The effects of maternal anxiety during pregnancy on IGF2/H19 methylation in cord blood
Identifieur interne : 000540 ( Pmc/Checkpoint ); précédent : 000539; suivant : 000541The effects of maternal anxiety during pregnancy on IGF2/H19 methylation in cord blood
Auteurs : T. Mansell [Australie] ; B. Novakovic [Australie] ; B. Meyer [Australie] ; P. Rzehak [Australie, Allemagne] ; P. Vuillermin [Australie] ; A-L Ponsonby [Australie] ; F. Collier [Australie] ; D. Burgner [Australie] ; R. Saffery [Australie] ; J. Ryan [Australie, France]Source :
- Translational Psychiatry [ 2158-3188 ] ; 2016.
Abstract
Compelling evidence suggests that maternal mental health in pregnancy can influence fetal development. The imprinted genes, insulin-like growth factor 2 (
Url:
DOI: 10.1038/tp.2016.32
PubMed: 27023171
PubMed Central: 4872456
Affiliations:
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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">The effects of maternal anxiety during pregnancy on <italic>IGF2</italic>
/<italic>H19</italic>
methylation in cord blood</title>
<author><name sortKey="Mansell, T" sort="Mansell, T" uniqKey="Mansell T" first="T" last="Mansell">T. Mansell</name>
<affiliation wicri:level="1"><nlm:aff id="aff1"><institution>Cancer & Disease Epigenetics, Murdoch Childrens Research Institute, Royal Childrens Hospital</institution>
, Parkville, VIC,<country>Australia</country>
</nlm:aff>
<country xml:lang="fr">Australie</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="aff2"><institution>Department of Paediatrics, The University of Melbourne</institution>
, Parkville, VIC,<country>Australia</country>
</nlm:aff>
<country xml:lang="fr">Australie</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Novakovic, B" sort="Novakovic, B" uniqKey="Novakovic B" first="B" last="Novakovic">B. Novakovic</name>
<affiliation wicri:level="1"><nlm:aff id="aff1"><institution>Cancer & Disease Epigenetics, Murdoch Childrens Research Institute, Royal Childrens Hospital</institution>
, Parkville, VIC,<country>Australia</country>
</nlm:aff>
<country xml:lang="fr">Australie</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="aff2"><institution>Department of Paediatrics, The University of Melbourne</institution>
, Parkville, VIC,<country>Australia</country>
</nlm:aff>
<country xml:lang="fr">Australie</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
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</author>
<author><name sortKey="Meyer, B" sort="Meyer, B" uniqKey="Meyer B" first="B" last="Meyer">B. Meyer</name>
<affiliation wicri:level="1"><nlm:aff id="aff1"><institution>Cancer & Disease Epigenetics, Murdoch Childrens Research Institute, Royal Childrens Hospital</institution>
, Parkville, VIC,<country>Australia</country>
</nlm:aff>
<country xml:lang="fr">Australie</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="aff2"><institution>Department of Paediatrics, The University of Melbourne</institution>
, Parkville, VIC,<country>Australia</country>
</nlm:aff>
<country xml:lang="fr">Australie</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Rzehak, P" sort="Rzehak, P" uniqKey="Rzehak P" first="P" last="Rzehak">P. Rzehak</name>
<affiliation wicri:level="1"><nlm:aff id="aff1"><institution>Cancer & Disease Epigenetics, Murdoch Childrens Research Institute, Royal Childrens Hospital</institution>
, Parkville, VIC,<country>Australia</country>
</nlm:aff>
<country xml:lang="fr">Australie</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="aff3"><institution>Ludwig-Maximilians-University of Munich, Division of Metabolic and Nutritional Medicine, Dr. von Hauner Children's Hospital, University of Munich Medical Centre</institution>
, Munich,<country>Germany</country>
</nlm:aff>
<country xml:lang="fr">Allemagne</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Vuillermin, P" sort="Vuillermin, P" uniqKey="Vuillermin P" first="P" last="Vuillermin">P. Vuillermin</name>
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, Parkville, VIC,<country>Australia</country>
</nlm:aff>
<country xml:lang="fr">Australie</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
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<affiliation wicri:level="1"><nlm:aff id="aff2"><institution>Department of Paediatrics, The University of Melbourne</institution>
, Parkville, VIC,<country>Australia</country>
</nlm:aff>
<country xml:lang="fr">Australie</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="aff4"><institution>Child Health Research Unit, Barwon Health</institution>
, Geelong, VIC,<country>Australia</country>
</nlm:aff>
<country xml:lang="fr">Australie</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="aff5"><institution>School of Medicine, Deakin University</institution>
, Geelong, VIC,<country>Australia</country>
</nlm:aff>
<country xml:lang="fr">Australie</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
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<author><name sortKey="Ponsonby, A L" sort="Ponsonby, A L" uniqKey="Ponsonby A" first="A-L" last="Ponsonby">A-L Ponsonby</name>
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<country xml:lang="fr">Australie</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
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<country xml:lang="fr">Australie</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
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<author><name sortKey="Collier, F" sort="Collier, F" uniqKey="Collier F" first="F" last="Collier">F. Collier</name>
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, Geelong, VIC,<country>Australia</country>
</nlm:aff>
<country xml:lang="fr">Australie</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="aff5"><institution>School of Medicine, Deakin University</institution>
, Geelong, VIC,<country>Australia</country>
</nlm:aff>
<country xml:lang="fr">Australie</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Burgner, D" sort="Burgner, D" uniqKey="Burgner D" first="D" last="Burgner">D. Burgner</name>
<affiliation wicri:level="1"><nlm:aff id="aff1"><institution>Cancer & Disease Epigenetics, Murdoch Childrens Research Institute, Royal Childrens Hospital</institution>
, Parkville, VIC,<country>Australia</country>
</nlm:aff>
<country xml:lang="fr">Australie</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="aff2"><institution>Department of Paediatrics, The University of Melbourne</institution>
, Parkville, VIC,<country>Australia</country>
</nlm:aff>
<country xml:lang="fr">Australie</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Saffery, R" sort="Saffery, R" uniqKey="Saffery R" first="R" last="Saffery">R. Saffery</name>
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, Parkville, VIC,<country>Australia</country>
</nlm:aff>
<country xml:lang="fr">Australie</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="aff2"><institution>Department of Paediatrics, The University of Melbourne</institution>
, Parkville, VIC,<country>Australia</country>
</nlm:aff>
<country xml:lang="fr">Australie</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Ryan, J" sort="Ryan, J" uniqKey="Ryan J" first="J" last="Ryan">J. Ryan</name>
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</nlm:aff>
<country xml:lang="fr">Australie</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="aff2"><institution>Department of Paediatrics, The University of Melbourne</institution>
, Parkville, VIC,<country>Australia</country>
</nlm:aff>
<country xml:lang="fr">Australie</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="aff6"><institution>Inserm U1061, Hopital La Colombiere, Universite Montpellier</institution>
, Montpellier,<country>France</country>
</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="aff7"><institution>Department of Epidemiology and Preventative Medicine, School of Public Health and Preventative Medicine, Monash University</institution>
, Prahran, VIC,<country>Australia</country>
</nlm:aff>
<country xml:lang="fr">Australie</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
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<sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">The effects of maternal anxiety during pregnancy on <italic>IGF2</italic>
/<italic>H19</italic>
methylation in cord blood</title>
<author><name sortKey="Mansell, T" sort="Mansell, T" uniqKey="Mansell T" first="T" last="Mansell">T. Mansell</name>
<affiliation wicri:level="1"><nlm:aff id="aff1"><institution>Cancer & Disease Epigenetics, Murdoch Childrens Research Institute, Royal Childrens Hospital</institution>
, Parkville, VIC,<country>Australia</country>
</nlm:aff>
<country xml:lang="fr">Australie</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="aff2"><institution>Department of Paediatrics, The University of Melbourne</institution>
, Parkville, VIC,<country>Australia</country>
</nlm:aff>
<country xml:lang="fr">Australie</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Novakovic, B" sort="Novakovic, B" uniqKey="Novakovic B" first="B" last="Novakovic">B. Novakovic</name>
<affiliation wicri:level="1"><nlm:aff id="aff1"><institution>Cancer & Disease Epigenetics, Murdoch Childrens Research Institute, Royal Childrens Hospital</institution>
, Parkville, VIC,<country>Australia</country>
</nlm:aff>
<country xml:lang="fr">Australie</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="aff2"><institution>Department of Paediatrics, The University of Melbourne</institution>
, Parkville, VIC,<country>Australia</country>
</nlm:aff>
<country xml:lang="fr">Australie</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Meyer, B" sort="Meyer, B" uniqKey="Meyer B" first="B" last="Meyer">B. Meyer</name>
<affiliation wicri:level="1"><nlm:aff id="aff1"><institution>Cancer & Disease Epigenetics, Murdoch Childrens Research Institute, Royal Childrens Hospital</institution>
, Parkville, VIC,<country>Australia</country>
</nlm:aff>
<country xml:lang="fr">Australie</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="aff2"><institution>Department of Paediatrics, The University of Melbourne</institution>
, Parkville, VIC,<country>Australia</country>
</nlm:aff>
<country xml:lang="fr">Australie</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Rzehak, P" sort="Rzehak, P" uniqKey="Rzehak P" first="P" last="Rzehak">P. Rzehak</name>
<affiliation wicri:level="1"><nlm:aff id="aff1"><institution>Cancer & Disease Epigenetics, Murdoch Childrens Research Institute, Royal Childrens Hospital</institution>
, Parkville, VIC,<country>Australia</country>
</nlm:aff>
<country xml:lang="fr">Australie</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="aff3"><institution>Ludwig-Maximilians-University of Munich, Division of Metabolic and Nutritional Medicine, Dr. von Hauner Children's Hospital, University of Munich Medical Centre</institution>
, Munich,<country>Germany</country>
</nlm:aff>
<country xml:lang="fr">Allemagne</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Vuillermin, P" sort="Vuillermin, P" uniqKey="Vuillermin P" first="P" last="Vuillermin">P. Vuillermin</name>
<affiliation wicri:level="1"><nlm:aff id="aff1"><institution>Cancer & Disease Epigenetics, Murdoch Childrens Research Institute, Royal Childrens Hospital</institution>
, Parkville, VIC,<country>Australia</country>
</nlm:aff>
<country xml:lang="fr">Australie</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="aff2"><institution>Department of Paediatrics, The University of Melbourne</institution>
, Parkville, VIC,<country>Australia</country>
</nlm:aff>
<country xml:lang="fr">Australie</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="aff4"><institution>Child Health Research Unit, Barwon Health</institution>
, Geelong, VIC,<country>Australia</country>
</nlm:aff>
<country xml:lang="fr">Australie</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="aff5"><institution>School of Medicine, Deakin University</institution>
, Geelong, VIC,<country>Australia</country>
</nlm:aff>
<country xml:lang="fr">Australie</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Ponsonby, A L" sort="Ponsonby, A L" uniqKey="Ponsonby A" first="A-L" last="Ponsonby">A-L Ponsonby</name>
<affiliation wicri:level="1"><nlm:aff id="aff1"><institution>Cancer & Disease Epigenetics, Murdoch Childrens Research Institute, Royal Childrens Hospital</institution>
, Parkville, VIC,<country>Australia</country>
</nlm:aff>
<country xml:lang="fr">Australie</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="aff2"><institution>Department of Paediatrics, The University of Melbourne</institution>
, Parkville, VIC,<country>Australia</country>
</nlm:aff>
<country xml:lang="fr">Australie</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Collier, F" sort="Collier, F" uniqKey="Collier F" first="F" last="Collier">F. Collier</name>
<affiliation wicri:level="1"><nlm:aff id="aff4"><institution>Child Health Research Unit, Barwon Health</institution>
, Geelong, VIC,<country>Australia</country>
</nlm:aff>
<country xml:lang="fr">Australie</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="aff5"><institution>School of Medicine, Deakin University</institution>
, Geelong, VIC,<country>Australia</country>
</nlm:aff>
<country xml:lang="fr">Australie</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Burgner, D" sort="Burgner, D" uniqKey="Burgner D" first="D" last="Burgner">D. Burgner</name>
<affiliation wicri:level="1"><nlm:aff id="aff1"><institution>Cancer & Disease Epigenetics, Murdoch Childrens Research Institute, Royal Childrens Hospital</institution>
, Parkville, VIC,<country>Australia</country>
</nlm:aff>
<country xml:lang="fr">Australie</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="aff2"><institution>Department of Paediatrics, The University of Melbourne</institution>
, Parkville, VIC,<country>Australia</country>
</nlm:aff>
<country xml:lang="fr">Australie</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Saffery, R" sort="Saffery, R" uniqKey="Saffery R" first="R" last="Saffery">R. Saffery</name>
<affiliation wicri:level="1"><nlm:aff id="aff1"><institution>Cancer & Disease Epigenetics, Murdoch Childrens Research Institute, Royal Childrens Hospital</institution>
, Parkville, VIC,<country>Australia</country>
</nlm:aff>
<country xml:lang="fr">Australie</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="aff2"><institution>Department of Paediatrics, The University of Melbourne</institution>
, Parkville, VIC,<country>Australia</country>
</nlm:aff>
<country xml:lang="fr">Australie</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Ryan, J" sort="Ryan, J" uniqKey="Ryan J" first="J" last="Ryan">J. Ryan</name>
<affiliation wicri:level="1"><nlm:aff id="aff1"><institution>Cancer & Disease Epigenetics, Murdoch Childrens Research Institute, Royal Childrens Hospital</institution>
, Parkville, VIC,<country>Australia</country>
</nlm:aff>
<country xml:lang="fr">Australie</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="aff2"><institution>Department of Paediatrics, The University of Melbourne</institution>
, Parkville, VIC,<country>Australia</country>
</nlm:aff>
<country xml:lang="fr">Australie</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="aff6"><institution>Inserm U1061, Hopital La Colombiere, Universite Montpellier</institution>
, Montpellier,<country>France</country>
</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="aff7"><institution>Department of Epidemiology and Preventative Medicine, School of Public Health and Preventative Medicine, Monash University</institution>
, Prahran, VIC,<country>Australia</country>
</nlm:aff>
<country xml:lang="fr">Australie</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
</analytic>
<series><title level="j">Translational Psychiatry</title>
<idno type="eISSN">2158-3188</idno>
<imprint><date when="2016">2016</date>
</imprint>
</series>
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</sourceDesc>
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<front><div type="abstract" xml:lang="en"><p>Compelling evidence suggests that maternal mental health in pregnancy can influence fetal development. The imprinted genes, insulin-like growth factor 2 (<italic>IGF2</italic>
) and <italic>H19,</italic>
are involved in fetal growth and each is regulated by DNA methylation. This study aimed to determine the association between maternal mental well-being during pregnancy and differentially methylated regions (DMRs) of <italic>IGF2</italic>
(DMR0) and the <italic>IGF2/H19</italic>
imprinting control region (ICR) in newborn offspring. Maternal depression, anxiety and perceived stress were assessed at 28 weeks of pregnancy in the Barwon Infant Study (<italic>n</italic>
=576). DNA methylation was measured in purified cord blood mononuclear cells using the Sequenom MassArray Platform. Maternal anxiety was associated with a decrease in average ICR methylation (Δ=−2.23% 95% CI=−3.68 to −0.77%), and across all six of the individual CpG units in anxious compared with non-anxious groups. Birth weight and sex modified the association between prenatal anxiety and infant methylation. When stratified into lower (⩽3530 g) and higher (>3530 g) birth weight groups using the median birth weight, there was a stronger association between anxiety and ICR methylation in the lower birth weight group (Δ=−3.89% 95% CI=−6.06 to −1.72%), with no association in the higher birth weight group. When stratified by infant sex, there was a stronger association in female infants (Δ=−3.70% 95% CI=−5.90 to −1.51%) and no association in males. All the linear regression models were adjusted for maternal age, smoking and folate intake. These findings show that maternal anxiety in pregnancy is associated with decreased <italic>IGF2</italic>
/<italic>H19</italic>
ICR DNA methylation in progeny at birth, particularly in female, low birth weight neonates. ICR methylation may help link poor maternal mental health and adverse birth outcomes, but further investigation is needed.</p>
</div>
</front>
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<pmc article-type="research-article"><pmc-dir>properties open_access</pmc-dir>
<front><journal-meta><journal-id journal-id-type="nlm-ta">Transl Psychiatry</journal-id>
<journal-id journal-id-type="iso-abbrev">Transl Psychiatry</journal-id>
<journal-title-group><journal-title>Translational Psychiatry</journal-title>
</journal-title-group>
<issn pub-type="epub">2158-3188</issn>
<publisher><publisher-name>Nature Publishing Group</publisher-name>
</publisher>
</journal-meta>
<article-meta><article-id pub-id-type="pmid">27023171</article-id>
<article-id pub-id-type="pmc">4872456</article-id>
<article-id pub-id-type="pii">tp201632</article-id>
<article-id pub-id-type="doi">10.1038/tp.2016.32</article-id>
<article-categories><subj-group subj-group-type="heading"><subject>Original Article</subject>
</subj-group>
</article-categories>
<title-group><article-title>The effects of maternal anxiety during pregnancy on <italic>IGF2</italic>
/<italic>H19</italic>
methylation in cord blood</article-title>
<alt-title alt-title-type="running">Maternal anxiety and infant <italic>IGF2</italic>
/<italic>H19</italic>
methylation</alt-title>
</title-group>
<contrib-group><contrib contrib-type="author"><name><surname>Mansell</surname>
<given-names>T</given-names>
</name>
<xref ref-type="aff" rid="aff1">1</xref>
<xref ref-type="aff" rid="aff2">2</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Novakovic</surname>
<given-names>B</given-names>
</name>
<xref ref-type="aff" rid="aff1">1</xref>
<xref ref-type="aff" rid="aff2">2</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Meyer</surname>
<given-names>B</given-names>
</name>
<xref ref-type="aff" rid="aff1">1</xref>
<xref ref-type="aff" rid="aff2">2</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Rzehak</surname>
<given-names>P</given-names>
</name>
<xref ref-type="aff" rid="aff1">1</xref>
<xref ref-type="aff" rid="aff3">3</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Vuillermin</surname>
<given-names>P</given-names>
</name>
<xref ref-type="aff" rid="aff1">1</xref>
<xref ref-type="aff" rid="aff2">2</xref>
<xref ref-type="aff" rid="aff4">4</xref>
<xref ref-type="aff" rid="aff5">5</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Ponsonby</surname>
<given-names>A-L</given-names>
</name>
<xref ref-type="aff" rid="aff1">1</xref>
<xref ref-type="aff" rid="aff2">2</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Collier</surname>
<given-names>F</given-names>
</name>
<xref ref-type="aff" rid="aff4">4</xref>
<xref ref-type="aff" rid="aff5">5</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Burgner</surname>
<given-names>D</given-names>
</name>
<xref ref-type="aff" rid="aff1">1</xref>
<xref ref-type="aff" rid="aff2">2</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Saffery</surname>
<given-names>R</given-names>
</name>
<xref ref-type="aff" rid="aff1">1</xref>
<xref ref-type="aff" rid="aff2">2</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Ryan</surname>
<given-names>J</given-names>
</name>
<xref ref-type="aff" rid="aff1">1</xref>
<xref ref-type="aff" rid="aff2">2</xref>
<xref ref-type="aff" rid="aff6">6</xref>
<xref ref-type="aff" rid="aff7">7</xref>
<xref ref-type="corresp" rid="caf1">*</xref>
</contrib>
<contrib contrib-type="author"><collab>BIS investigator team<contrib-group><contrib contrib-type="author"><name><surname>Vuillermin</surname>
<given-names>Peter</given-names>
</name>
</contrib>
<contrib contrib-type="author"><name><surname>Ponsonby</surname>
<given-names>Anne-Louise</given-names>
</name>
</contrib>
<contrib contrib-type="author"><name><surname>Carlin</surname>
<given-names>John B</given-names>
</name>
</contrib>
<contrib contrib-type="author"><name><surname>Allen</surname>
<given-names>Katie J</given-names>
</name>
</contrib>
<contrib contrib-type="author"><name><surname>Tang</surname>
<given-names>Mimi L</given-names>
</name>
</contrib>
<contrib contrib-type="author"><name><surname>Saffery</surname>
<given-names>Richard</given-names>
</name>
</contrib>
<contrib contrib-type="author"><name><surname>Ranganathan</surname>
<given-names>Sarath</given-names>
</name>
</contrib>
<contrib contrib-type="author"><name><surname>Burgner</surname>
<given-names>David</given-names>
</name>
</contrib>
<contrib contrib-type="author"><name><surname>Dwyer</surname>
<given-names>Terry</given-names>
</name>
</contrib>
<contrib contrib-type="author"><name><surname>Jachno</surname>
<given-names>Kim</given-names>
</name>
</contrib>
<contrib contrib-type="author"><name><surname>Sly</surname>
<given-names>Peter</given-names>
</name>
</contrib>
</contrib-group>
</collab>
<xref ref-type="author-notes" rid="d34e221">*</xref>
<xref ref-type="author-notes" rid="note1"><sup>8</sup>
</xref>
</contrib>
<aff id="aff1"><label>1</label>
<institution>Cancer & Disease Epigenetics, Murdoch Childrens Research Institute, Royal Childrens Hospital</institution>
, Parkville, VIC,<country>Australia</country>
</aff>
<aff id="aff2"><label>2</label>
<institution>Department of Paediatrics, The University of Melbourne</institution>
, Parkville, VIC,<country>Australia</country>
</aff>
<aff id="aff3"><label>3</label>
<institution>Ludwig-Maximilians-University of Munich, Division of Metabolic and Nutritional Medicine, Dr. von Hauner Children's Hospital, University of Munich Medical Centre</institution>
, Munich,<country>Germany</country>
</aff>
<aff id="aff4"><label>4</label>
<institution>Child Health Research Unit, Barwon Health</institution>
, Geelong, VIC,<country>Australia</country>
</aff>
<aff id="aff5"><label>5</label>
<institution>School of Medicine, Deakin University</institution>
, Geelong, VIC,<country>Australia</country>
</aff>
<aff id="aff6"><label>6</label>
<institution>Inserm U1061, Hopital La Colombiere, Universite Montpellier</institution>
, Montpellier,<country>France</country>
</aff>
<aff id="aff7"><label>7</label>
<institution>Department of Epidemiology and Preventative Medicine, School of Public Health and Preventative Medicine, Monash University</institution>
, Prahran, VIC,<country>Australia</country>
</aff>
</contrib-group>
<author-notes><corresp id="caf1"><label>*</label>
<institution>Murdoch Childrens Research Institute, Royal Children's Hospital</institution>
, Flemington Road, Parkville, VIC 3052, <country>Australia</country>
. E-mail: <email>joanne.ryan@mcri.edu.au</email>
</corresp>
<fn fn-type="present-address" id="note1"><label>8</label>
<p>Members of the BIS investigator team are listed before References.</p>
</fn>
<fn fn-type="author-notes" id="d34e221"><label>*</label>
<p>BARWON BIS INVESTIGATOR TEAM
Peter Vuillermin: Barwon Health and Deakin University, Geelong, VIC, Australia; The Murdoch Childrens Research Institute, Parkville, VIC, Australia; The University of Melbourne, Parkville, VIC, Australia. Anne-Louise Ponsonby, John B Carlin, Katie J Allen, Mimi L Tang, Richard Saffery, Sarath Ranganathan: The Murdoch Childrens Research Institute, Parkville, VIC, Australia; The University of Melbourne, Parkville, VIC, Australia. David Burgner: The Murdoch Childrens Research Institute, Parkville, VIC, Australia; The University of Melbourne, Parkville, VIC, Australia; Monash University, Clayton, VIC, Australia. Terry Dwyer: The Murdoch Childrens Research Institute, Parkville, VIC, Australia; The George Institute for Global Health, Oxford, UK. Kim Jachno: The Murdoch Childrens Research Institute, Parkville, VIC, Australia. Peter Sly: University of Queensland, Queensland Children's Medical Research Institute, Brisbane, QLD, Australia.</p>
</fn>
</author-notes>
<pub-date pub-type="ppub"><month>03</month>
<year>2016</year>
</pub-date>
<pub-date pub-type="epub"><day>29</day>
<month>03</month>
<year>2016</year>
</pub-date>
<pub-date pub-type="pmc-release"><day>1</day>
<month>3</month>
<year>2016</year>
</pub-date>
<volume>6</volume>
<issue>3</issue>
<fpage>e765</fpage>
<lpage></lpage>
<history><date date-type="received"><day>26</day>
<month>10</month>
<year>2015</year>
</date>
<date date-type="rev-recd"><day>01</day>
<month>02</month>
<year>2016</year>
</date>
<date date-type="accepted"><day>04</day>
<month>02</month>
<year>2016</year>
</date>
</history>
<permissions><copyright-statement>Copyright © 2016 Macmillan Publishers Limited</copyright-statement>
<copyright-year>2016</copyright-year>
<copyright-holder>Macmillan Publishers Limited</copyright-holder>
<license license-type="open-access" xlink:href="http://creativecommons.org/licenses/by/4.0/"><pmc-comment>author-paid</pmc-comment>
<license-p>This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit <ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/licenses/by/4.0/">http://creativecommons.org/licenses/by/4.0/</ext-link>
</license-p>
</license>
</permissions>
<abstract><p>Compelling evidence suggests that maternal mental health in pregnancy can influence fetal development. The imprinted genes, insulin-like growth factor 2 (<italic>IGF2</italic>
) and <italic>H19,</italic>
are involved in fetal growth and each is regulated by DNA methylation. This study aimed to determine the association between maternal mental well-being during pregnancy and differentially methylated regions (DMRs) of <italic>IGF2</italic>
(DMR0) and the <italic>IGF2/H19</italic>
imprinting control region (ICR) in newborn offspring. Maternal depression, anxiety and perceived stress were assessed at 28 weeks of pregnancy in the Barwon Infant Study (<italic>n</italic>
=576). DNA methylation was measured in purified cord blood mononuclear cells using the Sequenom MassArray Platform. Maternal anxiety was associated with a decrease in average ICR methylation (Δ=−2.23% 95% CI=−3.68 to −0.77%), and across all six of the individual CpG units in anxious compared with non-anxious groups. Birth weight and sex modified the association between prenatal anxiety and infant methylation. When stratified into lower (⩽3530 g) and higher (>3530 g) birth weight groups using the median birth weight, there was a stronger association between anxiety and ICR methylation in the lower birth weight group (Δ=−3.89% 95% CI=−6.06 to −1.72%), with no association in the higher birth weight group. When stratified by infant sex, there was a stronger association in female infants (Δ=−3.70% 95% CI=−5.90 to −1.51%) and no association in males. All the linear regression models were adjusted for maternal age, smoking and folate intake. These findings show that maternal anxiety in pregnancy is associated with decreased <italic>IGF2</italic>
/<italic>H19</italic>
ICR DNA methylation in progeny at birth, particularly in female, low birth weight neonates. ICR methylation may help link poor maternal mental health and adverse birth outcomes, but further investigation is needed.</p>
</abstract>
</article-meta>
</front>
<floats-group><fig id="fig1"><label>Figure 1</label>
<caption><p>Population distribution of <italic>IGF2</italic>
/<italic>H19</italic>
ICR DMR methylation levels in infants born to anxious and non-anxious mothers. *<italic>P</italic>
⩽0.016. Error bars are standard deviation. DMR, differentially methylated region; ICR, imprinting control region.</p>
</caption>
<graphic xlink:href="tp201632f1"></graphic>
</fig>
<fig id="fig2"><label>Figure 2</label>
<caption><p>Population distribution of <italic>IGF2</italic>
/<italic>H19</italic>
ICR DMR methylation levels in non-anxious and anxious groups, stratified by both infant sex and birth weight. *<italic>P</italic>
=0.0001. BW, birth weight; DMR, differentially methylated region; ICR, imprinting control region.</p>
</caption>
<graphic xlink:href="tp201632f2"></graphic>
</fig>
<table-wrap id="tbl1"><label>Table 1</label>
<caption><title>Average methylation of <italic>IGF2</italic>
DMR0 and <italic>IGF2</italic>
/<italic>H19</italic>
ICR DMR according to participant characteristics</title>
</caption>
<table frame="hsides" rules="groups" border="1"><colgroup><col align="left"></col>
<col align="center"></col>
<col align="char" char="."></col>
<col align="center"></col>
<col align="char" char="."></col>
</colgroup>
<thead valign="bottom"><tr><th align="left" valign="top" charoff="50"><italic>Characteristics</italic>
</th>
<th colspan="2" align="center" valign="top" charoff="50"><italic>Average IGF2 DMR0 methylation</italic>
<hr></hr>
</th>
<th colspan="2" align="center" valign="top" charoff="50"><italic>Average IGF2/H19 ICR methylation</italic>
<hr></hr>
</th>
</tr>
<tr><th align="left" valign="top" charoff="50"> </th>
<th align="center" valign="top" charoff="50">r</th>
<th align="center" valign="top" char="." charoff="50">P</th>
<th align="center" valign="top" charoff="50">r</th>
<th align="center" valign="top" char="." charoff="50">P</th>
</tr>
</thead>
<tbody valign="top"><tr><td align="left" valign="top" charoff="50">Maternal age (years)</td>
<td align="center" valign="top" charoff="50">0.021</td>
<td align="char" valign="top" char="." charoff="50">0.64</td>
<td align="center" valign="top" charoff="50">0.025</td>
<td align="char" valign="top" char="." charoff="50">0.60</td>
</tr>
<tr><td> </td>
<td colspan="2" align="left" valign="top" charoff="50"> </td>
<td align="center" valign="top" charoff="50"> </td>
<td align="char" valign="top" char="." charoff="50"> </td>
<td align="left" valign="top" charoff="50"> </td>
</tr>
<tr><td align="left" valign="top" charoff="50"> </td>
<td align="char" valign="top" char="(" charoff="50"><italic>Mean % (55)</italic>
</td>
<td align="center" valign="top" char="." charoff="50">P</td>
<td align="char" valign="top" char="(" charoff="50"><italic>Mean (55)</italic>
</td>
<td align="center" valign="top" char="." charoff="50">P</td>
<td> </td>
</tr>
<tr><td align="left" valign="top" charoff="50">Maternal education</td>
<td align="char" valign="top" char="(" charoff="50"> </td>
<td align="char" valign="top" char="." charoff="50">0.26</td>
<td align="char" valign="top" char="(" charoff="50"> </td>
<td align="char" valign="top" char="." charoff="50">0.17</td>
<td> </td>
</tr>
<tr><td align="left" valign="top" charoff="50"> ⩽Year 10</td>
<td align="char" valign="top" char="(" charoff="50">52.55 (5.12)</td>
<td align="char" valign="top" char="." charoff="50"> </td>
<td align="char" valign="top" char="(" charoff="50">44.20 (5.50)</td>
<td align="char" valign="top" char="." charoff="50"> </td>
<td> </td>
</tr>
<tr><td align="left" valign="top" charoff="50"> Year 11 or 12</td>
<td align="char" valign="top" char="(" charoff="50">51.67 (6.43)</td>
<td align="char" valign="top" char="." charoff="50"> </td>
<td align="char" valign="top" char="(" charoff="50">41.25 (6.44)</td>
<td align="char" valign="top" char="." charoff="50"> </td>
<td> </td>
</tr>
<tr><td align="left" valign="top" charoff="50"> University graduate or above</td>
<td align="char" valign="top" char="(" charoff="50">52.86 (6.13)</td>
<td align="char" valign="top" char="." charoff="50"> </td>
<td align="char" valign="top" char="(" charoff="50">41.92 (6.71)</td>
<td align="char" valign="top" char="." charoff="50"> </td>
<td> </td>
</tr>
<tr><td align="left" valign="top" charoff="50"> Other</td>
<td align="char" valign="top" char="(" charoff="50">52.68 (5.74)</td>
<td align="char" valign="top" char="." charoff="50"> </td>
<td align="char" valign="top" char="(" charoff="50">41.58 (5.04)</td>
<td align="char" valign="top" char="." charoff="50"> </td>
<td> </td>
</tr>
<tr><td> </td>
<td colspan="2" align="left" valign="top" charoff="50"> </td>
<td align="char" valign="top" char="." charoff="50"> </td>
<td align="char" valign="top" char="." charoff="50"> </td>
<td align="char" valign="top" char="." charoff="50"> </td>
</tr>
<tr><td align="left" valign="top" charoff="50">Paternal education</td>
<td align="char" valign="top" char="(" charoff="50"> </td>
<td align="char" valign="top" char="." charoff="50">0.96</td>
<td align="center" valign="top" charoff="50"> </td>
<td align="char" valign="top" char="." charoff="50">0.59</td>
<td> </td>
</tr>
<tr><td align="left" valign="top" charoff="50"> ⩽Year 10</td>
<td align="char" valign="top" char="(" charoff="50">52.22 (6.21)</td>
<td align="char" valign="top" char="." charoff="50"> </td>
<td align="char" valign="top" char="(" charoff="50">42.55 (5.98)</td>
<td align="char" valign="top" char="." charoff="50"> </td>
<td> </td>
</tr>
<tr><td align="left" valign="top" charoff="50"> Year 11 or 12</td>
<td align="char" valign="top" char="(" charoff="50">52.63 (6.00)</td>
<td align="char" valign="top" char="." charoff="50"> </td>
<td align="char" valign="top" char="(" charoff="50">42.07 (6.18)</td>
<td align="char" valign="top" char="." charoff="50"> </td>
<td> </td>
</tr>
<tr><td align="left" valign="top" charoff="50"> University graduate or above</td>
<td align="char" valign="top" char="(" charoff="50">52.36 (6.50)</td>
<td align="char" valign="top" char="." charoff="50"> </td>
<td align="char" valign="top" char="(" charoff="50">41.36 (6.45)</td>
<td align="char" valign="top" char="." charoff="50"> </td>
<td> </td>
</tr>
<tr><td align="left" valign="top" charoff="50"> Other</td>
<td align="char" valign="top" char="(" charoff="50">52.34 (5.54)</td>
<td align="char" valign="top" char="." charoff="50"> </td>
<td align="char" valign="top" char="(" charoff="50">41.33 (7.23)</td>
<td align="char" valign="top" char="." charoff="50"> </td>
<td> </td>
</tr>
<tr><td> </td>
<td colspan="2" align="left" valign="top" charoff="50"> </td>
<td align="char" valign="top" char="." charoff="50"> </td>
<td align="char" valign="top" char="." charoff="50"> </td>
<td align="char" valign="top" char="." charoff="50"> </td>
</tr>
<tr><td align="left" valign="top" charoff="50">Infant ancestry</td>
<td align="char" valign="top" char="(" charoff="50"> </td>
<td align="char" valign="top" char="." charoff="50">0.15</td>
<td align="center" valign="top" charoff="50"> </td>
<td align="char" valign="top" char="." charoff="50">0.21</td>
<td> </td>
</tr>
<tr><td align="left" valign="top" charoff="50"> British</td>
<td align="char" valign="top" char="(" charoff="50">52.04 (6.20)</td>
<td align="char" valign="top" char="." charoff="50"> </td>
<td align="char" valign="top" char="(" charoff="50">42.18 (5.58)</td>
<td align="char" valign="top" char="." charoff="50"> </td>
<td> </td>
</tr>
<tr><td align="left" valign="top" charoff="50"> Mixed</td>
<td align="char" valign="top" char="(" charoff="50">52.66 (6.18)</td>
<td align="char" valign="top" char="." charoff="50"> </td>
<td align="char" valign="top" char="(" charoff="50">41.28 (6.76)</td>
<td align="char" valign="top" char="." charoff="50"> </td>
<td> </td>
</tr>
<tr><td align="left" valign="top" charoff="50"> Non-British</td>
<td align="char" valign="top" char="(" charoff="50">53.59 (5.32)</td>
<td align="char" valign="top" char="." charoff="50"> </td>
<td align="char" valign="top" char="(" charoff="50">42.60 (7.65)</td>
<td align="char" valign="top" char="." charoff="50"> </td>
<td> </td>
</tr>
<tr><td align="left" valign="top" charoff="50"> </td>
<td align="char" valign="top" char="(" charoff="50"> </td>
<td align="char" valign="top" char="." charoff="50"> </td>
<td align="center" valign="top" charoff="50"> </td>
<td align="char" valign="top" char="." charoff="50"> </td>
<td> </td>
</tr>
<tr><td colspan="5" align="left" valign="top" charoff="50"><italic>Smoking during pregnancy</italic>
</td>
<td> </td>
</tr>
<tr><td align="left" valign="top" charoff="50"> No</td>
<td align="char" valign="top" char="(" charoff="50">52.49 (6.12)</td>
<td align="char" valign="top" char="." charoff="50">0.69</td>
<td align="char" valign="top" char="(" charoff="50">41.91 (6.55)</td>
<td align="char" valign="top" char="." charoff="50">0.39</td>
<td> </td>
</tr>
<tr><td align="left" valign="top" charoff="50"> Yes</td>
<td align="char" valign="top" char="(" charoff="50">52.84 (5.52)</td>
<td align="char" valign="top" char="." charoff="50"> </td>
<td align="char" valign="top" char="(" charoff="50">41.05 (4.54)</td>
<td align="char" valign="top" char="." charoff="50"> </td>
<td> </td>
</tr>
<tr><td align="left" valign="top" charoff="50"> </td>
<td align="char" valign="top" char="(" charoff="50"> </td>
<td align="char" valign="top" char="." charoff="50"> </td>
<td align="center" valign="top" charoff="50"> </td>
<td align="char" valign="top" char="." charoff="50"> </td>
<td> </td>
</tr>
<tr><td colspan="5" align="left" valign="top" charoff="50"><italic>Alcohol during pregnancy</italic>
</td>
<td> </td>
</tr>
<tr><td align="left" valign="top" charoff="50"> No</td>
<td align="char" valign="top" char="(" charoff="50">52.51 (6.15)</td>
<td align="char" valign="top" char="." charoff="50">0.80</td>
<td align="char" valign="top" char="(" charoff="50">41.75 (6.38)</td>
<td align="char" valign="top" char="." charoff="50">0.63</td>
<td> </td>
</tr>
<tr><td align="left" valign="top" charoff="50"> Yes</td>
<td align="char" valign="top" char="(" charoff="50">52.29 (5.86)</td>
<td align="char" valign="top" char="." charoff="50"> </td>
<td align="char" valign="top" char="(" charoff="50">42.16 (6.07)</td>
<td align="char" valign="top" char="." charoff="50"> </td>
<td> </td>
</tr>
<tr><td align="left" valign="top" charoff="50"> </td>
<td align="char" valign="top" char="(" charoff="50"> </td>
<td align="char" valign="top" char="." charoff="50"> </td>
<td align="center" valign="top" charoff="50"> </td>
<td align="char" valign="top" char="." charoff="50"> </td>
<td> </td>
</tr>
<tr><td colspan="5" align="left" valign="top" charoff="50"><italic>Gestational diabetes</italic>
</td>
<td> </td>
</tr>
<tr><td align="left" valign="top" charoff="50"> No</td>
<td align="char" valign="top" char="(" charoff="50">52.41 (6.10)</td>
<td align="char" valign="top" char="." charoff="50">0.06</td>
<td align="char" valign="top" char="(" charoff="50">41.85 (6.30)</td>
<td align="char" valign="top" char="." charoff="50">0.28</td>
<td> </td>
</tr>
<tr><td align="left" valign="top" charoff="50"> Yes</td>
<td align="char" valign="top" char="(" charoff="50">54.74 (5.90)</td>
<td align="char" valign="top" char="." charoff="50"> </td>
<td align="char" valign="top" char="(" charoff="50">40.29 (7.92)</td>
<td align="char" valign="top" char="." charoff="50"> </td>
<td> </td>
</tr>
<tr><td align="left" valign="top" charoff="50"> </td>
<td align="char" valign="top" char="(" charoff="50"> </td>
<td align="char" valign="top" char="." charoff="50"> </td>
<td align="center" valign="top" charoff="50"> </td>
<td align="char" valign="top" char="." charoff="50"> </td>
<td> </td>
</tr>
<tr><td colspan="5" align="left" valign="top" charoff="50"><italic>Hypertension</italic>
</td>
<td> </td>
</tr>
<tr><td align="left" valign="top" charoff="50"> No</td>
<td align="char" valign="top" char="(" charoff="50">52.64 (5.88)</td>
<td align="char" valign="top" char="." charoff="50">0.13</td>
<td align="char" valign="top" char="(" charoff="50">41.81 (6.31)</td>
<td align="char" valign="top" char="." charoff="50">0.74</td>
<td> </td>
</tr>
<tr><td align="left" valign="top" charoff="50"> Yes</td>
<td align="char" valign="top" char="(" charoff="50">51.22 (8.06)</td>
<td align="char" valign="top" char="." charoff="50"> </td>
<td align="char" valign="top" char="(" charoff="50">41.48 (7.16)</td>
<td align="char" valign="top" char="." charoff="50"> </td>
<td> </td>
</tr>
<tr><td align="left" valign="top" charoff="50"> </td>
<td align="char" valign="top" char="(" charoff="50"> </td>
<td align="char" valign="top" char="." charoff="50"> </td>
<td align="center" valign="top" charoff="50"> </td>
<td align="char" valign="top" char="." charoff="50"> </td>
<td> </td>
</tr>
<tr><td colspan="5" align="left" valign="top" charoff="50"><italic>Preeclampsia</italic>
</td>
<td> </td>
</tr>
<tr><td align="left" valign="top" charoff="50"> No</td>
<td align="char" valign="top" char="(" charoff="50">52.55 (6.00)</td>
<td align="char" valign="top" char="." charoff="50">0.48</td>
<td align="char" valign="top" char="(" charoff="50">41.83 (6.24)</td>
<td align="char" valign="top" char="." charoff="50">0.25</td>
<td> </td>
</tr>
<tr><td align="left" valign="top" charoff="50"> Yes</td>
<td align="char" valign="top" char="(" charoff="50">51.34 (9.39)</td>
<td align="char" valign="top" char="." charoff="50"> </td>
<td align="char" valign="top" char="(" charoff="50">39.58 (11.04)</td>
<td align="char" valign="top" char="." charoff="50"> </td>
<td> </td>
</tr>
<tr><td align="left" valign="top" charoff="50"> </td>
<td align="char" valign="top" char="(" charoff="50"> </td>
<td align="char" valign="top" char="." charoff="50"> </td>
<td align="center" valign="top" charoff="50"> </td>
<td align="char" valign="top" char="." charoff="50"> </td>
<td> </td>
</tr>
<tr><td colspan="5" align="left" valign="top" charoff="50"><italic>Child sex</italic>
</td>
<td> </td>
</tr>
<tr><td align="left" valign="top" charoff="50"> Male</td>
<td align="char" valign="top" char="(" charoff="50">52.20 (5.85)</td>
<td align="char" valign="top" char="." charoff="50">0.20</td>
<td align="char" valign="top" char="(" charoff="50">41.74 (6.26)</td>
<td align="char" valign="top" char="." charoff="50">0.68</td>
<td> </td>
</tr>
<tr><td align="left" valign="top" charoff="50"> Female</td>
<td align="char" valign="top" char="(" charoff="50">52.87 (6.38)</td>
<td align="char" valign="top" char="." charoff="50"> </td>
<td align="char" valign="top" char="(" charoff="50">41.98 (6.60)</td>
<td align="char" valign="top" char="." charoff="50"> </td>
<td> </td>
</tr>
<tr><td> </td>
<td colspan="2" align="left" valign="top" charoff="50"> </td>
<td align="center" valign="top" charoff="50"> </td>
<td align="char" valign="top" char="." charoff="50"> </td>
<td align="left" valign="top" charoff="50"> </td>
</tr>
<tr><td align="left" valign="top" charoff="50"> </td>
<td align="center" valign="top" charoff="50">r</td>
<td align="center" valign="top" char="." charoff="50">P</td>
<td align="center" valign="top" charoff="50">r</td>
<td align="center" valign="top" char="." charoff="50">P</td>
<td> </td>
</tr>
<tr><td align="left" valign="top" charoff="50">Child gestational age (days)</td>
<td align="center" valign="top" charoff="50">−0.020</td>
<td align="center" valign="top" char="." charoff="50">0.67</td>
<td align="center" valign="top" charoff="50">0.060</td>
<td align="center" valign="top" char="." charoff="50">0.24</td>
<td> </td>
</tr>
<tr><td align="left" valign="top" charoff="50">Child birth weight (g)</td>
<td align="center" valign="top" charoff="50">−0.011</td>
<td align="center" valign="top" char="." charoff="50">0.80</td>
<td align="center" valign="top" charoff="50">−0.032</td>
<td align="center" valign="top" char="." charoff="50">0.49</td>
<td> </td>
</tr>
<tr><td align="left" valign="top" charoff="50">Antenatal folate (nmol l<sup>−1</sup>
)</td>
<td align="center" valign="top" charoff="50">0.019</td>
<td align="center" valign="top" char="." charoff="50">0.67</td>
<td align="center" valign="top" charoff="50">0.031</td>
<td align="center" valign="top" char="." charoff="50">0.51</td>
<td> </td>
</tr>
</tbody>
</table>
<table-wrap-foot><fn id="t1-fn1"><p>Abbreviations: DMR, differentially methylated region; ICR, imprinting control region.</p>
</fn>
</table-wrap-foot>
</table-wrap>
<table-wrap id="tbl2"><label>Table 2</label>
<caption><title>Difference in DNA methylation levels between neonates born to anxious versus non-anxious mothers, stratified by birth weight</title>
</caption>
<table frame="hsides" rules="groups" border="1"><colgroup><col align="left"></col>
<col align="char" char="."></col>
<col align="center"></col>
<col align="char" char="."></col>
<col align="char" char="."></col>
<col align="center"></col>
<col align="char" char="."></col>
</colgroup>
<thead valign="bottom"><tr><th align="left" valign="top" charoff="50"><italic>CpG unit</italic>
</th>
<th colspan="3" align="center" valign="top" char="." charoff="50"><italic>Lower birth weight (</italic>
<italic>⩽</italic>
<italic>3530 g)</italic>
<hr></hr>
</th>
<th colspan="3" align="center" valign="top" char="." charoff="50"><italic>Higher birth weight (>3530 g)</italic>
<hr></hr>
</th>
</tr>
<tr><th align="left" valign="top" charoff="50"> </th>
<th align="center" valign="top" char="." charoff="50"><italic>Δ</italic>
</th>
<th align="center" valign="top" charoff="50"><italic>95% CI</italic>
</th>
<th align="center" valign="top" char="." charoff="50">P</th>
<th align="center" valign="top" char="." charoff="50"><italic>Δ</italic>
</th>
<th align="center" valign="top" charoff="50"><italic>95% CI</italic>
</th>
<th align="center" valign="top" char="." charoff="50">P</th>
</tr>
</thead>
<tbody valign="top"><tr><td colspan="7" align="left" valign="top" charoff="50"><italic>IGF2 DMR0</italic>
</td>
</tr>
<tr><td align="left" valign="top" charoff="50"> 3</td>
<td align="char" valign="top" char="." charoff="50">−1.66%</td>
<td align="center" valign="top" charoff="50">−3.91 to 0.59%</td>
<td align="char" valign="top" char="." charoff="50">0.15</td>
<td align="char" valign="top" char="." charoff="50">−1.96%</td>
<td align="center" valign="top" charoff="50">−4.10 to 0.18%</td>
<td align="char" valign="top" char="." charoff="50">0.072</td>
</tr>
<tr><td align="left" valign="top" charoff="50"> 4</td>
<td align="char" valign="top" char="." charoff="50">0.30%</td>
<td align="center" valign="top" charoff="50">−2.23 to 2.84%</td>
<td align="char" valign="top" char="." charoff="50">0.81</td>
<td align="char" valign="top" char="." charoff="50">0.40%</td>
<td align="center" valign="top" charoff="50">−2.89 to 3.70%</td>
<td align="char" valign="top" char="." charoff="50">0.81</td>
</tr>
<tr><td align="left" valign="top" charoff="50"> 6.7</td>
<td align="char" valign="top" char="." charoff="50">−0.88%</td>
<td align="center" valign="top" charoff="50">−2.78 to 1.01%</td>
<td align="char" valign="top" char="." charoff="50">0.36</td>
<td align="char" valign="top" char="." charoff="50">0.79%</td>
<td align="center" valign="top" charoff="50">−0.86 to 2.14%</td>
<td align="char" valign="top" char="." charoff="50">0.34</td>
</tr>
<tr><td align="left" valign="top" charoff="50"> Average</td>
<td align="char" valign="top" char="." charoff="50">−1.00%</td>
<td align="center" valign="top" charoff="50">−2.71 to 0.70%</td>
<td align="char" valign="top" char="." charoff="50">0.25</td>
<td align="char" valign="top" char="." charoff="50">−0.09%</td>
<td align="center" valign="top" charoff="50">−2.04 to 1.85%</td>
<td align="char" valign="top" char="." charoff="50">0.92</td>
</tr>
<tr><td align="left" valign="top" charoff="50"> </td>
<td align="char" valign="top" char="." charoff="50"> </td>
<td align="center" valign="top" charoff="50"> </td>
<td align="char" valign="top" char="." charoff="50"> </td>
<td align="char" valign="top" char="." charoff="50"> </td>
<td align="center" valign="top" charoff="50"> </td>
<td align="char" valign="top" char="." charoff="50"> </td>
</tr>
<tr><td colspan="7" align="left" valign="top" charoff="50"><italic>IGF2</italic>
/<italic>H19</italic>
ICR</td>
</tr>
<tr><td align="left" valign="top" charoff="50"> 1</td>
<td align="char" valign="top" char="." charoff="50">−4.33%</td>
<td align="center" valign="top" charoff="50">−6.83 to −1.84%</td>
<td align="char" valign="top" char="." charoff="50">0.0007</td>
<td align="char" valign="top" char="." charoff="50">−0.70%</td>
<td align="center" valign="top" charoff="50">−2.83 to 1.44%</td>
<td align="char" valign="top" char="." charoff="50">0.52</td>
</tr>
<tr><td align="left" valign="top" charoff="50"> 5.6.7.8</td>
<td align="char" valign="top" char="." charoff="50">−3.40%</td>
<td align="center" valign="top" charoff="50">−5.71 to −1.10%</td>
<td align="char" valign="top" char="." charoff="50">0.0040</td>
<td align="char" valign="top" char="." charoff="50">−0.45%</td>
<td align="center" valign="top" charoff="50">−2.63 to 1.73%</td>
<td align="char" valign="top" char="." charoff="50">0.68</td>
</tr>
<tr><td align="left" valign="top" charoff="50"> 11.12</td>
<td align="char" valign="top" char="." charoff="50">−3.82%</td>
<td align="center" valign="top" charoff="50">−6.10 to −1.55%</td>
<td align="char" valign="top" char="." charoff="50">0.0011</td>
<td align="char" valign="top" char="." charoff="50">−0.47%</td>
<td align="center" valign="top" charoff="50">−2.53 to 1.63%</td>
<td align="char" valign="top" char="." charoff="50">0.66</td>
</tr>
<tr><td align="left" valign="top" charoff="50"> 13.14</td>
<td align="char" valign="top" char="." charoff="50">−4.57%</td>
<td align="center" valign="top" charoff="50">−6.99 to −2.14%</td>
<td align="char" valign="top" char="." charoff="50">0.0003</td>
<td align="char" valign="top" char="." charoff="50">−0.25%</td>
<td align="center" valign="top" charoff="50">−2.31 to 1.80%</td>
<td align="char" valign="top" char="." charoff="50">0.81</td>
</tr>
<tr><td align="left" valign="top" charoff="50"> 21.22</td>
<td align="char" valign="top" char="." charoff="50">−3.76%</td>
<td align="center" valign="top" charoff="50">−6.49 to −1.04%</td>
<td align="char" valign="top" char="." charoff="50">0.0071</td>
<td align="char" valign="top" char="." charoff="50">0.27%</td>
<td align="center" valign="top" charoff="50">−2.35 to 2.88%</td>
<td align="char" valign="top" char="." charoff="50">0.84</td>
</tr>
<tr><td align="left" valign="top" charoff="50"> 23</td>
<td align="char" valign="top" char="." charoff="50">−2.21%</td>
<td align="center" valign="top" charoff="50">−5.19 to 0.78%</td>
<td align="char" valign="top" char="." charoff="50">0.15</td>
<td align="char" valign="top" char="." charoff="50">−1.49%</td>
<td align="center" valign="top" charoff="50">−4.47 to 1.49%</td>
<td align="char" valign="top" char="." charoff="50">0.33</td>
</tr>
<tr><td align="left" valign="top" charoff="50"> Average</td>
<td align="char" valign="top" char="." charoff="50">−3.89%</td>
<td align="center" valign="top" charoff="50">−6.06 to −1.72%</td>
<td align="char" valign="top" char="." charoff="50">0.0005</td>
<td align="char" valign="top" char="." charoff="50">−0.59%</td>
<td align="center" valign="top" charoff="50">−2.54 to 1.37%</td>
<td align="char" valign="top" char="." charoff="50">0.55</td>
</tr>
</tbody>
</table>
<table-wrap-foot><fn id="t2-fn1"><p>Abbreviations: DMR, differentially methylated region; ICR, imprinting control region.</p>
</fn>
</table-wrap-foot>
</table-wrap>
</floats-group>
</pmc>
<affiliations><list><country><li>Allemagne</li>
<li>Australie</li>
<li>France</li>
</country>
</list>
<tree><country name="Australie"><noRegion><name sortKey="Mansell, T" sort="Mansell, T" uniqKey="Mansell T" first="T" last="Mansell">T. Mansell</name>
</noRegion>
<name sortKey="Burgner, D" sort="Burgner, D" uniqKey="Burgner D" first="D" last="Burgner">D. Burgner</name>
<name sortKey="Burgner, D" sort="Burgner, D" uniqKey="Burgner D" first="D" last="Burgner">D. Burgner</name>
<name sortKey="Collier, F" sort="Collier, F" uniqKey="Collier F" first="F" last="Collier">F. Collier</name>
<name sortKey="Collier, F" sort="Collier, F" uniqKey="Collier F" first="F" last="Collier">F. Collier</name>
<name sortKey="Mansell, T" sort="Mansell, T" uniqKey="Mansell T" first="T" last="Mansell">T. Mansell</name>
<name sortKey="Meyer, B" sort="Meyer, B" uniqKey="Meyer B" first="B" last="Meyer">B. Meyer</name>
<name sortKey="Meyer, B" sort="Meyer, B" uniqKey="Meyer B" first="B" last="Meyer">B. Meyer</name>
<name sortKey="Novakovic, B" sort="Novakovic, B" uniqKey="Novakovic B" first="B" last="Novakovic">B. Novakovic</name>
<name sortKey="Novakovic, B" sort="Novakovic, B" uniqKey="Novakovic B" first="B" last="Novakovic">B. Novakovic</name>
<name sortKey="Ponsonby, A L" sort="Ponsonby, A L" uniqKey="Ponsonby A" first="A-L" last="Ponsonby">A-L Ponsonby</name>
<name sortKey="Ponsonby, A L" sort="Ponsonby, A L" uniqKey="Ponsonby A" first="A-L" last="Ponsonby">A-L Ponsonby</name>
<name sortKey="Ryan, J" sort="Ryan, J" uniqKey="Ryan J" first="J" last="Ryan">J. Ryan</name>
<name sortKey="Ryan, J" sort="Ryan, J" uniqKey="Ryan J" first="J" last="Ryan">J. Ryan</name>
<name sortKey="Ryan, J" sort="Ryan, J" uniqKey="Ryan J" first="J" last="Ryan">J. Ryan</name>
<name sortKey="Rzehak, P" sort="Rzehak, P" uniqKey="Rzehak P" first="P" last="Rzehak">P. Rzehak</name>
<name sortKey="Saffery, R" sort="Saffery, R" uniqKey="Saffery R" first="R" last="Saffery">R. Saffery</name>
<name sortKey="Saffery, R" sort="Saffery, R" uniqKey="Saffery R" first="R" last="Saffery">R. Saffery</name>
<name sortKey="Vuillermin, P" sort="Vuillermin, P" uniqKey="Vuillermin P" first="P" last="Vuillermin">P. Vuillermin</name>
<name sortKey="Vuillermin, P" sort="Vuillermin, P" uniqKey="Vuillermin P" first="P" last="Vuillermin">P. Vuillermin</name>
<name sortKey="Vuillermin, P" sort="Vuillermin, P" uniqKey="Vuillermin P" first="P" last="Vuillermin">P. Vuillermin</name>
<name sortKey="Vuillermin, P" sort="Vuillermin, P" uniqKey="Vuillermin P" first="P" last="Vuillermin">P. Vuillermin</name>
</country>
<country name="Allemagne"><noRegion><name sortKey="Rzehak, P" sort="Rzehak, P" uniqKey="Rzehak P" first="P" last="Rzehak">P. Rzehak</name>
</noRegion>
</country>
<country name="France"><noRegion><name sortKey="Ryan, J" sort="Ryan, J" uniqKey="Ryan J" first="J" last="Ryan">J. Ryan</name>
</noRegion>
</country>
</tree>
</affiliations>
</record>
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