Associations between prenatal maternal stress, maternal inflammation during pregnancy, and children's internalizing and externalizing symptoms throughout childhood

Zahra M Clayborne; Runyu Zou; Stephen E Gilman; Golam M Khandaker; Deshayne B Fell; Ian Colman; Hanan El Marroun

doi:10.1016/j.bbi.2023.08.017

Associations between prenatal maternal stress, maternal inflammation during pregnancy, and children's internalizing and externalizing symptoms throughout childhood

Zahra M Clayborne^*, Runyu Zou, Stephen E Gilman, Golam M Khandaker, Deshayne B Fell, Ian Colman, Hanan El Marroun

^*Corresponding author for this work

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

Abstract

BACKGROUND: Maternal immune activation is a potential mechanism underlying associations between maternal stress during pregnancy and offspring mental health problems. This study examined associations between prenatal maternal stress, maternal inflammation during pregnancy, and children's internalizing and externalizing symptoms from 3 to 10 years of age, and whether maternal inflammation mediated the associations between prenatal maternal stress and children's internalizing and externalizing symptoms.

METHODS: This study comprised 4,902 mother-child dyads in the Generation R study. Prenatal maternal stress was assessed using self-reported data collected during pregnancy and analyzed as a latent variable consisting of four stress domains. Maternal inflammation during pregnancy was assessed using serum concentrations of C-reactive protein (CRP) measured at a median of 13.5 weeks' gestation. Child internalizing and externalizing symptoms were assessed using the Child Behavior Checklist (CBCL) by maternal report at ages 3 years, 5 years, and 10 years; paternal-reported CBCL data were also available at 3 years and 10 years.

RESULTS: Prenatal maternal stress was associated with maternal-reported internalizing and externalizing symptoms of the child at 3, 5, and 10 years of age, and with paternal-reported internalizing and externalizing symptoms at 3 and 10 years. Prenatal maternal stress was associated with maternal CRP concentrations prior to, but not after, covariate adjustment. Maternal CRP concentrations during pregnancy were associated with paternal-reported internalizing symptoms of offspring at 10 years of age prior to, but not after, covariate adjustment. There was no evidence that CRP concentrations mediated the associations between prenatal maternal stress and children's internalizing or externalizing symptoms.

CONCLUSIONS: Maternal stress during pregnancy is associated with higher levels of internalizing and externalizing symptoms in children, but this association is not because of differences in maternal immune activation linked to maternal stress. Replication of these findings in other cohorts is required; examination of other biomarkers or variation in immune activity during pregnancy would also benefit from further exploration.

Original language	English
Pages (from-to)	165-172
Number of pages	8
Journal	Brain, Behavior, and Immunity
Volume	114
Early online date	20 Aug 2023
DOIs	https://doi.org/10.1016/j.bbi.2023.08.017
Publication status	Published - Nov 2023
Externally published	Yes

Bibliographical note

Funding Information:
This study was supported by Stichting Volksbond Rotterdam, the NARSAD Young Investigator Grant 27853 from the Brain & Behavior Research Foundation, the Aspasia grant No. 015.016.056 of the Netherlands Organization for Health Research and Development, grant agreement 733206 (LifeCycle) from the European Union's Horizon 2020 Research and Innovation Program (LifeCycle, Grant Agreement 733 206 & HappyMums 101057390). (Prof. Dr. El Marroun); grant 201606100056 from the China Scholarship Council (Dr. Zou); the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, project ZIAHD008976 (Dr. Gilman); the Wellcome Trust, grant 201486/Z/16/Z, the Medical Research Council, UK, grants MC_PC_17213, MR/S037675/1, MC_UU_00032/06, and MR/W014416/1 (Dr. Khandaker); and the Canada Research Chairs program (Dr. Colman). The general design of the Generation R Study is made possible by financial support from the Erasmus Medical Center, Rotterdam, the Erasmus University Rotterdam, the Netherlands Organization for Health Research and Development, the Netherlands Organization for Scientific Research, the Ministry of Health, Welfare, and Sport, and the Ministry of Youth and Families. The funding sources had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Funding Information:
The Generation R Study is conducted by the Erasmus Medical Center in close collaboration with the Municipal Health Service Rotterdam area, the Rotterdam Homecare Foundation, and the Stichting Trombosedienst & Artsenlaboratorium Rijnmond, Rotterdam, the Netherlands. We acknowledge the contribution of general practitioners, hospitals, midwives, and pharmacies in Rotterdam.

Publisher Copyright:
© 2023 Elsevier Inc.

Keywords

Cohort study
Externalizing symptoms
Inflammation
Internalizing symptoms
Prenatal stress

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1016/j.bbi.2023.08.017

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title = "Associations between prenatal maternal stress, maternal inflammation during pregnancy, and children's internalizing and externalizing symptoms throughout childhood",

abstract = "BACKGROUND: Maternal immune activation is a potential mechanism underlying associations between maternal stress during pregnancy and offspring mental health problems. This study examined associations between prenatal maternal stress, maternal inflammation during pregnancy, and children's internalizing and externalizing symptoms from 3 to 10 years of age, and whether maternal inflammation mediated the associations between prenatal maternal stress and children's internalizing and externalizing symptoms.METHODS: This study comprised 4,902 mother-child dyads in the Generation R study. Prenatal maternal stress was assessed using self-reported data collected during pregnancy and analyzed as a latent variable consisting of four stress domains. Maternal inflammation during pregnancy was assessed using serum concentrations of C-reactive protein (CRP) measured at a median of 13.5 weeks' gestation. Child internalizing and externalizing symptoms were assessed using the Child Behavior Checklist (CBCL) by maternal report at ages 3 years, 5 years, and 10 years; paternal-reported CBCL data were also available at 3 years and 10 years.RESULTS: Prenatal maternal stress was associated with maternal-reported internalizing and externalizing symptoms of the child at 3, 5, and 10 years of age, and with paternal-reported internalizing and externalizing symptoms at 3 and 10 years. Prenatal maternal stress was associated with maternal CRP concentrations prior to, but not after, covariate adjustment. Maternal CRP concentrations during pregnancy were associated with paternal-reported internalizing symptoms of offspring at 10 years of age prior to, but not after, covariate adjustment. There was no evidence that CRP concentrations mediated the associations between prenatal maternal stress and children's internalizing or externalizing symptoms.CONCLUSIONS: Maternal stress during pregnancy is associated with higher levels of internalizing and externalizing symptoms in children, but this association is not because of differences in maternal immune activation linked to maternal stress. Replication of these findings in other cohorts is required; examination of other biomarkers or variation in immune activity during pregnancy would also benefit from further exploration.",

keywords = "Cohort study, Externalizing symptoms, Inflammation, Internalizing symptoms, Prenatal stress",

author = "Clayborne, {Zahra M} and Runyu Zou and Gilman, {Stephen E} and Khandaker, {Golam M} and Fell, {Deshayne B} and Ian Colman and {El Marroun}, Hanan",

note = "Funding Information: This study was supported by Stichting Volksbond Rotterdam, the NARSAD Young Investigator Grant 27853 from the Brain & Behavior Research Foundation, the Aspasia grant No. 015.016.056 of the Netherlands Organization for Health Research and Development, grant agreement 733206 (LifeCycle) from the European Union's Horizon 2020 Research and Innovation Program (LifeCycle, Grant Agreement 733 206 & HappyMums 101057390). (Prof. Dr. El Marroun); grant 201606100056 from the China Scholarship Council (Dr. Zou); the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, project ZIAHD008976 (Dr. Gilman); the Wellcome Trust, grant 201486/Z/16/Z, the Medical Research Council, UK, grants MC_PC_17213, MR/S037675/1, MC_UU_00032/06, and MR/W014416/1 (Dr. Khandaker); and the Canada Research Chairs program (Dr. Colman). The general design of the Generation R Study is made possible by financial support from the Erasmus Medical Center, Rotterdam, the Erasmus University Rotterdam, the Netherlands Organization for Health Research and Development, the Netherlands Organization for Scientific Research, the Ministry of Health, Welfare, and Sport, and the Ministry of Youth and Families. The funding sources had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. Funding Information: The Generation R Study is conducted by the Erasmus Medical Center in close collaboration with the Municipal Health Service Rotterdam area, the Rotterdam Homecare Foundation, and the Stichting Trombosedienst & Artsenlaboratorium Rijnmond, Rotterdam, the Netherlands. We acknowledge the contribution of general practitioners, hospitals, midwives, and pharmacies in Rotterdam. Publisher Copyright: {\textcopyright} 2023 Elsevier Inc.",

year = "2023",

month = nov,

doi = "10.1016/j.bbi.2023.08.017",

language = "English",

volume = "114",

pages = "165--172",

journal = "Brain, Behavior, and Immunity",

issn = "0889-1591",

publisher = "Academic Press Inc.",

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Associations between prenatal maternal stress, maternal inflammation during pregnancy, and children's internalizing and externalizing symptoms throughout childhood. / Clayborne, Zahra M; Zou, Runyu; Gilman, Stephen E et al.
In: Brain, Behavior, and Immunity, Vol. 114, 11.2023, p. 165-172.

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

TY - JOUR

T1 - Associations between prenatal maternal stress, maternal inflammation during pregnancy, and children's internalizing and externalizing symptoms throughout childhood

AU - Clayborne, Zahra M

AU - Zou, Runyu

AU - Gilman, Stephen E

AU - Khandaker, Golam M

AU - Fell, Deshayne B

AU - Colman, Ian

AU - El Marroun, Hanan

N1 - Funding Information: This study was supported by Stichting Volksbond Rotterdam, the NARSAD Young Investigator Grant 27853 from the Brain & Behavior Research Foundation, the Aspasia grant No. 015.016.056 of the Netherlands Organization for Health Research and Development, grant agreement 733206 (LifeCycle) from the European Union's Horizon 2020 Research and Innovation Program (LifeCycle, Grant Agreement 733 206 & HappyMums 101057390). (Prof. Dr. El Marroun); grant 201606100056 from the China Scholarship Council (Dr. Zou); the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, project ZIAHD008976 (Dr. Gilman); the Wellcome Trust, grant 201486/Z/16/Z, the Medical Research Council, UK, grants MC_PC_17213, MR/S037675/1, MC_UU_00032/06, and MR/W014416/1 (Dr. Khandaker); and the Canada Research Chairs program (Dr. Colman). The general design of the Generation R Study is made possible by financial support from the Erasmus Medical Center, Rotterdam, the Erasmus University Rotterdam, the Netherlands Organization for Health Research and Development, the Netherlands Organization for Scientific Research, the Ministry of Health, Welfare, and Sport, and the Ministry of Youth and Families. The funding sources had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. Funding Information: The Generation R Study is conducted by the Erasmus Medical Center in close collaboration with the Municipal Health Service Rotterdam area, the Rotterdam Homecare Foundation, and the Stichting Trombosedienst & Artsenlaboratorium Rijnmond, Rotterdam, the Netherlands. We acknowledge the contribution of general practitioners, hospitals, midwives, and pharmacies in Rotterdam. Publisher Copyright: © 2023 Elsevier Inc.

PY - 2023/11

Y1 - 2023/11

N2 - BACKGROUND: Maternal immune activation is a potential mechanism underlying associations between maternal stress during pregnancy and offspring mental health problems. This study examined associations between prenatal maternal stress, maternal inflammation during pregnancy, and children's internalizing and externalizing symptoms from 3 to 10 years of age, and whether maternal inflammation mediated the associations between prenatal maternal stress and children's internalizing and externalizing symptoms.METHODS: This study comprised 4,902 mother-child dyads in the Generation R study. Prenatal maternal stress was assessed using self-reported data collected during pregnancy and analyzed as a latent variable consisting of four stress domains. Maternal inflammation during pregnancy was assessed using serum concentrations of C-reactive protein (CRP) measured at a median of 13.5 weeks' gestation. Child internalizing and externalizing symptoms were assessed using the Child Behavior Checklist (CBCL) by maternal report at ages 3 years, 5 years, and 10 years; paternal-reported CBCL data were also available at 3 years and 10 years.RESULTS: Prenatal maternal stress was associated with maternal-reported internalizing and externalizing symptoms of the child at 3, 5, and 10 years of age, and with paternal-reported internalizing and externalizing symptoms at 3 and 10 years. Prenatal maternal stress was associated with maternal CRP concentrations prior to, but not after, covariate adjustment. Maternal CRP concentrations during pregnancy were associated with paternal-reported internalizing symptoms of offspring at 10 years of age prior to, but not after, covariate adjustment. There was no evidence that CRP concentrations mediated the associations between prenatal maternal stress and children's internalizing or externalizing symptoms.CONCLUSIONS: Maternal stress during pregnancy is associated with higher levels of internalizing and externalizing symptoms in children, but this association is not because of differences in maternal immune activation linked to maternal stress. Replication of these findings in other cohorts is required; examination of other biomarkers or variation in immune activity during pregnancy would also benefit from further exploration.

AB - BACKGROUND: Maternal immune activation is a potential mechanism underlying associations between maternal stress during pregnancy and offspring mental health problems. This study examined associations between prenatal maternal stress, maternal inflammation during pregnancy, and children's internalizing and externalizing symptoms from 3 to 10 years of age, and whether maternal inflammation mediated the associations between prenatal maternal stress and children's internalizing and externalizing symptoms.METHODS: This study comprised 4,902 mother-child dyads in the Generation R study. Prenatal maternal stress was assessed using self-reported data collected during pregnancy and analyzed as a latent variable consisting of four stress domains. Maternal inflammation during pregnancy was assessed using serum concentrations of C-reactive protein (CRP) measured at a median of 13.5 weeks' gestation. Child internalizing and externalizing symptoms were assessed using the Child Behavior Checklist (CBCL) by maternal report at ages 3 years, 5 years, and 10 years; paternal-reported CBCL data were also available at 3 years and 10 years.RESULTS: Prenatal maternal stress was associated with maternal-reported internalizing and externalizing symptoms of the child at 3, 5, and 10 years of age, and with paternal-reported internalizing and externalizing symptoms at 3 and 10 years. Prenatal maternal stress was associated with maternal CRP concentrations prior to, but not after, covariate adjustment. Maternal CRP concentrations during pregnancy were associated with paternal-reported internalizing symptoms of offspring at 10 years of age prior to, but not after, covariate adjustment. There was no evidence that CRP concentrations mediated the associations between prenatal maternal stress and children's internalizing or externalizing symptoms.CONCLUSIONS: Maternal stress during pregnancy is associated with higher levels of internalizing and externalizing symptoms in children, but this association is not because of differences in maternal immune activation linked to maternal stress. Replication of these findings in other cohorts is required; examination of other biomarkers or variation in immune activity during pregnancy would also benefit from further exploration.

KW - Cohort study

KW - Externalizing symptoms

KW - Inflammation

KW - Internalizing symptoms

KW - Prenatal stress

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U2 - 10.1016/j.bbi.2023.08.017

DO - 10.1016/j.bbi.2023.08.017

M3 - Article

C2 - 37607663

SN - 0889-1591

VL - 114

SP - 165

EP - 172

JO - Brain, Behavior, and Immunity

JF - Brain, Behavior, and Immunity

ER -

Associations between prenatal maternal stress, maternal inflammation during pregnancy, and children's internalizing and externalizing symptoms throughout childhood

Abstract

Bibliographical note

Keywords

UN SDGs

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