The Journal of Maternal-Fetal & Neonatal Medicine

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Prenatal and perinatal risk factors of

schizophrenia

Giampiero Meli, Birgit Öttl, Angela Paladini & Luigi Cataldi

To cite this article: Giampiero Meli, Birgit Öttl, Angela Paladini & Luigi Cataldi (2012) Prenatal and
perinatal risk factors of schizophrenia, The Journal of Maternal-Fetal & Neonatal Medicine, 25:12,
2559-2563, DOI: 10.3109/14767058.2012.699118

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The Journal of Maternal-Fetal and Neonatal Medicine, 2012; 25(12): 2559–2563
© 2012 Informa UK, Ltd.
ISSN 1476-7058 print/ISSN 1476-4954 online
DOI: 10.3109/14767058.2012.699118
Review
Prenatal and perinatal risk factors of schizophrenia
Giampiero Meli1, Birgit Öttl2, Angela Paladini3 & Luigi Cataldi4
1Department of Neuroscience, Institute of Psychiatry, Catholic University of Sacred Heart, Rome, Italy, 2Technical University of Munich,
Germany, 3Campus Bio Medico University School of Medicine, Rome, Italy, and 4Division of Neonatology, Department of Paediatric
Sciences, Catholic University of Sacred Heart, Rome, Italy
Schizophrenia could be considered the most severe of all psychi-
atric disorders. It shows a heterogeneous clinical picture and
presents an etiopathogenesis that is not cleared sufficiently.
Even if the etiopathogenesis remains a puzzle, there is a scien-
tific consensus that it is an expression of interaction between
genotype and environmental factors. In the present article,
following a study of literature and the accumulated evidence,
the role of prenatal and perinatal factors in the development
of schizophrenia will be revised and synthesized. We think that
better knowledge of the risk factors could be helpful not only
for better comprehension of the pathogenesis but especially to
optimize interventions for prevention of the disorder.
Keywords:  Schizophrenia, neurodevelopment, risk factors,
infections, prenatal and perinatal
Introduction
Schizophrenia could be considered the most serious of psychi-
atric disorders. It shows a heterogeneous clinical picture and
the etiopathogenesis has not yet been clearly identified. It is
characterized by a progressive course, a tendency to chronicity
and an elevated risk of suicide. Schizophrenia brings with it
significant disturbances of thought and perception, of effect
and behaviour and an impairment of social and working func-
tioning [1,2].
The diagnostic criteria used by the DSM IV-TR for the diag-
nosis of schizophrenia are:
1. Characteristic symptoms: Two or more of the following, each
present for much of the time during a one-month period (or
less, if symptoms remitted with treatment).
• Delusions
• Hallucinations
•  Disorganized speech, which is a manifestation of formal
thought disorder
• Grossly disorganized behavior (e.g. dressing inappropri-
ately, crying frequently) or catatonic behavior
• Negative symptoms: Blunted affect (lack or decline in
emotional response), alogia (lack or decline in speech), or
avolition (lack or decline in motivation)
Correspondence: Giampiero Meli, Department of Neuroscience, Institute of Psychiatry, Catholic University of Sacred Heart, Rome, Italy.
E-mail: giampieromeli1@alice.it
2559
If the delusions are judged to be bizarre, or hallucinations
consist of hearing one voice participating in a running commen-
tary of the patient's actions or of hearing two or more voices
conversing with each other, only that symptom is required above.
The speech disorganization criterion is only met if it is severe
enough to substantially impair communication.
2.  Social or occupational dysfunction: For a significant portion of
the time since the onset of the disturbance, one or more major
areas of functioning such as work, interpersonal relations, or
self-care, are markedly below the level achieved prior to the
onset.
3. Significant duration: Continuous signs of the disturbance
persist for at least 6 months. This six-month period must
include at least 1 month of symptoms (or less, if symptoms
remitted with treatment) that meet Criterion A and it could
include periods of prodromal or residual symptoms. During
these prodromal or residual periods, the signs of the distur-
bance may be manifested by only negative symptoms or two or
more symptoms listed in Criterion A present in an attenuated
form (e.g. odd beliefs, unusual perceptual experiences).
4. Exclusion of schizoaffective disorder and mood disorder with
psychotic features.
5. Substance/general medical condition exclusion: the distur-
bance is not due to the direct physiological effects of a
substance (e.g. a drug of abuse, a medication) or a general
medical condition.
6. Relationship to a pervasive developmental disorder: If there
is a history of autistic disorder or another pervasive devel-
opment disorder, the additional diagnosis of schizophrenia
is made only if prominent delusions or hallucinations are
also present for at least a month (or less if successfully
treated) [3].
Schizophrenia affects around 1% of people at some point in
their life, the estimate varies from 0.5% to 1% in different parts of
the world. It affects men and women equally, even if it typically
appears earlier in men. The peak ages of onset are 15–25 years for
males and 25–35 years for females. Paranoid schizophrenia may
be more common in men, and symptoms tend to be more severe.
Onset under the age of ten and after the age of 50 years is quite
rare [1,2,4].
2560   G. Meli et al.
Schizophrenia and alteration of neurodevelopment
Even if the etiopathogenesis of schizophrenia remains a puzzle,
there is a scientific consensus regarding it as an expression of
interaction between genotype and environmental factors [5].
The genetic vulnerability is demonstrated by the fact, that schizo-
phrenia occurs in 10% of people who have a first-degree rela-
tive with the disorder. People who have second-degree relatives
(aunts, uncles, grandparents, or cousins) with the disease also
develop schizophrenia more often than the general population.
The risk is highest for a monozygotic twin of a person with
schizophrenia with a 40–60 % chance of developing the disorder
while 12–15% of the dizygotic twins are concordant for schizo-
phrenia. Recent research suggests the involvement of different
chromosomal regions. The short arm of chromosome 6 seems to
be the most involved [1].
The role of the environmental factors in the development of
schizophrenia has been studied by many retrospective studies,
most of these were epidemiological studies, that have empha-
sized how congenital brain anomalies result to be risk factors
for the development of schizophrenia. In the last years, through
various studies conducted with pregnant women and newborns,
it has been shown in an even more defined manner, that variant
pre- and perinatal environmental factors seem to be involved
in alteration of neurodevelopment and in the pathogenesis of
schizophrenia [6–9]. The hypothesis that sees alterations in the
neurodevelopment for the basis of schizophrenia is supported
by the following findings regarding the season of birth and
birth in an urban environment. There are epidemiological
evidences that demonstrate a major incidence of schizophrenia
in subjects born during the winter and the beginning of spring.
Subjects born during this period have a 5–15% increased risk
of schizophrenia [10–12]. The season of the birth could be
important due to a possibility of in-utero infection, as certain
infections have a seasonal pattern. Furthermore, there is robust
and consistent evidence from epidemiological studies showing
that births in urban areas are associated with an increased
risk of developing schizophrenia. The risk may be increased
by exposing the pregnant women to infectious agents – due to
the major density of population of the urban areas respect to
rural zones – to toxins associated with pollution, low prenatal
vitamin D and stress [13–15].
A recent hypothesis of the etiopathogenesis of schizophrenia
is the one sustained of Kinney et al., it’s known as the “unifying
hypothesis”. It proposes that schizophrenia often involves pre- or
perinatal exposure to adverse factors that produce a latent immune
vulnerability. When this vulnerability is manifested, beginning
around puberty with changes in immune function and involution
of the thymus, individuals become more susceptible to infec-
tions and immune dysfunctions that contribute to schizophrenia.
Kinney’s hypothesis suggests theoretical bridges between different
lines of evidence on schizophrenia and offers explanations for
many puzzling findings about schizophrenia. For example, the
hypothesis helps account for why schizophrenia patients tend to
have had increased exposure to neurotropic infections, but most
individuals with such exposure do not develop schizophrenia, and
why prenatal hardships increase risk for schizophrenia, but the
onset of symptoms typically does not occur until after puberty. The
disregulation of the immunitary system produces a neuroinflam-
mation, with alterations of the glutamatergic and dopaminergic
transmission, responsible of the positive and negative symptoms
of the disorder. The evidence of an inflammatory process on the
basis of schizophrenia has been demonstrated by the detection
The Journal of Maternal-Fetal and Neonatal Medicine
of elevated levels of PCR in the serum of patients with a severe
clinical expression and an imbalance between the two types of
immune response, with an inhibition of the type 1 response and
an hyperactivation of the type 2 one [16].
Risk factors for schizophrenia during pregnancy and birth
Paternal age
An advanced paternal age is one of the longest studied risk
factors for schizophrenia [17]. The first evidence that supports
an association between advanced paternal age and schizophrenia
goes back 50 years [18]. Despite various studies, it was not clear
if the paternal age, the maternal age or both, could be respon-
sible until Hare and Moran isolated the effects of advanced
paternal age [19]. No further studies were conducted for 20
years until Malaspina, in the Jerusalem Perinatal Study (JPS), a
wide study on a cohort of children born between 1960 and 1970,
demonstrated the univocal association between an advanced
paternal age and the risk of schizophrenia in the offspring [20].
Subsequently other studies conducted in different parts of the
world replicated an association between advancing paternal age
and risk of schizophrenia in the offspring. In the JPS, this associ-
ation is explained with a possible new mutation in the masculine
germinal cells. Recently another possible cause has been identi-
fied in an aberrant epigenetic regulation transmissible from the
father to the fetus [21].
Maternal stress
Different studies suggest that maternal stress during pregnancy
can produce an increased risk of schizophrenia in the offspring.
In two studies, children born to mothers that have experienced
death or severe pathologies of relatives demonstrated a higher
risk of schizophrenia [22,23]. Ecological studies have explored
the effect of stressful events during pregnancy. Invasion of the
Netherlands by Germany during World War II was associated
with an increased risk of schizophrenia in the offspring of mothers
exposed to this stress during the first and second trimester [24].
Exposure to the Israeli Six Day War during the second month
of fetal life was related to an increased risk of schizophrenia in
female offspring [25].
Nevertheless not all of the studies have shown significant
results. An increased risk of schizophrenia in the offspring of
mothers who experienced a flood disaster in the Netherlands
has been observed – but the results were not statistically signifi-
cant [26].
Two studies of birth cohorts focussed on data collected during
undesired pregnancies, which could be associated with maternal
stress. These studies have evidenced an increased risk of schizo-
phrenia in the offspring [27,28]. The mechanism through which
stress increases the risk seems to be mediated of increased levels
of maternal or fetal glucocorticoids. High levels of CRH (corti-
cotrophin-releasing hormone) induce a small for gestational age
status (SGA) of the newborn. SGA has been documented widely
as a risk factor for the development of schizophrenia [29,54–56].
Maternal stress and glucocorticoids could induce an increased
risk of schizophrenia also by a disregulation of the immunitary
system in the offspring [16].
Infections
Infections are considered as plausible risk factors for schizo-
phrenia, as it is commonly known that infections are undoubtedly
responsible for congenital anomalies of the brain, neurocognitive
disfunction and behavioural disorders. Not only studies based on

data of ecological exposure as that who focussed on the type A2
influenza pandemic of 1957, but also the most significant studies
of cohorts on individuals born in a determined period and in a
determined region has demonstrated a correlation between fetal
exposure to determined infections (e.g. influenza virus, rubella,
toxoplasma, type 2 herpes virus) and the increased risk of schizo-
phrenia in the newborns. Investigators assume that stimulation of
the cytokine response could be the one mechanism that mediates
the association between fetal exposure to infection and the later
development of schizophrenia.
This is plausible as all of the analyzed infections in studies
of schizophrenia demonstrate a variation in cytokine levels. An
excess of maternal pro-inflammatory cytokines (IL-8, TNF-α)
has been associated with several neurodevelopemental disorders.
The cytokine induced mechanism includes the stimulation of
microglia and astroglia in the fetal brain with the production of
nitric excitatory amino acids, toxic for the neurons. Furthermore,
cytokines could disturb maturation of oligodendrocytes, contrib-
uting to abnormalities of the white matter, shown in post-mortem
studies of schizophrenia. Recent data has supported the impor-
tant role of cytokines for the development of the central nervous
system. Cytokines result to be implicated in the neural induction,
in the neurogenesis and neuronal differentiation. Chemokines in
particular seem to play a key role in the neuronal migration, the
proliferation and the connection between the axons. Cytokines
also influence different functions of the microglia, which are
indispensable for the homeostasis of the central nervous system
and the immune surveillance. These findings suggest that there
is an obvious association between the immunitary system and
neurodevelopment as immune dysfunctions can impair different
brain maturational events, shown previously to be involved in the
pathogenesis of schizophrenia [30].
Nutrition
The correlation between schizophrenia and the season of birth
has brought investigators to hypothesize that prenatal nutritional
factors could be co-involved in the development of the disorder
due to the fact that a number of nutrients underlie variations of
the intake during the course of the year, for example vitamin D,
in relation to solar exposure [31]. Different retrospective studies
based on ecological data collected during the “Dutch Hunger
Winter” of 1944–45 [32,33] and the Chinese famine years in
1959–61 [34,35] have evidenced a relation between prenatal
malnutrition and an increased risk of schizophrenia. Such
studies, however, have a limited significance, as all studies are
based on ecological data. In these, the result is not completely
clear if only nutritional deprivation or many accompanying
factors as infective epidemics, stress, ingestion of toxic substances
alone or in combination could determine the observed results.
In consequence, investigators used animal models to study the
relation between schizophrenia and specific nutritional deficits.
Within the nutritional deficiencies the attention has been focused
particularly on folate, iron and vitamin D.
Folate
Folate is a single-carbon donor which plays different important
roles in the cellular physiology, including nucleotide synthesis,
DNA repair and methylation. Low-serum folate levels result in
elevated levels of homocysteine, as folate donates a methyl group
to homocysteine, in order to make the conversion to methionine
possible. This reaction is catalyzed by the methionine synthase.
Vitamin B 12 acts as a cofactor in this pathway [36]. Serum homo-
cysteine presents a marker of folate levels, but homocysteine and
© 2012 Informa UK, Ltd.
Risk factors of schizophrenia  2561
its derivatives could play other roles being able to alter neurode-
velopment, including antagonism for the N-methyl-D-aspartate
receptor (NMDAR) that has been shown to be involved in schizo-
phrenia [37]. In the Child Health and Developmental Study
(CHDS), conducted on a cohort of children born between 1959
and 1967 in California, elevated serum homocysteine levels in the
third trimester were associated with an increased risk of schizo-
phrenia [38].
Iron
Prenatal iron depletion is a possible schizophrenia risk factor, as
this nutrient plays an important role in myelination and in dopa-
minergic neurotransmission [39,40]. Oligodendrocytes need
iron for appropriate myelin production. Deficits of myelin and
oligodendrocytes have been demonstrated in affected subjects in
post-mortem studies [41,42]. More recent schizophrenia studies
of post-mortem brains showed also modifications of ferritin and
transferrin, a further hint for iron abnormalities in schizophrenia
[43]. During pregnancy the lack of iron conduces to an increment
of dopamine metabolites in the offspring’s caudate; as dopami-
nergic dysfunction is widely acknowledged as being a character-
istic of schizophrenia [44–46]. Furthermore iron deficiency could
increase the risk of schizophrenia causing anemia and as a result of
this fetal hypoxia [47–49]. The Child Health and Developmental
Study has shown that a maternal haemoglobin concentration
of 10 g/dl or less is associated with a four-fold increased risk of
schizophrenia [38].
Vitamin D
Several lines of evidence suggest that low levels of vitamin D
constitute a risk factor for schizophrenia [50]:
1. There are higher rates of schizophrenia for subjects born in
winter and early spring – this is the period in which reduced
solar light determines lower levels of vitamin D [50].
2. Individuals with darker skin, who have lower levels of vitamin
D, have an increased risk of schizophrenia as shown in previous
studies [51,52].
3. Animal models suggest that the prenatal vitamin D deficiency
is associated with structural and functional brain deficits that
have been observed in schizophrenia [50].
Obstetric complications
Non-specific complications of pregnancy and delivery, generally
known as “obstetric complications” contribute to the suscepti-
bility for schizophrenia. Three meta-analysis’ have shown the
association between obstetric complications and schizophrenia.
The meta-analysis by Cannon et al. was based on population
studies. Significant results have been found linked to three
obstetric complications: complications of pregnancy (bleeding,
preeclampsia, diabetes, rhesus incompatibility) fetal abnormali-
ties of growth and development (low birth weight, congenital
malformations, small head circumference) and complications of
delivery (asphyxia, uterine atony, emergency Cesarean section).
Effect sizes for hardly all of these complications were under two,
greater than three-fold effects were found in diabetes, placental
abruption, low birth weight, and emergency Cesarean section [53].
A previous meta-analysis by Geddes and Lawrie, based on case-
control studies found a pooled odds ratio of 2.0 (95% CI 1.6–2.4)
for the effects of the obstetric complications on schizophrenia
[54]. A final meta-analysis has been done by Geddes and collabo-
rators on 12 case-control studies, utilizing the Lewis–Murray
2562   G. Meli et al.
Scale for Obstetric Complications. Significant associations have
been evidenced for premature rupture of membranes, prematu-
rity, resuscitation or use of the incubator. Less relevant results
have been observed for low birthweight and use of forceps during
delivery [55]. The authors pointed to several limitations of these
studies. The different obstetric complications could influence the
development of schizophrenia in the offspring through a possible
common pathogenic mechanism which could be fetal or perinatal
hypoxia [47–49].
Conclusion
In this review, through detailed study of scientific literature,
we would like to offer a summary of the prenatal and perinatal
factors which could increase the risk to develop schizophrenia
in the future. The knowledge of these environmental risk factors
should be useful for a better comprehension of mechanisms
that contribute to the pathogenesis of schizophrenia and for an
optimal planning of appropriate methods in preventing schizo-
phrenia. There are already many public health approaches to
reducing or eliminating exposure to several of the environmental
exposures discussed above. With regard to microbial agents, for
example, influenza vaccination is a cornerstone of the prevention
of infection with this pathogen, and many genital or reproductive
infections are treatable with antibiotics and preventable by use of
barrier contraceptives. Folic acid supplementation during preg-
nancy has already been demonstrated to reduce the incidence of
neural tube defects and is routinely given during pregnancy. Iron
supplementation has also long been administered to pregnant
women to improve maternal and fetal health. At psychosocial
level, efforts are made by many countries to reduce economic,
medical, social disparities [56].
The future directions for research that might be helpful to
optimize the measures to prevent schizophrenia are epigenetic
studies. It is likely that epigenetic factors are also important for
the development of the schizophrenia. It is know that epigenetic
processes can be induced by following exposure to environmental
factors produce long-term alterations in phenotype. These studies
thus may offer new possibilities for preventive and therapeutic
interventions [57].
Declaration of Interest: The authors report no conflicts of
interest. The authors alone are responsible for the content and
writing of the paper.
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