Stress during Pregnancy and Offspring Pediatric Disease: A National Cohort Study
Identifieur interne : 000149 ( Pmc/Corpus ); précédent : 000148; suivant : 000150Stress during Pregnancy and Offspring Pediatric Disease: A National Cohort Study
Auteurs : Marion Tegethoff ; Naomi Greene ; J Rn Olsen ; Emmanuel Schaffner ; Gunther MeinlschmidtSource :
- Environmental Health Perspectives [ 0091-6765 ] ; 2011.
Abstract
Background: Identifying risk factors for adverse health outcomes in children is important. The intrauterine environment plays a pivotal role for health and disease across life.
Objectives: We conducted a comprehensive study to determine whether common psychosocial stress during pregnancy is a risk factor for a wide spectrum of pediatric diseases in the offspring.
Methods: The study was conducted using prospective data in a population-based sample of mothers with live singleton births (
Results: Median age at end of follow-up was 6.2 (range, 3.6–8.9) years. Life stress (highest compared with lowest quartile) was associated with an increased risk of conditions originating in the perinatal period [odds ratio (OR) = 1.13; 95% confidence interval (CI): 1.06, 1.21] and congenital malformations (OR=1.17; CI: 1.06, 1.28) and of the first diagnosis of infection [hazard ratio (HR) = 1.28; CI: 1.17, 1.39], mental disorders (age 0–2.5 years: HR = 2.03; CI: 1.32, 3.14), and eye (age 0–4.5 years: HR = 1.27; CI: 1.06, 1.53), ear (HR = 1.36; CI: 1.23, 1.51), respiratory (HR = 1.27; CI; 1.19, 1.35), digestive (HR = 1.23; CI: 1.11, 1.37), skin (HR = 1.24; CI: 1.09, 1.43), musculoskeletal (HR = 1.15; CI: 1.01–1.30), and genitourinary diseases (HR = 1.25; CI; 1.08, 1.45). Emotional stress was associated with an increased risk for the first diagnosis of infection (HR = 1.09; CI: 1.01, 1.18) and a decreased risk for the first diagnosis of endocrine (HR = 0.81; CI; 0.67, 0.99), eye (HR = 0.84; CI; 0.71, 0.99), and circulatory diseases (age 0–3 years: HR = 0.63; CI: 0.42, 0.95).
Conclusions: Maternal life stress during pregnancy may be a common risk factor for impaired child health. The results suggest new approaches to reduce childhood diseases.
Url:
DOI: 10.1289/ehp.1003253
PubMed: 21775267
PubMed Central: 3226491
Links to Exploration step
PMC:3226491Le document en format XML
<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Stress during Pregnancy and Offspring Pediatric Disease: A National Cohort Study</title><author><name sortKey="Tegethoff, Marion" sort="Tegethoff, Marion" uniqKey="Tegethoff M" first="Marion" last="Tegethoff">Marion Tegethoff</name><affiliation><nlm:aff id="aff1"><addr-line>Division of Clinical Psychology and Psychiatry, and</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff2"><addr-line>Division of Clinical Psychology and Psychotherapy, Department of Psychology, University of Basel, Basel, Switzerland</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff3"><addr-line>Department of Neurobehavioral Genetics, Institute of Psychobiology, University of Trier, Trier, Germany</addr-line></nlm:aff></affiliation></author><author><name sortKey="Greene, Naomi" sort="Greene, Naomi" uniqKey="Greene N" first="Naomi" last="Greene">Naomi Greene</name><affiliation><nlm:aff id="aff4"><addr-line>Department of Epidemiology, School of Public Health, University of California at Los Angeles, Los Angeles, California, USA</addr-line></nlm:aff></affiliation></author><author><name sortKey="Olsen, J Rn" sort="Olsen, J Rn" uniqKey="Olsen J" first="J Rn" last="Olsen">J Rn Olsen</name><affiliation><nlm:aff id="aff4"><addr-line>Department of Epidemiology, School of Public Health, University of California at Los Angeles, Los Angeles, California, USA</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff5"><addr-line>The Danish Epidemiology Science Centre, Department of Epidemiology, Institute of Public Health, University of Aarhus, Aarhus, Denmark</addr-line></nlm:aff></affiliation></author><author><name sortKey="Schaffner, Emmanuel" sort="Schaffner, Emmanuel" uniqKey="Schaffner E" first="Emmanuel" last="Schaffner">Emmanuel Schaffner</name><affiliation><nlm:aff id="aff6"><addr-line>Division of Applied Statistics in Life Sciences, Department of Psychology, University of Basel, Basel, Switzerland</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff7"><addr-line>National Centre of Competence in Research, Swiss Etiological Study of Adjustment and Mental Health (sesam), Basel, Switzerland</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff8"><addr-line>Biostatistics and Computational Sciences, Department of Epidemiology and Public Health, Swiss Tropical and Public Health Institute, Basel, Switzerland</addr-line></nlm:aff></affiliation></author><author><name sortKey="Meinlschmidt, Gunther" sort="Meinlschmidt, Gunther" uniqKey="Meinlschmidt G" first="Gunther" last="Meinlschmidt">Gunther Meinlschmidt</name><affiliation><nlm:aff id="aff2"><addr-line>Division of Clinical Psychology and Psychotherapy, Department of Psychology, University of Basel, Basel, Switzerland</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff7"><addr-line>National Centre of Competence in Research, Swiss Etiological Study of Adjustment and Mental Health (sesam), Basel, Switzerland</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff9"><addr-line>Division of Clinical Psychology and Epidemiology, Department of Psychology, University of Basel, Basel, Switzerland</addr-line></nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">21775267</idno><idno type="pmc">3226491</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3226491</idno><idno type="RBID">PMC:3226491</idno><idno type="doi">10.1289/ehp.1003253</idno><date when="2011">2011</date><idno type="wicri:Area/Pmc/Corpus">000149</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000149</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Stress during Pregnancy and Offspring Pediatric Disease: A National Cohort Study</title><author><name sortKey="Tegethoff, Marion" sort="Tegethoff, Marion" uniqKey="Tegethoff M" first="Marion" last="Tegethoff">Marion Tegethoff</name><affiliation><nlm:aff id="aff1"><addr-line>Division of Clinical Psychology and Psychiatry, and</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff2"><addr-line>Division of Clinical Psychology and Psychotherapy, Department of Psychology, University of Basel, Basel, Switzerland</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff3"><addr-line>Department of Neurobehavioral Genetics, Institute of Psychobiology, University of Trier, Trier, Germany</addr-line></nlm:aff></affiliation></author><author><name sortKey="Greene, Naomi" sort="Greene, Naomi" uniqKey="Greene N" first="Naomi" last="Greene">Naomi Greene</name><affiliation><nlm:aff id="aff4"><addr-line>Department of Epidemiology, School of Public Health, University of California at Los Angeles, Los Angeles, California, USA</addr-line></nlm:aff></affiliation></author><author><name sortKey="Olsen, J Rn" sort="Olsen, J Rn" uniqKey="Olsen J" first="J Rn" last="Olsen">J Rn Olsen</name><affiliation><nlm:aff id="aff4"><addr-line>Department of Epidemiology, School of Public Health, University of California at Los Angeles, Los Angeles, California, USA</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff5"><addr-line>The Danish Epidemiology Science Centre, Department of Epidemiology, Institute of Public Health, University of Aarhus, Aarhus, Denmark</addr-line></nlm:aff></affiliation></author><author><name sortKey="Schaffner, Emmanuel" sort="Schaffner, Emmanuel" uniqKey="Schaffner E" first="Emmanuel" last="Schaffner">Emmanuel Schaffner</name><affiliation><nlm:aff id="aff6"><addr-line>Division of Applied Statistics in Life Sciences, Department of Psychology, University of Basel, Basel, Switzerland</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff7"><addr-line>National Centre of Competence in Research, Swiss Etiological Study of Adjustment and Mental Health (sesam), Basel, Switzerland</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff8"><addr-line>Biostatistics and Computational Sciences, Department of Epidemiology and Public Health, Swiss Tropical and Public Health Institute, Basel, Switzerland</addr-line></nlm:aff></affiliation></author><author><name sortKey="Meinlschmidt, Gunther" sort="Meinlschmidt, Gunther" uniqKey="Meinlschmidt G" first="Gunther" last="Meinlschmidt">Gunther Meinlschmidt</name><affiliation><nlm:aff id="aff2"><addr-line>Division of Clinical Psychology and Psychotherapy, Department of Psychology, University of Basel, Basel, Switzerland</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff7"><addr-line>National Centre of Competence in Research, Swiss Etiological Study of Adjustment and Mental Health (sesam), Basel, Switzerland</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff9"><addr-line>Division of Clinical Psychology and Epidemiology, Department of Psychology, University of Basel, Basel, Switzerland</addr-line></nlm:aff></affiliation></author></analytic><series><title level="j">Environmental Health Perspectives</title><idno type="ISSN">0091-6765</idno><idno type="eISSN">1552-9924</idno><imprint><date when="2011">2011</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>Background: Identifying risk factors for adverse health outcomes in children is important. The intrauterine environment plays a pivotal role for health and disease across life.</p><p>Objectives: We conducted a comprehensive study to determine whether common psychosocial stress during pregnancy is a risk factor for a wide spectrum of pediatric diseases in the offspring.</p><p>Methods: The study was conducted using prospective data in a population-based sample of mothers with live singleton births (<italic>n</italic> = 66,203; 71.4% of those eligible) from the Danish National Birth Cohort. We estimated the association between maternal stress during pregnancy (classified based on two <italic>a priori</italic>–defined indicators of common stress forms, life stress and emotional stress) and offspring diseases during childhood (grouped into 16 categories of diagnoses from the <italic>International Classification of Diseases, 10th Revision</italic>, based on data from national registries), controlling for maternal stress after pregnancy.</p><p>Results: Median age at end of follow-up was 6.2 (range, 3.6–8.9) years. Life stress (highest compared with lowest quartile) was associated with an increased risk of conditions originating in the perinatal period [odds ratio (OR) = 1.13; 95% confidence interval (CI): 1.06, 1.21] and congenital malformations (OR=1.17; CI: 1.06, 1.28) and of the first diagnosis of infection [hazard ratio (HR) = 1.28; CI: 1.17, 1.39], mental disorders (age 0–2.5 years: HR = 2.03; CI: 1.32, 3.14), and eye (age 0–4.5 years: HR = 1.27; CI: 1.06, 1.53), ear (HR = 1.36; CI: 1.23, 1.51), respiratory (HR = 1.27; CI; 1.19, 1.35), digestive (HR = 1.23; CI: 1.11, 1.37), skin (HR = 1.24; CI: 1.09, 1.43), musculoskeletal (HR = 1.15; CI: 1.01–1.30), and genitourinary diseases (HR = 1.25; CI; 1.08, 1.45). Emotional stress was associated with an increased risk for the first diagnosis of infection (HR = 1.09; CI: 1.01, 1.18) and a decreased risk for the first diagnosis of endocrine (HR = 0.81; CI; 0.67, 0.99), eye (HR = 0.84; CI; 0.71, 0.99), and circulatory diseases (age 0–3 years: HR = 0.63; CI: 0.42, 0.95).</p><p>Conclusions: Maternal life stress during pregnancy may be a common risk factor for impaired child health. The results suggest new approaches to reduce childhood diseases.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Aman, J" uniqKey="Aman J">J Aman</name></author><author><name sortKey="Hansson, U" uniqKey="Hansson U">U Hansson</name></author><author><name sortKey="Ostlund, I" uniqKey="Ostlund I">I Ostlund</name></author><author><name sortKey="Wall, K" uniqKey="Wall K">K Wall</name></author><author><name sortKey="Persson, B" uniqKey="Persson B">B. 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Salmon</name></author></analytic></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct></listBibl></div1></back></TEI><pmc article-type="research-article"><pmc-dir>properties open_access</pmc-dir>
<front><journal-meta><journal-id journal-id-type="nlm-ta">Environ Health Perspect</journal-id><journal-id journal-id-type="iso-abbrev">Environ. Health Perspect</journal-id><journal-id journal-id-type="publisher-id">EHP</journal-id><journal-title-group><journal-title>Environmental Health Perspectives</journal-title></journal-title-group><issn pub-type="ppub">0091-6765</issn><issn pub-type="epub">1552-9924</issn><publisher><publisher-name>National Institute of Environmental Health Sciences</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">21775267</article-id><article-id pub-id-type="pmc">3226491</article-id><article-id pub-id-type="publisher-id">ehp.1003253</article-id><article-id pub-id-type="doi">10.1289/ehp.1003253</article-id><article-categories><subj-group subj-group-type="heading"><subject>Research</subject></subj-group></article-categories><title-group><article-title>Stress during Pregnancy and Offspring Pediatric Disease: A National Cohort Study</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Tegethoff</surname><given-names>Marion</given-names></name><xref ref-type="aff" rid="aff1"><sup>1</sup></xref><xref ref-type="aff" rid="aff2"><sup>2</sup></xref><xref ref-type="aff" rid="aff3"><sup>3</sup></xref></contrib><contrib contrib-type="author"><name><surname>Greene</surname><given-names>Naomi</given-names></name><xref ref-type="aff" rid="aff4"><sup>4</sup></xref></contrib><contrib contrib-type="author"><name><surname>Olsen</surname><given-names>Jørn</given-names></name><xref ref-type="aff" rid="aff4"><sup>4</sup></xref><xref ref-type="aff" rid="aff5"><sup>5</sup></xref></contrib><contrib contrib-type="author"><name><surname>Schaffner</surname><given-names>Emmanuel</given-names></name><xref ref-type="aff" rid="aff6"><sup>6</sup></xref><xref ref-type="aff" rid="aff7"><sup>7</sup></xref><xref ref-type="aff" rid="aff8"><sup>8</sup></xref></contrib><contrib contrib-type="author" corresp="yes"><name><surname>Meinlschmidt</surname><given-names>Gunther</given-names></name><xref ref-type="aff" rid="aff2"><sup>2</sup></xref><xref ref-type="aff" rid="aff7"><sup>7</sup></xref><xref ref-type="aff" rid="aff9"><sup>9</sup></xref></contrib><aff id="aff1"><label>1</label><addr-line>Division of Clinical Psychology and Psychiatry, and</addr-line></aff><aff id="aff2"><label>2</label><addr-line>Division of Clinical Psychology and Psychotherapy, Department of Psychology, University of Basel, Basel, Switzerland</addr-line></aff><aff id="aff3"><label>3</label><addr-line>Department of Neurobehavioral Genetics, Institute of Psychobiology, University of Trier, Trier, Germany</addr-line></aff><aff id="aff4"><label>4</label><addr-line>Department of Epidemiology, School of Public Health, University of California at Los Angeles, Los Angeles, California, USA</addr-line></aff><aff id="aff5"><label>5</label><addr-line>The Danish Epidemiology Science Centre, Department of Epidemiology, Institute of Public Health, University of Aarhus, Aarhus, Denmark</addr-line></aff><aff id="aff6"><label>6</label><addr-line>Division of Applied Statistics in Life Sciences, Department of Psychology, University of Basel, Basel, Switzerland</addr-line></aff><aff id="aff7"><label>7</label><addr-line>National Centre of Competence in Research, Swiss Etiological Study of Adjustment and Mental Health (sesam), Basel, Switzerland</addr-line></aff><aff id="aff8"><label>8</label><addr-line>Biostatistics and Computational Sciences, Department of Epidemiology and Public Health, Swiss Tropical and Public Health Institute, Basel, Switzerland</addr-line></aff><aff id="aff9"><label>9</label><addr-line>Division of Clinical Psychology and Epidemiology, Department of Psychology, University of Basel, Basel, Switzerland</addr-line></aff></contrib-group><author-notes><corresp id="cor1">Address correspondence to G. Meinlschmidt, University of Basel, Missionsstrasse 60/62, CH-4055 Basel, Switzerland. Telephone: 41-61-267-02-75. Fax: 41-61-267-06-59. E-mail: <email>gunther.meinlschmidt@unibas.ch</email></corresp></author-notes><pub-date pub-type="epub"><day>21</day><month>7</month><year>2011</year></pub-date><pub-date pub-type="ppub"><month>11</month><year>2011</year></pub-date><volume>119</volume><issue>11</issue><fpage>1647</fpage><lpage>1652</lpage><history><date date-type="received"><day>26</day><month>11</month><year>2010</year></date><date date-type="accepted"><day>18</day><month>7</month><year>2011</year></date></history><permissions><copyright-year>2011</copyright-year><license xlink:href="http://creativecommons.org/publicdomain/mark/1.0/" license-type="public-domain"><license-p>Publication of EHP lies in the public domain and is therefore without copyright. All text from EHP may be reprinted freely. Use of materials published in EHP should be acknowledged (for example, ?Reproduced with permission from Environmental Health Perspectives?); pertinent reference information should be provided for the article from which the material was reproduced. Articles from EHP, especially the News section, may contain photographs or illustrations copyrighted by other commercial organizations or individuals that may not be used without obtaining prior approval from the holder of the copyright. </license-p></license></permissions><abstract><p>Background: Identifying risk factors for adverse health outcomes in children is important. The intrauterine environment plays a pivotal role for health and disease across life.</p><p>Objectives: We conducted a comprehensive study to determine whether common psychosocial stress during pregnancy is a risk factor for a wide spectrum of pediatric diseases in the offspring.</p><p>Methods: The study was conducted using prospective data in a population-based sample of mothers with live singleton births (<italic>n</italic> = 66,203; 71.4% of those eligible) from the Danish National Birth Cohort. We estimated the association between maternal stress during pregnancy (classified based on two <italic>a priori</italic>–defined indicators of common stress forms, life stress and emotional stress) and offspring diseases during childhood (grouped into 16 categories of diagnoses from the <italic>International Classification of Diseases, 10th Revision</italic>, based on data from national registries), controlling for maternal stress after pregnancy.</p><p>Results: Median age at end of follow-up was 6.2 (range, 3.6–8.9) years. Life stress (highest compared with lowest quartile) was associated with an increased risk of conditions originating in the perinatal period [odds ratio (OR) = 1.13; 95% confidence interval (CI): 1.06, 1.21] and congenital malformations (OR=1.17; CI: 1.06, 1.28) and of the first diagnosis of infection [hazard ratio (HR) = 1.28; CI: 1.17, 1.39], mental disorders (age 0–2.5 years: HR = 2.03; CI: 1.32, 3.14), and eye (age 0–4.5 years: HR = 1.27; CI: 1.06, 1.53), ear (HR = 1.36; CI: 1.23, 1.51), respiratory (HR = 1.27; CI; 1.19, 1.35), digestive (HR = 1.23; CI: 1.11, 1.37), skin (HR = 1.24; CI: 1.09, 1.43), musculoskeletal (HR = 1.15; CI: 1.01–1.30), and genitourinary diseases (HR = 1.25; CI; 1.08, 1.45). Emotional stress was associated with an increased risk for the first diagnosis of infection (HR = 1.09; CI: 1.01, 1.18) and a decreased risk for the first diagnosis of endocrine (HR = 0.81; CI; 0.67, 0.99), eye (HR = 0.84; CI; 0.71, 0.99), and circulatory diseases (age 0–3 years: HR = 0.63; CI: 0.42, 0.95).</p><p>Conclusions: Maternal life stress during pregnancy may be a common risk factor for impaired child health. The results suggest new approaches to reduce childhood diseases.</p></abstract><kwd-group kwd-group-type="author"><kwd>antenatal stress</kwd><kwd>child health and development</kwd><kwd>intrauterine exposure</kwd><kwd>prenatal exposure delayed effects</kwd><kwd>prenatal programming</kwd><kwd>psychosocial stress</kwd></kwd-group></article-meta></front><body><p>Early-life factors can predispose individuals to diseases over the life course (<xref rid="r31" ref-type="bibr">Gluckman et al. 2008</xref>). Follow-up studies have shown that fetal growth impairment is linked to an increased risk of morbidity and premature mortality (<xref rid="r4" ref-type="bibr">Barker et al. 1993</xref>; <xref rid="r24" ref-type="bibr">Forsen et al. 2000</xref>). However, fetal growth is probably only a crude indicator of complex developmental processes that are subject to genetic factors and various intrauterine exposures that may affect gene expression and influence disease susceptibility. Therefore, the effects of intrauterine exposures on postnatal outcomes should be studied more directly (<xref rid="r27" ref-type="bibr">Gillman 2002</xref>), and the National Institutes of Health and the World Health Organization (WHO) have advised that the role of maternal stress during pregnancy should be given high research priority (<xref rid="r53" ref-type="bibr">National Institutes of Health 2003</xref>; WHO 2006). Follow-up studies have raised concerns that offspring of mothers exposed to stress during pregnancy may have an increased risk of specific diseases such as malformations, asthma, and mental and behavioral disorders (<xref rid="r13" ref-type="bibr">Cookson et al. 2009</xref>; <xref rid="r35" ref-type="bibr">Hansen et al. 2000</xref>; <xref rid="r57" ref-type="bibr">O’Connor et al. 2002</xref>). However, a comprehensive study covering a larger spectrum of diseases is needed.</p><p>The purpose of this study was to assess the association between common psychosocial stress during pregnancy and the risk of a wide range of offspring diseases in a population-based birth cohort with prospective data linked with a national hospital register. The decision to give an overview of a broad range of diseases accounts for the large body of evidence linking maternal adversities with changes in numerous physiological systems in the offspring (<xref rid="r20" ref-type="bibr">Entringer et al. 2008</xref>; <xref rid="r22" ref-type="bibr">Field et al. 2002</xref>; <xref rid="r45" ref-type="bibr">Lin et al. 2004</xref>; <xref rid="r51" ref-type="bibr">Monk et al. 2004</xref>, <xref rid="r50" ref-type="bibr">2011</xref>; <xref rid="r56" ref-type="bibr">O’Connor et al. 2005</xref>).</p><sec sec-type="methods"><title>Methods</title><p><italic>Study cohort.</italic> This study is based on prospective data from the Danish National Birth Cohort, including births between 1996 and 2003 (<xref rid="r60" ref-type="bibr">Olsen et al. 2001</xref>). Participants gave written informed consent, and the Danish National Committee for Biomedical Research Ethics, Copenhagen, approved the study on behalf of all committees in the country. About 50% of all general practitioners in the country took part in the recruitment, and 60% of the invited women participated. Of these, we considered as eligible all pregnancies with live singleton births (see “Results”).</p><p><italic>Stress exposure.</italic> We obtained information on maternal stress from a telephone interview taken around 30 weeks of gestation. We studied two <italic>a priori</italic>–defined types of stress—emotional stress and life stress—as used in previous studies (<xref rid="r69" ref-type="bibr">Sondergaard et al. 2003</xref>; <xref rid="r76" ref-type="bibr">Tegethoff et al. 2010a</xref>, <xref rid="r77" ref-type="bibr">2010b</xref>). The separation of these two types of maternal stress is theoretically based on the well-described stressor specificity of biological responses, which may differentially affect the fetus (<xref rid="r61" ref-type="bibr">Pacak and Palkovits 2001</xref>; <xref rid="r65" ref-type="bibr">Richardson et al. 2006</xref>). Virtually all available studies investigating maternal stress have used one of these two types of stress measures (<xref rid="r9" ref-type="bibr">Beydoun and Saftlas 2008</xref>; <xref rid="r46" ref-type="bibr">Lobel 1994</xref>). The applied instruments were developed to be feasible in a large cohort study. Emotional stress and life stress were each assessed by nine questions, each covering the time period since the beginning of pregnancy. Answers (no = 0, a little = 1, a lot = 2) were added up into a score for each stress type (range, 0–18). The scale for emotional stress covers self-reported feelings (e.g., anxiety, nervousness; for detailed description of items, see <xref ref-type="table" rid="t1">Table 1</xref>). Items were selected from the Symptom Check List-90 (<xref rid="r16" ref-type="bibr">Derogatis 1977</xref>) and The General Health Questionnaire (<xref rid="r32" ref-type="bibr">Goldberg 1972</xref>) to cover frequent symptoms of anxiety and depression. Life stress was assessed using an inventory based on the major categories of the Life Events Questionnaire (<xref rid="r55" ref-type="bibr">Norbeck 1984</xref>) on whether the women felt burdened in major areas of life such as work, housing, and human relations (for detailed description of items, see <xref ref-type="table" rid="t1">Table 1</xref>). For additional information on scale validation, see Supplemental Material, Additional Methods 1 (<ext-link ext-link-type="uri" xlink:href="http://dx.doi.org/10.1289/ehp.1003253">http://dx.doi.org/10.1289/ehp.1003253</ext-link>). We addressed up to two missing answers per stress type by using person-specific mean substitution. Women with more than two missing answers were excluded. In the analyses, we included life stress and emotional stress as categorical independent variables, with the limits between the categories defined by cutoffs as close as possible to the quartiles of the distributions of the respective stress scores (<xref ref-type="table" rid="t2">Table 2</xref>). Even though some overlap of emotional stress and life stress was expected, a low correlation between these constructs (Spearman rho correlation: <italic>r</italic> = 0.46; <italic>p</italic> < 0.001) affirmed their discriminant validity. To account for overlap, the analysis of the associations between life stress and child diseases was adjusted for emotional stress, and vice versa.</p><table-wrap id="t1" orientation="portrait" position="float"><label>Table 1</label><caption><p>Items used to assess life stress and emotional stress.</p></caption><table frame="hsides" rules="groups" border="0"><thead><tr><th colspan="2" rowspan="1">Life stress</th><th colspan="2" rowspan="1">Emotional stress</th></tr><tr><th colspan="2" rowspan="1">Have you felt burdened during pregnancy by any of the things I am going to ask now. You may answer: no, a little, or a lot.</th><th colspan="2" rowspan="1">Now I am going to ask you how you have been feeling during pregnancy. You may answer: no, a little, or a lot.</th></tr></thead><tbody><tr><td colspan="2" rowspan="1">Have you been burdened by . <italic>. .</italic></td><td rowspan="1" colspan="1"></td><td colspan="2" rowspan="1">Have you felt . . .</td></tr><tr><td rowspan="1" colspan="1">1.</td><td rowspan="1" colspan="1"><italic>. . . </italic>financial circumstances?</td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1">1.</td><td rowspan="1" colspan="1"><italic>. . . </italic>scared for no reason?</td></tr><tr><td rowspan="1" colspan="1">2.</td><td rowspan="1" colspan="1"><italic>. . . </italic>your housing situation?</td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1">2.</td><td rowspan="1" colspan="1"><italic>. . . </italic>hopeless about the future?</td></tr><tr><td rowspan="1" colspan="1">3.</td><td rowspan="1" colspan="1"><italic>. . . </italic>your work situation?</td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1">3.</td><td rowspan="1" colspan="1"><italic>. . . </italic>constantly under strain?</td></tr><tr><td rowspan="1" colspan="1">4.</td><td rowspan="1" colspan="1"><italic>. . . </italic>the relationship to your partner?</td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1">4.</td><td rowspan="1" colspan="1"><italic>. . . </italic>nervous or shaky inside?</td></tr><tr><td rowspan="1" colspan="1">5.</td><td rowspan="1" colspan="1"><italic>. . . </italic>relationships to family and friends?</td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1">5.</td><td rowspan="1" colspan="1"><italic>. . . </italic>blue?</td></tr><tr><td rowspan="1" colspan="1">6.</td><td rowspan="1" colspan="1"><italic>. . . </italic>your pregnancy?</td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1">6.</td><td rowspan="1" colspan="1"><italic>. . . </italic>easily annoyed or irritated?</td></tr><tr><td rowspan="1" colspan="1">7.</td><td rowspan="1" colspan="1"><italic>. . . </italic>own diseases?</td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1">7.</td><td rowspan="1" colspan="1"><italic>. . . </italic>that everything was an effort?</td></tr><tr><td rowspan="1" colspan="1">8.</td><td rowspan="1" colspan="1"><italic>. . . </italic>disease of your partner, family members, or close friends?</td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1">8.</td><td rowspan="1" colspan="1"><italic>. . . </italic>tense or keyed up?</td></tr><tr><td rowspan="1" colspan="1">9.</td><td rowspan="1" colspan="1"><italic>. . . </italic>other things?</td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1">9.</td><td rowspan="1" colspan="1"><italic>. . . </italic>that everything was getting on top of you? </td></tr><tr><td colspan="5" rowspan="1"></td></tr></tbody></table></table-wrap><table-wrap id="t2" orientation="portrait" position="float"><label>Table 2</label><caption><p>Sample characteristics (<italic>n </italic>= 66,203).</p></caption><table frame="hsides" rules="groups" border="0"><thead><tr><th rowspan="1" colspan="1">Characteristic</th><th colspan="2" rowspan="1"><italic>n</italic> (%)<italic>a</italic></th></tr></thead><tbody><tr><td rowspan="1" colspan="1">Maternal age (years)</td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1"></td></tr><tr><td rowspan="1" colspan="1">< 27</td><td rowspan="1" colspan="1">13,614</td><td rowspan="1" colspan="1">(20.6)</td></tr><tr><td rowspan="1" colspan="1">27–29</td><td rowspan="1" colspan="1">17,880</td><td rowspan="1" colspan="1">(27.0)</td></tr><tr><td rowspan="1" colspan="1">30–32</td><td rowspan="1" colspan="1">16,517</td><td rowspan="1" colspan="1">(25.0)</td></tr><tr><td rowspan="1" colspan="1">> 32</td><td rowspan="1" colspan="1">18,192</td><td rowspan="1" colspan="1">(27.5)</td></tr><tr><td rowspan="1" colspan="1">Parity</td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1"></td></tr><tr><td rowspan="1" colspan="1">Primiparous</td><td rowspan="1" colspan="1">29,574</td><td rowspan="1" colspan="1">(44.7)</td></tr><tr><td rowspan="1" colspan="1">Multiparous</td><td rowspan="1" colspan="1">34,240</td><td rowspan="1" colspan="1">(51.7)</td></tr><tr><td rowspan="1" colspan="1">Unknown</td><td rowspan="1" colspan="1">2,389</td><td rowspan="1" colspan="1">(3.6)</td></tr><tr><td rowspan="1" colspan="1">General maternal health</td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1"></td></tr><tr><td rowspan="1" colspan="1">Very good</td><td rowspan="1" colspan="1">33,454</td><td rowspan="1" colspan="1">(50.5)</td></tr><tr><td rowspan="1" colspan="1">Average</td><td rowspan="1" colspan="1">28,114</td><td rowspan="1" colspan="1">(42.5)</td></tr><tr><td rowspan="1" colspan="1">Bad</td><td rowspan="1" colspan="1">2,263</td><td rowspan="1" colspan="1">(3.4)</td></tr><tr><td rowspan="1" colspan="1">Unknown</td><td rowspan="1" colspan="1">2,372</td><td rowspan="1" colspan="1">(3.6)</td></tr><tr><td rowspan="1" colspan="1">Socioeconomic status</td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1"></td></tr><tr><td rowspan="1" colspan="1">High</td><td rowspan="1" colspan="1">32,627</td><td rowspan="1" colspan="1">(49.3)</td></tr><tr><td rowspan="1" colspan="1">Medium</td><td rowspan="1" colspan="1">23,299</td><td rowspan="1" colspan="1">(35.2)</td></tr><tr><td rowspan="1" colspan="1">Low</td><td rowspan="1" colspan="1">5,220</td><td rowspan="1" colspan="1">(7.9)</td></tr><tr><td rowspan="1" colspan="1">Unknown</td><td rowspan="1" colspan="1">5,057</td><td rowspan="1" colspan="1">(7.6)</td></tr><tr><td rowspan="1" colspan="1">Infant sex</td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1"></td></tr><tr><td rowspan="1" colspan="1">Male</td><td rowspan="1" colspan="1">33,779</td><td rowspan="1" colspan="1">(51.0)</td></tr><tr><td rowspan="1" colspan="1">Female</td><td rowspan="1" colspan="1">32,424</td><td rowspan="1" colspan="1">(49.0)</td></tr><tr><td rowspan="1" colspan="1">Hypertension during pregnancy</td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1"></td></tr><tr><td rowspan="1" colspan="1">Yes</td><td rowspan="1" colspan="1">8,824</td><td rowspan="1" colspan="1">(13.3)</td></tr><tr><td rowspan="1" colspan="1">No</td><td rowspan="1" colspan="1">57,192</td><td rowspan="1" colspan="1">(86.4)</td></tr><tr><td rowspan="1" colspan="1">Unknown</td><td rowspan="1" colspan="1">187</td><td rowspan="1" colspan="1">(0.3)</td></tr><tr><td rowspan="1" colspan="1">Gestational diabetes</td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1"></td></tr><tr><td rowspan="1" colspan="1">Yes</td><td rowspan="1" colspan="1">1,632</td><td rowspan="1" colspan="1">(2.5)</td></tr><tr><td rowspan="1" colspan="1">No</td><td rowspan="1" colspan="1">64,225</td><td rowspan="1" colspan="1">(97.0)</td></tr><tr><td rowspan="1" colspan="1">Unknown</td><td rowspan="1" colspan="1">346</td><td rowspan="1" colspan="1">(0.5)</td></tr><tr><td rowspan="1" colspan="1">Smoking</td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1"></td></tr><tr><td rowspan="1" colspan="1">Yes</td><td rowspan="1" colspan="1">17,020</td><td rowspan="1" colspan="1">(25.7)</td></tr><tr><td rowspan="1" colspan="1">No</td><td rowspan="1" colspan="1">47,255</td><td rowspan="1" colspan="1">(71.4)</td></tr><tr><td rowspan="1" colspan="1">Unknown</td><td rowspan="1" colspan="1">1,928</td><td rowspan="1" colspan="1">(2.9)</td></tr><tr><td colspan="3" rowspan="1">Maternal life stress during pregnancy<italic>b</italic> (score)</td></tr><tr><td rowspan="1" colspan="1">Low (0)</td><td rowspan="1" colspan="1">19,793</td><td rowspan="1" colspan="1">(29.9)</td></tr><tr><td rowspan="1" colspan="1">Low-medium (> 0 to ≤ 1)</td><td rowspan="1" colspan="1">14,488</td><td rowspan="1" colspan="1">(21.9)</td></tr><tr><td rowspan="1" colspan="1">Medium-high (> 1 to ≤ 3)</td><td rowspan="1" colspan="1">20,377</td><td rowspan="1" colspan="1">(30.8)</td></tr><tr><td rowspan="1" colspan="1">High (> 3)</td><td rowspan="1" colspan="1">11,545</td><td rowspan="1" colspan="1">(17.4)</td></tr><tr><td colspan="3" rowspan="1">Maternal emotional stress during pregnancy<italic>b</italic> (score)</td></tr><tr><td rowspan="1" colspan="1">Low (≤ 1)</td><td rowspan="1" colspan="1">25,083</td><td rowspan="1" colspan="1">(37.9)</td></tr><tr><td rowspan="1" colspan="1">Low-medium (> 1 to ≤ 2)</td><td rowspan="1" colspan="1">11,432</td><td rowspan="1" colspan="1">(17.3)</td></tr><tr><td rowspan="1" colspan="1">Medium-high (> 2 to ≤ 4)</td><td rowspan="1" colspan="1">15,971</td><td rowspan="1" colspan="1">(24.1)</td></tr><tr><td rowspan="1" colspan="1">High (> 4)</td><td rowspan="1" colspan="1">13,717</td><td rowspan="1" colspan="1">(20.7)</td></tr><tr><td colspan="3" rowspan="1">Maternal life stress after pregnancy<italic>b</italic> (score)</td></tr><tr><td rowspan="1" colspan="1">Low (0)</td><td rowspan="1" colspan="1">32,296</td><td rowspan="1" colspan="1">(48.8)</td></tr><tr><td rowspan="1" colspan="1">Low-medium (> 0 to ≤ 1)</td><td rowspan="1" colspan="1">13,829</td><td rowspan="1" colspan="1">(20.9)</td></tr><tr><td rowspan="1" colspan="1">Medium-high (> 1 to ≤ 2)</td><td rowspan="1" colspan="1">9,725</td><td rowspan="1" colspan="1">(14.7)</td></tr><tr><td rowspan="1" colspan="1">High (> 2)</td><td rowspan="1" colspan="1">10,353</td><td rowspan="1" colspan="1">(15.6)</td></tr><tr><td colspan="3" rowspan="1">Maternal emotional stress after pregnancy<italic>b</italic> (score)</td></tr><tr><td rowspan="1" colspan="1">Low (0)</td><td rowspan="1" colspan="1">22,313</td><td rowspan="1" colspan="1">(33.7)</td></tr><tr><td rowspan="1" colspan="1">Low-medium (> 0 to ≤ 1)</td><td rowspan="1" colspan="1">12,557</td><td rowspan="1" colspan="1">(19.0)</td></tr><tr><td rowspan="1" colspan="1">Medium-high (> 1 to ≤ 3)</td><td rowspan="1" colspan="1">15,847</td><td rowspan="1" colspan="1">(23.9)</td></tr><tr><td rowspan="1" colspan="1">High (> 3)</td><td rowspan="1" colspan="1">15,486</td><td rowspan="1" colspan="1">(23.4)</td></tr><tr><td colspan="3" rowspan="1"><bold>a</bold>Percentages may not total 100 because of rounding. <bold>b</bold>Stress groups were defined by the closest possible cutoffs to the quartiles of their distribution.<bold></bold></td></tr></tbody></table></table-wrap><p><italic>Outcome measures.</italic> Information on children’s diseases was derived from the Danish National Hospital Register (Copenhagen, Denmark), which contains information on all inpatients and outpatients in Danish hospitals and provides reporting of diagnoses, the validity of which has been demonstrated for several diseases (<xref rid="r2" ref-type="bibr">Andersen et al. 1999</xref>; <xref rid="r11" ref-type="bibr">Christensen et al. 2007</xref>; <xref rid="r52" ref-type="bibr">Moth et al. 2007</xref>; <xref rid="r71" ref-type="bibr">Sorensen and Larsen 1994</xref>; <xref rid="r83" ref-type="bibr">Vestergaard et al. 2006</xref>). All hospital diagnoses, based on the Danish version of the <italic>International Classification of Diseases, 10th Revision</italic> (ICD-10) (<xref rid="r15" ref-type="bibr">Danish National Board of Health 1993</xref>), were divided into major diagnostic categories (dichotomous) selected <italic>a priori</italic> according to chapters 1–14 and 16 and 17 of the ICD-10, which cover all relevant diagnoses during childhood. Additionally, we used a dichotomous overall category (“any disease”), indicating whether any disease in any of the categories had been diagnosed [see Supplemental Material, <xref ref-type="table" rid="t1">Table 1</xref> (<ext-link ext-link-type="uri" xlink:href="http://dx.doi.org/10.1289/ehp.1003253">http://dx.doi.org/10.1289/ehp.1003253</ext-link>) for details concerning the major diagnostic categories and numbers of diagnoses for specific outcomes within each category in the study cohort].</p><p><italic>Statistical analyses.</italic> We used the Wilcoxon signed-rank test to compare the score reflecting maternal stress during pregnancy with the score reflecting maternal stress after pregnancy for each stress type.</p><p>For conditions that may have onset after the perinatal period (diagnostic categories 1–14) and for “any disease,” we estimated the associations of maternal life stress and emotional stress during pregnancy with the risk of the offspring for the first diagnosis of a disease within each major diagnostic category by conducting separate Cox proportional hazards regression models for each of the diagnostic categories. Data on timing of competing events, such as deaths and emigration, were not available in this data source, but these events are uncommon in Denmark (WHO 2005). In each Cox proportional hazards regression model, data on all children without a diagnosis in the respective category were censored at the end of follow-up (31 December 2006). Age in days was used as time variable. We tested the proportional hazards assumption by visually checking Schoenfeld residuals and the test of Grambsch and Therneau. If the assumption was not met, we stratified the data by age (<xref ref-type="table" rid="t3">Table 3</xref>) based on the Schoenfeld residuals to ensure that the proportional hazards assumption was met. For conditions originating in the perinatal period and for malformations, we used separate logistic regression models to estimates associations with maternal life stress and emotional stress. Low-stress groups were used as reference categories. We tested for trends using log-rank–based trend tests of the survivor function stratifying for the other covariates or by repeating logistic regressions with the stress categories modeled as a continuous ordinal variable.</p><table-wrap id="t3" orientation="portrait" position="float"><label>Table 3</label><caption><p>Cox regression models of offspring diseases predicted by stress during pregnancy.</p></caption><table frame="hsides" rules="groups" border="0"><thead><tr><th rowspan="2" colspan="1">ICD-10 category and name</th><th rowspan="2" colspan="1">No. of children with a diagnosis </th><th colspan="8" rowspan="1">Life stress Adjusted<italic>a</italic> HR (95% CI)</th><th rowspan="2" colspan="1">Life stress <italic>p</italic> for trend</th><th colspan="8" rowspan="1">Emotional stress Adjusted<italic>a</italic> HR (95% CI)</th><th rowspan="2" colspan="1">Emotional stress <italic>p</italic> for trend</th></tr><tr><th colspan="2" rowspan="1">Low-medium vs. low</th><th colspan="2" rowspan="1">Medium-high vs. low</th><th colspan="2" rowspan="1">High vs. low</th><th colspan="2" rowspan="1">Low-medium vs. low</th><th colspan="2" rowspan="1">Medium-high vs. low</th><th colspan="2" rowspan="1">High vs. low</th></tr></thead><tbody><tr><td rowspan="1" colspan="1"> 1. Infections, parasitic diseases</td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1">6,674</td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1">1.08</td><td rowspan="1" colspan="1">(1.00, 1.16)</td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1">1.10</td><td rowspan="1" colspan="1">(1.03, 1.18)</td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1">1.28</td><td rowspan="1" colspan="1">(1.17, 1.39)</td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1">< 0.001</td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1">0.99</td><td rowspan="1" colspan="1">(0.92, 1.07)</td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1">1.06</td><td rowspan="1" colspan="1">(0.99, 1.13)</td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1">1.09</td><td rowspan="1" colspan="1">(1.01, 1.18)</td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1">0.008</td></tr><tr><td rowspan="1" colspan="1"> 2. Neoplasms</td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1">711</td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1">0.93</td><td rowspan="1" colspan="1">(0.75, 1.16)</td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1">1.06</td><td rowspan="1" colspan="1">(0.86, 1.30)</td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1">0.94</td><td rowspan="1" colspan="1">(0.73, 1.22)</td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1">0.99</td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1">0.96</td><td rowspan="1" colspan="1">(0.76, 1.20)</td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1">1.07</td><td rowspan="1" colspan="1">(0.86, 1.32)</td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1">1.13</td><td rowspan="1" colspan="1">(0.89, 1.44)</td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1">0.35</td></tr><tr><td rowspan="1" colspan="1"> 3. Diseases of blood, immune system</td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1">512</td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1">1.01</td><td rowspan="1" colspan="1">(0.78, 1.31)</td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1">1.01</td><td rowspan="1" colspan="1">(0.78, 1.30)</td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1">1.19</td><td rowspan="1" colspan="1">(0.89, 1.59)</td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1">0.49</td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1">1.17</td><td rowspan="1" colspan="1">(0.90, 1.52)</td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1">1.17</td><td rowspan="1" colspan="1">(0.91, 1.50)</td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1">1.12</td><td rowspan="1" colspan="1">(0.85, 1.48)</td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1">0.51</td></tr><tr><td rowspan="1" colspan="1"> 4. Endocrine, metabolic disorders</td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1">1,178</td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1">1.03</td><td rowspan="1" colspan="1">(0.87, 1.22)</td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1">1.09</td><td rowspan="1" colspan="1">(0.93, 1.28)</td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1">1.20</td><td rowspan="1" colspan="1">(0.99, 1.47)</td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1">0.09</td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1">1.03</td><td rowspan="1" colspan="1">(0.87, 1.21)</td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1">0.87</td><td rowspan="1" colspan="1">(0.74, 1.03)</td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1">0.81</td><td rowspan="1" colspan="1">(0.67, 0.99)</td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1">0.02</td></tr><tr><td rowspan="1" colspan="1"> 5. Mental and behavioral disorders<italic>b</italic></td><td rowspan="3" colspan="1"></td><td rowspan="1" colspan="1">543</td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1">1.12</td><td rowspan="1" colspan="1">(0.87, 1.44)</td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1">0.88</td><td rowspan="1" colspan="1">(0.68, 1.13)</td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1">0.86</td><td rowspan="1" colspan="1">(0.65, 1.14)</td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1">0.076</td></tr><tr><td rowspan="1" colspan="1">≤ 2.5 years</td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1">1.49</td><td rowspan="1" colspan="1">(0.98, 2.25)</td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1">1.34</td><td rowspan="1" colspan="1">(0.90, 2.01)</td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1">2.03</td><td rowspan="1" colspan="1">(1.32, 3.14)</td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1">0.007</td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1"></td></tr><tr><td rowspan="1" colspan="1">> 2.5 years</td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1">0.78</td><td rowspan="1" colspan="1">(0.55, 1.10)</td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1">1.06</td><td rowspan="1" colspan="1">(0.78, 1.43)</td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1">1.11</td><td rowspan="1" colspan="1">(0.78, 1.58)</td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1">0.747</td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1"></td></tr><tr><td rowspan="1" colspan="1"> 6. Diseases of nervous system</td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1">1,268</td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1">1.00</td><td rowspan="1" colspan="1">(0.85, 1.18)</td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1">1.06</td><td rowspan="1" colspan="1">(0.90, 1.23)</td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1">1.17</td><td rowspan="1" colspan="1">(0.96, 1.42)</td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1">0.21</td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1">0.85</td><td rowspan="1" colspan="1">(0.72, 1.01)</td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1">0.97</td><td rowspan="1" colspan="1">(0.83, 1.13)</td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1">0.86</td><td rowspan="1" colspan="1">(0.72, 1.04)</td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1">0.15</td></tr><tr><td rowspan="1" colspan="1"> 7. Diseases of eye<italic>b</italic></td><td rowspan="3" colspan="1"></td><td rowspan="1" colspan="1">1,451</td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1"></td></tr><tr><td rowspan="1" colspan="1">≤ 4.5 years</td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1">0.98</td><td rowspan="1" colspan="1">(0.83, 1.16)</td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1">0.99</td><td rowspan="1" colspan="1">(0.84, 1.15)</td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1">1.27</td><td rowspan="1" colspan="1">(1.06, 1.53)</td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1">0.34</td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1">0.95</td><td rowspan="1" colspan="1">(0.82, 1.11)</td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1">0.98</td><td rowspan="1" colspan="1">(0.84, 1.13)</td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1">0.84</td><td rowspan="1" colspan="1">(0.71, 0.99)</td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1">0.14</td></tr><tr><td rowspan="1" colspan="1">> 4.5 years</td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1">1.27</td><td rowspan="1" colspan="1">(0.89, 1.82)</td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1">1.62</td><td rowspan="1" colspan="1">(1.18, 2.22)</td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1">1.19</td><td rowspan="1" colspan="1">(0.80, 1.78)</td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1">0.13</td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1"></td></tr><tr><td rowspan="1" colspan="1"> 8. Diseases of ear</td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1">4,344</td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1">1.04</td><td rowspan="1" colspan="1">(0.95, 1.14)</td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1">1.15</td><td rowspan="1" colspan="1">(1.05, 1.25)</td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1">1.36</td><td rowspan="1" colspan="1">(1.23, 1.51)</td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1">< 0.001</td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1">1.06</td><td rowspan="1" colspan="1">(0.97, 1.16)</td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1">1.03</td><td rowspan="1" colspan="1">(0.95, 1.12)</td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1">1.04</td><td rowspan="1" colspan="1">(0.95, 1.15)</td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1">0.25</td></tr><tr><td rowspan="1" colspan="1"> 9. Diseases of circulatory system<italic>b</italic></td><td rowspan="3" colspan="1"></td><td rowspan="1" colspan="1">362</td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1">1.14</td><td rowspan="1" colspan="1">(0.85, 1.54)</td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1">1.03</td><td rowspan="1" colspan="1">(0.77, 1.38)</td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1">1.29</td><td rowspan="1" colspan="1">(0.91, 1.84)</td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1">0.07</td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1"></td></tr><tr><td rowspan="1" colspan="1">≤ 3.0 years</td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1">0.84</td><td rowspan="1" colspan="1">(0.57, 1.24)</td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1">0.70</td><td rowspan="1" colspan="1">(0.49, 1.02)</td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1">0.63</td><td rowspan="1" colspan="1">(0.42, 0.95)</td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1">0.08</td></tr><tr><td rowspan="1" colspan="1">> 3.0 years</td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1">0.95</td><td rowspan="1" colspan="1">(0.58, 1.55)</td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1">0.61</td><td rowspan="1" colspan="1">(0.37, 1.01)</td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1">1.16</td><td rowspan="1" colspan="1">(0.74, 1.82)</td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1">0.93</td></tr><tr><td rowspan="1" colspan="1">10. Diseases of respiratory system</td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1">12,442</td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1">1.04</td><td rowspan="1" colspan="1">(0.99, 1.10)</td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1">1.14</td><td rowspan="1" colspan="1">(1.08, 1.20)</td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1">1.27</td><td rowspan="1" colspan="1">(1.19, 1.35)</td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1">< 0.001</td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1">0.98</td><td rowspan="1" colspan="1">(0.93, 1.04)</td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1">0.97</td><td rowspan="1" colspan="1">(0.92, 1.02)</td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1">1.00</td><td rowspan="1" colspan="1">(0.94, 1.06)</td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1">0.98</td></tr><tr><td rowspan="1" colspan="1">11. Diseases of digestive system</td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1">4,032</td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1">1.06</td><td rowspan="1" colspan="1">(0.97, 1.17)</td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1">1.21</td><td rowspan="1" colspan="1">(1.11, 1.31)</td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1">1.23</td><td rowspan="1" colspan="1">(1.11, 1.37)</td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1">< 0.001</td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1">0.99</td><td rowspan="1" colspan="1">(0.90, 1.09)</td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1">1.03</td><td rowspan="1" colspan="1">(0.95, 1.13)</td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1">0.97</td><td rowspan="1" colspan="1">(0.87, 1.07)</td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1">0.71</td></tr><tr><td rowspan="1" colspan="1">12. Diseases of skin</td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1">2,500</td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1">0.95</td><td rowspan="1" colspan="1">(0.85, 1.07)</td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1">1.06</td><td rowspan="1" colspan="1">(0.95, 1.19)</td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1">1.24</td><td rowspan="1" colspan="1">(1.09, 1.43)</td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1">0.005</td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1">0.97</td><td rowspan="1" colspan="1">(0.86, 1.09)</td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1">0.92</td><td rowspan="1" colspan="1">(0.82, 1.03)</td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1">0.93</td><td rowspan="1" colspan="1">(0.82, 1.06)</td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1">0.33</td></tr><tr><td rowspan="1" colspan="1">13. Diseases of musculoskeletal system</td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1">3,107</td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1">1.03</td><td rowspan="1" colspan="1">(0.93, 1.14)</td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1">1.06</td><td rowspan="1" colspan="1">(0.96, 1.17)</td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1">1.15</td><td rowspan="1" colspan="1">(1.01, 1.30)</td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1">0.01</td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1">0.99</td><td rowspan="1" colspan="1">(0.89, 1.10)</td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1">0.91</td><td rowspan="1" colspan="1">(0.83, 1.01)</td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1">0.99</td><td rowspan="1" colspan="1">(0.88, 1.11)</td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1">0.67</td></tr><tr><td rowspan="1" colspan="1">14. Diseases of genitourinary system</td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1">2,243</td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1">1.13</td><td rowspan="1" colspan="1">(1.00, 1.27)</td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1">1.19</td><td rowspan="1" colspan="1">(1.06, 1.34)</td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1">1.25</td><td rowspan="1" colspan="1">(1.08, 1.45)</td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1">0.02</td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1">0.96</td><td rowspan="1" colspan="1">(0.85, 1.09)</td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1">1.09</td><td rowspan="1" colspan="1">(0.97, 1.22)</td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1">0.97</td><td rowspan="1" colspan="1">(0.85, 1.11)</td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1">0.86</td></tr><tr><td rowspan="1" colspan="1">Any</td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1">34,665</td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1">1.02</td><td rowspan="1" colspan="1">(0.99, 1.05)</td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1">1.11</td><td rowspan="1" colspan="1">(1.08, 1.14)</td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1">1.16</td><td rowspan="1" colspan="1">(1.12, 1.20)</td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1">< 0.001</td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1">1.00</td><td rowspan="1" colspan="1">(0.97, 1.03)</td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1">1.01</td><td rowspan="1" colspan="1">(0.98, 1.04)</td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1">1.03</td><td rowspan="1" colspan="1">(0.99, 1.06)</td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1">0.07</td></tr><tr><td colspan="25" rowspan="1">HRs for the offspring having an initial diagnosis within the respective diagnostic category (outcomes) according to maternal life stress and emotional stress during pregnancy (predictors) (<italic>n</italic> = 66,203). Information on diagnoses of the children was obtained from the database-linked Danish National Hospital Register, which contains information on all diagnoses of inpatients and outpatients in Danish hospitals. In each diagnostic category, we used the initial diagnosis.<bold></bold><bold>a</bold>Model stratified for socioeconomic status, parity, maternal age, general maternal health, and infant sex, and adjusted for postnatal life stress and postnatal emotional stress of the mother. <bold>b</bold>Data were split at indicated times.</td></tr></tbody></table></table-wrap><p>We calculated all standard errors using the clustered sandwich estimator to correct for possible dependence between health outcomes in infants born to the same mother (<italic>n</italic> = 3,029). Moreover, to control for previous reproductive experiences and their possible effect on exposures (<xref rid="r59" ref-type="bibr">Olsen 2008</xref>), we repeated all analyses including only the first pregnancy of each woman in the cohort.</p><p>To obtain less-confounded estimates, we adjusted for potential predictors of child health, selected <italic>a priori</italic>, including socioeconomic status (<xref rid="r29" ref-type="bibr">Gissler et al. 1998</xref>) (based on occupation of the mother; see <xref rid="r7" ref-type="bibr">Bech et al. 2005</xref>), parity (<xref rid="r19" ref-type="bibr">Dockerty et al. 2001</xref>), maternal age (<xref rid="r37" ref-type="bibr">Hassold and Chiu 1985</xref>), self-reported general maternal health (<xref rid="r84" ref-type="bibr">Waters et al. 2000</xref>), and infant sex (<xref rid="r28" ref-type="bibr">Gissler et al. 1999</xref>), categorized as indicated in <xref ref-type="table" rid="t2">Table 2</xref>. Moreover, for explorative purposes, we repeated the analyses, controlling for self-reported hypertension during pregnancy (<xref rid="r21" ref-type="bibr">Fatemeh et al. 2010</xref>), gestational diabetes (<xref rid="r1" ref-type="bibr">Aman et al. 2011</xref>), and maternal smoking during pregnancy (<xref rid="r67" ref-type="bibr">Shea and Steiner 2008</xref>) as potential mediators (categorized as yes, no, or unknown). In addition, we repeated the analyses, controlling for birth weight and length of gestation (<xref rid="r27" ref-type="bibr">Gillman 2002</xref>) (continuous) as potential mediators. We obtained information on socioeconomic status, parity, and general maternal health from an interview around 12 weeks of gestation; on smoking, hypertension, and gestational diabetes from interviews around 12 weeks of gestation, 30 weeks of gestation, and 6 months postpartum; and on sex, maternal age at delivery, birth weight, and length of gestation from the Danish Medical Birth Registry (Copenhagen, Denmark). We extended the model by adjusting for postnatal exposure to maternal stress assessed, according to the method described for maternal stress during pregnancy, at 6 months postpartum, covering the time since parturition. High maternal stress may be a consequence rather than a cause of offspring disease within the first 6 months of life (<xref rid="r26" ref-type="bibr">Fowlie and McHaffie 2004</xref>). Therefore, we repeated the analyses after excluding all cases having their first diagnosis within the first 7 months of life.</p><p>All hypothesis tests were two-tailed, with the level of significance set at 0.05. We addressed loss to follow-up and missing data by restricting analyses to mother–child pairs with complete data on stress. For those with missing information on a particular covariate, we included an additional “missing” category for the respective variable.</p></sec><sec><title>Results</title><p><italic>Study cohort characteristics.</italic> Complete information on maternal stress during and after pregnancy and on diagnoses was available for 66,203 (99%) of the eligible mother–child pairs that participated in all of the relevant interviews [see Supplemental Material, Figure 1 (<ext-link ext-link-type="uri" xlink:href="http://dx.doi.org/10.1289/ehp.1003253">http://dx.doi.org/10.1289/ehp.1003253</ext-link>) for details regarding study recruitment and observations included in this analysis]. Sample characteristics are provided in <xref ref-type="table" rid="t2">Table 2</xref> (for additional information on the sample characteristics according to the stress categories, see Supplemental Material, <xref ref-type="table" rid="t2">Table 2</xref>). Median age at the end of follow-up was 6.2 (range, 3.6–8.9) years. Life and emotional stress were reported as stronger before than after birth (life stress: z = 94.81, <italic>p</italic> < 0.001; emotional stress: z = 66.18, <italic>p</italic> < 0.001, Wilcoxon signed-rank tests). Cumulative lifetime incidences of all diagnostic categories are shown according to quartile of prenatal life or emotional stress in Supplemental Material, Figure 2.</p><p><italic>Regression analyses.</italic> After adjustment, maternal life stress during pregnancy was associated with an increased disease risk in 11 of 16 diagnostic categories, including an increased risk for the first diagnosis of infectious and parasitic diseases, mental and behavioral disorders (up to 2.5 years of age), diseases of the eye, ear, respiratory system, digestive system, skin, musculoskeletal and genitourinary systems, and of any disease (<xref ref-type="table" rid="t3">Table 3</xref>). Maternal life stress during pregnancy was associated with an increased risk of conditions originating in the perinatal period and of congenital malformations (<xref ref-type="table" rid="t4">Table 4</xref>).</p><table-wrap id="t4" orientation="portrait" position="float"><label>Table 4</label><caption><p>Logistic regression models of offspring diseases predicted by stress during pregnancy.</p></caption><table frame="hsides" rules="groups" border="0"><thead><tr><th rowspan="2" colspan="1">No. of children with a diagnosis</th><th colspan="8" rowspan="1">Life stress Adjusted<italic>a</italic> OR (95% CI)</th><th colspan="8" rowspan="1">Emotional stress Adjusted<italic>a</italic> OR (95% CI)</th><th rowspan="2" colspan="1">Emotional stress <italic>p</italic> for trend</th></tr><tr><th rowspan="1" colspan="1">ICD-10 category and name</th><th colspan="2" rowspan="1">Low-medium vs. low</th><th colspan="2" rowspan="1">Medium-high vs. low</th><th colspan="2" rowspan="1">High vs. low</th><th rowspan="1" colspan="1">Life stress <italic>p</italic> for trend</th><th colspan="2" rowspan="1">Low-medium vs. low</th><th colspan="2" rowspan="1">Medium-high vs. low</th><th colspan="2" rowspan="1">High vs. low</th></tr></thead><tbody><tr><td colspan="2" rowspan="1">16. Conditions originating in perinatal period</td><td rowspan="1" colspan="1">12,590</td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1">1.03</td><td rowspan="1" colspan="1">(0.97, 1.09)</td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1">1.11</td><td rowspan="1" colspan="1">(1.06, 1.18)</td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1">1.13</td><td rowspan="1" colspan="1">(1.06, 1.21)</td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1">< 0.001</td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1">1.01</td><td rowspan="1" colspan="1">(0.95, 1.07)</td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1">1.02</td><td rowspan="1" colspan="1">(0.97, 1.07)</td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1">1.04</td><td rowspan="1" colspan="1">(0.98, 1.10)</td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1">0.24</td></tr><tr><td rowspan="1" colspan="1">17. Malformations</td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1">5,534</td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1">1.03</td><td rowspan="1" colspan="1">(0.95, 1.12)</td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1">1.13</td><td rowspan="1" colspan="1">(1.05, 1.21)</td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1">1.17</td><td rowspan="1" colspan="1">(1.06, 1.28)</td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1">< 0.001</td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1">1.00</td><td rowspan="1" colspan="1">(0.92, 1.08)</td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1">1.00</td><td rowspan="1" colspan="1">(0.93, 1.08)</td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1">1.03</td><td rowspan="1" colspan="1">(0.95, 1.12)</td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1">0.54</td></tr><tr><td colspan="25" rowspan="1">Abbreviations: CI, confidence interval; OR, odds ratio. ORs for the offspring having conditions originating in the perinatal period and malformations (outcomes) according to maternal life stress and emotional stress during pregnancy (predictors) (<italic>n</italic> = 66,203). <bold>a</bold>Models adjusted for socioeconomic status, parity, maternal age, general maternal health, and infant sex.</td></tr></tbody></table></table-wrap><p>Maternal emotional stress during pregnancy was associated with an increased risk for the first diagnosis of infectious and parasitic diseases and a decreased risk for the first diagnosis of endocrine and metabolic disorders, diseases of the eye, and the circulatory system (up to 3 years of age). However, a significantly reduced risk of diseases of the eye and the circulatory system was seen only in offspring of highly stressed mothers. Crude estimates of the associations between maternal stress during pregnancy and offspring diseases (i.e., estimates not adjusted for any potential confounders) are provided in Supplemental Material, <xref ref-type="table" rid="t3">Table 3</xref> (<ext-link ext-link-type="uri" xlink:href="http://dx.doi.org/10.1289/ehp.1003253">http://dx.doi.org/10.1289/ehp.1003253</ext-link>).</p><p>When we repeated the adjusted analyses using only the first pregnancy of each woman in the cohort and when we repeated the adjusted analyses controlling for smoking, hypertension, and gestational diabetes, or for birth weight and length of gestation, the estimates were of similar magnitude as those presented in <xref ref-type="table" rid="t3">Tables 3</xref> and <xref ref-type="table" rid="t4">4</xref> (data not shown). Repeating the analyses after excluding cases having their first diagnosis before assessment of maternal stress after pregnancy did not appreciably change the magnitude of the significant estimates in the models [all changes in hazard ratio (HR) were < 0.10]. However, the prenatal life stress–associated risk for the first onset of mental disorders within the first 2.5 years of life decreased markedly [4th quartile vs. 1st quartile: HR =1.43; 95% confidence interval (CI): 0.82, 2.47 compared with HR = 2.03; CI: 1.32, 3.14].</p></sec><sec><title>Discussion and Conclusions</title><p>In this large population-based cohort study, maternal life stress during pregnancy was associated with an increased risk of a wide range of diseases during childhood. These findings are in line with data from animal models indicating changes in different physiological systems after maternal stress during pregnancy (<xref rid="r25" ref-type="bibr">Fowden et al. 2006</xref>). To our knowledge, this is the first comprehensive study of the relationship between maternal stress during pregnancy and a wide spectrum of offspring diseases during childhood.</p><p>Our study has important strengths, including prospective data collection for 66,203 mother–child pairs and linkage to a comprehensive medical registry with complete information on hospital discharge diagnoses. Although associations were of low to moderate strength, our results have broad relevance for the general population, because our definition of maternal stress focuses on everyday occurrences (rather than rare disasters or severe life events), and we focused on the whole range of illnesses, including very common diseases, which suggests that a substantial part of the population may be adversely affected by maternal stress. We adjusted for several potential confounders, but our results still may be biased by residual or uncontrolled confounding by factors such as chemical exposures. Temporal sequence, consistency of findings across a variety of categories, and evidence of a dose–response relationship support the possibility of a causal link (<xref rid="r34" ref-type="bibr">Grimes and Schulz 2002</xref>). We controlled for potential bias by maternal stress after pregnancy, which might increase the likelihood that a mother would seek to have her child hospitalized. In addition, it is unlikely that maternal stress would influence hospital treatment, because in the Danish health care system, 99% of the population must be referred for elective hospital treatment by a general practitioner, and both referrals and hospital treatment are free of charge for patients (<xref rid="r73" ref-type="bibr">Strandberg-Larsen et al. 2007</xref>). Moreover, we controlled for potential bias by reverse causation between child disease and maternal stress after pregnancy. One limitation is that we did not have data on the timing of the maternal stress exposure during pregnancy, which may play a role in the relationship between stress and long-term health, given that each organ system has a specific critical period in which it is most susceptible to intrauterine perturbations (<xref rid="r35" ref-type="bibr">Hansen et al. 2000</xref>; <xref rid="r39" ref-type="bibr">Khashan et al. 2008</xref>). However, life stress and emotional stress generally reflect chronic states of adversity (<xref rid="r48" ref-type="bibr">McEwen and Stellar 1993</xref>). Of all eligible mother–child pairs, 72% participated in the relevant interviews, and 99% of these were included in our analyses. Given the low loss to follow-up, the high percentage of complete data, and linkage to the Danish National Hospital Register, we think measurable selection bias is unlikely. However, missing stress interview data for 7,487 mother–child pairs [8% of those eligible; Supplemental Material, Figure 1 (<ext-link ext-link-type="uri" xlink:href="http://dx.doi.org/10.1289/ehp.1003253">http://dx.doi.org/10.1289/ehp.1003253</ext-link>)] may have been a consequence of premature birth in some cases, as the interview was not conducted if birth had already occurred. Therefore, the observed associations between stress during pregnancy and offspring health should not be generalized to children born extremely preterm (< 30 weeks of gestation). Finally, the different ICD-10 categories are heterogeneous with regard to grouping criteria (e.g., by organ system vs. etiology), but the ICD-10 has high reliability at the category level (<xref rid="r72" ref-type="bibr">Stausberg et al. 2008</xref>) and is the international standard diagnostic classification system of diseases.</p><p>Our findings on maternal life stress during pregnancy corroborate and extend the results of previous studies (<xref rid="r35" ref-type="bibr">Hansen et al. 2000</xref>; <xref rid="r44" ref-type="bibr">Li et al. 2008</xref>) to common forms of maternal stress and a broader range of disease outcomes. For example, in line with other studies (<xref rid="r8" ref-type="bibr">Beversdorf et al. 2005</xref>; <xref rid="r43" ref-type="bibr">Laplante et al. 2004</xref>), our data provide evidence for an increased risk of mental disorders during the first 2.5 years of life in offspring of mothers reporting high life stress during pregnancy compared with mothers reporting low life stress. However, we cannot rule out the possibility that this result was biased by reverse causation between offspring disease and postnatal life stress. In the present study, emotional stress during pregnancy was associated with an increased risk of infectious diseases only, whereas previous studies observed associations between emotional problems during pregnancy and other outcomes, including malformations, asthma, and mental disorders (<xref rid="r13" ref-type="bibr">Cookson et al. 2009</xref>; <xref rid="r57" ref-type="bibr">O’Connor et al. 2002</xref>; <xref rid="r66" ref-type="bibr">Schneid-Kofman et al. 2008</xref>; <xref rid="r80" ref-type="bibr">Van den Bergh and Marcoen 2004</xref>; <xref rid="r81" ref-type="bibr">Van den Bergh et al. 2005a</xref>, <xref rid="r82" ref-type="bibr">2005b</xref>). Discrepancies among studies may partly reflect differences in disease outcome or emotional stress classifications. For example, we classified outcomes based on clinical diagnoses (instead of subclinical dysfunction) in the offspring, and defined emotional stress across the entire range rather than focusing on more severe psychopathology, as in <xref rid="r66" ref-type="bibr">Schneid-Kofman et al. (2008)</xref>. Moreover, discrepancies between findings may be explained by differential mutual control for life stress and emotional stress and by differential control for maternal stress after pregnancy.</p><p>The decreased risk of certain diseases predicted by maternal emotional stress during pregnancy is in line with some previous evidence on beneficial effects of maternal stress on offspring development and brain maturation (<xref rid="r18" ref-type="bibr">DiPietro et al. 2006</xref>). However, some of these associations were seen only in offspring of highly stressed mothers, with marginal statistical significance. Hence, it is too early to conclude whether common forms of maternal emotional stress during pregnancy have the potential to protect certain organ systems against disease.</p><p>The observed association between maternal stress during pregnancy and child health may represent long-term consequences of subtle adaptations in multiple organ systems to the intrauterine environment (<xref rid="r5" ref-type="bibr">Bateson et al. 2004</xref>). The potential biological mechanisms underlying such developmental plasticity, including epigenetic processes (<xref rid="r30" ref-type="bibr">Gluckman et al. 2009</xref>) and changes at the molecular, cellular, and organ level in the offspring, provide new ideas to the fetal origin of chronic disease concept (<xref rid="r25" ref-type="bibr">Fowden et al. 2006</xref>; <xref rid="r31" ref-type="bibr">Gluckman et al. 2008</xref>; <xref rid="r78" ref-type="bibr">Tegethoff et al. 2009</xref>). Specifically, in relation to maternal stress during pregnancy, numerous subclinical alterations in physiology, including changes in immune, brain, cardiovascular, autonomic, endocrine, and metabolic function, have been described, such as changes in fetal heart rate, insulin resistance, increased concentrations of immunoglobulin E in cord blood and changes in hypothalamic–pituitary–adrenal (HPA) axis function (<xref rid="r20" ref-type="bibr">Entringer et al. 2008</xref>; <xref rid="r22" ref-type="bibr">Field et al. 2002</xref>; <xref rid="r45" ref-type="bibr">Lin et al. 2004</xref>; <xref rid="r51" ref-type="bibr">Monk et al. 2004</xref>, <xref rid="r50" ref-type="bibr">2011</xref>; <xref rid="r56" ref-type="bibr">O’Connor et al. 2005</xref>). Indeed, changes in HPA axis activity have been associated not only with maternal stress during pregnancy (<xref rid="r38" ref-type="bibr">Kapoor et al. 2008</xref>), but also with a wide range of diseases, including mental disorders (<xref rid="r33" ref-type="bibr">Goodyer et al. 2001</xref>), respiratory diseases (<xref rid="r63" ref-type="bibr">Priftis et al. 2009</xref>), diseases of the skin (<xref rid="r10" ref-type="bibr">Buske-Kirschbaum et al. 2010</xref>), and infectious diseases (<xref rid="r3" ref-type="bibr">Bailey et al. 2003</xref>). However, although the HPA axis has long been proposed as a causal link between early adversity and lifelong disease risk (<xref rid="r62" ref-type="bibr">Phillips 2007</xref>), it also has been suggested that HPA-related hormones may be noncausal markers of other causal mechanisms (<xref rid="r41" ref-type="bibr">Kramer et al. 2009</xref>, <xref rid="r42" ref-type="bibr">2010</xref>). There also is some evidence that maternal stress affects placental HSD11B2, which in turn regulates the bioavailability of glucocorticoids in fetal organs (<xref rid="r36" ref-type="bibr">Harris and Seckl 2011</xref>). Elevated stress levels across pregnancy have also been associated with changes in production of pro-inflammatory cytokines in the offspring (<xref rid="r14" ref-type="bibr">Coussons-Read et al. 2007</xref>). Dysregulation of cytokine production has been associated with certain mental disorders (<xref rid="r12" ref-type="bibr">Conti and Fulcheri 2010</xref>; <xref rid="r64" ref-type="bibr">Raison et al. 2010</xref>); infectious diseases (<xref rid="r74" ref-type="bibr">Subauste et al. 1995</xref>); diseases of the eye, such as conjunctivitis (<xref rid="r54" ref-type="bibr">Niederkorn 2008</xref>); ear, such as otitis media (<xref rid="r68" ref-type="bibr">Smirnova et al. 2002</xref>); respiratory system, such as asthma (<xref rid="r23" ref-type="bibr">Finkelman et al. 2010</xref>); digestive system, such as disorders related to gastrointestinal motility (<xref rid="r17" ref-type="bibr">De Winter and De Man 2010</xref>); urogenital system, such as urinary tract infection (<xref rid="r47" ref-type="bibr">Mak and Kuo 2006</xref>); and skin, such as atopic dermatitis (<xref rid="r49" ref-type="bibr">Miraglia del Giudice et al. 2006</xref>). Other mechanisms, such as catecholamines (<xref rid="r36" ref-type="bibr">Harris and Seckl 2011</xref>), intrauterine artery resistance, and intrauterine perception and learning (<xref rid="r40" ref-type="bibr">Kinsella and Monk 2009</xref>), also may be involved in offspring disease programming.</p><p>As yet, we cannot exclude the possibility that associations between stress during pregnancy and child diseases are mediated by maternal behavioral factors, such as stress-related changes in lifestyle, or health-related factors. Adjusting for maternal smoking during pregnancy, hypertension, and diabetes did not alter associations between maternal stress during pregnancy and child health. Maternal nutrition is another candidate mediator, because stress is related to quality of nutrition (<xref rid="r79" ref-type="bibr">Torres and Nowson 2007</xref>), and a relationship between nutrition during pregnancy and a range of offspring diseases has been well documented (<xref rid="r75" ref-type="bibr">Symonds et al. 2007</xref>). Moreover, alcohol consumption during pregnancy has been associated with birth defects (<xref rid="r58" ref-type="bibr">O’Leary et al. 2010</xref>) and impaired offspring development and behavior (<xref rid="r6" ref-type="bibr">Bay and Kesmodel 2010</xref>; <xref rid="r70" ref-type="bibr">Sood et al. 2001</xref>), indicating that alcohol may mediate associations between maternal stress and child health. Adjusting for birth weight and length of gestation had little effect on associations.</p><p>The observed associations between maternal stress during pregnancy and offspring health may have implications for public health and health care policy: First, further investment in the reduction of life stress during pregnancy may be an important opportunity to improve child health. Second, our findings encourage consideration of preventive strategies for infants of mothers who were highly stressed during pregnancy.</p><p>This study suggests that maternal life stress during pregnancy may be a common risk factor for a wide range of diseases in the offspring; however, we found almost no evidence for adverse health consequences of maternal emotional stress during pregnancy. Future studies should <italic>a</italic>) focus on the underlying mechanisms of these relationships, <italic>b</italic>) analyze the associations between selected forms of maternal stress during pregnancy and specific offspring diseases, including more detailed information on disease characteristics and information from further health registries, and <italic>c</italic>) identify modifiable determinants within this context to improve preventive approaches and interventions.</p></sec><sec><title>Supplemental Material</title><supplementary-material content-type="local-data" id="ehp-1003253-s001"><label>(892 KB) PDF</label><media xlink:href="ehp.1003253.s001.pdf" mimetype="application" mime-subtype="pdf" orientation="portrait" xlink:type="simple" id="d35e2312" position="anchor"><caption><p>Click here for additional data file.</p></caption></media></supplementary-material></sec></body><back><ack><p>We thank J. Meyer for critical reading of the manuscript. Validation of the stress scores was undertaken, in part, with data from the National Centre of Competence in Research, Swiss Etiological Study of Adjustment and Mental Health (sesam), funded by Swiss National Science Foundation project 51A240–104890.</p></ack><fn-group><fn fn-type="financial-disclosure"><p>The work for this manuscript was performed at the University of Basel, Basel, Switzerland, and at the University of California Los Angeles, Los Angeles, California, USA. The Danish National Birth Cohort was established by the Danish Epidemiology Science Centre, Department of Epidemiology, Institute of Public Health, University of Aarhus, Aarhus, Denmark. The Danish National Research Foundation established the Danish Epidemiology Science Centre, which initiated and created the Danish National Birth Cohort. The cohort is furthermore a result of a major grant from this foundation. Additional support for the Danish National Birth Cohort was obtained from the Pharmacy Foundation (<ext-link ext-link-type="uri" xlink:href="http://www.pharmacyfoundation.org">http://www.pharmacyfoundation.org</ext-link>), the Egmont Foundation (<ext-link ext-link-type="uri" xlink:href="http://www.egmont.com/the-egmont-foundation">www.egmont.com/the-egmont-foundation</ext-link>), the March of Dimes Birth Defects Foundation (<ext-link ext-link-type="uri" xlink:href="http://www.marchofdimes.com">http://www.marchofdimes.com</ext-link>), the Augustinus Foundation (Augustinus Fonden, København, Denmark), and the Health Foundation (<ext-link ext-link-type="uri" xlink:href="http://www.health.org.uk/">http://www.health.org.uk/</ext-link>). This project was financed by the German National Academic Foundation (to M.T.) and Swiss National Science Foundation project 51A240–104890 (to G.M.). 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