Psychological Medicine (2015), 45, 985999.

Cambridge University Press 2014 OR I G I N A L A R T I C L E

doi:10.1017/S0033291714001998

Late preterm birth, post-term birth, and abnormal

fetal growth as risk factors for severe mental
disorders from early to late adulthood

M. Lahti1*, J. G. Eriksson2,3,4,5,6, K. Heinonen1, E. Kajantie2,7, J. Lahti1, K. Wahlbeck2,8, S. Tuovinen1,

A.-K. Pesonen1, M. Mikkonen2, C. Osmond9, D. J. P. Barker and K. Rikknen1
1
Institute of Behavioural Sciences, University of Helsinki, Finland
2
National Institute for Health and Welfare, Helsinki, Finland
3
Institute of Clinical Medicine, University of Helsinki, Finland
4
Vaasa Central Hospital, Vaasa, Finland
5
Unit of General Practice, Helsinki University Central Hospital, Helsinki, Finland
6
Folkhlsan Research Centre, Helsinki, Finland
7
Childrens Hospital, Helsinki University Central Hospital and University of Helsinki, Helsinki, Finland
8
The Finnish Association for Mental Health, Helsinki, Finland
9
MRC Lifecourse Epidemiology Unit, University of Southampton, UK

Background. Late preterm births constitute the majority of preterm births. However, most evidence suggesting that
preterm birth predicts the risk of mental disorders comes from studies on earlier preterm births. We examined if
late preterm birth predicts the risks of severe mental disorders from early to late adulthood. We also studied whether
adulthood mental disorders are associated with post-term birth or with being born small (SGA) or large (LGA) for
gestational age, which have been previously associated with psychopathology risk in younger ages.

Method. Of 12 597 Helsinki Birth Cohort Study participants, born 19341944, 664 were born late preterm, 1221
post-term, 287 SGA, and 301 LGA. The diagnoses of mental disorders were identied from national hospital discharge
and cause of death registers from 1969 to 2010. In total, 1660 (13.2%) participants had severe mental disorders.

Results. Individuals born late preterm did not differ from term-born individuals in their risk of any severe mental
disorder. However, men born late preterm had a signicantly increased risk of suicide. Post-term birth predicted
signicantly increased risks of any mental disorder in general and particularly of substance use and anxiety disorders.
Individuals born SGA had signicantly increased risks of any mental and substance use disorders. Women born LGA
had an increased risk of psychotic disorders.

Conclusions. Although men born late preterm had an increased suicide risk, late preterm birth did not exert widespread
effects on adult psychopathology. In contrast, the risks of severe mental disorders across adulthood were increased
among individuals born SGA and individuals born post-term.

Received 16 October 2013; Revised 13 June 2014; Accepted 25 July 2014; First published online 5 September 2014

Key words: Anxiety disorders, gestational age, longitudinal cohort study, mental disorders, mood disorders, personality
disorders, psychotic disorders, SGA and LGA birth, substance use disorders, suicides.

Introduction diagnostic boundaries (Abel et al. 2010; Fazel et al.

2012; DOnofrio et al. 2013). However, most of this evi-
Several studies have shown that preterm birth predicts
dence comes from studies comparing preterm indivi-
an increased risk of mental disorders in childhood,
duals born at the lowest end of gestational age or
adolescence, and young adulthood (Abel et al. 2010;
birth weight distributions with individuals born at
Loe et al. 2011; El Marroun et al. 2012; Fazel et al.
term and/or with normal weight. Nevertheless, late
2012; Nosarti et al. 2012; DOnofrio et al. 2013). This
preterm births, dened as birth from 34 + 0 to 36 + 6
risk extends to different mental disorders across
weeks+days of gestation, constitute over 70% of all pre-
term births (Davidoff et al. 2006; Moster et al. 2008).
Only a few studies to date have assessed the long-
* Address for correspondence: M. Lahti, Ph.D., Institute of
term consequences of late prematurity on mental dis-
Behavioural Sciences, University of Helsinki, Siltavuorenpenger 1 A,
PO Box 9, FI 00014 University of Helsinki, Finland.
orders. Previous evidence suggests that late preterm
(Email: marius.lahti@helsinki.) birth predicts an increased risk of any mental disorder
Deceased. and particularly of internalizing disorders in childhood
986 M. Lahti et al.
(Talge et al. 2010; Rogers et al. 2013). Signicant as-
sociations to attention decit hyperactive disorder
have also been reported (Linnet et al. 2006; Talge
et al. 2010), but the ndings are inconsistent (Rogers
et al. 2013). In a study with a follow-up to young adult-
hood, individuals born late preterm had increased
risks of schizophrenia and of disorders of psychologi-
cal development, behaviour, and emotion (Moster
et al. 2008). Another register study showed that a com-
bined group of individuals born moderately (at 32 + 0
to 33 + 6 weeks+days of gestation) or late preterm had
increased risks of any severe mental disorder, mood,
non-affective psychotic, organic, and stress-related
disorders, substance dependence, and of suicide and
suicide attempts in adolescence and young adulthood
(Lindstrm et al. 2009; Nosarti et al. 2012). However,
to our knowledge, no previous study has offered a life-
course perspective examining whether the possible ef-
fects of late preterm birth on mental disorders extend
across adult ages from young to old adulthood.
Some studies suggest that the increased risk for men-
tal disorders associated with preterm birth may charac-
terize especially those preterm individuals who were
born small for gestational age [SGA; dened as birth
size at 42 standard deviations (S.D.s) or below the
5th or 10th percentile of that predicted by their gesta-
tional age; Laursen et al. 2007; Rikknen et al. 2008;
Strang-Karlsson et al. 2008; Monls Gustafsson et al.
2009]. In fact, previous studies have shown that at
least until young adulthood, individuals born SGA
are at increased risk of severe mental disorders inde-
pendently of their gestational age (Abel et al. 2010;
Niederkrotenthaler et al. 2012; Nosarti et al. 2012).
However, we know of no studies that would have
examined whether the effects of SGA birth on mental
disorders persist from early to late adulthood.
Finally, scarce evidence suggests that post-term
(542 weeks of gestation; Lindstrm et al. 2005;
El Marroun et al. 2012) and large for gestational age
(LGA; 5+2 S.D.s or above 90th or 95th percentile;
van Lieshout & Boyle, 2011) births may also predict
increased risk of psychopathology in childhood and
in adolescence. However, to our knowledge, no studies
have systematically assessed the effects of post-term
birth on mental health in adulthood. Moreover, for
LGA birth, such studies are scarce, and the existing
studies have yielded inconsistent ndings (Moilanen
et al. 2010; Keskinen et al. 2013).
Hence, in the current study, we examine whether
each of these prenatal risk factors contribute to the
risks of mental disorders severe enough to lead to hos-
pitalization or contribute to death from early to late
adulthood. More specically, our rst study objective
was to examine from a life-course perspective if indivi-
duals born late preterm differ from their term-born
counterparts in their risks of severe mental disorders
across adult ages. As a second study question, we stud-
ied if the effects of SGA birth across the gestational age
distribution, from late preterm to post-term birth, on
mental disorders persist across adult ages. We also
add to the literature by examining whether post-term
or LGA births increase the risk of severe mental dis-
orders in adulthood. Based on previous ndings in
younger cohorts, we hypothesized that late preterm
and post-term births and SGA and LGA births each
set forth predisposing effects on the risks of severe
mental disorders.
Method
The study sample
Our study cohort was the Helsinki Birth Cohort Study
(HBCS). The HBCS comprises 13 345 singleton live
births [6975 men (52.3%) and 6370 women (47.7%)]
at the two public maternity hospitals in Helsinki,
Finland, between 1934 and 1944. The HBCS, described
in detail elsewhere (Osmond et al. 2007), has been
approved by the Ethics Committee of the National
Public Health Institute. For the current study, we
excluded all individuals with biologically implausible
values for gestational age, both as absolute values
and compared to their birth weight. Namely, we
excluded individuals with gestational age below
26 weeks or above 44 weeks, and preterm individuals
with disproportionally large birth weight for gesta-
tional age (> + 2 S.D.; Kajantie et al. 2010). These criteria
led to the exclusion of 535 (4.0%) individuals. Further-
more, since we focused on late preterm births, and our
study sample did not provide sufcient statistical
power to study the risks of mental disorders among
individuals born very or moderately preterm, we
excluded 128 (1.0%) participants born before
34 weeks of gestation. From the current study, we
also excluded 54 (0.4%) cohort members with missing
or imprecise data in the Finnish Hospital Discharge
Register (HDR) or the Causes of Death Register
(CDR) or who had died with missing data on year of
death or moved abroad with missing data on year of
moving abroad, and 31 (0.2%) individuals who had
been hospitalized for or who had died from injuries
of undetermined intent.
The current study sample thus comprised 12 597
individuals, 6563 (52.1%) men and 6034 (47.9%)
women. Compared to the included participants,
the excluded cohort members came more often from
families where the father was a manual worker (63.4
v. 56.7%, p = 0.001) or where the mother was unmarried
(7.4% v. 4.7%, p = 0.002). In comparison to the included
participants, the excluded cohort members with

adequate data on gestational age were more often born
SGA (7.0% v. 2.3%, p < 0.001), and the excluded cohort
members with adequate diagnostic data had a higher
risk of severe mood disorders [hazard ratio (HR) =
1.45, p = 0.01].
Gestational age and fetal growth
We extracted data on the date of mothers last men-
strual period and on infants date of birth and birth
weight from hospital birth records. Gestational age
was calculated by subtracting the date of birth from
mothers self-reported date of last menstrual period.
The participants were divided into three groups
by their gestational age: late preterm (3436 weeks),
term (3741 weeks), and post-term (4243 weeks)
birth. We dened SGA birth in sex-stratied models
as birth weight at or below 2 S.D. of that predicted
by gestational age, appropriate for gestational age
(AGA) birth as birth weight between 2 and +2 S.D.
of that predicted by gestational age, and LGA birth
as birth weight at or above +2 S.D. that predicted by
gestational age (Lee et al. 2003). Since there are
no ofcial growth charts available in Finland for
19341944, we dened these indices of fetal growth
based on the distributions of birth weight and gesta-
tional age in our own study cohort.
Diagnoses of mental disorders
We identied the diagnoses of mental disorders from
the HDR and CDR. Our diagnostic follow-up extended
across 42 years of adult life, from 1969 to 2010. At the
end of the follow-up, the participants were aged be-
tween 66 and 76 years. The HDR carries the primary
and up to three subsidiary discharge diagnoses of all
hospitalizations and the CDR carries the primary,
underlying, and contributory causes of death for all
deaths in Finland. Both registers have been in use since
1969 when a personal identication number was
given to each Finnish citizen. In Finland, International
Classication of Diseases, eighth revision (ICD-8) was
in use in clinical practice between 1969 and 1986;
ICD-9, the Diagnostic and Statistical Manual of Mental
Disorders, Third Revision was used between 1987
and 1995; and ICD-10 has been in use since 1996.
The HDR (Sund, 2012) and the CDR (Lahti & Penttil,
2001) are valid and reliable research tools. Of mental
disorders, the HDR diagnoses of schizophrenia
(Pihlajamaa et al. 2008), bipolar disorder (Kiesepp
et al. 2000), and any psychotic disorder (Perl et al.
2007) each demonstrate high specicity levels. Also
the validity of the HDR ICD-8 diagnoses of alcohol de-
pendence and psychosis has gained research support
(Poikolainen, 1983).
Risk factors for severe mental disorders across adulthood 987
In addition to assessing the associations of late
preterm, post-term, SGA, and LGA birth with severe
mental disorders as one broad diagnostic category,
we assessed associations to seven specic diagnostic
categories; substance use, (non-affective) psychotic,
mood, anxiety, and personality disorders and suicides
and suicide attempts. The diagnostic codes correspond-
ing to the different diagnostic categories are shown in
Table 1, together with the number and the percentage
of participants with each diagnosis and the median age
at and the age range of rst diagnosis. Between 1969
and 2010, there were 1660 participants (13.2%; 1058
men and 602 women) who had been hospitalized
with a diagnosis of mental disorder as a hospital dis-
charge diagnosis or had died with a diagnosis of sev-
ere mental disorder included in the death certicate.
The median age at rst diagnosis of any severe mental
disorder was 43.4 years (range 19.076.6 years).
Suicide is often under-diagnosed (Kapusta et al.
2011), and it is uncertain if the diagnoses of injuries
of undetermined intent represent suicide in individual
cases. Hence, to maximize the reliability of our suicide
assessment and to minimize the amount of false nega-
tive diagnosis, individuals with a diagnosis of injuries
of undetermined intent or of poisonings of usually self-
inicted intent with no history of psychopathology
were excluded from the study. We identied these
exclusion diagnoses with the diagnostic codes E98
from ICD-8, E97 from ICD-9, and Y10Y34, T39 and
T42T43 from ICD-10.
Furthermore, for the analyses on the specic
diagnostic categories, we excluded from the control
outcome group all participants with other mental dis-
orders. Thus, the comparison outcome group for all
the analyses included 10 937 individuals (5505 men
and 5432 women) with no diagnosis of severe mental
disorder or of injuries of undetermined intent at
any time point. On the other hand, all individuals
with a particular diagnosis were included as diag-
nostic cases for that diagnosis, independently of
whether or not they had other types of comorbid
psychopathology.
Confounders and covariates
The potential confounders of the associations between
the prenatal risk factors and mental disorders that
were used in the analyses were sex, year of birth, socio-
economic position in childhood, and mothers marital
status at childbirth. The latter two were used since
they have frequently been associated with preterm
birth and with fetal growth (Zeitlin et al. 2002;
Blumenshine et al. 2010; El-Sayed et al. 2012) and
with an increased risk of mental disorders (Mkikyr
 988
M. Lahti et al.
Table 1. International classication of disease diagnostic codes on mental disorders severe enough to warrant or contribute to hospital treatment (HDR) or to be the underlying, intermediate or contributing
cause of death (CDR). The prevalence and percentage of subjects with each diagnosis, and median age at rst diagnosis for each diagnostic category

Diagnostic codes Prevalence (%)

Median age (in years) at
Diagnostic category ICD diagnostic codes All subjects Men Women rst diagnosis (range)

Any mental disordera ICD-8: 291, 295, 296305, 306.4306.5, 306.8, 306.98, 307; E95 1660 (13.2%) 1058 (16.1%) 602 (10.0%) 43.4 (19.076.6)
ICD-9: 291292, 295298, 300304, 305, 3071A, 3074,
3075A3075B, 3078A, 3079X, 3090A, 3092C3099X, 312; E95
ICD-10: F1F6, R45.8, X60X84; Y87.0
Substance use disordersb ICD-8: 291, 303304 872 (6.9%) 694 (10.6%) 178 (2.9%) 45.9 (25.576.6)
(ICD-10: Mental and behavioural disorders ICD-9: 291292, 303305
due to psychoactive substance use) ICD-10: F10F19
Psychotic disorders ICD-8: 295, 297, 298.10299.99 331 (2.6%) 175 (2.7%) 156 (2.6%) 38.4 (19.073.6)
(ICD-10: Schizophrenia, schizotypal, and ICD-9: 295, 297298
delusional disorders) ICD-10: F20F29
Mood disorders ICD-8: 296, 298.00, 300.40, 300.41, 301.10 577 (4.6%) 283 (4.3%) 294 (4.9%) 48.0 (24.575.2)
[ICD-10: Mood (affective) disorders] ICD-9: 296, 3004A, 3011D
ICD-10: F30F39
Anxiety disorders ICD-8: 300.00300.30, 300.50300.99, 305, 306.80, 307.99 318 (2.5%) 159 (2.4%) 159 (2.6%) 40.1 (25.671.0)
(ICD-10: Neurotic, stress-related and ICD-9: 3000A3003A, 3006A3009X, 3078A, 309
somatoform disorders) ICD-10: F40F48
Personality disorders ICD-8: 301.00, 301.20301.99 195 (1.5%) 109 (1.7%) 86 (1.4%) 41.3 (24.866.6)
(ICD-10: Specic and mixed
personality disorders) ICD-9: 3010A, 3012A3015A, 3016A3018X
ICD-10: F60F61
Suicides ICD-8 & ICD-9: E95 126 (1.0%) 98 (1.5%) 28 (0.5%) 48.8 (29.070.5)
(ICD-10: Intentional self-harm) ICD-10: R45.8, X60X84; Y87.0
Suicide attempts ICD-8: E95 83 (0.7%) 39 (0.6%) 44 (0.7%) 38.4 (19.649.4)
(ICD-8: Intentional self-harm)

HDR, Finnish Hospital Discharge Register; CDR, Cause of Death Register.

a
The diagnoses (corresponding to codes F50F59 or F62F69 in ICD-10) were included in the Any mental disorder category, but were not assessed as a separate category.
b
For the diagnoses of substance intoxications (ICD-9; 305ICD-10: F1x.0, only the primary diagnoses from the HDR and the CDR were included in the diagnostic categories. All
other diagnostic entities include primary and up to three subsidiary hospital discharge diagnoses, and primary, underlying and contributory causes of death.
 Risk factors for severe mental disorders across adulthood 989

Table 2. Birth and sociodemographic characteristics of the study sample

All subjects Men Women

Characteristic N (%) N (%) N (%)

Gestation length
3436 weeks 664 (6.2%) 369 (5.6%) 295 (4.9%)
3741 weeks 10 712 (84.2%) 5579 (85.0%) 5133 (85.1%)
5 42 weeks 1221 (9.6%) 615 (9.4%) 606 (10.0%)
Birth weight adjusted for length of gestation
SGA (42 S.D.) 287 (2.3%) 140 (2.1%) 147 (2.4%)
AGA (< 2 to <2 S.D.) 12 009 (95.3%) 6261 (95.4%) 5748 (95.3%)
LGA (52 S.D.) 301 (2.4%) 162 (2.5%) 139 (2.3%)
Year of birth
19341938 2866 (22.8%) 1479 (22.5%) 1387 (23.0%)
19391944 9731 (77.2%) 5084 (77.5%) 4647 (77.0%)
Mothers marital status at childbirth
Married 11 956 (94.9%) 6227 (94.8%) 5729 (94.9%)
Unmarried 588 (4.7%) 301 (4.6%) 287 (4.8%)
Widowed, divorced or unknown 53 (0.4%) 35 (0.5%) 18 (0.3%)
Fathers highest attained occupational status
Manual worker 7146 (56.7%) 3704 (56.4%) 3442 (57.0%)
Clerical worker 5122 (40.7%) 2708 (41.3%) 2414 (40.0%)
Unknown 329 (2.6%) 151 (2.3%) 178 (2.9%)

SGA, Small for gestational age; AGA, appropriate for gestational age; LGA, large for gestational age.

et al. 1998; Fergusson et al. 2007; Rikknen et al. 2011;
Bjrngaard et al. 2013).
Data on socioeconomic position in childhood,
dened as fathers highest attained occupational status
[manual worker, (lower or upper) clerical worker, or
unknown] was extracted from birth, child welfare,
and school records. Data on year of birth, on sex and
on mothers marital status at childbirth (married, un-
married, or divorced, widowed, or unknown) were
extracted from birth records. Most (87.3%) of the par-
ticipants with fathers occupation unknown were
born to unmarried mothers, suggesting that the miss-
ing paternal occupation data was mostly due to the
lack of fathers presence in early family life. Therefore
we decided to treat them as an own socioeconomic
category and include them in the analyses.
Statistical analyses
The associations of the sociodemographic covariates
(sex, year of birth, socioeconomic position in
childhood, and marital status at childbirth) with late
preterm and post-term birth, with SGA and
LGA birth, and with severe mental disorders were
examined with 2 and Cox Proportional Hazards
models analyses. Next, we examined the associations
of late preterm, post-term, SGA and LGA births with
severe mental disorders with Cox Proportional
Hazards models. The subjects were followed up
either until their death, migration, rst hospitalization
for mental disorders, or until 31 December 2010.
Since suicide attempts were encoded to the HDR
only during the use of ICD-8, the analyses on suicide
attempts comprised a follow-up extending until
31 December 1986.
First we examined the effects of late preterm and
post-term birth and of SGA and LGA birth with severe
mental disorders in separate models, which were stra-
tied for year of birth and sex, and adjusted for socio-
economic position in childhood and marital status at
childbirth. Thereafter, we ran multivariate models
where all the independent variables were entered sim-
ultaneously, in order to examine whether their effects
occurred independently of each other. Since previous
studies have shown that there are sex differences in
the prevalence of certain mental disorders (Kessler
et al. 2005; de Graaf et al. 2012: Steel et al. 2014), and
in the early life risk factors for mental disorders
(Monls Gustafsson et al. 2009), sex was used as a po-
tential confounder, and all the analyses were also re-
peated separately for men and women.
Results
Table 2 shows the birth and the sociodemographic
characteristics of the sample. Compared to individuals
990 M. Lahti et al.
born in the later years (between 1939 and 1944), indivi-
duals born in the earlier years (between 1934 and 1938)
had signicantly more often been born late preterm
(6.3% v. 5.0%, p = 0.01) and less often post-term (8.4%
v. 10.1, p = 0.01). The offspring of unmarried mothers
were more often born late preterm (8.8% v. 5.1%, p <
0.001) and SGA (4.1% v. 2.2%, p = 0.003) and less
often LGA (0.5% v. 2.5%, p = 0.002) than the offspring
of married mothers. Our indicators of fetal growth
and gestational age were also signicantly associated
with each other [2(4) = 58.7, p < 0.001]. Compared to
individuals born at term, individuals born late preterm
were more often born SGA (3.6% v. 1.9%, p = 0.002) and
less often born LGA (0.8% v. 2.5%, p = 0.004). Also indi-
viduals born post-term were more often born SGA
than individuals born at term (4.9% v. 1.9%, p < 0.001).
On the other hand, men had higher risks of any
severe mental disorder, substance use disorders,
and suicides than women (Table 1, p values <0.001).
Individuals born between 1939 and 1944 had higher
risks of any mental (HR = 1.18, p = 0.01), substance use
(HR = 1.24, p = 0.01), personality (HR = 1.95, p = 0.002),
anxiety (HR = 1.44, p = 0.01), and mood (HR = 1.28, p =
0.02) disorders than the individuals born in the earlier
years. The offspring of manual worker fathers had
higher risks of any severe mental disorder (HR = 1.15,
p = 0.005) and of substance use disorders (HR = 1.23,
p = 0.003) than the offspring of clerical workers.
Marital status at childbirth was not signicantly asso-
ciated with the risks of severe mental disorders
(p values 50.13).
Late preterm and post-term birth
Table 3 shows that stratifying for year of birth and
adjusting for socioeconomic position in childhood
and marital status at childbirth, late preterm birth
was not signicantly associated with the risks of any
severe mental disorder or of the specic mental dis-
orders in the analyses of all participants (Table 3,
p values 50.09) or among women (p values 50.23).
However, compared to men born at term, men born
late preterm had a signicantly increased, twofold
risk of suicides (p = 0.03), Fig. 1 shows the survival
function to committed suicides for men born late pre-
term, term, and post-term. As shown in Table 3, this
association remained signicant after further adjust-
ment for SGA/AGA/LGA status as an indicator of
fetal growth (p = 0.04).
Conversely, compared to term-born participants,
individuals born post-term had 1.2-, 1.3-, and 1.4-fold
signicantly increased risks of any severe mental
disorder (p = 0.04), substance use disorders (p = 0.01),
and anxiety disorders (p = 0.03) disorders, respectively
(Table 3). Sex-specic analyses showed that post-term
birth predicted the risks of severe mental disorders
especially among men, such that men born
post-term had a 1.2-fold risk of any severe mental dis-
order (Table 3, p = 0.02), a 1.3-fold risk of substance
use disorders (p = 0.02), and a 1.6-fold risk of anxiety
disorders (p = 0.04). Further adjustments for fetal
growth did not lead to noticeable changes in the
previously signicant ndings (all p values 40.05).
Post-term birth had no signicant effects on mental
disorders among women (p values 50.32).
SGA and LGA status at birth
Table 4 shows that compared to individuals born
AGA, individuals born SGA had a 1.4-fold increased
risk of any severe mental disorder (p = 0.02) and a
1.7-fold increased risk of substance use disorders
(p = 0.01). The association between SGA birth and
substance use disorders was more evident and statisti-
cally signicant among women, for whom SGA
birth predicted a 2.4-fold increased risk of substance
use disorders (p = 0.01). These effects of SGA birth on
mental disorders remained signicant after adjust-
ments for gestational age (Table 4, all p values
40.01). In contrast, SGA birth had no signicant
effects on severe mental disorders among men
(p values 50.07). LGA birth was not signicantly asso-
ciated with the risks of severe mental disorders in the
analyses of all participants (p values 50.19, Table 4)
or among men (p values 50.17). However, women
born LGA had at a 2.4-fold, signicantly increased
risk of psychotic disorders (p = 0.02), compared to
women born AGA. Also this association remained
signicant after adjustment for gestational age (p =
0.01).
Interactions by sex
Since some of the ndings were more evident among
one or the other sex, we examined in separate Cox
models whether there were signicant interactions
of late preterm or post-term birth and/or of SGA or
LGA births with sex in predicting the risks of severe
mental disorders. We found a signicant interaction
between LGA status at birth and sex in predicting
the risk of psychotic disorders (p = 0.04), but there
were no other signicant interactions by sex (all
p values 50.21).
Discussion
In this longitudinal cohort study from birth to late
adulthood, late preterm birth was not associated with
the risk of any severe mental disorder, but it predicted
a signicantly increased risk of suicides among men.
 Risk factors for severe mental disorders across adulthood 991

Table 3. Gestational age and severe mental disorders. Hazard ratios (HR) and 95% condence intervals (CI) for the associations between late
preterm and post-term birth with severe mental disorders. Term-born subjects are the reference group.

All subjects Men Women

Gestational age . . . 3436 weeks 542 weeks 3436 weeks 542 weeks 3436 weeks 542 weeks
Diagnostic category HR (95% CI) HR (95% CI) HR (95% CI) HR (95% CI) HR (95% CI) HR (95% CI)

Any mental disorder

Model 1a 1.06 (0.861.31) 1.17 (1.011.37) 1.09 (0.841.41) 1.25 (1.031.51) 1.03 (0.711.50) 1.06 (0.821.38)
Model 2b 1.06 (0.861.31) 1.16 (1.001.36) 1.09 (0.841.41) 1.24 (1.021.51) 1.02 (0.701.47) 1.04 (0.801.35)
Substance use disorders
Model 1a 1.14 (0.861.51) 1.31 (1.071.61) 1.22 (0.901.65) 1.33 (1.051.67) 0.84 (0.391.79) 1.25 (0.801.95)
Model 2b 1.13 (0.851.50) 1.30 (1.061.60) 1.21 (0.891.64) 1.32 (1.051.67) 0.81 (0.381.73) 1.19 (0.761.87)
Psychotic disorders
Model 1a 1.34 (0.872.05) 1.03 (0.721.49) 1.17 (0.632.17) 1.10 (0.671.82) 1.54 (0.852.80) 0.97 (0.571.66)
Model 2b 1.33 (0.872.04) 1.03 (0.711.48) 1.15 (0.622.12) 1.10 (0.661.82) 1.55 (0.862.82) 0.99 (0.581.69)
Mood disorders
Model 1a 0.82 (0.541.23) 1.17 (0.901.52) 0.65 (0.341.22) 1.18 (0.811.73) 1.02 (0.591.75) 1.16 (0.811.66)
Model 2b 0.81 (0.541.23) 1.16 (0.901.51) 0.65 (0.341.22) 1.18 (0.811.73) 1.01 (0.591.73) 1.15 (0.801.64)
Anxiety disorders
Model 1a 0.89 (0.521.53) 1.42 (1.031.97) 0.59 (0.241.45) 1.61 (1.022.52) 1.24 (0.632.44) 1.27 (0.792.03)
Model 2b 0.89 (0.521.52) 1.41 (1.021.96) 0.59 (0.241.45) 1.60 (1.022.52) 1.24 (0.632.44) 1.27 (0.792.04)
Personality disorders
Model 1a 0.85 (0.441.67) 0.84 (0.501.40) 0.83 (0.342.04) 0.89 (0.451.77) 0.92 (0.332.52) 0.77 (0.351.67)
Model 2b 0.85 (0.431.67) 0.84 (0.501.40) 0.82 (0.332.02) 0.89 (0.451.76) 0.93 (0.342.56) 0.78 (0.361.69)
Suicides
Model 1a 1.67 (0.893.12) 1.18 (0.662.10) 2.00 (1.033.88) 1.36 (0.722.56) 0.63 (0.084.66) 0.67 (0.162.82)
Model 2b 1.70 (0.913.17) 1.18 (0.662.11) 2.01 (1.033.90) 1.36 (0.722.56) 0.66 (0.094.93) 0.69 (0.162.90)
Suicide attempts
Model 1a 0.71 (0.222.25) 1.59 (0.862.94) 1.56 (0.475.14) 2.27 (0.995.19) 0 (N.A.) 1.10 (0.432.81)
Model 2b 0.69 (0.222.21) 1.56 (0.842.89) 1.50 (0.454.94) 2.28 (1.005.21) 0 (N.A.) 1.10 (0.432.81)

N.A.,Not applicable.
a
The analyses are stratied for sex and year of birth and adjusted for socioeconomic position in childhood and mothers
marital status at childbirth.
b
The analyses are stratied for sex and year of birth and adjusted for fetal growth, socioeconomic position in childhood
and mothers marital status at childbirth.
Bold font indicates signicant effects.

On the other hand, both birth as SGA and as post-term
emerged as signicant risk factors for any severe men-
tal disorder and for substance use disorders across
adult life. Of other mental disorders, post-term birth
also predicted the risk of anxiety disorders. LGA
birth predicted an increased risk of psychotic disorders
among women. These effects of late preterm and post-
term birth and of SGA and LGA status at birth on
severe mental disorders occurred independently of
each other. Our study with its long diagnostic follow-
up adds signicantly to the previous literature by
suggesting that these prenatal risk factors exert long-
lasting effects on severe mental disorders throughout
adult ages.
Late preterm birth predicted an increased risk of sui-
cides among men. Correspondingly, a previous study
showed that moderate or late preterm birth predicted
an increased risk of suicides and/or suicide attempts
in young adulthood (Lindstrm et al. 2009) but
whether this effect was more pronounced on commit-
ted or attempted suicide was not specied. However,
in contrast to studies in younger cohorts showing pre-
disposing effects of late preterm birth on any mental
disorder and on internalizing disorders in childhood
(Talge et al. 2010; Rogers et al. 2013), or of moderate
or late preterm birth on severe mental disorders across
diagnostic boundaries in young adulthood (Moster
et al. 2008; Lindstrm et al. 2009; Nosarti et al. 2012),
992 M. Lahti et al.
Fig. 1. Gestational age and survival function to committed suicide among men. This gure shows the KaplanMeier survival
function plots to committed suicide for men born late preterm, term, and post-term.
here late preterm birth was not associated with other
types of severe psychopathology from early to late
adulthood.
As a novel contribution, we demonstrated that indi-
viduals born post-term had increased risks of any
severe mental disorder and particularly of substance
use and anxiety disorders in adulthood. Correspond-
ing effects have been reported previously on psycho-
pathology risk in childhood. Namely, El Marroun
et al. (2012) found that children born post-term had
more emotional and behavioural disorders at the
ages of 1.5 and 3 years, and another study found that
children born post-term have an increased risk of
neurodevelopmental disorders (Lindstrm et al. 2005).
Collectively these ndings highlight the importance
of assessing post-term birth as a possible independent
risk factor for mental disorders. Nevertheless, studies
on psychopathology risk among individuals born
post-term are still scarce and the ndings warrant
replication.
In agreement with a representative study with a
follow-up extending to young adulthood (Abel et al.
2010), SGA birth predicted increased risks of any
severe mental disorder and of substance use disorders
throughout adulthood in our study. However, in the
study by Abel et al. (2010), SGA birth also predicted
increased risks of schizophrenia and of anxiety dis-
orders while we found no signicant effects of SGA
birth on non-affective psychotic disorders or on anxi-
ety disorders. The differences in the ndings may be
due to the different ages covered in the diagnostic
follow-ups; our follow-up extended to between 65
and 75 years of age, while Abel et al. (2010) followed
up the subjects only until young adulthood. In
contrast, in our study, among women, LGA birth pre-
dicted an increased risk of psychotic disorders.
Previous studies have shown that LGA birth may
predict psychopathology risk in childhood and
adolescence (van Lieshout & Boyle, 2011), but ndings
on adulthood effects are scarce and inconsistent
(Moilanen et al. 2010; Keskinen et al. 2013).
We also examined whether the associations varied
by sex. The effects of SGA and LGA birth on severe
mental disorders were more evident among women,
while late preterm and post-term birth had stronger ef-
fects on psychopathology risk among men. Previous
ndings on the sex-specicity of the effects of these
prenatal risk factors on mental disorders are inconsist-
ent (Monls Gustafsson et al. 2009; Abel et al. 2010).
Importantly, however, here signicant interactions
with sex emerged only for LGA birth in predicting
psychotic disorders, not for the other examined risk
factors. Hence, the potential sex-specicity of our
ndings must be interpreted with much caution.
Potential contributing factors to our signicant nd-
ings may include exposure to prenatal malnutrition,
to substance use during pregnancy, and to perinatal
complications, overexposure to glucocorticoids as a
consequence of maternal psychosocial stress during
pregnancy, and exposure to pregnancy disorders
such as pre-eclampsia and gestational diabetes. Of
pregnancy disorders, gestational diabetes predicts
increased risks of preterm (Hedderson et al. 2003;
Fadl et al. 2010; Zhang et al. 2012) and LGA
 Risk factors for severe mental disorders across adulthood 993

Table 4. Fetal growth and severe mental disorders. Hazard ratios (HR) and 95% condence intervals (95% CI) for individuals born with birth
weight for gestational age at below 2 S.D.: [small for gestational age (SGA)] or above >2 S.D. (large for gestational age (LGA)]. Individuals born
with birth weight appropriate for gestational age (AGA; between 2 and 2 S.D.) are used as the reference group

All subjects Men Women

SGA LGA SGA LGA SGA LGA

Diagnostic category HR (95% CI) HR (95% CI) HR (95% CI) HR (95% CI) HR (95% CI) HR (95% CI)

Any mental disorder

Model 1a 1.41 (1.071.87) 1.02 (0.741.41) 1.34 (0.931.94) 1.03 (0.691.53) 1.54 (0.992.38) 1.01 (0.601.73)
Model 2b 1.39 (1.051.85) 1.03 (0.751.41) 1.32 (0.911.91) 1.03 (0.691.53) 1.53 (0.992.37) 1.02 (0.601.73)
Substance use disorders
Model 1a 1.67 (1.162.41) 1.01 (0.651.57) 1.50 (0.972.32) 0.95 (0.571.59) 2.40 (1.224.70) 1.31 (0.543.19)
Model 2b 1.64 (1.142.37) 1.01 (0.651.58) 1.48 (0.962.28) 0.95 (0.571.59) 2.35 (1.194.64) 1.32 (0.543.22)
Psychotic disorders
Model 1a 1.41 (0.752.66) 1.21 (0.622.36) 1.67 (0.743.77) 0.25 (0.041.79) 1.15 (0.433.12) 2.41 (1.184.93)
Model 2b 1.39 (0.742.62) 1.23 (0.632.39) 1.66 (0.733.75) 0.25 (0.041.80) 1.12 (0.413.03) 2.43 (1.194.96)
Mood disorders
Model 1a 1.42 (0.872.30) 1.38 (0.862.20) 1.25 (0.592.65) 1.12 (0.532.38) 1.59 (0.853.00) 1.59 (0.872.92)
Model 2b 1.41 (0.872.29) 1.37 (0.862.20) 1.26 (0.592.66) 1.10 (0.522.34) 1.56 (0.832.95) 1.61 (0.872.95)
Anxiety disorders
Model 1a 1.50 (0.802.83) 1.38 (0.732.59) 1.88 (0.834.25) 1.33 (0.543.25) 1.15 (0.423.10) 1.36 (0.553.35)
Model 2b 1.47 (0.782.76) 1.39 (0.742.61) 1.88 (0.834.26) 1.30 (0.533.17) 1.09 (0.402.96) 1.39 (0.563.41)
Personality disorders
Model 1a 0.94 (0.352.53) 0.68 (0.222.12) 1.36 (0.434.30) 0.80 (0.203.26) 0.49 (0.073.56) 0.52 (0.073.73)
Model 2b 0.96 (0.352.58) 0.67 (0.212.10) 1.37 (0.444.34) 0.79 (0.203.23) 0.51 (0.073.70) 0.51 (0.073.69)
Suicides
Model 1a 0.38 (0.052.73) 1.35 (0.503.66) 0.50 (0.073.62) 0.88 (0.223.58) 0 (N.A.) 3.25 (0.7713.73)
Model 2b 0.37 (0.052.65) 1.39 (0.513.77) 0.49 (0.073.51) 0.92 (0.233.75) 0 (N.A.) 3.21 (0.7613.60)
Suicide attempts
Model 1a 1.67 (0.535.31) 0.52 (0.073.78) 2.56 (0.6110.63) 0 (N.A.) 1.05 (0.147.69) 1.08 (0.157.85)
Model 2b 1.60 (0.505.11) 0.52 (0.073.75) 2.47 (0.5910.30) 0 (N.A.) 1.09 (0.158.05) 1.07 (0.157.79)

N.A.,Not applicable.
a
The analyses are stratied for sex and year of birth and adjusted for socioeconomic position in childhood and mothers
marital status at childbirth.
b
The analyses are stratied for sex and year of birth and adjusted for gestational age, socioeconomic position in childhood
and mothers marital status at childbirth.
Bold font indicates signicant effects.

(Hedderson et al. 2003; Fadl et al. 2010) births, while
hypertensive disorders during pregnancy are asso-
ciated with an increased likelihood of preterm
(Clausson et al. 1998; Hedderson et al. 2003; Kajantie
et al. 2009; Ferrazzani et al. 2011; Zhang et al. 2012)
and SGA (Clausson et al. 1998; Ferrazzani et al. 2011;
Leviton et al. 2013) births. Also maternal smoking
(Clausson et al. 1998; Heaman et al. 2013) and psycho-
social stress (Zhang et al. 2012; Heaman et al. 2013)
during pregnancy are both associated with increased
risks of preterm and SGA deliveries. Particular types
of malnutrition during pregnancy have been shown
to contribute to the risks of SGA (Dwarkanath et al.
2013), LGA (Knudsen et al. 2013) and preterm
(Zhang et al. 2012; Leventakou et al. 2014) births.
On the other hand, compared to term-born indivi-
duals, certain perinatal complications (e.g. asphyxia)
are more common both among individuals born post-
term (Thorngren-Jerneck & Herbst, 2001; Olesen et al.
2003) and among individuals born preterm (Gouyon
et al. 2010). All these factors have also been associated
with increased risks of certain mental disorders
(Dalman et al. 2001; Gardener et al. 2009; Rikknen
et al. 2009; Ekblad et al.2010; Rice et al. 2010;
Tuovinen et al. 2010; Bao et al. 2012; Fazel et al. 2012).
Previous studies have found that neurological im-
pairments are more common among individuals
born late preterm (Petrini et al. 2009) post-term
994 M. Lahti et al.
(Lindstrm et al. 2005; Moster et al. 2010) and SGA
(Leviton et al. 2013). Altered neurodevelopment as a
consequence of prenatal adversity and contributing
to the risk of mental disorders may hence have contrib-
uted to our ndings (Loe et al. 2011).
More specically, neurobiological explanations
underlying our ndings may involve possibly epi-
genetic changes in the functioning of the brains stress
system, as a consequence of prenatal adversity, and
contributing to an increased risk of mental disorders
(Lupien et al. 2009; Bock et al. 2014). The brains stress
system includes the hypothalamus-pituitary-adrenal
(HPA) axis and the interconnected brain regions amyg-
dala, hippocampus, and the prefrontal cortex (Lupien
et al. 2009; Bock et al. 2014). SGA (De Bie et al. 2011;
Parikh et al. 2013) and preterm (Parikh et al. 2013;
Thompson et al. 2013) births, individual differences
in birth size (De Bie et al. 2011; Reynolds et al. 2005),
and particular prenatal adversities (Entringer et al.
2009; Buss et al. 2012; OConnor et al. 2013; Rifkin-
Graboi et al. 2013; Bock et al. 2014) have each been asso-
ciated with long-lasting structural and functional
changes in the brain regions implicated in the stress
system. Furthermore, maternal cortisol levels during
pregnancy have been shown to predict psychiatric
symptoms in the offspring (Buss et al. 2012), and this
effect was partially mediated by changes in childs
amygdala volume. In addition, altered functioning
of the brains stress system has been found among
patients with different mental disorders, for example
among patients with depression (Vreeburg et al. 2010;
Stetler & Miller, 2011; Carvalho Fernando et al. 2012),
anxiety disorders (Ipser et al. 2013), post-traumatic
stress disorder (Morris et al. 2012; Patel et al. 2012),
and borderline personality disorder (Carrasco et al.
2007; Carvalho Fernando et al. 2012; Ruocco et al. 2012).
On a cellular level, the effects may be mediated
by epigenetic changes affecting gene expression.
Epigenetic DNA methylation changes are found
among patients with mental disorders (Dempster
et al. 2011; Sabunciyan et al. 2012). Such methylation
changes are also associated with individual differences
in birth size (Shams et al. 1998; Dy et al. 2008; Michels
et al. 2011; Brzsnyi et al. 2012; Liu et al. 2012; Marsit
et al. 2012) and gestation length (Demendi et al. 2012;
Marsit et al. 2012) and with specic prenatal or neo-
natal adversities (Oberlander et al. 2008; Liu et al.
2012; Wehkalampi et al. 2013), possibly particularly
in genes regulating HPA axis function (Shams et al.
1998; Dy et al. 2008; Oberlander et al. 2008; Brzsnyi
et al. 2012; Demendi et al. 2012; Liu et al. 2012;
Marsit et al. 2012; Wehkalampi et al. 2013). For
example, reduced expression of the placental 11-
hydroxysteroid dehydrogenase 2 (11-HSD2) gene reg-
ulating the 11-HSD2 enzyme that protects the fetus
from circulating maternal glucocorticoids is found
among individuals born SGA (Shams et al. 1998; Dy
et al. 2008; Brzsnyi et al. 2012) and among indivi-
duals born preterm (Demendi et al. 2012). Evidence
from animal studies and from epigenetic and ob-
servational studies in humans suggest that lower
placental 11-HSD2 activity is also associated with
poorer neurobehavioural development in the offspring
(Welberg et al. 2000; Rikknen et al. 2009; Marsit et al.
2012). Hence, epigenetic changes in gene expression
as a consequence of prenatal adversity, inuencing
neurodevelopment and thereby affecting the risk of
mental disorders may possibly have played an under-
lying role in our ndings. Furthermore, there is
evidence of differential prenatal epigenetic program-
ming effects for boys and girls (Liu et al. 2012), which
may help in explaining the potential sex-specicity of
the ndings. However, since there is a hereditary com-
ponent affecting gestation length and prenatal growth
(Clausson et al. 2000; Silventoinen et al. 2008; Oberg
et al. 2013) and the risk of mental disorders (Kendler
et al. 2011), genetic predispositions may also have con-
tributed to our ndings.
The strengths of our study include the hospital birth
record-based data on gestational age and on birth size
and the long diagnostic follow-up period enabling us
to examine effects on psychopathology throughout a
wide age interval in adulthood. However, there are
also limitations. Since we extracted data on mental dis-
orders diagnoses only from the HDR and CDR, our
ndings generalize best to severe mental disorders re-
quiring hospitalization or contributing to death. Using
only these registers misses the outpatient diagnosis,
and the generalizability of our ndings to less severe
psychopathology is limited. The use of only hospital
discharge and causes of death registers for diagnosis
identication also accounts for the rather low preva-
lence of anxiety and mood disorders in our sample.
It is also of note that we did not nd the sex-difference
in the prevalence of mood or anxiety disorders that is
usually consistently observed in population-based epi-
demiological studies (Kessler et al. 2005; Steel et al.
2014).
Furthermore, since we had diagnostic data available
only from 1969 onwards, we were unable to identify
those individuals who were hospitalized or who had
died with mental disorders before this year, before
they reached the ages 2435 years and were not hos-
pitalized again thereafter. Many mental disorders
have their onset in childhood, adolescence, or early
adulthood, and we lack information from those age
periods in our sample. Our ndings hence best gen-
eralize to mental disorders that lead to hospitalization
or contribute to death between the ages 2435 and
6576 years. There are hence some false negatives in
 Risk factors for severe mental disorders across adulthood
our sample: participants who had severe mental dis-
orders early but not later in adulthood. A bias intro-
duced to the ndings by this lack of information is
possible. However, considering that a major aim of
the current study was to study if corresponding effects
to those found previously in younger cohorts are also
found on mental disorders later in life, then for this
purpose the age range for the diagnostic follow-up is
well-justied. Corresponding effects to younger ages
were indeed found, especially for SGA and post-term
births. On the other hand, the number of individuals
in the prenatal risk conditions was too small to
reliably study interactions between these factors in pre-
dicting mental disorders, although such interactions
have been suggested by some previous research
(Laursen et al. 2007; Monls Gustafsson et al. 2009).
Furthermore, we had no data on parental mental dis-
orders that may modify the effects of prenatal ad-
versity on mental disorders (Niederkrotenthaler et al.
2012; Keskinen et al. 2013). Because suicide attempts
were encoded to the HDR only until 1986, the diag-
nostic follow-up period for them was not comparable
to the other diagnoses. This probably also explains
the lower number of suicide attempts than committed
suicides in our study sample. Overall, the two changes
to the diagnostic classication system during the
follow-up may have created heterogeneity to the diag-
nostic groups, which is an inherent problem to register-
based studies with long follow-ups.
In conclusion, although late preterm birth predicted
the risk of suicides among men, it did not have more
widespread effects on severe mental disorders from
early to late adulthood. On the other hand, SGA
birth exerted predisposing effects on severe mental
disorders across adult ages. Post-term birth emerged
as a novel prenatal risk factor for severe adult mental
disorders. LGA birth predicted the risk of psychotic
disorders among women. Our longitudinal study
ndings suggest that the effects of prenatal develop-
mental adversity on severe mental disorders may ex-
tend throughout adulthood.
Acknowledgements
This study was supported by grants from the Academy
of Finland (grant numbers 261661, 140278, 135132,
132614, 129911, and 129457), University of Helsinki,
the Finnish Foundation of Cardiovascular Research,
the Finnish Diabetes Research Foundation, the
Finnish Medical Society, Finska Lkaresllskapet, the
National Doctoral Programme of Psychology, the
Pivikki and Sakari Sohlberg Foundation, the Juho
Vainio Foundation, the Yrj Jahnsson Foundation,
Samfundet Folkhlsan, the Signe and Ane Gyllen-
berg Foundation, the Jalmari and Rauha Ahokas
995
Foundation, the Emil Aaltonen Foundation, the
Finnish Ministry of Education and the Finnish
Foundation for Paediatric Research. The funders were
not involved in the conduct of the study or in the
collection, management, analysis or interpretation of the
data.
Declaration of Interest
None.
References
Abel KM, Wicks S, Susser ES, Dalman C, Pedersen MG,
Mortensen PB, Webb RT (2010). Birth weight,
schizophrenia, and adult mental disorder: is risk conned
to the smallest babies? Archives of General Psychiatry 67,
923930.
Bao Y, Ibram G, Blaner WS, Quesenberry CP, Shen L,
McKeague IW, Schaefer CA, Susser ES, Brown AS (2012).
Low maternal retinol as a risk factor for schizophrenia in
adult offspring. Schizophrenia Research 137, 159165.
Bjrngaard JH, Bjerkeset O, Vatten L, Janszky I, Gunnell D,
Romundstad P (2013). Maternal age at child birth, birth
order, and suicide at a young age: a sibling comparison.
American Journal of Epidemiology 177, 638644.
Blumenshine P, Egerter S, Barclay CJ, Cubbin C,
Braveman PA (2010). Socioeconomic disparities in
adverse birth outcomes: a systematic review. American
Journal of Preventive Medicine 39, 263272.
Bock J, Rether K, Grger N, Xie L, Braun K (2014).
Perinatal programming of emotional brain circuits: an
integrative view from systems to molecules. Frontiers in
Neuroscience 8, 11.
Brzsnyi B, Demendi C, Pajor A, Rig J Jr., Marosi K,
Agota A, Nagy ZB, Jo JG (2012). Gene expression patterns
of the 11-hydroxysteroid dehydrogenase 2 enzyme in
human placenta from intrauterine growth restriction: the
role of impaired feto-maternal glucocorticoid metabolism.
European Journal of Obstetrics, Gynecology, and Reproductive
Biology 161, 1217.
Buss C, Davis EP, Shahbaba B, Pruessner JC, Head K,
Sandman CA (2012). Maternal cortisol over the course
of pregnancy and subsequent child amygdala and
hippocampus volumes and affective problems. Proceedings
of the National Academy of Sciences of USA 109, E1312E1319.
Carrasco JL, Daz-Mars M, Pastrana JI, Molina R,
Brotons L, Lpez-Ibor MI, Lpez-Ibor JJ (2007).
Hypothalamicpituitaryadrenal axis response in
borderline personality disorder without post-traumatic
features. British Journal of Psychiatry 190, 357358.
Carvalho Fernando S, Beblo T, Schlosser N, Terfehr K,
Otte C, Lwe B, Wolf OT, Spitzer C, Driessen M,
Wingenfeld K (2012). Associations of childhood trauma
with hypothalamicpituitaryadrenal function in
borderline personality disorder and major depression.
Psychoneuroendocrinology 37, 16591668.
Clausson B, Cnattingius S, Axelsson O (1998). Preterm and
term births of small for gestational age infants: a
996 M. Lahti et al.
population-based study of risk factors among nulliparous
women. British Journal of Obstetrics and Gynaecology 105,
10111017.
Clausson B, Lichtenstein P, Cnattingius S (2000).
Genetic inuence on birthweight and gestational length
determined by studies in offspring of twins. British Journal
of Obstetrics & Gynaecology 107, 375381.
Dalman C, Thomas HV, David AS, Gentz J, Lewis G,
Allebeck P (2001). Signs of asphyxia at birth and risk of
schizophrenia. Population-based case-control study. British
Journal of Psychiatry 179, 403408.
Davidoff MJ, Dias T, Damus K, Russell R, Bettegowda VR,
Dolan S, Schwarz RH, Green NS, Petrini J (2006). Changes
in the gestational age distribution among U.S. singleton
births: impact on rates of late preterm birth, 1992 to 2002.
Seminars in Perinatology 30, 815.
De Bie HM, Oostrom KJ, Boersma M, Veltman DJ,
Barkhof F, Delemarre-van de Waal HA, van den
Heuvel MP (2011). Global and regional differences in brain
anatomy of young children born small for gestational age.
PLoS One 6, e24116.
de Graaf R, tenHave M, van Gool C, van Dorsselaer S
(2012). Prevalence of mental disorders and trends from
1996 to 2009. Results from the Netherlands Mental Health
Survey and Incidence Study-2. Social Psychiatry and
Psychiatric Epidemiology 47, 203213.
Demendi C, Brzsnyi B, Pajor A, Rig J Jr., Nagy ZB,
Szentpteri I, Jo JG (2012). Abnormal fetomaternal
glucocorticoid metabolism in the background of premature
delivery: placental expression patterns of the 11-
hydroxysteroid dehydrogenase 2 gene. European Journal of
Obstetrics, Gynecology, and Reproductive Biology 165, 210214.
Dempster EL, Pidsley R, Schalkwyk LC, Owens S,
Georgiades A, Kane F, Kalidindi S, Picchioni M,
Kravariti E, Toulopoulou T, Murray RM, Mill J (2011).
Disease-associated epigenetic changes in monozygotic
twins discordant for schizophrenia and bipolar disorder.
Human Molecular Genetics 20, 47864796.
DOnofrio BM, Class QA, Rickert ME, Larsson H,
Lngstrm N, Lichtenstein P (2013). Preterm birth
and mortality and morbidity: a population-based
quasi-experimental study. JAMA Psychiatry 70, 12311240.
Dwarkanath P, Barzilay JR, Thomas T, Thomas A, Bhat S,
Kurpad AV (2013). High folate and low vitamin B-12
intakes during pregnancy are associated with
small-for-gestational age infants in South Indian women: a
prospective observational cohort study. American Journal of
Clinical Nutrition 98, 14501458.
Dy J, Guan H, Sampath-Kumar R, Richardson BS, Yang K
(2008). Placental 11beta-hydroxysteroid dehydrogenase
type 2 is reduced in pregnancies complicated with
idiopathic intrauterine growth Restriction: evidence that
this is associated with an attenuated ratio of cortisone to
cortisol in the umbilical artery. Placenta 29, 193200.
Ekblad M, Gissler M, Lehtonen L, Korkeila J (2010). Prenatal
smoking exposure and the risk of psychiatric morbidity into
young adulthood. Archives of General Psychiatry 67, 841849.
El Marroun H, Zeegers M, Steegers EA, van der Ende J,
Schenk JJ, Hofman A, Jaddoe VW, Verhulst FC,
Tiemeier H (2012). Post-term birth and the risk of
behavioural and emotional problems in early childhood.
International Journal of Epidemiology 41, 773781.
El-Sayed AM, Tracy M, Galea S (2012). Life course variation
in the relation between maternal marital status and preterm
birth. Annals of Epidemiology 22, 168174.
Entringer S, Kumsta R, Hellhammer DH, Wadhwa PD,
Wst S (2009). Prenatal exposure to maternal psychosocial
stress and HPA axis regulation in young adults. Hormones
and Behaviour 55, 292298.
Fadl HE, stlund IK, Magnuson AF, Hanson US (2010).
Maternal and neonatal outcomes and time trends of
gestational diabetes mellitus in Sweden from 1991 to 2003.
Diabetes Medicine 27, 436441.
Fazel S, Bakiyeva L, Cnattingius S, Grann M, Hultman CM,
Lichtenstein P, Geddes JR (2012). Perinatal risk factors in
offenders with severe personality disorder: a
population-based investigation. Journal of Personality
Disorders 26, 737750.
Fergusson DM, Boden JM, Horwood LJ (2007). Exposure to
single parenthood in childhood and later mental health,
educational, economic, and criminal behavior outcomes.
Archives of General Psychiatry 64, 10891095.
Ferrazzani S, Luciano R, Garofalo S, DAndrea V, De
Carolis S, De Carolis MP, Paolucci V, Romagnoli C,
Caruso A (2011). Neonatal outcome in hypertensive
disorders of pregnancy. Early Human Development 87,
445449.
Gardener H, Spiegelman D, Buka SL (2009). Prenatal risk
factors for autism: comprehensive meta-analysis. British
Journal of Psychiatry 195, 714.
Gouyon JB, Vintejoux A, Sagot P, Burguet A, Quantin C,
Ferdynus C; Burgundy Perinatal Network. (2010). Neonatal
outcome associated with singleton birth at 3441 weeks of
gestation. International Journal of Epidemiology 39, 769776.
Heaman M, Kingston D, Chalmers B, Sauve R, Lee L,
Young D (2013). Risk factors for preterm birth and small-
for-gestational-age births among Canadian women.
Paediatric and Perinatal Epidemiology 27, 5461.
Hedderson MM, Ferrara A, Sacks DA (2003). Gestational
diabetes mellitus and lesser degrees of pregnancy
hyperglycemia: association with increased risk of
spontaneous preterm birth. Obstetrics and Gynecology 102,
850;856.
Ipser JC, Singh L, Stein DJ (2013). Meta-analysis of
functional brain imaging in specic phobia. Psychiatry and
Clinical Neurosciences 67, 311322.
Kajantie E, Eriksson JG, Osmond C, Thornburg K,
Barker DJ (2009). Pre-eclampsia is associated with
increased risk of stroke in the adult offspring: the
Helsinki birth cohort study. Stroke 40, 11761180.
Kajantie E, Osmond C, Barker DJ, Eriksson JG (2010).
Preterm birth a risk factor for type 2 diabetes? The
Helsinki birth cohort study. Diabetes Care 33, 26232625.
Kapusta ND, Tran US, Rockett IR, De Leo D, Naylor CP,
Niederkrotenthaler T, Voracek M, Etzersdorfer E,
Sonneck G (2011). Declining autopsy rates and suicide
misclassication: a cross-national analysis of 35 countries.
Archives of General Psychiatry 68, 10501057.

Kendler KS, Aggen SH, Knudsen GP, Rysamb E,
Neale MC, Reichborn-Kjennerud T (2011). The structure
of genetic and environmental risk factors for syndromal
and subsyndromal common DSM-IV axis I and all axis II
disorders. American Journal of Psychiatry 168, 2939.
Keskinen E, Miettunen J, Koivumaa-Honkanen H, Mki P,
Isohanni M, Jskelinen E (2013). Interaction between
parental psychosis and risk factors during pregnancy and
birth for schizophrenia the Northern Finland 1966 Birth
Cohort study. Schizophrenia Research 145, 5662.
Kessler RC, Berglund P, Demler O, Jin R, Merikangas KR,
Walters EE (2005). Lifetime prevalence and age-of-onset
distributions of DSM-IV disorders in the National
Comorbidity Survey Replication. Archives of General
Psychiatry 62, 593602.
Kiesepp T, Partonen T, Kaprio J, Lnnqvist J (2000).
Accuracy of register- and record-based bipolar I
diagnoses in Finland a study of twins. Acta
Neuropsychiatrica 12, 106109.
Knudsen VK, Heitmann BL, Halldorsson TI, Srensen TI,
Olsen SF (2013). Maternal dietary glycaemic load during
pregnancy and gestational weight gain, birth weight and
postpartum weight retention: a study within the Danish
National Birth Cohort. British Journal of Nutrition 109,
14711478.
Lahti RA, Penttil A (2001). The validity of death certicates:
routine validation of death certication and its effects on
mortality statistics. Forensic Science International 115, 1532.
Laursen TM, Munk-Olsen T, Nordentoft M, Bo
Mortensen P (2007). A comparison of selected risk factors
for unipolar depressive disorder, bipolar affective disorder,
schizoaffective disorder, and schizophrenia from a Danish
population-based cohort. Journal of Clinical Psychiatry 68,
16731681.
Lee PA, Chernausek SD, Hokken-Koelega AC,
Czernichow P.; International Small for Gestational
Age Advisory Board (2003). International Small for
Gestational Age Advisory Board consensus development
conference statement: management of short children born
small for gestational age, April 24-October 1, 2001. Pediatrics
111, 12531261.
Leventakou V, Roumeliotaki T, Martinez D, Barros H,
Brantsaeter AL, Casas M, Charles MA, Cordier S,
Eggesb M, van Eijsden M, Forastiere F, Gehring U,
Govarts E, Halldrsson TI, Hanke W, Haugen M,
Heppe DH, Heude B, Inskip HM, Jaddoe VW, Jansen M,
Kelleher C, Meltzer HM, Merletti F, Molt-Puigmart C,
Mommers M, Murcia M, Oliveira A, Olsen SF, Pele F,
Polanska K, Porta D, Richiardi L, Robinson SM, Stigum H,
Strm M, Sunyer J, Thijs C, Viljoen K, Vrijkotte TG,
Wijga AH, Kogevinas M, Vrijheid M, Chatzi L (2014). Fish
intake during pregnancy, fetal growth, and gestational
length in 19 European birth cohort studies. American Journal
of Clinical Nutrition 99, 506516.
Leviton A, Fichorova RN, OShea TM, Kuban K, Paneth N,
Dammann O, Allred EN; ELGAN Study Investigators
(2013). Two-hit model of brain damage in the very preterm
newborn: small for gestational age and postnatal systemic
inammation. Pediatric Research 73, 362370.
Risk factors for severe mental disorders across adulthood 997
Lindstrm K, Fernell E, Westgren M (2005). Developmental
data in preschool children born after prolonged pregnancy.
Acta Paediatrica 94, 11921197.
Lindstrm K, Lindblad F, Hjern A (2009). Psychiatric
morbidity in adolescents and young adults born preterm: a
Swedish national cohort study. Pediatrics 123, e47e53.
Linnet KM, Wisborg K, Agerbo E, Secher NJ, Thomsen PH,
Henriksen TB (2006). Gestational age, birth weight, and the
risk of hyperkinetic disorder. Archives of Disease in Childhood
91, 655660.
Liu Y, Murphy SK, Murtha AP, Fuemmeler BF,
Schildkraut J, Huang Z, Overcash F, Kurtzberg J, Jirtle R,
Iversen ES, Forman MR, Hoyo C (2012). Depression in
pregnancy, infant birth weight and DNA methylation of
imprint regulatory elements. Epigenetics 7, 735746.
Loe IM, Lee ES, Luna B, Feldman HM (2011). Behavior
problems of 916 year old preterm children: biological,
sociodemographic, and intellectual contributions. Early
Human Development 87, 247252.
Lupien SJ, McEwen BS, Gunnar MR, Heim C (2009). Effects
of stress throughout the lifespan on the brain, behaviour
and cognition. Nature Reviews Neuroscience 10, 434445.
Mkikyr T, Sauvola A, Moring J, Veijola J, Nieminen P,
Jrvelin MR, Isohanni M (1998). Hospital-treated psychiatric
disorders in adults with a single- parent and two-parent
family background: a 28-year follow-up of the 1966 Northern
Finland birth cohort. Family Process 37, 335344.
Marsit CJ, Maccani MA, Padbury JF, Lester BM (2012).
Placental 11-beta hydroxysteroid dehydrogenase
methylation is associated with newborn growth and a
measure of neurobehavioral outcome. PLoS ONE 7, e33794.
Michels KB, Harris HR, Barault L (2011). Birthweight,
maternal weight trajectories and global DNA methylation
of LINE-1 repetitive elements. PLoS ONE 6, e25254.
Moilanen K, Jokelainen J, Jones PB, Hartikainen AL,
Jrvelin MR, Isohanni M (2010). Deviant intrauterine
growth and risk of schizophrenia: a 34-year follow-up of
the Northern Finland 1966 Birth Cohort. Schizophrenia
Research 124, 223230.
Monls Gustafsson W, Josefsson A, Ekholm Selling K,
Sydsj G (2009). Preterm birth or foetal growth impairment
and psychiatric hospitalization in adolescence and early
adulthood in a Swedish population-based birth cohort.
Acta Psychiatrica Scandinavica 119, 5461.
Morris MC, Compas BE, Garber J (2012). Relations among
posttraumatic stress disorder, comorbid major depression,
and HPA function: a systematic review and meta-analysis.
Clinical Psychology Revievs 32, 301315.
Moster D, Lie RT, Markestad T (2008). Long-term medical
and social consequences of preterm birth. New England
Journal of Medicine 359, 262273.
Moster D, Wilcox AJ, Vollset SE, Markestad T, Lie RT
(2010). Cerebral palsy among term and postterm births.
Journal of American Medical Association 304, 976982.
Niederkrotenthaler T, Rasmussen F, Mittendorfer-Rutz E
(2012). Perinatal conditions and parental age at birth as
risk markers for subsequent suicide attempt and suicide:
a population based case-control study. European Journal of
Epidemiology 27, 729738.
998 M. Lahti et al.
Nosarti C, Reichenberg A, Murray RM, Cnattingius S,
Lambe MP, Yin L, MacCabe J, Rifkin L, Hultman CM
(2012). Preterm birth and psychiatric disorders in young
adult life. Archives of General Psychiatry 69, E1E8.
Oberg AS, Frisell T, Svensson AC, Iliadou AN (2013).
Maternal and fetal genetic contributions to postterm birth:
familial clustering in a population-based sample of 475,429
Swedish births. American Journal of Epidemiology 177,
531537.
Oberlander TF, Weinberg J, Papsdorf M, Grunau R, Misri S,
Devlin AM (2008). Prenatal exposure to maternal
depression, neonatal methylation of human glucocorticoid
receptor gene (NR3C1) and infant cortisol stress responses.
Epigenetics 3, 97106.
OConnor TG, Bergman K, Sarkar P, Glover V (2013).
Prenatal cortisol exposure predicts infant cortisol
response to acute stress. Developmental Psychobiology 55,
142155.
Olesen AW, Westergaard JG, Olsen J (2003). Perinatal and
maternal complications related to postterm delivery: a
national register-based study, 19781993. American Journal
of Obstetrics and Gynecology 189, 222227.
Osmond C, Kajantie E, Forsn TJ, Eriksson JG, Barker DJ
(2007). Infant growth and stroke in adult life: the Helsinki
birth cohort study. Stroke 38, 264270.
Parikh NA, Lasky RE, Kennedy KA, McDavid G, Tyson JE
(2013). Perinatal factors and regional brain volume
abnormalities at term in a cohort of extremely low birth
weight infants. PLoS One 8, e62804.
Patel R, Spreng RN, Shin LM, Girard TA (2012).
Neurocircuitry models of posttraumatic stress disorder and
beyond: a meta-analysis of functional neuroimaging
studies. Neuroscience and Biobehavioral Reviews 36,
21302142.
Perl J, Suvisaari J, Saarni SI, Kuoppasalmi K, Isomets E,
Pirkola S, Partonen T, Tuulio-Henriksson A, Hintikka J,
Kiesepp T, Hrknen T, Koskinen S, Lnnqvist J (2007).
Lifetime prevalence of psychotic and bipolar I disorders
in a general population. Archives of General Psychiatry 64, 1928.
Petrini JR, Dias T, McCormick MC, Massolo ML, Green NS,
Escobar GJ (2009). Increased risk of adverse neurological
development for late preterm infants. Journal of Pediatrics
154, 169176.
Pihlajamaa J, Suvisaari J, Henriksson M, Heil H,
Karjalainen E, Koskela J, Cannon M, Lnnqvist J (2008).
The validity of schizophrenia diagnosis in the Finnish
Hospital Discharge Register: ndings from a 10-year birth
cohort sample. Nordic Journal of Psychiatry 62, 198203.
Poikolainen K (1983). Accuracy of hospital discharge data:
ve alcohol-related diseases. Drug and Alcohol Dependence
12, 315322.
Rikknen K, Lahti M, Heinonen K, Pesonen AK,
Wahlbeck K, Kajantie E, Osmond C, Barker DJ,
Eriksson JG (2011). Risk of severe mental disorders in
adults separated temporarily from their parents in
childhood: the Helsinki birth cohort study. Journal of
Psychiatric Research 45, 332338.
Rikknen K, Pesonen AK, Heinonen K, Kajantie E, Hovi P,
Jrvenp AL, Eriksson JG, Andersson S (2008).
Depression in young adults with very low birth weight: the
Helsinki study of very low-birth-weight adults. Archives of
General Psychiatry 65, 290296.
Rikknen K, Pesonen AK, Heinonen K, Lahti J, Komsi N,
Eriksson JG, Seckl JR, Jrvenp AL, Strandberg TE
(2009). Maternal licorice consumption and detrimental
cognitive and psychiatric outcomes in children. American
Journal of Epidemiology 170, 11371146.
Reynolds RM, Walker BR, Syddall HE, Andrew R,
Wood PJ, Phillips DI (2005). Is there a gender difference
in the associations of birthweight and adult
hypothalamic-pituitary-adrenal axis activity? European
Journal of Endocrinology 152, 249253.
Rice F, Harold GT, Boivin J, van den Bree M, Hay DF,
Thapar A (2010). The links between prenatal stress and
offspring development and psychopathology:
disentangling environmental and inherited inuences.
Psychological Medicine 40, 335345.
Rifkin-Graboi A, Bai J, Chen H, Hameed WB, Sim LW,
Tint MT, Leutscher-Broekman B, Chong YS,
Gluckman PD, Fortier MV, Meaney MJ, Qiu A (2013).
Prenatal maternal depression associates with
microstructure of right amygdala in neonates at birth.
Biological Psychiatry 74, 837844.
Rogers CE, Lenze SN, Luby JL (2013). Late preterm birth,
maternal depression, and risk of preschool psychiatric
disorders. Journal of the American Academy of Child and
Adolescent Psychiatry 52, 309318.
Ruocco AC, Amirthavasagam S, Zakzanis KK (2012).
Amygdala and hippocampal volume reductions as
candidate endophenotypes for borderline personality
disorder: a meta-analysis of magnetic resonance imaging
studies. Psychiatry Research 201, 245252.
Sabunciyan S, Aryee MJ, Irizarry RA, Rongione M,
Webster MJ, Kaufman WE, Murakami P, Lessard A,
Yolken RH, Feinberg AP, Potash JB; GenRED Consortium
(2012). Genome-wide DNA methylation scan in major
depressive disorder. PLoS ONE 7, e34451.
Shams M, Kilby MD, Somerset DA, Howie AJ, Gupta A,
Wood PJ, Afnan M, Stewart PM (1998). 11Beta-
hydroxysteroid dehydrogenase type 2 in human pregnancy
and reduced expression in intrauterine growth restriction.
Human Reproduction 13, 799804.
Silventoinen K, Pietilinen KH, Tynelius P, Srensen TI,
Kaprio J, Rasmussen F (2008). Genetic regulation of growth
from birth to 18 years of age: the Swedish young male twins
study. American Journal of Human Biology 20, 292298.
Steel Z, Marnane C, Iranpour C, Chey T, Jackson JW,
Patel V, Silove D (2014). The global prevalence of common
mental disorders: a systematic review and meta-analysis
19802013. International Journal of Epidemiology 43, 476493.
Stetler C, Miller GE (2011). Depression and
hypothalamic-pituitary-adrenal activation: a quantitative
summary of four decades of research. Psychosomatic
Medicine 73, 114126.
Strang-Karlsson S, Rikknen K, Pesonen AK, Kajantie E,
Paavonen EJ, Lahti J, Hovi P, Heinonen K, Jrvenp AL,
Eriksson JG, Andersson S (2008). Very low birth weight
and behavioral symptoms of attention decit hyperactivity
 Risk factors for severe mental disorders across adulthood
disorder in young adulthood: the Helsinki study of
very-low-birth-weight adults. American Journal of Psychiatry
165, 13451353.
Sund R (2012). Quality of the Finnish Hospital Discharge
Register: a systematic review. Scandinavian Journal of Public
Health 40, 505515.
Talge NM, Holzman C, Wang J, Lucia V, Gardiner J,
Breslau N (2010). Late-preterm birth and its association
with cognitive and socioemotional outcomes at 6 years of
age. Pediatrics 126, 11241131.
Thompson DK, Adamson C, Roberts G, Faggian N,
Wood SJ, Wareld SK, Doyle LW, Anderson PJ, Egan GF,
Inder TE (2013). Hippocampal shape variations at term
equivalent age in very preterm infants compared with term
controls: perinatal predictors and functional signicance at
age 7. Neuroimage 70, 278287.
Thorngren-Jerneck K, Herbst A (2001). Low 5-minute Apgar
score: a population-based register study of 1 million term
births. Obstetrics and Gynecology 98, 6570.
Tuovinen S, Rikknen K, Kajantie E, Pesonen AK,
Heinonen K, Osmond C, Barker D, Eriksson JG (2010).
Depressive symptoms in adulthood and intrauterine
exposure to pre-eclampsia: the Helsinki Birth Cohort
Study. British Journal of Obstetrics & Gynaecology 117,
12361242.
van Lieshout RJ, Boyle MH (2011). Canadian youth born
large or small for gestational age and externalizing and
999
internalizing problems. Canadian Journal of Psychiatry 56,
227234.
Vreeburg SA, Zitman FG, van Pelt J, Derijk RH,
Verhagen JC, van Dyck R, Hoogendijk WJ, Smit JH,
Penninx BW (2010). Salivary cortisol levels in persons with
and without different anxiety disorders. Psychosomatic
Medicine 72, 340347.
Wehkalampi K, Muurinen M, Wirta SB, Hannula-Jouppi K,
Hovi P, Jrvenp AL, Eriksson JG, Andersson S, Kere J,
Kajantie E (2013). Altered Methylation of IGF2 Locus
20 Years after Preterm Birth at Very Low Birth Weight.
PLoS ONE 8, e67379.
Welberg LA, Seckl JR, Holmes MC (2000). Inhibition of
11beta-hydroxysteroid dehydrogenase, the foeto-placental
barrier to maternal glucocorticoids, permanently programs
amygdala GR mRNA expression and anxiety-like
behaviour in the offspring. European Journal of Neuroscience
12, 10471054.
Zeitlin JA, Saurel-Cubizolles MJ, Ancel PY, the EUROPOP
Group (2002). Marital status, cohabitation, and the risk of
preterm birth in Europe: where births outside marriage are
common and uncommon. Paediatric and Perinatal
Epidemiology 16, 124130.
Zhang YP, Liu XH, Gao SH, Wang JM, Gu YS, Zhang JY,
Zhou X, Li QX (2012). Risk factors for preterm birth in ve
Maternal and Child Health hospitals in Beijing. PLoS One 7,
e52780.
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