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Stress during pregnancy and offspring pediatric disease: a
national cohort study
Authors: Marion Tegethoff, Naomi Greene, Jern Olsen, Emmanuel Schaffner and Gunther Meinlschmidt
Date: Nov. 2011
From: Environmental Health Perspectives(Vol. 119, Issue 11)
Publisher: National Institute of Environmental Health Sciences
Document Type: Report
Length: 6,395 words
Content Level: (Level 5)
Lexile Measure: 1500L
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 (n =
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 a priori–defined indicators of common stress forms, life stress and emotional stress) and
offspring diseases during childhood (grouped into 16 categories of diagnoses from the International Classification of Diseases, 10th
Revision, based on data from national registries), controlling for maternal stress after pregnancy.
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 0-2.5 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.
Key WORDS: antenatal stress, child health and development, intrauterine exposure, prenatal exposure delayed effects, prenatal
programming, psychosocial stress. Environ Health Perspect 119:1647–1652 (2011).
http://dx.doi.org.libproxy.csun.edu/10.1289/ehp.1003253[Online 21 July 2011]
Early-life factors can predispose individuals to diseases over the life course (Gluckman et al. 2008). Followup studies have shown
that fetal growth impairment is linked to an increased risk of morbidity and premature mortality (Barker et al. 1993; Forsen et al.
2000). 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 (Gillman 2002), 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 (National Institutes of Health 2003; WHO 2006). Followup 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 (Cookson et al. 2009; Hansen et al. 2000; O’Connor et al. 2002). However, a comprehensive study covering a
larger spectrum of diseases is needed.
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 (Entringer et al. 2008; Field et al. 2002; Lin et al. 2004; Monk et al. 2004,
2011; O’Connor etal. 2005).
Study cohort. This study is based on prospective data from the Danish National Birth Cohort, including births between 1996 and 2003
(Olsen ct al. 2001). Participants gave written informed consent, and the Danish National Committee lor 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”). Stress exposure. We obtained information on maternal stress from a telephone inter?view taken
around 30 weeks of gestation. We studied two a priori-defined types of stress-emotional stress and life stress-as used in previous
studies (Sondergaard et al. 2003; Tegethoffet al. 2010a, 2010b). The separa?tion 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 (Pacak
and Palkovits 2001; Richardson et al. 2006). Virtually ail available studies investigating maternal stress have used one of these two
types of stress measures (Beydoun and Saftlas 2008; Lobel 1994). 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 cover?ing the rime 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 emo?tional stress covers self-reported feelings (e.g., anxiety, nervousness; lor detailed description of items, see Table 1).
Items were selected from the Symptom Check List-90 (Derogatis 1977) and The General Health Questionnaire (Goldberg 1972) 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 (Norbeck 1984) on whether the women felt burdened in major areas of life such as work, housing, and
human relations (for detailed description of items, see Table 1). For additional information on scale validation, see Supplemental
Material, AdditionalMethods 1 (http://dx.doi.org.libproxy.csun.edu/10.1289/ chp. 1003253). We addressed up to two miss?ing
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 (Table 2). Even
though some overlap of emotional stress and life stress was expected, a low correlation between these constructs (Spearman rho
correlation: r = 0.46; p 32 18,192(27.5) Parity Primiparous 29,574 (44.7) Multiparous 34,240(51.7) Unknown
2,389 (3.6) General maternal health Very good 33,454 (50.5) Average 28,114(42.5) Bad 2,263 (3.4) Unknown 2,372 (3.6)
Socioeconomic status High 32,627 (49.3) Medium 23,299 (35.2) Low 5,220 (7.9) Unknown 5,057 (7.6) Infant sex Male
33,779(51.0) Female 32,424 (49.0) Hypertension during pregnancy Yes 8,824(13.3) No 57,192(86.4) Unknown 187(0.3)
Gestational diabetes Yes 1,632(2.5) No 64,225 (97.0) Unknown 346 (0.5) Smoking Yes 17.020(25.7) No 47.255(71.4) Unknown
1,928(2.9) Maternal life stress during pregnancy(b) (score) Low (0) 19,793(29.9) Low-medium (> 0 to [less than or equal
to]1) 14,488(21.9) Medium-high (>1 to [less than or equal to] 3) 20,377 (30.8) High(>3) 11,545(17.4) Maternal emotional
stress during pregnancy(b) (score) Low([less than or equal to]1) 25, 083(37.9) Low-medium (> 1 to[less than or equal to]
2) 11,432(17.3) Medium-high (>2 to [less than or equal to]4) 15,971(24.1) High(>4) 13,717(20.7) Maternal life stress
after pregnancy(b) (score) Low (0) 32,296 (48.8) Low-medium (>0 to [less than or equal to]1) 13,829 (20.9) Medium-high (>
1 to[less than or equal to] 2) 9,725(14.7) High (>2) 10.353(15.6) Maternal emotional stress after pregnancy(b) (score)
Low(0) 22,313(33.7) Low-medium (>0 to [less than or equal to]1) 12,557(19.0) Medium-high (>1 to [less than or equal to]3)
15,847 (23.9) High (>3) 15,486(23.4) (a.) Percentages may not total 100 because of rounding. (b.) Stress groups were
defined by the closest possible cutoffs to the quartiles of their distribution.
Outcome measures. 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 (Andersen et al. 1999; Christensen et al. 2007; Moth et al. 2007;
Sorensen and Larsen 1994; Vestcrgaard et al. 2006). All hospital diagnoses, based on the Danish version of the International
Classification of Diseases 10th Revision (ICD-10) (Danish National Board of Health 1993), were divided into major diagnostic
categories (dichotomous) selected a priori 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, Table 1
(http://dx.doi.org.libproxy.csun.edu/10.1289/ehp.1003253) for details concerning the major diagnostic categories and numbers of
diagnoses for specific outcomes within each category in the study cohort].
Statistical analyses. We used the Wilcoxon signedrank test to compare the score reflecting maternal stress during pregnancy with the
score reflecting maternal stress after pregnancy for each stress type.
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, hut
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
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 (n = 3,029). Moreover, to control for previous reproductive experiences and their
possible effect on exposures (Olsen 2008), we repeated all analyses including only the first pregnancy of each woman in the cohort.
To obtain less-confounded estimates, we adjusted for potential predictors of child health, selected a priori including socioeconomic
status (Gissler et al. 1998) (based on occupation of the mother; see Bech et al. 2005), parity (Dockerty et al. 2001), maternal age
(Hassold and Chiu 1985), self-reported general maternal health (Waters et al. 2000), and infant sex (Gissler et al. 1999), categorized
as indicated in Table 2. Moreover, for explorative purposes, we repeated rhe maiyses, controlling for self-reported hypertension
during pregnancy (Fatemeh et al. 2010), gestational diabetes (Aman et al. 2011), and maternal smoking during pregnancy (Shea and
Steiner 2008) as potential mediators (categorized as yes, no, or unknown). In addition, we repeated the analyses, controlling for birth
weight and length of gestation (Gillman 2002) (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 (Fowlie and McHaffie 2004). Therefore, we repeated the analyses after
excluding all cases having their first diagnosis within the first 7 months of life.
All hypothesis cescs were two-tailed, with the level of significance set at 0.05. We addressed loss to followup 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.
Study cohort characteristics. 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
(http://dx.doi,org/10.1289/ehp.1003253) for details regarding study recruitment and observations included in this analysis]. Sample
characteristics are provided in Table 2 (for additional information on the sample characteristics according to the stress categories,
see Supplemental Material, Table 2). 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, p
2.5 years 0.78(0.55,1.10) 1.06(0.78,1.43) 6. Diseases of 1,268 1.00(0.85.1.18) 1.06(0.90,1.23) nervous system 7. Diseases
of 1,451 eye(b) [less then or 0.98(0.83,1.16) 0.99(0.84,1.15) equal to]4.5 years > 4.5 years 1.27(0.89,1.82)
1.62(188.8.131.52) 8. Diseases of 4,344 1.04(0.95,1.14) 1.15(1.05,1.25) ear 9. Diseases of 362 1.14(0.85,1.54)
1.03(0.77,1.38) circulatory system(b) [less then or equal to] 3.0 years > 3.0 years 10. Diseases of 12,442
1.04(0.99.1.10) 1.14(1.08.1.20) respiratory system 11. Diseases of 4,032 1.06(0.97,1.17) 1.21(1.11,1.31) digestive system
12. Diseases of 2,500 0.95(0.85,1.07) 1.06(0.95,1.19) skin 13. Diseases of 3,107 1.03(0.93,1.14) 1.06(0.96,1.17)
musculoskeletal system 14. Diseases of 2,243 1.13(1.00,1.27) 1.19(1.06,1.34) genitourinary system Any 34,665
1.02(0.99,1.05) 1.11(1.08,1.14) ICD-10 category and name High vs. low Life Strees p for trend 1. Infections, parasitic
1.28(1.17,1.39) 2.5 years 1.11 0.747 (0.78,1.58) 6. Diseases of nervous 1.17(0.96,1.42)
0.21 system 7. Diseases of eye * [less than 1.27(1.06,1.53) 0.34 or equal to]4.5 years > 4.5 years 1.19(0.80,1.78) 0.13
8. Diseases of ear 1.36(1.23,1.51)
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