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Journal of Child Psychology and Psychiatry **:* (2017), pp **–** doi:10.1111/jcpp.12856

Childhood developmental vulnerabilities associated

with early life exposure to infectious and
noninfectious diseases and maternal mental illness
Melissa J. Green,1,2 Maina Kariuki,1,2 Kimberlie Dean,1,2,3 Kristin R. Laurens,1,4
Stacy Tzoumakis,1,2,5 Felicity Harris,1,2 and Vaughan J. Carr1,2,6
1
School of Psychiatry, University of New South Wales, UNSW Sydney, Sydney, NSW; 2Neuroscience Research
Australia, Sydney, NSW; 3Justice Health & Forensic Mental Health Network, Sydney, NSW; 4School of Psychology,
Australian Catholic University, Brisbane, QLD; 5School of Social Sciences, University of New South Wales, Sydney,
NSW; 6Department of Psychiatry, School of Clinical Sciences, Monash University, Melbourne, Vic., Australia

Background: Fetal exposure to infectious and noninfectious diseases may influence early childhood developmental
functioning, on the path to later mental illness. Here, we investigated the effects of in utero exposure to maternal
infection and noninfectious diseases during pregnancy on offspring developmental vulnerabilities at age 5 years, in
the context of estimated effects for early childhood exposures to infectious and noninfectious diseases and maternal
mental illness. Methods: We used population data for 66,045 children from an intergenerational record linkage
study (the New South Wales Child Development Study), for whom a cross-sectional assessment of five developmental
competencies (physical, social, emotional, cognitive, and communication) was obtained at school entry, using the
Australian Early Development Census (AEDC). Child and maternal exposures to infectious or noninfectious diseases
were determined from the NSW Ministry of Health Admitted Patients Data Collection (APDC) and maternal mental
illness exposure was derived from both APDC and Mental Health Ambulatory Data collections. Multinomial logistic
regression analyses were used to examine unadjusted and adjusted associations between these physical and mental
health exposures and child developmental vulnerabilities at age 5 years. Results: Among the physical disease
exposures, maternal infectious diseases during pregnancy and early childhood infection conferred the largest
associations with developmental vulnerabilities at age 5 years; maternal noninfectious illness during pregnancy also
retained small but significant associations with developmental vulnerabilities even when adjusted for other physical
and mental illness exposures and covariates known to be associated with early childhood development (e.g., child’s
sex, socioeconomic disadvantage, young maternal age, prenatal smoking). Among all exposures examined, maternal
mental illness first diagnosed prior to childbirth conferred the greatest odds of developmental vulnerability at age
5 years. Conclusions: Prenatal exposure to infectious or noninfectious diseases appear to influence early childhood
physical, social, emotional and cognitive developmental vulnerabilities that may represent intermediate phenotypes
for subsequent mental disorders. Keywords: Risk factors; infection; CNS; developmental epidemiology;
developmental psychopathology; maternal factors.

2016), and autism (Patterson, 2011) in offspring.

Introduction
Maternal immune mechanisms are known to play a
Mental disorders are believed to emerge from multiple
critical role during pregnancy (Morelli, Mandal, Gold-
cumulative and interactive effects of inherited genetic
smith, Kashani, & Ponzio, 2015) with influences on
vulnerabilities and adverse exposures at various
fetal brain development (Smith, Li, Garbett, Mirnics, &
stages of the life course (Marin, 2016). While the
Patterson, 2008) and associated gene regulation
strongest known risk factor for any mental illness is a
(Fatemi et al., 2008), impacting early cognitive and
familial history of mental disorder, physical risk factors
social functions associated with schizophrenia and
such as those associated with inflammatory processes
autism (Meyer, Schwendener, Feldon, & Yee, 2006;
are increasingly implicated in the development of a
Smith et al., 2008; Wang et al., 2013). Early signs of
variety of mental disorders. For example, individuals
exposure to immune activation mechanisms may
exposed to infectious diseases prenatally and in child-
therefore be evident in neurodevelopmental function-
hood show small but significant increases in risk for
ing in childhood, and may represent intermediate
adult schizophrenia (Arias et al., 2012; Khandaker,
phenotypes for later mental disorder.
Zimbron, Dalman, Lewis, & Jones, 2012; Khandaker,
While prenatal exposure to infectious diseases
Zimbron, Lewis, & Jones, 2013) and mood disorders
typically confers a 1.5–2-fold increased risk for adult
(Benros et al., 2013; Kohler et al., 2016). Animal
psychotic disorder (Brown, 2012; Hamdani et al.,
studies further suggest that maternal immune activa-
2013; Jablensky, Morgan, Zubrick, Bower, & Yel-
tion via infectious agents potentiates risk for depres-
lachich, 2005; Selten & Morgan, 2010), one recent
sion, anxiety (Enayati et al., 2012; Ronovsky et al.,
study showed similar effect sizes for noninfectious
diseases during gestation in increasing risk for adult
Conflict of interest statement: No conflicts declared. schizophrenia (Sorensen, Nielsen, Benros, Pedersen,

© 2017 Association for Child and Adolescent Mental Health.

Published by John Wiley & Sons Ltd, 9600 Garsington Road, Oxford OX4 2DQ, UK and 350 Main St, Malden, MA 02148, USA
2 Melissa J. Green et al.
& Mortensen, 2015). The primacy of infectious agents
in conferring risk for later mental disorders should
therefore not be assumed. Moreover, comparable
increases in risk for schizophrenia and mood disor-
ders are also associated with exposure to infection
during childhood (Abrahao, Focaccia, & Gattaz, 2005;
Benros et al., 2011, 2013; Blomstrom et al., 2014;
Dalman et al., 2008; Kohler et al., 2016; Koponen
et al., 2004; Liang & Chikritzhs, 2012) and adoles-
cence (Nielsen, Benros, & Mortensen, 2014; Nielsen,
Laursen, & Mortensen, 2013; Sorensen et al., 2015),
suggesting that events in developmental periods other
than gestation also contribute to risk of mental
disorders. Indeed, two recent studies have reported
small but significant associations between early
childhood vulnerability indicators and childhood
infection (Kariuki et al., 2016), as well as with other
chronic health conditions (Bell, Bayliss, Glauert,
Harrison, & Ohan, 2016).
With much recent evidence suggesting that there
may be shared genetic risk for physical and mental
disorders (Plummer, Gordon, & Levitt, 2016), con-
sideration of associations between early life exposure
to physical disease exposures and age 5 develop-
mental functioning, in the context of effects of
maternal illness exposure, is warranted. The present
study thus set out to examine associations between
exposure to maternal and childhood infectious and
noninfectious diseases and age 5 developmental
vulnerabilities in a large population cohort, with a
primary aim to investigate the importance of the
pregnancy period (relative to postbirth childhood
periods) and the strength of associations for infec-
tious relative to noninfectious exposures during these
periods. Specifically, we examined independent
associations between childhood functioning on five
developmental domains (physical, social, emotional,
cognitive, communication) and: (a) fetal exposure to
maternal infection or noninfectious diseases; (b)
child exposure maternal infectious and noninfec-
tious disease exposure during postnatal develop-
ment; (c) childhood infectious and noninfectious
disease exposure during postnatal development,
and; (d) maternal mental illness (first health service
contact before or after the child’s birth), as well as
the effects of each of these risk factors in the
presence of each other. We expected to see signifi-
cant developmental effects of fetal exposures to
maternal infection and noninfectious diseases (Sor-
ensen et al., 2015) when considered in the context of
small, independent effects of exposure to infections
in childhood and maternal mental illness, on devel-
opmental vulnerabilities at age 5 years.
Method
Study setting and record linkage
Data were drawn from a multiagency administrative record
linkage study combined with cross-sectional survey data for a
cohort of 87,026 children and their parents (Carr et al., 2016).
Probabilistic record linkage was conducted by the NSW Centre
for Health Record Linkage (CHeReL; http://www.cherel.org.a
u/) according to nationally legislated privacy protocols, com-
bining routinely collected administrative records related to
each child’s birth, health, education, and welfare status, as
well as parental (health) records for 72,245 children (83% of
the cohort) whose births were registered in the state of New
South Wales (NSW), Australia (Carr et al., 2016); the false
positive linkage rate was ≤0.5%.
Participants
A total of 66,045 children (50.5% male; mean age = 5.65 years,
SD = 0.37) and their mothers were included in the analysis.
Exclusion criteria were: unavailability of parental data
(n = 14,781); being identified on the AEDC as having a chronic
medical, physical, or intellectually disabling condition requir-
ing special assistance in the classroom (n = 3,129), missing
AEDC scores on one or more domains (n = 491), and being
born among children registered as multiple births (2,580).
Figure 1 presents a summary of the sample selection
procedure.
Exposures
Infectious and noninfectious diseases. Exposure to
maternal infectious and noninfectious diseases was examined
in two developmental periods: (a) during gestation, and (b)
during early childhood (up to 4 years after childbirth). We also
derived an index of (c) the child’s exposure to infection and
noninfectious diseases during the first 4 years of life. The
specific ICD-10 codes used to define infectious and noninfec-
tious conditions in all exposure periods are presented in
Table S1. For each exposure period, a diagnosis of infection
was given primacy over any observation of a noninfectious
disease to ensure that exposure groups (for infection or
noninfection) within each time period were mutually exclusive.
The following methods were used to derive each exposure set:
1. Maternal infectious or noninfectious diseases during the
pregnancy period were derived from the NSW Ministry of
Health’s Admitted Patient Data Collection (APDC; 2001–
2009) for the period of gestation (beginning 8 months prior
to the last day of the month before the child’s birth, since we
had access only to the month and year of birth); maternal
infection included any ICD code representing infection
(Table S1) recorded as the primary or secondary diagnosis;
noninfectious disease status was assigned only if no infec-
tious disease was recorded, and was gleaned only from
primary diagnoses. The top 20 infectious and noninfectious
Sample (n) Cases removed
87,026
Children without linked parent records
(n = 14,781)
72,245
Children designated as “special needs”
(n = 3,129)
69,116
Children with ≥1 invalid AEDC domains
(n = 491)
68,625
Siblings from mulple births (n = 2,580)
66,045
Figure 1 Sample selection procedure
© 2017 Association for Child and Adolescent Mental Health.
 Early life infection and childhood developmental vulnerability
diseases for which mothers were hospitalized during the
pregnancy are presented in Table S2.
2. Maternal infectious or noninfectious conditions after preg-
nancy were derived from APDC records, for a period
beginning on the first day of the fourth month after
childbirth (i.e., allowing a 3-month window following the
birth month), up to the child’s age 4 years (see Table S3).
Both primary and secondary diagnosis defined infection
exposures in this period; noninfectious disease status was
assigned from primary diagnoses only if no infectious
disease was recorded.
3. Childhood infectious or noninfectious conditions were
defined by the observation of any admission to hospital in
this period (beginning the month after birth, up to age
4 years) for which a relevant ICD code was recorded as the
primary (or secondary, in the case of infection) diagnosis
(see Table S4).
Maternal Mental Illness first diagnosed before or
after childbirth. Maternal mental illness was defined as
any mental disorder diagnosis (ICD 10 Chapter V, F00-99
codes or R45.81, X84, 99.1) recorded in any episode of care
within health records from the NSW Ministry of Health’s APDC
(2001–2009) or Mental Health Ambulatory (i.e., community or
outpatient) data collection (MHA; 2001–2009) linked via birth
registration records (NSW Registry of Births, Deaths and
Marriages; RBDM; 2000–2009) to the child’s registered mother
(n = 7,485). Mental health-related ICD-10 codes were catego-
rized into six broad, mutually exclusive, diagnostic categories
including severe (psychotic) mental illness (n = 719; nonaffec-
tive psychoses, affective psychoses, drug-induced psychoses,
and schizoaffective disorder); common mental disorders
(n = 5071; nonpsychotic depressive disorder and all anxiety/
neurotic disorders); personality disorder (n = 453; all types of
personality disorders); substance abuse (n = 1,953; both
intoxication and substance use disorders); other adult-onset
(n = 2,750) illness; other child-onset illness (n = 120). Offspring
could be exposed to more than one broad diagnosis group if
their mother’s health records contained multiple mental
health-related diagnostic codes that fell among a number of
broad classification categories. See Table S5 for information on
ICD codes used to define exposure, and the diagnoses included
within each of the above broad categories, and Table S6 for a
summary of the most common maternal mental health condi-
tions recorded for mothers with mental illness exposure.
Indices of any maternal illness first diagnosed (i.e., first mental
health contact) before the child’s birth month, or in the first
month after the child’s birth, were used in focal analyses.
Multiple exposure patterns
Proportional childhood health exposures among the maternal
pregnancy exposure groups and maternal illness exposure
groups are presented in Tables S7 and S8, respectively.
Differences in the relative proportions of mothers and children
hospitalized for infectious or noninfectious diseases among
those exposed also to maternal mental illness, and among
exposure groups defined for the pregnancy period, were
investigated using z-tests. These tests show that childhood
infections, but not noninfectious diseases, were more likely to
be present in the offspring of mothers who had infectious
(34.9%) and, to a lesser extent, noninfectious diseases (30.2%)
during pregnancy, relative to children with no gestational
exposures (22.0%). Maternal infections postpregnancy (i.e., in
the first 4 years of the child’s life), but not maternal noninfec-
tious diseases during that period (for which statistically
significant differences were of small magnitude), were also
more likely among mothers who had infections during preg-
nancy (21.0%) and, to a lesser extent, noninfectious diseases
during pregnancy (12.7%), relative to no maternal gestational
© 2017 Association for Child and Adolescent Mental Health.
3
exposures (7.7%). Relative to mothers with no mental illness,
higher rates of maternal infection (6.0% vs. 2.2%) and nonin-
fectious diseases (23.9% vs. 13.8%) during pregnancy were
observed in mothers with mental illness; there were also
increased rates of maternal infection and noninfectious dis-
ease in the first 4 years of the child’s life, and increase rates of
childhood infection and noninfectious disease, in the children
exposed to maternal mental illness (Table S8).
Outcome variables: early childhood developmental
vulnerability
Individual child records from the Commonwealth Department
of Education’s Australian Early Development Census (AEDC;
2009) were used to estimate early childhood developmental
vulnerability. The AEDC is a population measure of the extent
to which children have gained the necessary competencies on
five developmental domains to engage effectively in school-
based learning (Brinkman, Gregory, Goldfeld, Lynch, & Hardy,
2014), each with acceptable reliability (Cronbach’s alpha;
Janus, Brinkman, & Duku, 2011): social competence (SOCIAL;
a = .95), emotional maturity (EMOTIONAL; a = .93), physical
health and wellbeing (PHYSICAL; a = .80), language and cog-
nition (COGNITIVE; a = .91), and communication and general
knowledge (COMMUNICATION; a = .90). The 104-item instru-
ment was developed in Canada (Janus & Offord, 2007) and
cross-national comparison has demonstrated similar psycho-
metric properties across Canada, Australia, the United States,
and Jamaica (Janus et al., 2011).
The physical health and wellbeing (PHYSICAL) domain of the
AEDC represents gross and fine motor skills, physical inde-
pendence, and physical readiness for the school day (e.g.,
tired, hungry, or unkempt); the social competence (SOCIAL)
domain includes ratings of overall social competence, respon-
sibility and respect, approach to learning (e.g., works inde-
pendently and adapts to routines), and readiness to explore
new things (e.g., books, toys, games); the emotional maturity
(EMOTIONAL) domain indexes prosocial and helping behav-
iors, anxious and fearful behavior, aggressive behavior, and
hyperactivity and inattention; the language and cognitive skills
(COGNITIVE) domain measures basic literacy, advanced liter-
acy, basic numeracy, and interest in literacy, numeracy and
memory; and the communication skills and general knowledge
(COMMUNICATION) domain indexes broad developmental
competencies and skills in communication and general knowl-
edge (e.g., understands and uses language effectively).
The AEDC was completed by the child’s school teacher on
the basis of at least 1 month’s knowledge of the child; most
assessments were completed between 1 May and 31 July 2009
with approximately 5 months of teacher knowledge of the
child. Scores on the AEDC represent age-normed performance
levels: those children scoring in the lowest 10% of the national
population (on any domain) are regarded as developmentally
vulnerable in that domain (Brinkman et al., 2007). We inves-
tigated the effects of the defined health exposures on AEDC
VULNERABILITY (lowest 10th percentiles), and AEDC AT-RISK
categories (11–25th percentiles) relative to children scoring in
the ON-TRACK range (≥26th percentiles) for each of the five
AEDC domains separately within multinomial logistic regres-
sion models.
Covariates
A number of demographic and perinatal risk factors were
examined as covariates (Curtin, Madden, Staines, & Perry,
2013). These included: child’s sex, English as a Second
Language (ESL), and Socio-Economic Index for Areas (SEIFA)
(ABS, 2011) (where the lowest quintile was classified as
‘disadvantaged’, and quintiles 2–5 were grouped as ‘not
disadvantaged’ and used as the reference category) which were
4 Melissa J. Green et al.

all derived from the AEDC; maternal age at the child’s birth Table 1 Prevalence of maternal and childhood infectious and
(<25 years) was derived from the NSW RBDM; and prenatal noninfectious diseases, maternal mental illness (exposure
smoking exposure was derived from the NSW Ministry of variables), early childhood developmental vulnerability and
Health’s Perinatal Data Collection (PDC; 2000–2006). at-risk status on the AEDC (outcome variables), and sociode-
mographic covariates for the sample of 66,045 children and
their mothers
Statistical analysis
N %
All analyses were conducted using IBM SPSS Version 24 (IBM,
2016). A series of bivariate (unadjusted) multinomial logistic Exposure variables
regressions (MLR) firstly estimated the independent effects of Maternal hospitalization during pregnancy
all physical and mental health exposure variables. One final Infectious disease 1,764 2.7
MLR model for each AEDC outcome was then used to estimate Noninfectious disease 9,844 14.9
the adjusted associations between AEDC developmental VUL- Maternal hospitalization (child age ≤4 years)
NERABILITY (and AT-RISK) status and all physical and mental Infectious disease 5,787 8.8
health exposures, in the context of demographic and perinatal Noninfectious disease 34,525 52.3
covariates. Child hospitalization (≤4 years)
Infectious disease 15,553 23.5
Noninfectious disease 21,740 32.9
Any maternal mental illness 7,485 11.3
Results First mental health contact before 4,409 6.7
Sample characteristics childbirth
First mental health contact after childbirth 3,076 4.7
The prevalence of exposures, outcomes, and covari- Outcome variables
ates for the 66,045 children contributing to the AEDC Developmental vulnerability
(≤10 centiles)
analyses are presented in Table 1. The distribution
Physical health and wellbeing 5,389 8.1
of developmental VULNERABILITY and AT-RISK Social competence 5,483 8.3
outcomes on AEDC domains are presented in Emotional maturity 4,723 7.2
Table 2 for each exposure group, and the distribu- Language and cognitive skills 3,519 5.3
tion of values on covariates for each of the exposure Communication skills and general 5,378 8.1
knowledge
groups is presented in Table S9.
AEDC Developmental at-risk (11–25th centiles)
Physical health and wellbeing 8,446 12.8
Social competence 9,108 13.8
Unadjusted models
Emotional maturity 9,288 14.1
Unadjusted odds ratios (ORs and 95% Confidence Language and cognitive skills 5,957 9.0
Communication skills and general 10,079 15.3
intervals; CIs) estimating the association between each
knowledge
exposure variable and early childhood developmental Socio-demographic covariates
VULNERABILITY and AT-RISK status for each AEDC Child sex (male) 33,357 50.5
domain are presented in Table 3 and the results for Child speaks English as a Second Language 10,547 16.0
VULNERABILITY are illustrated in Figure 2A. All phys- SEIFA Socioeconomic Status (disadvantaged) 15,520 23.5
Maternal age at child’s birth (<25 years) 11,780 17.8
ical health exposures had significant unadjusted
Prenatal maternal smoking exposure 9,218 14.0
effects on VULNERABILITY and AT-RISK status for all
AEDC domains, except for maternal noninfectious AEDC, Australian Early Development Census; SEIFA, Socio-
disease exposure postpregnancy (and we note that Economic Index for Areas.
some effects were not robust on the COMMUNICATION
domain). Of these risk factors, exposure to maternal disease during pregnancy were both associated with
mental illness before childbirth had the largest unad- increased likelihood of developmental vulnerability
justed effects on VULNERABILITY (ORs ranging from across all developmental domains; maternal infec-
1.83 to 2.65) and AT-RISK status (ORs ranging from tious or noninfectious diseases in early childhood
1.60 to 2.10). For all exposures, effects on AT-RISK years were associated with no such increase. Asso-
status were consistently smaller than those for VUL- ciations for infectious disease exposures were sub-
NERABILITY on all AEDC domains. stantially reduced in magnitude when maternal
mental illness exposures were taken into account.
Interestingly, maternal noninfectious diseases
Adjusted models
during the early years of the child’s life were asso-
Table 4 presents the ORs (95% CIs) for the full ciated with a reduced likelihood of developmental
models estimating associations between all infec- vulnerability.
tious and noninfectious disease exposures, and
maternal mental illness with onset before and after
childbirth, with VULNERABILITY and AT-RISK sta- Discussion
tus for each of the five AEDC domains, adjusted for We demonstrate pervasive effects of fetal exposure to
demographic and perinatal factors. The findings are both maternal infection and noninfectious diseases,
illustrated in Figure 2B for the VULNERABILITY and for child infectious disease exposure during the
outcomes. Maternal infection and noninfectious first 4 years of life, on a range of developmental

© 2017 Association for Child and Adolescent Mental Health.

 Table 2 Distribution of AEDC vulnerability and risk in the full sample, and in each of the maternal and child health exposure groups

On-track Physical Social Emotional Cognitive Communication

n % n % n % n % n % n %

AEDC VULNERABILITY (lowest 10 centiles)

Full sample 37,214 56.3 5,359 8.1 5,483 8.3 4,723 7.2 3,519 5.3 5,378 8.1
Maternal infection during pregnancy 827 46.9 219 12.4 214 12.1 183 10.4 156 8.8 178 10.1
Maternal noninfectious disease during pregnancy 5,194 52.8 938 9.5 967 9.8 809 8.2 627 6.4 826 8.4
Maternal infection child age ≤4 years 2,957 51.1 625 10.8 617 10.7 527 9.1 444 7.7 577 10.0
Maternal noninfectious disease child age ≤4 years 19,821 57.4 2,704 7.8 2,720 7.9 2,331 6.8 1,760 7.2 2,660 7.7

© 2017 Association for Child and Adolescent Mental Health.

Childhood infection ≤4 years 8,162 52.5 1,557 10.0 1,571 10.1 1,344 8.6 1,053 6.8 1,445 9.3
Childhood noninfectious disease ≤4 years 12,258 56.4 1,748 8.0 1,796 8.3 1,539 7.1 1,110 5.1 1,698 7.8
First maternal mental illness before childbirth 1,919 43.5 668 15.2 824 18.7 821 18.6 598 13.6 822 18.6
First maternal mental illness after childbirth 1,509 49.1 434 14.1 542 17.6 514 16.7 347 11.3 512 16.6

AEDC AT-RISK (11–25th centiles)

Full sample 37,214 56.3 8,446 12.8 9,108 13.8 9,288 14.1 5,957 9.0 10,079 15.3
Maternal infection during pregnancy 827 46.9 268 15.2 294 16.7 297 16.8 192 10.9 340 19.3
Maternal noninfectious disease during pregnancy 5,194 52.8 1,357 13.8 1,502 15.3 1,506 15.3 1,039 10.6 1,629 16.5
Maternal infection child age ≤4 years 2,957 51.1 809 14.0 967 16.7 941 16.3 634 11.0 958 16.6
Maternal noninfectious disease child age ≤4 years 19,821 57.4 4,314 12.5 4,630 13.4 4,797 13.9 2,953 8.6 5,097 14.8
Childhood infection ≤4 years 8,162 52.5 2,154 13.8 2,385 15.3 2,436 15.7 1,631 10.5 2,540 16.3
Childhood noninfectious disease ≤4 years 12,258 56.4 2,827 13.0 3,039 14.0 3,095 14.2 1,882 8.7 3,251 15.0
First maternal mental illness before childbirth 1,919 43.5 641 14.5 605 13.7 561 12.7 428 9.7 480 10.9
First maternal mental illness after childbirth 1,509 49.1 350 11.4 337 11.0 315 10.2 256 8.3 290 9.4

Children were excluded from the on-track group if they were Vulnerable or At Risk on any one AEDC domain.
Early life infection and childhood developmental vulnerability
5
6 Melissa J. Green et al.

Table 3 Unadjusted odds ratios (95% CIs) for four models estimating associations between developmental risk exposures and AEDC
outcome categories

AEDC domain

Exposure Physical Social Emotional Cognition Communication

Maternal infection during pregnancy

Vulnerable 1.97 (1.69, 2.28)* 1.88 (1.61, 2.19)* 1.85 (1.57, 2.18)* 2.15 (1.80, 2.56)* 1.53 (1.30, 1.81)*
At-risk 1.48 (1.29, 1.70)* 1.50 (1.31, 1.71)* 1.50 (1.31, 1.71)* 1.53 (1.31, 1.80)* 1.58 (1.39, 1.80)*
Maternal noninfectious disease during pregnancy
Vulnerable 1.34 (1.24, 1.45)* 1.35 (1.25, 1.46)* 1.30 (1.20, 1.41)* 1.38 (1.26, 1.51)* 1.13 (1.04, 1.23)*
At-risk 1.19 (1.12, 1.28)* 1.23 (1.16, 1.31)* 1.21 (1.14, 1.29)* 1.32 (1.23, 1.43)* 1.21 (1.13, 1.28)*
Maternal infection postpregnancy (child age ≤4 years)
Vulnerable 1.50 (1.36, 1.66)* 1.40 (1.27, 1.55)* 1.38 (1.24, 1.53)* 1.65 (1.47, 1.85)* 1.31 (1.19, 1.45)*
At-risk 1.19 (1.09, 1.16)* 1.34 (1.24, 1.46)* 1.29 (1.19, 1.40)* 1.31 (1.19, 1.44)* 1.16 (1.07, 1.26)
Maternal noninfectious disease postpregnancy (child age ≤4 years)
Vulnerable 0.97 (0.91, 1.03) 0.92 (0.87, 0.98) 0.91 (0.85, 0.97) 0.97 (0.90, 1.05) 0.90 (0.85, 0.96)
At-risk 0.95 (0.90, 0.99) 0.96 (0.91, 1.01) 0.98 (0.94, 1.03) 0.91 (0.86, 0.96 0.92 (0.88, 0.97)
Child infection (child age ≤4 years)
Vulnerable 1.56 (1.45, 1.67)* 1.53 (1.42, 1.64)* 1.50 (1.39, 1.62)* 1.60 (1.47, 1.74)* 1.33 (1.24, 1.43)*
At-risk 1.28 (1.20, 1.36)* 1.33 (1.26, 1.41)* 1.33 (1.26, 1.41)* 1.37 (1.28, 1.47)* 1.22 (1.15, 1.29)*
Child noninfectious disease (child age ≤4 years)
Vulnerable 1.17 (1.09, 1.25)* 1.16 (1.09, 1.24)* 1.15 (1.07, 1.23)* 1.12 (1.03, 1.22)* 1.04 (0.97, 1.11)
At-risk 1.12 (1.06, 1.18)* 1.13 (1.07, 1.19)* 1.13 (1.07, 1.19)* 1.06 (0.99, 1.13) 1.04 (0.99, 1.09)
Maternal mental illness before childbirth
Vulnerable 2.58 (2.35, 2.84)* 2.35 (2.13, 2.58)* 2.57 (2.32, 2.84)* 2.65 (2.38, 2.97)* 1.83 (1.65, 2.03)*
At-risk 1.60 (1.46, 1.76)* 1.87 (1.72, 2.04)* 1.82 (1.67, 2.08)* 2.10 (1.91, 2.31)* 1.66 (1.52, 1.80)*
Maternal mental illness after childbirth
Vulnerable 1.79 (1.59, 2.02)* 1.66 (1.47, 1.88)* 1.83 (1.62, 2.08)* 2.02 (1.76, 2.32) 1.41 (1.24, 1.60)*
At-risk 1.32 (1.19, 1.48)* 1.57 (1.42, 1.73)* 1.45 (1.31, 1.60)* 1.55 (1.37, 1.75) 1.31 (1.18, 1.45)*

AEDC, Australian Early Development Census.

*p < .001.

(A) (B)
2.8 2.8

Maternal mental illness 2.6 2.6

pre-childbirth
2.4 2.4
Maternal Infection during
pregnancy 2.2 2.2
Unadjusted odds ratios

Adjusted odds ratios

Maternal mental illness

2 2
post-childbirth
Child infection 1.8 1.8

1.6 1.6
Maternal Infection post-
pregnancy 1.4 1.4
Maternal non-infectious
illness during pregnancy 1.2 1.2

Child non-infectious illness 1 1

Maternal non-infectious 0.8 0.8

illness post-pregnancy

AEDC vulnerability AEDC vulnerability

Figure 2 Unadjusted (A) and adjusted* (B) odds ratios for maternal and child health exposures on developmental vulnerability for five
AEDC domains (for 95% confidence intervals see Tables 3 and 4). *Full models adjusted for child’s sex, English as a second language,
socioeconomic status, maternal age at child’s birth, maternal smoking during pregnancy

vulnerabilities in social, emotional, physical, and
cognitive domains of functioning. The odds of child-
hood vulnerability associated with prenatal expo-
sures to infection and noninfectious diseases were
reduced when exposure to maternal mental illness
was considered in the same model. The unexpected,
slightly reduced odds of developmental vulnerability
among children exposed to maternal noninfectious
diseases during the first 4 years of the child’s life is
an interesting finding that may reflect small but
protective effects of the birth of a younger sibling
within the first 4 years of a child’s life, since mater-
nal hospitalizations in this period comprised a high
proportion of pregnancy and birth-related condi-
tions. However, this remains speculative. Our main
findings thus suggest that immune activation or

© 2017 Association for Child and Adolescent Mental Health.

 Early life infection and childhood developmental vulnerability 7

Table 4 Adjusted odds ratios (and 95% CIs) for full models estimating associations between all exposures and five AEDC outcome
categories

AEDC Domain

Exposure Physical Social Emotional Cognition Communication

Maternal infection during pregnancy

Vulnerable 1.44 (1.22, 1.69)* 1.41 (1.20, 1.66)* 1.37 (1.15, 1.63)* 1.45 (1.20, 1.75)* 1.22 (1.03, 1.46)
At-risk 1.26 (1.10, 1.46)* 1.23 (1.07, 1.41) 1.24 (1.07, 1.42) 1.17 (0.99, 1.38) 1.33 (1.16, 1.51)*
Maternal noninfectious disease during pregnancy
Vulnerable 1.19 (1.10, 1.29)* 1.22 (1.13, 1.32)* 1.18 (1.08, 1.28)* 1.20 (1.09, 1.32)* 1.07 (0.99, 1.17)
At-risk 1.13 (1.06, 1.21)* 1.15 (1.07, 1.22)* 1.13 (1.06, 1.21)* 1.21 (1.12, 1.30)* 1.15 (1.08, 1.22)*
Maternal infection postpregnancy (child age ≤4 years)
Vulnerable 1.14 (1.01, 1.27) 1.09 (0.98, 1.20) 1.05 (0.94, 1.18) 1.19 (1.06, 1.35) 1.14 (1.02, 1.26)
At-risk 1.03 (0.94, 1,13) 1.12 (1.02, 1.22) 1.10 (1.01, 1.20) 1.05 (0.95, 1.16) 1.01 (0.92. 1.09)
Maternal noninfectious disease postpregnancy (child age ≤4 years)
Vulnerable 0.91 (0.85, 0.97) 0.87 (0.82, 0.92)* 0.84 (0.79, 0.90)* 0.89 (0.84, 0.98) 0.89 (0.83, 0.95)*
At-risk 0.92 (0.87, 0.96)* 0.92 (0.87, 0.96)* 0.94 (0.90, 0.99) 0.85 (0.80, 0.91)* 0.89 (0.85, 0.94)*
Child infection (child age ≤4 years)
Vulnerable 1.32 (1.23, 1.42)* 1.29 (1.19, 1.38)* 1.22 (1.13, 1.32)* 1.33 (1.21, 1.45)* 1.21 (1.12, 1.30)*
At-risk 1.30 (1.21, 1.40)* 1.17 (1.10, 1.24)* 1.17 (1.10, 1.24)* 1.20 (1.12, 1.29)* 1.12 (1.05, 1.18)*
Child noninfectious disease (child age ≤4 years)
Vulnerable 1.11 (1.03, 1.19) 1.09 (1.02, 1.17) 1.04 (0.98, 1.14) 1.08 (0.99, 1.18) 1.02 (0.95, 1.09)
At-risk 1.09 (1.02, 1.17) 1.07 (1.02, 1.14)* 1.06 (1.01, 1.12) 1.02 (0.95, 1.09) 1.01 (0.96, 1.07)
Maternal Mental illness before childbirth
Vulnerable 1.91 (1.73, 2.12)* 1.80 (1.62, 2.00)* 2.01 (1.80, 2.24)* 1.85 (1.64, 2.09)* 1.60 (1.43, 1.79)*
At-risk 1.34 (1.22, 1.47) 1.55 (1.42, 1.70)* 1.54 (1.41, 1.69) 1.65 (1.48, 1.82)* 1.37 (1.26, 1.50)*
Maternal Mental illness after childbirth
Vulnerable 1.50 (1.32, 1.70)* 1.44 (1.26, 1.64)* 1.59 (1.39, 1.82)* 1.63 (1.41, 1.89)* 1.36 (1.19, 1.56)*
At-risk 1.19 (1.06, 1.32) 1.41 (1.27, 1.57)* 1.30 (1.17, 1.46)* 1.35 (1.19, 1.54)* 1.21 (1.08, 1.34)*

Covariates: Child’s sex, English as a second language, area-based social economic factors, maternal age, maternal smoking during
pregnancy. AEDC, Australian Early Development Census.
*p < .001.

other mechanisms triggered by fetal exposure to
infectious or noninfectious disease processes may
affect early brain development, and that the variance
in developmental vulnerability explained by these
physical risk factors may be at least partly shared
with that explained by exposure to maternal mental
illness.
These findings are consistent with a growing body
of evidence for increased risk of adult mental disor-
der among offspring of mothers exposed to infection
during pregnancy (Brown, 2012; Hamdani et al.,
2013; Jablensky et al., 2005; Selten & Morgan,
2010), as well as individuals exposed to infectious
and autoimmune diseases throughout the life course
(Abrahao et al., 2005; Benros et al., 2011, 2013;
Blomstrom et al., 2014; Dalman et al., 2008; Kohler
et al., 2016; Koponen et al., 2004). Among all of the
risk exposures examined here, the highest odds of
developmental vulnerability were observed for off-
spring exposed to maternal mental illness first
diagnosed prior to the child’s birth, suggesting a
possible role for inherited genetic susceptibility to
mental disorder, rather than the effects of stress on
the child that may be associated with being exposed
to the behavior of a mentally ill mother during the
early childhood years. Associations between devel-
opmental vulnerability and prenatal (maternal)
infectious disease exposures were next greatest in
magnitude, followed by prenatal exposure to
noninfectious disease. While at least two previous
studies have shown that the risk of mental disorder
conferred by prenatal exposure to infection is
increased among the offspring of mothers with
schizophrenia (Blomstrom et al., 2014; Clarke, Tan-
skanen, Huttunen, Whittaker, & Cannon, 2009), our
study was underpowered to examine the interactive
effects of all physical and mental exposures, espe-
cially in relation to particular diagnoses.
One interpretation of these findings is that altered
immune system processes are associated with men-
tal illness itself, owing to shared genetic or other
mechanisms (Hartweg, Borges, Horta, Boweden, &
Smith, 2017). We indeed observed higher rates of all
physical health exposures among children whose
mothers had been diagnosed with a mental illness
(See Tables S7 and S8). This is consistent with recent
evidence for shared genetic vulnerability for mental
and physical disorders (Plummer et al., 2016). Con-
vergent findings from molecular genetics also indi-
cate that a significant proportion of genetic risk loci
are located in genes regulating the immune system
(Barnes, Mondelli, & Pariante, 2017; Ripke et al.,
2014), and emerging functional genomics studies
implicate immune system pathways in the neu-
ropathology of severe mental disorders (Avramopou-
los et al., 2015; Wu et al., 2016). An alternative
explanation of shared risk for physical and mental
disorders may give prominence to the role of social

© 2017 Association for Child and Adolescent Mental Health.

8 Melissa J. Green et al.
factors associated with mental illness (e.g., poor diet,
financial stress) in contributing to poor physical
health among mentally ill women and their families,
such that the markers of risk measured here in
relation to hospitalization for various medical condi-
tions may be proxy indicators of social disadvantage.
We indeed observed a slight over-representation of
children from the most disadvantaged socioeco-
nomic areas among those exposed to gestational
infection (see Table S9), and there were small to
moderate effects of socioeconomic disadvantage
(ORs ranging from 1.17 to 1.61) and prenatal smok-
ing (ORs ranging from 1.72 to 3.08) maintained in
adjusted models (see Tables S10 and S11).
Despite the key strengths of this study, some
limitations deserve consideration. First, the adminis-
trative data obtained from government agencies were
not originally collected for this study; random errors
in data entry or quality may exist but would have little
effect in a sample of this size. Second, parental data
were unavailable for children whose births were not
registered in the state of NSW, or for whom incorrect
or inadequate information was available in birth
registration data. However, the sample restricted to
those with parental records has been shown to be
representative of the entire state of NSW (Carr et al.,
2016) and hence would be broadly representative of
the Australian population of this age group. Third, we
did not attempt to establish the effects of specific
pathogens or maternal mental diagnoses (e.g.,
schizophrenia) on developmental vulnerabilities,
given the relatively small proportions exposed to
individual diagnoses. The composite index of mental
health exposure used here might have masked differ-
ential associations for different diagnoses (e.g., poten-
tial for postbirth diagnoses to be related to postnatal
stress), which could be further explored in future
studies. The small numbers of mothers exposed to
multiple mental and physical disorders also pre-
cluded formal testing of interactive effects of all
physical and maternal mental health conditions.
Finally, we were only able to account for relatively
severe infections, namely those associated with hos-
pital admissions, and were unable to consider infec-
tious diseases treated solely in primary care settings,
which are presumably less severe.
In conclusion, we provide evidence of small yet
pervasive effects of in utero exposure to infectious
and noninfectious diseases on developmental vul-
nerabilities in early childhood, together with simi-
larly small but significant effects of early childhood
infectious disease exposure. Exposure to maternal
mental illness showed the strongest association with
age 5 developmental vulnerability, and may share
risk mechanisms with prenatal infection and other
physical health exposures, but this will need to be
clarified in future studies. These results are highly
relevant to contemporary models of proinflammatory
processes affecting gene expression and neural
development on the pathway to adult mental
disorders (Khandaker, Pearson, Zammit, Lewis, &
Jones, 2014; Mansur et al., 2016), Increasingly. it
appears that a broad range of physical health
exposures in fetal and early development increase
the likelihood of childhood developmental vulnera-
bility at age 5 years, for which underlying mecha-
nisms common to both mental illness and physical
disease, particularly infectious disease, remain to be
elucidated.
Supporting information
Additional Supporting Information may be found in the
online version of this article:
Table S1. ICD-10 codes used to define of infection and
noninfectious diseases.
Table S2. Summary of the top 20 (A) infectious and (B)
noninfectious diseases for which mothers were hospi-
talized during the pregnancy period.
Table S3. Summary of the top 20 (A) infectious and (B)
noninfectious diseases for which mothers were hospi-
talized during the early childhood period (≤4 years).
Table S4. Summary of the top 20 (A) infectious and (B)
noninfectious diseases for which children were hospi-
talized during the early childhood period (≤4 years).
Table S5. ICD-10 codes used to define Broad Mental
Health conditions experienced by mothers of the child
cohort.
Table S6. Summary of the top 20 maternal mental
health conditions in mothers experiencing any mental
illness.
Table S7. Cross-tabulations showing the number of
children exposed to child and maternal hospitalizations
for infection and noninfectious disease among exposure
categories in the pregnancy period.
Table S8. Cross-tabulation showing the proportion
(and number) of children exposed to child and maternal
hospitalizations for infection and noninfection among
maternal illness exposure categories.
Table S9. Distribution of covariates for each of the
maternal and child physical health exposure groups.
Table S10. Summary of adjusted models (including
covariates) estimating associations between health
exposures and VULNERABLE status on each AEDC
domain.
Table S11. Summary of adjusted models (including
covariates) estimating associations between health
exposures and AT RISK status on each AEDC domain.
Acknowledgements
This research was conducted at the University of
New South Wales (UNSW) with financial support from
the Australian Research Council (Linkage Project
LP110100150, with the NSW Ministry of Health, NSW
Department of Education, and the NSW Department of
Family and Community Services representing the Link-
age Project Partners); the National Health and Medical
Research Council (NHMRC Project Grant APP1058652)
and the Australian Rotary Health (Mental Health
Research Grant 104090). Authors MK, KRL, FH, and
VJC were supported by funding from the Schizophrenia
Research Institute (Australia) using infrastructure
© 2017 Association for Child and Adolescent Mental Health.
 Early life infection and childhood developmental vulnerability 9

funding from the NSW Ministry of Health; MJG was
supported by a NHMRC R.D. Wright Biomedical Career
Development Fellowship (APP1061875). The research
was conducted using population data owned by the
Commonwealth Department of Education; the NSW
Ministry of Health; the NSW Registry of Births, Deaths
and Marriages; and the Australian Bureau of Statistics.
However, the information and views contained in this
study do not necessarily, or at all, reflect the views or
information held by these Departments. The authors
have declared that they have no competing or potential
conflicts of interest.
Correspondence
Melissa J. Green, UNSW Research Unit for Schizophre-
nia Epidemiology, O’Brien Centre Level 4, St Vincent’s
Hospital, 394-404 Victoria Street, Darlinghurst, NSW
2010, Australia; Email: melissa.green@unsw.edu.au

Key points
• Maternal history of mental disorder is the strongest known risk factor for developing mental illness; other risk
factors associated with inflammatory processes are increasingly associated with mental disorders.
• This study examined associations between fetal exposure to infectious or non-infectious diseases and early
childhood developmental functioning (as intermediate phenotypes on the path to later mental illness).
• Among the physical disease exposures, maternal infectious diseases during pregnancy and early childhood
infection conferred the largest associations with developmental vulnerabilities at age 5 years.
• Among all exposures examined, maternal mental illness first diagnosed prior to childbirth conferred the
greatest odds of developmental vulnerability at age 5 years.
• Early detection of risk for mental disorders might focus on key mental and physical health indicators during
the antenatal period.

development index (AEDI). International Journal of Epidemi-

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Accepted for publication: 21 November 2017
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