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Results
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–hild
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–.9) years. Life and emotional stress were
reported as stronger before than after birth
(life stress: z = 94.81, p < 0.001; emotional
stress: z = 66.18, p < 0.001, Wilcoxon signedrank
tests). Cumulative lifetime incidences of
all diagnostic categories are shown according
to quartile of prenatal life or emotional stress
in Supplemental Material, Figure 2.
Regression analyses. 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
(Table 3). Maternal life stress during pregnancy
was associated with an increased risk of
conditions originating in the perinatal period and of congenital malformations (Table 4).
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 firstdiagnosis 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, Table 3 (http://dx.doi.org/10.1289/
ehp.1003253).
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 Tables 3 and 4 (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–ssociated 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].
Discussion and Conclusions
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
(Fowden et al. 2006). 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.
Our study has important strengths, including
prospective data collection for 66,203
mother–hild 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–esponse
relationship support the possibility of
a causal link (Grimes and Schulz 2002). 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
(Strandberg-Larsen et al. 2007). 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
(Hansen et al. 2000; Khashan et al. 2008).
However, life stress and emotional stress generally
reflect chronic states of adversity (McEwen
and Stellar 1993). Of all eligible mother–hild
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–hild pairs [8% of those eligible;
Supplemental Material, Figure 1 (http://
dx.doi.org/10.1289/ehp.1003253)] 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 (Stausberg et al.
2008) and is the international standard diagnostic
classification system of diseases.
Our findings on maternal life stress during
pregnancy corroborate and extend the
results of previous studies (Hansen et al. 2000;
Li et al. 2008) to common forms of maternal
stress and a broader range of disease outcomes.
For example, in line with other studies
(Beversdorf et al. 2005; Laplante et al. 2004),
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 (Cookson et al. 2009;
Results
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–hild
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–.9) years. Life and emotional stress were
reported as stronger before than after birth
(life stress: z = 94.81, p < 0.001; emotional
stress: z = 66.18, p < 0.001, Wilcoxon signedrank
tests). Cumulative lifetime incidences of
all diagnostic categories are shown according
to quartile of prenatal life or emotional stress
in Supplemental Material, Figure 2.
Regression analyses. 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
(Table 3). Maternal life stress during pregnancy
was associated with an increased risk of
conditions originating in the perinatal period and of congenital malformations (Table 4).
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 firstdiagnosis 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, Table 3 (http://dx.doi.org/10.1289/
ehp.1003253).
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 Tables 3 and 4 (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–ssociated 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].
Discussion and Conclusions
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
(Fowden et al. 2006). 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.
Our study has important strengths, including
prospective data collection for 66,203
mother–hild 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–esponse
relationship support the possibility of
a causal link (Grimes and Schulz 2002). 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
(Strandberg-Larsen et al. 2007). 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
(Hansen et al. 2000; Khashan et al. 2008).
However, life stress and emotional stress generally
reflect chronic states of adversity (McEwen
and Stellar 1993). Of all eligible mother–hild
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–hild pairs [8% of those eligible;
Supplemental Material, Figure 1 (http://
dx.doi.org/10.1289/ehp.1003253)] 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 (Stausberg et al.
2008) and is the international standard diagnostic
classification system of diseases.
Our findings on maternal life stress during
pregnancy corroborate and extend the
results of previous studies (Hansen et al. 2000;
Li et al. 2008) to common forms of maternal
stress and a broader range of disease outcomes.
For example, in line with other studies
(Beversdorf et al. 2005; Laplante et al. 2004),
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 (Cookson et al. 2009;
