Meta-Analysis

. 2024 Nov 29;10(48):eadr2084.

doi: 10.1126/sciadv.adr2084. Epub 2024 Nov 27.

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

Siwen Wang¹, Emma Casey², Joanne Sordillo³, Sofía Aguilar-Lacasaña^{4

5

6}, Fernanda Morales Berstein^{7

8}, Richard J Biedrzycki⁹, Sonia Brescianini¹⁰, Su Chen¹¹, Amy Hough¹², Elena Isaevska¹³, Woo Jin Kim¹⁴, Marion Lecorguillé¹⁵, Sebastian Shaobo Li¹⁶, Christian M Page^{17

18}, Jaehyun Park¹⁹, Stefan Röder²⁰, Kristina Salontaji²¹, Gillian Santorelli¹², Yidan Sun^{22

23}, Sungho Won^{19

24}, Eric Zillich²⁵, Lea Zillich²⁵, Isabella Annesi-Maesano^{26

27}, S Hasan Arshad²⁸, Mariona Bustamante^{4

5

6}, Charlotte A M Cecil^{21

29}, Hannah R Elliott^{7

8}, Susan Ewart³⁰, Janine F Felix^{31

32}, Luigi Gagliardi³³, Siri E Håberg^{17

34}, Gunda Herberth²⁰, Barbara Heude¹⁵, John W Holloway³⁵, Anke Huels^{2

36}, Wilfried Karmaus³⁷, Gerard H Koppelman^{22

23}, Stephanie J London³⁸, Sunni L Mumford^{39

40}, Lorenza Nisticò¹⁰, Maja Popovic¹³, Franca Rusconi³³, Enrique F Schisterman^{39

40}, Dan J Stein⁴¹, Tabea Send⁴², Henning Tiemeier^{43

44}, Judith M Vonk^{23

45}, Martine Vrijheid^{4

5

6}, Joseph Leo Wiemels¹⁶, Stephanie H Witt²⁵, John Wright¹², Edwina H Yeung⁴⁰, Heather J Zar⁴⁶, Ana C Zenclussen²⁰, Hongmei Zhang³⁷, Jorge E Chavarro^{1

44}, Marie-France Hivert^{3

47}

Affiliations

¹ Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA 02215, USA.
² Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, GA 30322, USA.
³ Division of Chronic Disease Research Across the Lifecourse (CoRAL), Department of Population Medicine, Harvard Medical School, Harvard Pilgrim Health Care Institute, Boston, MA 02215, USA.
⁴ ISGlobal, Centre for Research in Environmental Epidemiology (CREAL), Barcelona 08003, Spain.
⁵ Universitat Pompeu Fabra (UPF), Barcelona 08005, Spain.
⁶ CIBER Epidemiología y Salud Pública, Madrid 28029, Spain.
⁷ MRC Integrative Epidemiology Unit at the University of Bristol, Bristol BS8 2BN, UK.
⁸ Population Health Sciences, Bristol Medical School, University of Bristol, Bristol BS8 1UD, UK.
⁹ Glotech Inc., contractor for Division of Population Health Research, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Rockville, MD 20850, USA.
¹⁰ Center for Behavioral Sciences and Mental Health, Istituto Superiore di Sanità, Rome 00161 Italy.
¹¹ Department of Biostatistics, College of Public Health, University of Nebraska Medical Center, Omaha, NE 68105, USA.
¹² Bradford Institute for Health Research, Bradford BD9 6RJ, UK.
¹³ Cancer Epidemiology Unit, Department of Medical Sciences, University of Turin, Turin 10126, Italy.
¹⁴ Department of Internal Medicine, Kangwon National University, Chuncheon 24289, Korea.
¹⁵ Université Paris Cité and Université Sorbonne Paris Nord, Inserm, INRAE, Center for Research in Epidemiology and StatisticS (CRESS), F-75004 Paris, France.
¹⁶ Center for Genetic Epidemiology, Department of Population and Public Health Sciences, University of Southern California, Los Angeles, CA 90033, USA.
¹⁷ Centre for Fertility and Health, Norwegian Institute of Public Health, P.O. box 222 Skøyen, 0213 Oslo, Norway.
¹⁸ Department of Physical Health and Aging, Division for Mental and Physical Health, Norwegian Institute of Public Health, P.O. box 222 Skøyen, 0213 Oslo, Norway.
¹⁹ Interdisciplinary Program of Bioinformatics, College of Natural Sciences, Seoul National University, Seoul 08826, Korea.
²⁰ Department of Environmental Immunology, Helmholtz Centre for Environmental Research - UFZ, Leipzig 04318, Germany.
²¹ Department of Child and Adolescent Psychiatry / Psychology, Erasmus MC, University Medical Center Rotterdam, Rotterdam 3015 GD, Netherlands.
²² University of Groningen, University Medical Center Groningen, Beatrix Children's Hospital, Department of Pediatric Pulmonology and Pediatric Allergology, Groningen 9700 RB, Netherlands.
²³ Groningen Research Institute for Asthma and COPD, Groningen 9700 RB, Netherlands.
²⁴ Department of Public Health Sciences, Seoul National University, Seoul 08826, South Korea.
²⁵ Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim 68159, Germany.
²⁶ Desbrest Institute of Epidemiology and Public Health, Univ Montpellier, INSERM, Montpellier, France.
²⁷ Division of Respiratory Medicine, Allergology, and of Thoracic Oncology, University Hospital of Montpellier, 34093 Montpellier, France.
²⁸ Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton SO16 6YD, UK.
²⁹ Department of Epidemiology, Erasmus MC, University Medical Center Rotterdam, Rotterdam 3015 GD, Netherlands.
³⁰ College of Veterinary Medicine, Michigan State University, East Lansing, MI 48824, USA.
³¹ The Generation R Study Group, Erasmus MC, University Medical Center Rotterdam, Rotterdam 3015 GD, Netherlands.
³² Department of Pediatrics, Erasmus MC, University Medical Center Rotterdam, Rotterdam 3015 GD, Netherlands.
³³ Department of Mother and Child Health, Azienda USL Toscana Nord Ovest, Pisa 56121, Italy.
³⁴ Department of Global Public Health and Primary Care, University of Bergen, Kalfarveien 31, N-5018 Bergen, Norway.
³⁵ Human Development and Health, Faculty of Medicine, University of Southampton, Southampton SO16 6YD, UK.
³⁶ Gangarosa Department of Environmental Health, Rollins School of Public Health, Emory University, Atlanta, GA 30322, USA.
³⁷ Division of Epidemiology, Biostatistics, and Environmental Health, School of Public Health, University of Memphis, Memphis, TN 38152, USA.
³⁸ National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA.
³⁹ Department of Biostatistics, Epidemiology and Informatics and Department of Obstetrics and Gynecology, Perelman School of Medicine, Philadelphia, PA 19087, USA.
⁴⁰ Epidemiology Branch, Division of Population Health Research, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, MD 20817 USA.
⁴¹ South African Medical Research Council (SAMRC) Unit on Risk and Resilience in Mental Disorders, Department of Psychiatry and Neuroscience Institute, University of Cape Town, Rondebosch 7700, South Africa.
⁴² Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim 68159, Germany.
⁴³ Department of Social and Behavioral Sciences, Harvard T.H. Chan School of Public Health, Boston, MA 02215, USA.
⁴⁴ Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA 02215, USA.
⁴⁵ University of Groningen, University Medical Center Groningen, Department of Epidemiology, Groningen 9700 RB, Netherlands.
⁴⁶ South African Medical Research Council (SAMRC) Unit on Child and Adolescent Health, Department of Paediatrics, University of Cape Town, Rondebosch 7700, South Africa.
⁴⁷ Diabetes Unit, Massachusetts General Hospital, Boston, MA 02114, USA.

PMID: 39602535
PMCID: PMC11601205
DOI: 10.1126/sciadv.adr2084

Meta-Analysis

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

Siwen Wang et al. Sci Adv. 2024.

. 2024 Nov 29;10(48):eadr2084.

doi: 10.1126/sciadv.adr2084. Epub 2024 Nov 27.

Authors

Affiliations

¹ Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA 02215, USA.
² Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, GA 30322, USA.
³ Division of Chronic Disease Research Across the Lifecourse (CoRAL), Department of Population Medicine, Harvard Medical School, Harvard Pilgrim Health Care Institute, Boston, MA 02215, USA.
⁴ ISGlobal, Centre for Research in Environmental Epidemiology (CREAL), Barcelona 08003, Spain.
⁵ Universitat Pompeu Fabra (UPF), Barcelona 08005, Spain.
⁶ CIBER Epidemiología y Salud Pública, Madrid 28029, Spain.
⁷ MRC Integrative Epidemiology Unit at the University of Bristol, Bristol BS8 2BN, UK.
⁸ Population Health Sciences, Bristol Medical School, University of Bristol, Bristol BS8 1UD, UK.
⁹ Glotech Inc., contractor for Division of Population Health Research, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Rockville, MD 20850, USA.
¹⁰ Center for Behavioral Sciences and Mental Health, Istituto Superiore di Sanità, Rome 00161 Italy.
¹¹ Department of Biostatistics, College of Public Health, University of Nebraska Medical Center, Omaha, NE 68105, USA.
¹² Bradford Institute for Health Research, Bradford BD9 6RJ, UK.
¹³ Cancer Epidemiology Unit, Department of Medical Sciences, University of Turin, Turin 10126, Italy.
¹⁴ Department of Internal Medicine, Kangwon National University, Chuncheon 24289, Korea.
¹⁵ Université Paris Cité and Université Sorbonne Paris Nord, Inserm, INRAE, Center for Research in Epidemiology and StatisticS (CRESS), F-75004 Paris, France.
¹⁶ Center for Genetic Epidemiology, Department of Population and Public Health Sciences, University of Southern California, Los Angeles, CA 90033, USA.
¹⁷ Centre for Fertility and Health, Norwegian Institute of Public Health, P.O. box 222 Skøyen, 0213 Oslo, Norway.
¹⁸ Department of Physical Health and Aging, Division for Mental and Physical Health, Norwegian Institute of Public Health, P.O. box 222 Skøyen, 0213 Oslo, Norway.
¹⁹ Interdisciplinary Program of Bioinformatics, College of Natural Sciences, Seoul National University, Seoul 08826, Korea.
²⁰ Department of Environmental Immunology, Helmholtz Centre for Environmental Research - UFZ, Leipzig 04318, Germany.
²¹ Department of Child and Adolescent Psychiatry / Psychology, Erasmus MC, University Medical Center Rotterdam, Rotterdam 3015 GD, Netherlands.
²² University of Groningen, University Medical Center Groningen, Beatrix Children's Hospital, Department of Pediatric Pulmonology and Pediatric Allergology, Groningen 9700 RB, Netherlands.
²³ Groningen Research Institute for Asthma and COPD, Groningen 9700 RB, Netherlands.
²⁴ Department of Public Health Sciences, Seoul National University, Seoul 08826, South Korea.
²⁵ Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim 68159, Germany.
²⁶ Desbrest Institute of Epidemiology and Public Health, Univ Montpellier, INSERM, Montpellier, France.
²⁷ Division of Respiratory Medicine, Allergology, and of Thoracic Oncology, University Hospital of Montpellier, 34093 Montpellier, France.
²⁸ Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton SO16 6YD, UK.
²⁹ Department of Epidemiology, Erasmus MC, University Medical Center Rotterdam, Rotterdam 3015 GD, Netherlands.
³⁰ College of Veterinary Medicine, Michigan State University, East Lansing, MI 48824, USA.
³¹ The Generation R Study Group, Erasmus MC, University Medical Center Rotterdam, Rotterdam 3015 GD, Netherlands.
³² Department of Pediatrics, Erasmus MC, University Medical Center Rotterdam, Rotterdam 3015 GD, Netherlands.
³³ Department of Mother and Child Health, Azienda USL Toscana Nord Ovest, Pisa 56121, Italy.
³⁴ Department of Global Public Health and Primary Care, University of Bergen, Kalfarveien 31, N-5018 Bergen, Norway.
³⁵ Human Development and Health, Faculty of Medicine, University of Southampton, Southampton SO16 6YD, UK.
³⁶ Gangarosa Department of Environmental Health, Rollins School of Public Health, Emory University, Atlanta, GA 30322, USA.
³⁷ Division of Epidemiology, Biostatistics, and Environmental Health, School of Public Health, University of Memphis, Memphis, TN 38152, USA.
³⁸ National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA.
³⁹ Department of Biostatistics, Epidemiology and Informatics and Department of Obstetrics and Gynecology, Perelman School of Medicine, Philadelphia, PA 19087, USA.
⁴⁰ Epidemiology Branch, Division of Population Health Research, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, MD 20817 USA.
⁴¹ South African Medical Research Council (SAMRC) Unit on Risk and Resilience in Mental Disorders, Department of Psychiatry and Neuroscience Institute, University of Cape Town, Rondebosch 7700, South Africa.
⁴² Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim 68159, Germany.
⁴³ Department of Social and Behavioral Sciences, Harvard T.H. Chan School of Public Health, Boston, MA 02215, USA.
⁴⁴ Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA 02215, USA.
⁴⁵ University of Groningen, University Medical Center Groningen, Department of Epidemiology, Groningen 9700 RB, Netherlands.
⁴⁶ South African Medical Research Council (SAMRC) Unit on Child and Adolescent Health, Department of Paediatrics, University of Cape Town, Rondebosch 7700, South Africa.
⁴⁷ Diabetes Unit, Massachusetts General Hospital, Boston, MA 02114, USA.

PMID: 39602535
PMCID: PMC11601205
DOI: 10.1126/sciadv.adr2084

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.

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Figures

**Fig. 1.. Fixed-effects meta-analysis of associations between cesarean delivery and DNAm in cord blood collected at birth.**
n = 9833 individuals, 19 cohorts. Model 2, adjusted for maternal smoking, socioeconomic status, parity, prepregnancy BMI, offspring sex, birth weight, gestational age, batch, and cell-type proportions. Individual cohorts may additionally have adjusted for ancestry and selection factors if applicable. (A) QQ plots for fixed-effects meta-analysis. (B) Manhattan plots for fixed-effects meta-analysis. Epigenome-wide significance was considered as P < 1 × 10⁻⁷ (dotted line).

**Fig. 2.. Fixed-effects meta-analysis of associations between cesarean delivery and DNAm in blood collected in childhood.**
n = 2429 individuals, six cohorts. Model 2, adjusted for maternal smoking, socioeconomic status, parity, prepregnancy BMI, offspring sex, birth weight, age at blood draw, batch, and cell-type proportions. Individual cohorts may additionally have adjusted for ancestry and selection factors if applicable. (A) QQ plots for fixed effects meta-analysis. (B) Manhattan plots for fixed-effects meta-analysis. Epigenome-wide significance was considered as P < 1 × 10⁻⁷ (dotted line).

**Fig. 3.. Fixed-effects meta-analysis of associations between cesarean delivery and cell-type proportions in cord blood collected at birth.**
n = 7616 individuals, 13 cohorts. FE model, fixed-effects model; nRBC, nucleated red blood cells. Models adjusted for maternal smoking, socioeconomic status, parity, prepregnancy BMI, offspring sex, birth weight, gestational age, and batch. Individual cohorts may additionally have adjusted for ancestry and selection factors if applicable. (A) CD4 T cells. (B) CD8 T cells. (C) Granulocytes. (D) NK cells. (E) Monocytes. (F) B cells. (G) nucleated red blood cells. Note: ALSPAC was excluded from the CD8 T cells analysis because of low estimated proportions. ALSPAC was excluded from the nucleated red blood cells analysis because these data were not available. Moba4 was excluded from the monocytes analysis because these data were not available.

**Fig. 4.. Fixed-effects meta-analysis of associations between cesarean delivery and cell-type proportions in blood collected in childhood.**
n = 1897 individuals, four cohorts. FE model, fixed effect model. Models adjusted for maternal smoking, socioeconomic status, parity, prepregnancy BMI, offspring sex, birth weight, age at blood draw, and batch. Individual cohorts may additionally have adjusted for ancestry and selection factors if applicable. (A) NK cells. (B) CD8 T cells. (C) CD4 T cells. (D) Monocytes. (E) Granulocytes. (F) B cells. Note: Project Viva was excluded from the CD8 T cells analysis because these data were not available.

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References

1. World Health Organization (2021); www.who.int/news/item/16-06-2021-caesarean-section-rates-continue-to-ris....
1. Sandall J., Tribe R. M., Avery L., Mola G., Visser G. H., Homer C. S., Gibbons D., Kelly N. M., Kennedy H. P., Kidanto H., Taylor P., Temmerman M., Short-term and long-term effects of caesarean section on the health of women and children. Lancet 392, 1349–1357 (2018). - PubMed
1. Chavarro J. E., Martin-Calvo N., Yuan C., Arvizu M., Rich-Edwards J. W., Michels K. B., Sun Q., Association of birth by cesarean delivery with obesity and type 2 diabetes among adult women. JAMA Netw. Open 3, e202605 (2020). - PMC - PubMed
1. Yuan C., Gaskins A. J., Blaine A. I., Zhang C., Gillman M. W., Missmer S. A., Field A. E., Chavarro J. E., Association between cesarean birth and risk of obesity in offspring in childhood, adolescence, and early adulthood. JAMA Pediatr. 170, e162385 (2016). - PMC - PubMed
1. Cho C. E., Norman M., Cesarean section and development of the immune system in the offspring. Am. J. Obstet. Gynecol. 208, 249–254 (2013). - PubMed

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

Affiliations

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

Authors

Affiliations

Abstract

Figures

References

Publication types

MeSH terms

Grants and funding

LinkOut - more resources

Full Text Sources

Medical

Miscellaneous