on offspring health.

Original language	English
Article number	eadr2084
Journal	Science advances
Volume	10
Issue number	48
DOIs	https://doi.org/10.1126/sciadv.adr2084
Publication status	Published - 27 Nov 2024

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Publisher Copyright:
© 2024 the Authors, some rights reserved.

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Wang, S., Casey, E., Sordillo, J., Aguilar-Lacasaña, S., Berstein, F. M., Biedrzycki, R. J., Brescianini, S., Chen, S., Hough, A., Isaevska, E., Kim, W. J., Lecorguillé, M., Li, S. S., Page, C. M., Park, J., Röder, S., Salontaji, K., Santorelli, G., Sun, Y., ... Hivert, M. F. (2024). Cesarean delivery and blood DNA methylation at birth and childhood: Meta-analysis in the Pregnancy and Childhood Epigenetics Consortium. Science advances, 10(48), Article eadr2084. https://doi.org/10.1126/sciadv.adr2084

@article{75a7b8d91a914f47849c23b3fe08de17,

title = "Cesarean delivery and blood DNA methylation at birth and childhood: Meta-analysis in the Pregnancy and Childhood Epigenetics Consortium",

abstract = "Children born via cesarean delivery have a higher risk of metabolic, immunological, and neurodevelopmental disorders compared to those born via vaginal delivery, although mechanisms remain unclear. We conducted a meta-analysis of epigenome-wide association studies to examine the associations between delivery mode and blood DNA methylation at birth and its persistence in early childhood. Participants were from 19 pregnancy cohorts (9833 term newborns) and 6 pediatric cohorts (2429 children aged 6 to 10 years). We identified six CpGs in cord blood associated with cesarean delivery (effect size range: 0.4 to 0.7\%, P < 1.0 {\texttimes} 10-7): MAP2K2 (cg19423175), LIM2 (cg01500140), CNP (cg13917614), BLM (cg18247172), RASA3 (cg22348356), and RUNX3 (cg20674490), independent of cell proportions and other confounders. In childhood, none of these CpGs were associated with cesarean delivery, and no additional CpGs were identified. Delivery mode was associated with cell proportions at birth but not in childhood. Further research is needed to elucidate cesarean delivery{\textquoteright}s molecular influence on offspring health.",

author = "Siwen Wang and Emma Casey and Joanne Sordillo and Sof{\'i}a Aguilar-Lacasa{\~n}a and Berstein, \{Fernanda Morales\} and Biedrzycki, \{Richard J.\} and Sonia Brescianini and Su Chen and Amy Hough and Elena Isaevska and Kim, \{Woo Jin\} and Marion Lecorguill{\'e} and Li, \{Sebastian Shaobo\} and Page, \{Christian M.\} and Jaehyun Park and Stefan R{\"o}der and Kristina Salontaji and Gillian Santorelli and Yidan Sun and Sungho Won and Eric Zillich and Lea Zillich and Isabella Annesi-Maesano and Arshad, \{S. Hasan\} and Mariona Bustamante and Cecil, \{Charlotte A.M.\} and Elliott, \{Hannah R.\} and Susan Ewart and Felix, \{Janine F.\} and Luigi Gagliardi and H{\aa}berg, \{Siri E.\} and Gunda Herberth and Barbara Heude and Holloway, \{John W.\} and Anke Huels and Wilfried Karmaus and Koppelman, \{Gerard H.\} and London, \{Stephanie J.\} and Mumford, \{Sunni L.\} and Lorenza Nistic{\`o} and Maja Popovic and Franca Rusconi and Schisterman, \{Enrique F.\} and Stein, \{Dan J.\} and Tabea Send and Henning Tiemeier and Vonk, \{Judith M.\} and Martine Vrijheid and Wiemels, \{Joseph Leo\} and Witt, \{Stephanie H.\} and John Wright and Yeung, \{Edwina H.\} and Zar, \{Heather J.\} and Zenclussen, \{Ana C.\} and Hongmei Zhang and Chavarro, \{Jorge E.\} and Hivert, \{Marie France\}",

note = "Publisher Copyright: {\textcopyright} 2024 the Authors, some rights reserved.",

year = "2024",

month = nov,

day = "27",

doi = "10.1126/sciadv.adr2084",

language = "English",

volume = "10",

journal = "Science advances",

issn = "2375-2548",

publisher = "American Association for the Advancement of Science",

number = "48",

}

Wang, S, Casey, E, Sordillo, J, Aguilar-Lacasaña, S, Berstein, FM, Biedrzycki, RJ, Brescianini, S, Chen, S, Hough, A, Isaevska, E, Kim, WJ, Lecorguillé, M, Li, SS, Page, CM, Park, J, Röder, S, Salontaji, K, Santorelli, G, Sun, Y, Won, S, Zillich, E, Zillich, L, Annesi-Maesano, I, Arshad, SH, Bustamante, M, Cecil, CAM, Elliott, HR, Ewart, S, Felix, JF, Gagliardi, L, Håberg, SE, Herberth, G, Heude, B, Holloway, JW, Huels, A, Karmaus, W, Koppelman, GH, London, SJ, Mumford, SL, Nisticò, L, Popovic, M, Rusconi, F, Schisterman, EF, Stein, DJ, Send, T, Tiemeier, H, Vonk, JM, Vrijheid, M, Wiemels, JL, Witt, SH, Wright, J, Yeung, EH, Zar, HJ, Zenclussen, AC, Zhang, H, Chavarro, JE & Hivert, MF 2024, 'Cesarean delivery and blood DNA methylation at birth and childhood: Meta-analysis in the Pregnancy and Childhood Epigenetics Consortium', Science advances, vol. 10, no. 48, eadr2084. https://doi.org/10.1126/sciadv.adr2084

TY - JOUR

T1 - Cesarean delivery and blood DNA methylation at birth and childhood

T2 - Meta-analysis in the Pregnancy and Childhood Epigenetics Consortium

AU - Wang, Siwen

AU - Casey, Emma

AU - Sordillo, Joanne

AU - Aguilar-Lacasaña, Sofía

AU - Berstein, Fernanda Morales

AU - Biedrzycki, Richard J.

AU - Brescianini, Sonia

AU - Chen, Su

AU - Hough, Amy

AU - Isaevska, Elena

AU - Kim, Woo Jin

AU - Lecorguillé, Marion

AU - Li, Sebastian Shaobo

AU - Page, Christian M.

AU - Park, Jaehyun

AU - Röder, Stefan

AU - Salontaji, Kristina

AU - Santorelli, Gillian

AU - Sun, Yidan

AU - Won, Sungho

AU - Zillich, Eric

AU - Zillich, Lea

AU - Annesi-Maesano, Isabella

AU - Arshad, S. Hasan

AU - Bustamante, Mariona

AU - Cecil, Charlotte A.M.

AU - Elliott, Hannah R.

AU - Ewart, Susan

AU - Felix, Janine F.

AU - Gagliardi, Luigi

AU - Håberg, Siri E.

AU - Herberth, Gunda

AU - Heude, Barbara

AU - Holloway, John W.

AU - Huels, Anke

AU - Karmaus, Wilfried

AU - Koppelman, Gerard H.

AU - London, Stephanie J.

AU - Mumford, Sunni L.

AU - Nisticò, Lorenza

AU - Popovic, Maja

AU - Rusconi, Franca

AU - Schisterman, Enrique F.

AU - Stein, Dan J.

AU - Send, Tabea

AU - Tiemeier, Henning

AU - Vonk, Judith M.

AU - Vrijheid, Martine

AU - Wiemels, Joseph Leo

AU - Witt, Stephanie H.

AU - Wright, John

AU - Yeung, Edwina H.

AU - Zar, Heather J.

AU - Zenclussen, Ana C.

AU - Zhang, Hongmei

AU - Chavarro, Jorge E.

AU - Hivert, Marie France

PY - 2024/11/27

Y1 - 2024/11/27

N2 - Children born via cesarean delivery have a higher risk of metabolic, immunological, and neurodevelopmental disorders compared to those born via vaginal delivery, although mechanisms remain unclear. We conducted a meta-analysis of epigenome-wide association studies to examine the associations between delivery mode and blood DNA methylation at birth and its persistence in early childhood. Participants were from 19 pregnancy cohorts (9833 term newborns) and 6 pediatric cohorts (2429 children aged 6 to 10 years). We identified six CpGs in cord blood associated with cesarean delivery (effect size range: 0.4 to 0.7%, P < 1.0 × 10-7): MAP2K2 (cg19423175), LIM2 (cg01500140), CNP (cg13917614), BLM (cg18247172), RASA3 (cg22348356), and RUNX3 (cg20674490), independent of cell proportions and other confounders. In childhood, none of these CpGs were associated with cesarean delivery, and no additional CpGs were identified. Delivery mode was associated with cell proportions at birth but not in childhood. Further research is needed to elucidate cesarean delivery’s molecular influence on offspring health.

AB - Children born via cesarean delivery have a higher risk of metabolic, immunological, and neurodevelopmental disorders compared to those born via vaginal delivery, although mechanisms remain unclear. We conducted a meta-analysis of epigenome-wide association studies to examine the associations between delivery mode and blood DNA methylation at birth and its persistence in early childhood. Participants were from 19 pregnancy cohorts (9833 term newborns) and 6 pediatric cohorts (2429 children aged 6 to 10 years). We identified six CpGs in cord blood associated with cesarean delivery (effect size range: 0.4 to 0.7%, P < 1.0 × 10-7): MAP2K2 (cg19423175), LIM2 (cg01500140), CNP (cg13917614), BLM (cg18247172), RASA3 (cg22348356), and RUNX3 (cg20674490), independent of cell proportions and other confounders. In childhood, none of these CpGs were associated with cesarean delivery, and no additional CpGs were identified. Delivery mode was associated with cell proportions at birth but not in childhood. Further research is needed to elucidate cesarean delivery’s molecular influence on offspring health.

UR - https://www.scopus.com/pages/publications/85210992195

U2 - 10.1126/sciadv.adr2084

DO - 10.1126/sciadv.adr2084

M3 - Article

C2 - 39602535

AN - SCOPUS:85210992195

SN - 2375-2548

VL - 10

JO - Science advances

JF - Science advances

IS - 48

M1 - eadr2084

ER -

Cesarean delivery and blood DNA methylation at birth and childhood: Meta-analysis in the Pregnancy and Childhood Epigenetics Consortium

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