Prenatal Nutritional Deficiency and Risk of Adult Schizophrenia
Alan S. Brown1,2and Ezra S. Susser2
2College of Physicians and Surgeons of Columbia University,
New York State Psychiatric Institute, Mailman School of Public
Health, 1051 Riverside Drive, Unit 23, New York, NY
Converging evidence suggests that a neurodevelopmental
disruption plays a role in the vulnerability to schizophrenia.
The authors review evidence supporting in utero exposure
to nutritional deficiency as a determinant of schizophrenia.
We first describe studies demonstrating that early gesta-
1944–1945 and to a severe famine in China are each asso-
ciated with an increased risk of schizophrenia in offspring.
The plausibility of several candidate micronutrients as po-
tential risk factors for schizophrenia and the biological
mechanisms that may underlie these associations are
then reviewed. These nutrients include folate, essential
fatty acids, retinoids, vitamin D, and iron. Following this
discussion, we describe the methodology and results of
an epidemiologic study based on a large birth cohort
that has tested the association between prenatal homocys-
teine, an indicator of serum folate, and schizophrenia risk.
The study capitalized on the use of archived prenatal serum
specimens that make it possible to obtain direct, prospec-
tive biomarkers of prenatal insults, including levels of var-
ious nutrients during pregnancy. Finally, we discuss several
strategies for subjecting the prenatal nutritional hypothesis
of schizophrenia to further testing. These approaches in-
clude direct assessment of additional prenatal nutritional
biomarkers in relation to schizophrenia in large birth
cohorts, studies of epigenetic effects of prenatal starvation,
association studies of genes relevant to folate and other
micronutrient deficiencies, and animal models. Given the
relatively high prevalence of nutritional deficiencies during
pregnancy, this work has the potential to offer substan-
tial benefits for the prevention of schizophrenia in the
Key words: prenatal/schizophrenia/nutrition
Evidence from variousdomains of research indicates that
a disturbance in early neurodevelopment may lead to
a vulnerability to schizophrenia in adolescence or adult-
vironment in the etiology of this disorder.1In this article,
we review and discuss the sources of evidence for testing
hypotheses about the relation of prenatal nutritional de-
ficiency to offspring risk of schizophrenia. The long in-
terval between an exposure in the prenatal period and
the risk of schizophrenia in adulthood and the difficulty
of obtaining precise data on prenatal nutritional intake
are among the considerable challenges faced by research-
ers in this field. Nonetheless, successful studies have been
built around historic events, a design sometimes referred
to as a ‘‘natural experiment.’’
We first describe studies linking prenatal exposure to
the Dutch Hunger Winter of 1944–1945 with offspring
schizophrenia and a recent worthy replication of this
deficiencies that might explain the results from these
studies. Next we describe how the intriguing findings
from these studies can be pursued in birth cohorts fol-
lowed up for schizophrenia, making use of archived bi-
ological specimens to measure prenatal nutritional
status. Finally, we discuss the approaches being devel-
oped for more powerful tests of these hypotheses, focus-
ing for illustrative purposes on the folate/homocysteine
The strongest evidence linking prenatal starvation to
schizophrenia derives from natural experiments. Natural
experiments are perhaps best known in the context of ge-
netic epidemiology where twin and adoption studies are
classic examples. However, natural experiments of a dif-
ferent kind can be built around circumscribed historical
as in the examples described below, but a beneficial event
can also be the basis for a natural experiment. The var-
ious kinds of natural experiment share 2 defining fea-
tures.2First, unlike an ordinary observational study,
people are selected into an exposed or unexposed group
by an event largely outside of their control. Second, un-
like an ordinary experiment, this event is not under the
control of the investigator. As a result of these features,
the design tends to be stronger than an ordinary
1To whom correspondence should be addressed; tel: 212-543-
5629, fax: 212-543-6225, e-mail: email@example.com.
Schizophrenia Bulletin vol. 34 no. 6 pp. 1054–1063, 2008
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observational study though not as strong as an ordinary
Dutch Hunger Winter
The first direct test of an association between prenatal
starvation and schizophrenia arose as a result of the
Dutch Hunger Winter of 1944–1945, one of the tragic
events of World War II.3The famine was precipitated
by a Nazi blockade of occupied Holland in October
1944, in retaliation for the support by the Dutch resis-
tance to the Allied command. Already compromised
by food shortages at the onset of the blockade, the
food situation worsened further due to an unusually se-
vere winter, which froze the canals used to transport
food. The famine grew steadily worse until it ended
with liberation in May 1945. During the height of the
famine in the 2–3 months prior to liberation, the daily
food ration was mainly bread and potatoes (by April
1945 the ration provided less than 500 calories daily),
supplemental food was scarce, and the population was
nutritionally depleted. Mortality was more than double,
and fertility (reflected in births 9 months later) was less
6 cities of western Holland.
Although tragic, the famine has provided a unique op-
portunity to examine health effects throughout life of
starvation during specific periods of gestation.4This
was made possible by the fact that the height of the fam-
ine was brief, clearly circumscribed in time, and afflicted
a population that maintained excellent records on both
food rations during the famine and on health outcomes
for several decades hence. An early neurodevelopmental
finding from the Dutch famine studies was an increase in
congenital neural defects, especially neural tube defects
including spina bifida and anencephaly, among a birth
cohort conceived during the height of the famine.3,5
This finding of an effect on neurodevelopment bolstered
the plausibility of prenatal famine as a cause of later
schizophrenia. It also provided a key component of
the rationale for the analytic design of the Dutch famine
study of schizophrenia.
In the schizophrenia study, we examined whether the
birth cohort with excess central nervous system (CNS)
anomalies also had an increased risk of schizophrenia.
The exposed cohort was defined by birth in the famine
cities during October 15–December 31, 1945; the height
of the famine corresponded to the periconceptional pe-
riod or early gestation for this cohort. The Dutch psychi-
atric registry was used to compare psychiatric outcomes
in adulthood for exposed and unexposed birth cohorts.
The primary outcome was a diagnosis of narrowly de-
fined schizophrenia by International Classification of Dis-
eases, Eighth/Ninth Revision, criteria (295.1, 2, 3, 6), as
categorized in the Dutch National Psychiatric Registry
for the years 1970–1992, during which time the subjects
were aged 24–48 years. The study found a significant, 2-
fold increase in the cumulative risk of schizophrenia in
the exposed birth cohort.5,6
Moreover, a subsequent study showed a 2-fold in-
creased risk of schizoid personality disorder in the
same exposed birth cohort.7In this instance, the outcome
datawere obtained from military induction examinations
conducted on all males when they reached age 18. Unlike
the schizophrenia result, which was based on the psychi-
atric registry data, this finding was not limited to treated
cases. It provides further evidence of an effect on schizo-
phrenia spectrum disorders (SSDs) from an independent
Inspection of the disease risks for successive birth
cohorts of 1944–1946 revealed striking peaks in the inci-
ital neural defects in this same birth cohort.8This
occurred in the context of an otherwise stable incidence
of these disorders among cohorts exposed to famine dur-
ingother periods ofgestation andcohorts whowerecom-
pletely unexposed to famine during pregnancy.
Chinese Famine Study
along the same lines in which the Dutch result could be
replicated or refuted. While famine is not uncommon in
the resources for assessing health outcomes are not avail-
able. In a recent study, however, the relation of prenatal
famine to risk of schizophrenia was successfully exam-
ined in a cohort in the Wuhu region of Anhui Province,
China.9In the late 1950s, a massive famine was precipi-
tated in China by the marked social and economic up-
heaval known as the Great Leap Forward, which
involved agricultural collectivization, use of flawed agri-
cultural practices, and diversion of agricultural labor to
other purposes. By some estimates, the famine caused
30–40 million deaths.10Anhui Province was one of the
In the Chinese study, monthly data on caloric rations
were not available. Nonetheless, the authors, based on
the Dutch results, could examine whether the risk of
schizophrenia was increased in the birth cohorts con-
ceived during the height of this famine. Accordingly,
the Wuhu birth cohorts of 1960 and 1961 were defined
as the exposed group. These cohorts were conceived in
the period of most severe famine for this region, as docu-
mented in historical records, and as reflected in birth
rates for 1960 and 1961 that were less than one-third
the average for 1956–1959.
Thus, the authors compared the cumulative risk of
schizophrenia among the birth cohorts of 1960 and
1961 with that of birth cohorts prior to and subsequent
from systematic review of the records of the sole
Prenatal Nutritional Deficiency and Schizophrenia
psychiatric hospital in the Wuhu region over the period
1971–2001. The increased risk—approximately 2-fold—
was similar to that of the Dutch famine. A key advantage
of the study was its much larger sample size. Replication
in apopulation ofverydistinct ethnicity and culture from
the Netherlands is consistent with a biological causation
Several limitations of these studies need to be consid-
ered. We first consider the Dutch famine. First, as in all
observational studies, there is the possibility that the
results may have been confounded by certain known
and unknown factors. One possible confounder that
needs to be considered is prenatal stress. The exposed
population was likely to have already been under severe
stress due to the combination of the famine, war, and
many other hardships, and prenatal stress has been asso-
ciated with schizophrenia in some though not all studies,
and there have been several limitations to this work.12–14
However, it is worth noting that other areas of the Neth-
erlands, which were also exposed to war and moderate
levels of starvation, did not evidence an increased risk
of schizophrenia.15A second potential confounder is so-
cial class of origin. We consider confounding by this fac-
tor to be unlikely because no associations have been
demonstrated between schizophrenia and social class
of origin in the Netherlands. Moreover, because the ex-
posed cohort was weighted toward the upper classes due
to greater fertility, this would tend to reduce the observed
association between prenatal famine and schizophrenia.5
Other limitations of the study included group data to de-
fine exposureand the inability totease apartthe effectsof
different types of nutritional deficiencies or of other sub-
potential. With regard to the former limitation, it should
be emphasized that the exposure was documented in de-
tail and was pervasive in the population.
While the Chinese famine study offered several
strengths, one weakness is that famine exposure data
were not available by month; hence, the precision of
the periods of famine cannot be as accurately estimated
as in the Dutch famine study. However, the pattern of
increased risk of schizophrenia by birth year is consistent
with an early gestational effect; this is discussed in more
detail in St Clair et al.9
Candidate Nutritional Deficiencies
We first consider specific candidate micronutrients that
might explain the association between early gestational
famine and schizophrenia. Several of the most prominent
candidates are as follows.
The coincidence of the peak in risk of schizophrenia and
schizoid personality disorder with congenital neural
defects in the Dutch famine cohort provides a potentially
valuable clue. One of the most consistent findings in the
literature on prenatal nutrition and CNS disturbances is
the association between periconceptional folate supple-
mentation and neural tube defects.16,17Studies have
shown convincingly that this simple dietary intervention
diminishes the likelihood of neural tube defects by as
much as 80%,17–19although the biological mechanism
for the protective effect remains unclear.
This intriguing coincidence led us to speculate early on
that the folate pathway might also be important in the
origins of schizophrenia.19,20Later, genetic association
studies of neural tube defects and of schizophrenia pro-
vided a further reason for considering folate as a candi-
date. Studies have suggested that mutations in known
genes involved in folate-dependent pathways increase li-
ability for neural tube defects. For example, a single-
nucleotide polymorphism C677T of the gene coding
for 5,10-methylenetetrahydrofolate reductase (MTHFR)
has been associated with neural tube defects.21Some,
though not all, studies have also shown an increase in fre-
quency of this variant allele in patients with schizophre-
nia (see Gilbody et al22for meta-analysis).
In addition, much has been learned in the past decade
about the key role of folate in health and development.
Folate is a generic term for a family of chemically similar
compounds that facilitate the transfer of one-carbon units
in metabolic pathways.23Because humans cannot synthe-
size folate, it must be obtained from the diet. Folate is
particularly important in the synthesis of purines and pyr-
interconversion of serine and glycine. Based on current
folate deficiency could plausibly influence the risk of off-
spring schizophrenia.24–28First, folate deficiency can im-
pede the synthesis and repair of DNA and might thereby
increase the risk of de novo mutations (J. M. McClellan,
MD, E. Susser, MD, DrPh, M. C. King, PhD, unpub-
lished data, 2007). Second, folate deficiency can impede
the production of methyl donors and the methylation of
DNA and might thereby affect the expression of genes
that regulate neurodevelopmental processes.29Third,
folate deficiency can impede the conversion of hcy to
methionine and might thereby lead to accumulation of
hcy with adverse effects on fetal brain development.
Essential Fatty Acids
Essential fatty acids (EFAs) play critical roles in brain
development. Humans do not have the ability to synthe-
size these fatty acids de novo and thus are largely depen-
dent upon dietary sources.30Docosohexaenoic acid
(DHA), an omega-3 fatty acid, is the primary structural
fatty acid in the brain, comprising 25%–30% of the struc-
tural fatty acids in the gray matter.30,31Maternal supple-
mentation with cod liver oil, which contains very
A. S. Brown & E. S. Susser
long-chain n-3 fatty acids, during pregnancy has been as-
sociated with higher IQ at age 4 years.32In that study,
umbilical plasma levels of DHA were correlated with in-
creased age 4 IQ and umbilical eicosopentanoic acid was
associated with improved mental processing skills in
childhood. Umbilical vessel EFA levels, including
DHA, have been correlated with decreased neonatal neu-
rological abnormalities.33In 2 additional studies, how-
ever, long-chain polyunsaturated fatty acid status at
birth was not associated with cognitive function at age
4 and 7.34,35Nonetheless, further investigation of mater-
adult outcomes, including risk of schizophrenia, may
Retinol (vitamin A) and other retinoids are essential
nutrients that are required by the early embryo and fetus
for gene expression, cell differentiation, proliferation,
and migration.36–39Vitamin A deficiency in animals
results in gross CNS malformations, including hydro-
veloped posterior hindbrain,43,44including loss of the
myelencephalon.45These and other findings suggest
that retinoid signaling plays a key role in morphogenesis
of the CNS.46Because retinoids also function as antiox-
idants,47they mayhelpprotect the developingbrain from
a number of potential insults that generate free radicals.
McGrath48has hypothesized that prenatal exposure to
vitamin D deficiency is a risk factor for schizophrenia.
The plausibility of this hypothesis is supported by the
role of this vitamin in cell growth and differentiation,
the excess of winter births in schizophrenia (a period
when vitamin D levels are low), and increased births
of preschizophrenic subjects in urban areas, where vita-
min D deficiency is higher. A preliminary study of mater-
nal vitamin D levels in archived prenatal sera from the
Collaborative Perinatal Project, however, showed no de-
crease in prenatal vitamin D in subjects who later devel-
Maternal iron deficiency is known to affect the develop-
ment of the fetal brain. This may occur through several
mechanisms during pregnancy. First, during pregnancy,
the needs of the growing fetus and placenta, as well as the
increasing maternal red blood cell mass, impose a sub-
stantial demand on maternal iron stores, reducing hemo-
globin levels and increasing the incidence of anemia,
which compromises oxygen delivery to the developing fe-
tus.50,51Indirect indicators of fetal hypoxia have been as-
sociated with increased susceptibility to schizophrenia52;
the hippocampus is believed to be particularly vulnerable
to hypoxic insult. Iron deficiency may also affect the de-
velopment of brain structures and functions of relevance
to schizophrenia, independent of anemia.51Iron metab-
tioning of dopaminergic neurotransmission50that has
long been implicated in the pathophysiology of schizo-
phrenia. Iron is also essential for normal myelination
that affects neural connectivity and myelin deficits
have been observed in schizophrenia.53
We have recently demonstrated that prenatal exposure
to low maternal hemoglobin, which is highly correlated
with iron, is associated with an increased risk of schizo-
phrenia in adult offspring.54
Although we consider it more likely that a micronutrient
is involved, protein-calorie malnutrition (PCM) should
also be considered as a potential explanation for the as-
sociation between famine and schizophrenia. There is
some support from preclinical studies for the biological
plausibility of prenatal PCM as a risk factor for schizo-
phrenia. Prenatal and early postnatal PCM are associated
with neurotransmitter, cellular, electrophysiological, and
behavioral disruptions that have been demonstrated in
schizophrenia. These include increased dopamine and se-
rotonin release and turnover and dysfunction in the hip-
pocampus, including decreased cell numbers, reduced
dendritic branching, establishment and maintenance of
long-term potentiation,55and behavioral deficits such
as impaired spatial performance.56Prenatal protein dep-
rivation has also been shown to reduce prepulse inhibi-
tion in rats in early adulthood but not prepubertally.57
Many studies have demonstrated that prepulse inhibition
is impaired in patients with schizophrenia. Furthermore,
prenatally deprived rats had an increase in binding of
the N-methyl-D-aspartic acid (NMDA) receptor, which
has been implicated in the pathophysiology of schizo-
phrenia,57,58as well as increased sensitivity to MK-801,
an NMDA receptor antagonist.59
Archived Biological Specimens
To study specific micronutrients, the most direct ap-
proach is to use archived prenatal biological specimens
from birth cohorts followed up for schizophrenia. The
first large birth cohort studies to collect and archive bi-
ological specimens from pregnant women were the Child
Health and Development Study (CHDS) and the Na-
tional Collaborative Perinatal Project.60–62These were
contemporaneous studies initiated in the 1950s in the
United States. Decades later, the archived sera from
both these cohorts are being used to study prenatal
nutrients and offspring risk of schizophrenia. The strat-
egy is that of a nested case-control design, ie, the cases of
Prenatal Nutritional Deficiency and Schizophrenia
schizophrenia in the cohort are ascertained and are
compared with a control group selected from the same
cohort.2Thus, the serologic study can be efficiently com-
pleted using a few hundred subjects rather than the many
thousands enrolled in the original cohort.
Although these 2 cohorts were the first to archive pre-
natal specimens, many other cohorts established in later
years have done so. We anticipate, therefore, that this
strategy will be widely applied because these other cohorts
pass through the age of risk for schizophrenia.63,64
A prototype for this approach is the Prenatal Determi-
nants of Schizophrenia (PDS) study60(for a detailed de-
scription see PDS design article). The cohort members in
the PDS study were derived from the CHDS.65During
1959–1966, the CHDS recruited virtually all pregnant
women receiving obstetric care from the Kaiser Perma-
nente Medical Care Plan, Northern California Region
(KPMCP) in Alameda County, CA. Their liveborn off-
spring (N = 19 044) were automatically enrolled in
KPMCP. Comprehensive data were prospectively col-
lected from maternal medical records, maternal inter-
views, and other sources. Approximately 30% of the
population of the county received their health care by
KPMCP. KPMCP membership was diverse; racially, ed-
ucationally, and occupationally, it was similar to the
employed population of the Bay Area of California at
the time, although there was underrepresentation of the
extremes of income.66The at-risk cohort comprised the
12 094 live births who were members of KPMCP between
January 1, 1981 (the year in which computerized registries
became available), and December 31, 1997.60Following
exclusion of subjects who did not receive a maternal in-
terview including important demographic and lifestyle
factors, and random selection of one subject per family
in order to eliminate nonindependent observations, the
final cohort consisted of 7796 subjects.
Potential cases of schizophrenia and other SSDs were
identified by a screening procedure involving computer-
ized record linkages between CHDS and KPMCP iden-
tifiers from inpatient and outpatient registries based on
diagnoses of International Classification of Diseases,
Ninth Revision, 295–299, and by a pharmacy registry,
based on prescriptions for antipsychotics. Psychiatric
and medical records were then reviewed for evidence
of psychotic symptoms by an experienced, board-
certified research psychiatrist. Subjects who screened in
for psychotic illnesses were administered the Diagnostic
Interview for Genetic Studies (DIGS),67and Diagnostic
and Statistical Manual of Mental Disorders, Fourth
Edition, diagnoses were assigned by consensus of 3 expe-
rienced research psychiatrists. Potential cases not inter-
viewed were diagnosed by chart review by experienced
clinicians, and all chart diagnoses were confirmed by a
research psychiatrist. This protocol resulted in 71 total
SSD cases, 44 of whom received the DIGS and 27 of
whom were diagnosed by chart review.
In the CHDS, a wealth of data were collected on pre-
were followed up through childhood. A maternal inter-
view included a detailed reproductive history; health-
related behaviors in mother and father; lifestyle habits,
including smoking, alcohol, and weight before and dur-
ing pregnancy; and detailed sociodemographic informa-
tion. Detailed data on medical conditions and prescribed
medications were abstracted from obstetric and medical
records for all enrolled mothers. Extensive data on labor
and delivery records were abstracted. Additional data in-
cluded blood groups and placental morphology.
As noted earlier, a remarkable feature of the study that
has made it possible to test hypotheses regarding specific
prenatal micronutrient deficiencies was the availability of
archived maternal sera, which were drawn during preg-
nancy, frozen, and archived for the past 40 years. Prena-
tal sera are available in virtually all pregnancies in the
cohort for later gestation and for about 40% during
the first trimester. The PDS study is well suited for
both cohort and nested case-control designs. The latter
design is particularly appropriate for serologic analyses,
given the prohibitive costs and logistics involved with
analyses of prenatal sera on a large cohort. In the nested
case-control design, the controls for each case were se-
lected to represent the population at risk at the time
the case was ascertained. Matching criteria for controls
included membership in KPMCP, date of birth, sex,
number of maternal serum samples drawn during the in-
dex pregnancy, and timing of the first maternal blood
draw during the index pregnancy. Matching for time
of KPMCP membership ensured that controls repre-
sented the population at risk at the time of case ascertain-
ment. Matching on birth date ensured control of
potential confounding by season of birth. Gender was
matched to allow for assessment of different effects for
men and women. Matching on maternal blood draws
was conducted to permit sufficient and comparable
data for serologic analyses.
Serologic analyses are presently underway to examine
the micronutrients described earlier. Both the potential
cent study from our group. hcy levels are a reliable
marker of serum folate, which is not measurable in ar-
chived sera. hcy has long been known to increase folate
deficiency states secondary to the critical role of folate in
the methylation of hcy and its conversion to methionine.
Using the archived sera of the PDS cohort, we found
that elevated hcy in the first trimester was associated with
a nearly 2-fold increase in risk of schizophrenia. We had
only a small number of subjects with available first tri-
mester sera, however, and the finding fell well short of
statistical significance. Moreover, in these subjects, the
sera were generally drawn during the latter period of
the first trimester, approximately 2 months or longer af-
ter the periconceptional period. Thus, the first trimester
A. S. Brown & E. S. Susser
results were inconclusive, though suggested that further
studies with a larger number of cases with first tri-
mester samples might substantiate the folate deficiency
The sample size did offer sufficient power to test the
hypothesis that elevated third trimester hcy was associ-
ated with risk of schizophrenia68because maternal ar-
chived serum specimens drawn during late pregnancy
were available for virtually all cohort members. We
found that subjects with elevated third trimester hcy, de-
fined as the highest tertile of the distribution, was asso-
ciated with a significant, greater than 2-fold increased
risk of schizophrenia in the offspring; the findings per-
sisted following adjustment for several potential con-
founders including maternal education, race, smoking,
The result for third trimester hcy does not necessarily
support an effect of folate deficiency in early gestation.
At physiologic glycine concentrations, hcy has NMDA
receptor antagonist properties, and dysfunction of the
NMDA receptor has been implicated in schizophre-
nia.69–71Moreover, perinatal administration of phency-
clidine, a known NMDA receptor antagonist, induces
a disruption in synaptogenesis, prepulse inhibition, and
working memory.72hcy is also known to cause placental
vasculopathy through several mechanisms,73–75which
might lead to fetal hypoxia, a putative risk factor for
schizophrenia.52We had therefore hypothesized that el-
evated third trimester hcy would be associated with risk
of schizophrenia, based on the late gestational effects of
NMDA receptor blockade on endophenotypes of schizo-
phrenia and on the increase in placental blood flow dur-
ing the third trimester. Because this is the first time that
elevated prenatal hcy has been associated with schizo-
phrenia, this finding requires replication in an indepen-
In thissection, weraise severalissues relevanttothe plau-
schizophrenia and of previous research on effects of mal-
nutrition on neurodevelopment.
We first consider the argument that one might expect
an increased incidence of schizophrenia in developing
countries, in which chronic malnutrition is widespread,
if prenatal nutritional deficiency is a bona fide risk factor
for schizophrenia. Two points are worth noting in this
phrenia is higher in countries that have more malnutri-
tion because to date no incidence studies have been
conducted in regions of developing countries that have
experienced chronic malnutrition. Second, such studies
may not reveal an effect of chronic or severe malnutrition
on risk of schizophrenia because the consequent effects
on child mortality will reduce survival to the age of
risk for schizophrenia. A second issue that requires con-
sideration is whether there are particular periods of ges-
tational exposure to malnutrition that confer greater
vulnerability to schizophrenia. Based on the Dutch
and China famine studies, it appears likely that exposure
during the first trimester plays an especially important
role, though studies of more specific exposures in non–
famine-exposed populations may yield different findings.
In our view, what is most important in the formulation of
gestational specific hypotheses is the interaction of the
nutritional exposure with the specific neurodevelopmen-
tal events within each window of gestation. Although
there are relatively few examples in the literature on
prenatal nutritional factors as causes of developmental
disorders, one of the most salient examples is periconcep-
tional folic acid deficiency as a cause of neural tube
defects. This is concordant with our findings on the
Dutch famine, and supports the biological plausibility
of first trimester exposure to famine and schizophrenia.
In 2 previous studies, our group demonstrated that expo-
sure to famine during the second and third trimester was
associated with a significantly risk of affective psychosis,
suggesting that the timing of exposure may have specific-
ity to the type and severity of disorder that ensues.76,77In
the Dutch famine, caloric rations of <1000 kcal were as-
sociated with an increased risk of schizophrenia, while
exposure to lesser severity of famine (1000–1500 kcal)
gesting that the degree of nutritional deficiency may also
Third, we consider the relative effects of nutritional
deficiency during the fetal period, compared with child-
hood. Clearly, both micro- and macronutrient deficiencies
during childhood are associated with neuropsychiatric
sequelae.78–80With regard to schizophrenia, vitamin D
supplementation during the first year of life was associ-
ated with reduced risk of the disorder in males but not
A fourth consideration is the degree to which the find-
ings are concordant with other epidemiologic findings of
schizophrenia. A markedly increased risk of schizophre-
nia has been found among first- and second-generation
immigrant populations. Conceivably, this finding might
be accounted for by greater prenatal malnutrition that
would be expected in immigrant groups due to lower so-
cioeconomic status and other factors. However, as ar-
gued by Cantor-Graae and Selten,82evidence relating
low social class of origin to schizophrenia is inconsistent,
and no effect of neighborhood levels of socioeconomic
status was found in migrant studies of schizophrenia.
Hence, at least insofar as social class differences are con-
cerned, there is as yet no compelling evidence that dietary
differences among immigrants explain the association
between migrant status and schizophrenia. A similar
argument may be made with regard to the well-replicated
Prenatal Nutritional Deficiency and Schizophrenia
association between urbanicity and schizophrenia,83in
which dietary deficiencies linked to social deprivation
prominent among inner city neighborhoods would be
a potential cause of the association.
Summary and Future Directions
Insummary, evidencefrom 2independentnaturalexperi-
ments supports the hypothesis that prenatal nutritional
deficiency is related to the development of schizophrenia.
pregnancy, even in well-fed populations,84this work
could stimulate public health efforts to ensure adequate
nutritional intake during pregnancy, which may not only
facilitate the prevention of schizophrenia but also result
in additional improvements in health outcomes for off-
spring throughout the life course.
We envision 5 strategies to further test this hypothesis.
The first is the direct test for associations between prena-
tal nutritional deficits and schizophrenia. This is being
accomplished through specific micronutrient assays of
archived maternal sera in birth cohorts that have been
followed through the age of risk for schizophrenia.
One caveat of this work in the PDS study is the relatively
low statistical power to detect small effects due to a mod-
est number of subjects with prenatal sera, particularly
during the first trimester. However, this limitation can
be potentially overcome by combining comparably
designed cohorts for selected analyses.61Moreover,
new cohorts with high-quality data including archivedbi-
ological prenatal specimens will be coming of age for risk
of schizophrenia over the ensuing years and may be used
for larger and more definitive studies. An example of this
strategy is a study of the impact of folate deficiency in
a birth cohort of 100 000 being collected in Norway.
In this cohort, the investigators are collecting samples
for genetic analyses on mother, father, and child, as
well as archiving prenatal biological specimens for anal-
ysis of nutrients. The neurodevelopmental outcomes are
being traced over the life course. Although it will be
2 decades before it is possible to study schizophrenia
in this cohort, the findings on earlier outcomes may yield
insights into the spectrum of manifestations consequent
to prenatal nutritional deficiency.
A second strategy is to assess the individuals who de-
veloped schizophrenia after prenatal exposure to famine.
The study in China now provides a large enough sample
for this purpose. The homogeneous environmental expo-
sure makes this a particularly good strategy for identify-
ing genes that play a role in schizophrenia.2,8For
example, this homogeneity increases the statistical power
for detecting genetic variants hypothesized to interact
with prenatal nutritional deficiency to cause schizophre-
nia. With the advance of genomic technology, this design
may also permit exploration of whether prenatal starva-
tion induced genetic mutations or epigenetic effects
that predispose to schizophrenia. For example, hcy
appears to act as a methyl donor following activation
to S-adenosylmethionine, influencing DNA methylation,
which could alter regulation of genes.85–87
A third approach is to investigate in general popula-
tions the genes that are salient to metabolic pathways in-
volving these nutrients. One such example is the C677T
variant in the MTHFR gene described above. Genetic
association studies of this variant have already been con-
are now underway in the hope of attaining more definitive
results. Complexities in these studies include thepossibility
that either the fetus or the mother’s genes or both could be
important to the in utero environment and that the genetic
in the presence of the relevant prenatal nutritional defi-
ciency (eg, folate deficiency for a MTHFR variant).
A fourth approach is the development of animal mod-
els of prenatal malnutrition. In an accumulating body of
research, investigators have explored the biological
mechanisms of action linking prenatal nutritional defi-
ciency to abnormalities of brain function that are salient
to the pathophysiology of schizophrenia. These include,
but are not limited to, studies of prenatal vitamin D de-
pletion88and PCM.57Further translational research on
nutritional animal models are expected to identify new
molecular targets on which future interventions might
be based. These types of studies are expected to flourish
with the rapid development of modern neuroscience and
molecular genetic approaches.
The National Institute of Mental Health (NIMH)
1K02MH65422-01 to A.S.B.; NIMH 1R01MH 63264-01
toA.S.B.; National Alliance forResearchon Schizophre-
nia and Depression (NARSAD) Independent Investiga-
tor Award to A.S.B.; NIMH 1R01MH 053147 to E.S.S.;
Independent Investigator Award to E.S.S.; National
Institute on Aging P01AG023028 to E.S.S.; National
Institute of Child Health and Human Development
(NIMH) N01-HD-1-3334 to B. Cohn; NICHD NO1-
HD-6-3258 to B. Cohn.
We wish to thank Catherine Schaefer, PhD, Barbara
Cohn, PhD, Barbara van den Berg, MD, Michaeline
Bresnahan, PhD, and Justin Penner, MA, for their
contributions to this work.
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