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Infectious Disease and Neurocognition
adversely aect fetal and infant brain development (Shook et al., 2022). Additional
long- term data from maternal exposure to SARS- CoV- 2 are needed to better ascertain its long- term eects on cognitive and neurological development.
Exposure to prenatal and childhood infections and
mental illness in childhood and adulthood
Numerous studies have found associations between exposure to prenatal maternal
infections and infections in early childhood and a range of neuropsychiatric disorders. Activation of the immune system in pregnant women from infectious diseases is associated with the development of autism spectrum disorder, bipolar
disorder, and schizophrenia in the children of these women. Complementing these
ndings are the results from work in animal models that show that immune activation in the pregnant mothers is associated with behavioral and neurobiological abnormalities in the ospring (Brown & Meyer, 2018; Estes & McAllister, 2016). Table
24.1 provides a sampling of papers on various infectious diseases and neuropsychiatric or neurocognitive outcomes.
Illustrating associations between exposure to infectious diseases in early childhood and the later occurrence of neuropsychiatric illness, a longitudinal study of
71,841 Australian children found that exposure to infectious diseases in early childhood from ages 1 to 4 years was associated with a shorter number of days to the rst
diagnosis of any mental disorder, externalizing mental disorders, and developmental
disorders including autism spectrum disorders in children ages 5– 14 years than in
children not exposed to infectious diseases (Green et al., 2021). In contrast, prenatal
exposure to maternal infection without exposure to early childhood infection was
not associated with a shorter number of days to the rst diagnosis of a mental disorder. Children exposed to both prenatal maternal infection and early childhood infection from ages 1 to 4 years had a higher prevalence of childhood mental disorders
than children exposed to only early childhood infection (Green et al., 2021).
While evidence associating maternal immune activation with the development of autism spectrum disorders is not without controversy (Estes & McAllister,
2016), exposure to prenatal and childhood infections has been associated with autism spectrum disorders (Sabourin et al., 2019), and some evidence suggests that
maternal immune activation can be a risk for the development of autism spectrum
disorders in the ospring (Brown & Meyer, 2018). A study from Denmark found
that the chemokine monocyte chemotactic protein 1, a type of cytokine involved
in neuroinammation, in amniotic uid was associated with autism spectrum disorders. Although the study was not designed to identify the cause of the chemokine elevation, the authors suggested that gestational exposure to infectious diseases
could be a factor (Abdallah et al., 2012). Using Danish health registers, Atladottir
et al. (2010) found that while maternal infections in general were not associated
with autism spectrum disorders in the ospring, maternal hospitalization in the rst
Infectious Diseases and Development 449
trimester of pregnancy for a viral infection and maternal bacterial infection during
the second trimester of pregnancy were associated with autism spectrum disorders
in the ospring, although the authors cautioned that more research is necessary to
fully characterize associations between maternal infections and the development of
autism spectrum disorders in the ospring. Similarly, Zerbo et al. (2015) based on a
sample from California found no overall association between gestational maternal
infection and autism spectrum disorders in the ospring but did nd an association between maternal infections diagnosed during a hospitalization, especially with
bacterial infections, the most common of which were urinary tract infections, and
autism spectrum disorders in the ospring. ey also found that two or more maternal infections were associated with autism spectrum disorders in the ospring.
Based on data from a longitudinal Norwegian sample, Hornig et al. (2018) found
that maternal fever during the second trimester of pregnancy was associated with
autism spectrum disorders in the ospring, with three or more fevers aer 12 weeks
of gestation being associated with an even higher risk of autism spectrum disorders
in the ospring. Although they did not identify specic types of infections involved
with the maternal fevers, the authors concluded that their ndings suggested that
maternal fever and associated immune responses were involved in some cases of autism spectrum disorders in the ospring. Using Swedish health records, al- Haddad
et al. (2019a) found associations between maternal infections during hospitalization
including urinary tract infections and autism in the ospring and noted that maternal infection or inammation may account for some cases of autism.
e nature of associations between infectious diseases and neuropsychiatric and
cognitive outcomes is likely complex. For example, the herpesvirus cytomegalovirus
has been associated with autism spectrum disorders. While there were no dierences in cytomegalovirus seroprevalence between people with tuberous sclerosis
complex, a genetic disorder highly associated with autism spectrum disorders, and
healthy controls, postnatal cytomegalovirus infection appeared to be a risk factor for
autism spectrum disorders in children with tuberous sclerosis complex (Yang et al.,
2022). While maternal inuenza infection appears associated with an increased risk
of schizophrenia in the ospring, ndings from studies examining associations between maternal inuenza infection and autism spectrum disorders have been mixed,
including a large study that found no association between maternal inuenza exposure at any time and autism spectrum disorders in the ospring (Zerbo et al., 2017).
Maternal exposure to inuenzas may be associated with an elevated risk of bipolar
disorder in the ospring, although the results of studies examining this association
have been mixed. In one study, maternal exposure to inuenza was associated with
a vefold increase of bipolar disorder with psychotic features in the ospring, although it was not associated with ospring bipolar disorder without psychotic features. e authors speculated that perhaps maternal inuenza infections were not
associated with bipolar disorder itself but rather with psychosis (Canetta et al., 2014).
Maternal exposure to Toxoplasma gondii, a protozoal parasite, also has been associ-
ated with bipolar disorder in the ospring (Brown & Meyer, 2018). Underscoring
Infectious Disease and Neurocognition
the complex relationship between maternal infection and bipolar disorder in the ospring were the result of another study using Swedish health records that found no
association between maternal infections during hospitalization and bipolar disorder
(al- Haddad et al., 2019a), suggesting that other factors might modify the association
between maternal infection and bipolar disorder in the ospring, including genetics
and inammation (al- Haddad et al., 2019a). However, al- Haddad et al. (2019a) did
nd an association between maternal infection including urinary tract infections
and depression in the ospring and between maternal infections and later suicide in
the ospring.
Childhood infection also might be associated with later depression. In a murine
model, exposure to lipopolysaccharide to model infection in pregnant mice was
associated with behaviors suggestive of anxiety and depression in male ospring
(Enayati et al., 2012). Using data from a large longitudinal cohort, Chaplin et al.
(2022) found that the number of common infections during childhood from ages
1.5 to 7.5 years was associated with depression at ages 13 and 14 years but not at
ages 18 or 19, with eect sizes increasing with greater infection exposure, ndings
suggesting that childhood infections could be associated with depression in adolescence. e authors speculated that the lack of associations at ages 18 and 19 years
could have been due to participant attrition (Chaplin et al., 2022).
In addition to associations between exposures to prenatal and childhood infections and autism spectrum disorders and aective disorders, infections occurring
in childhood and maternal infections during pregnancy have been associated with
development of schizophrenia in the ospring (Brown & Derkits, 2010; Debost
et al., 2019), although not all the relevant studies have identied associations between prenatal maternal infections and an elevated risk of schizophrenia in the ospring (al- Haddad et al., 2019a; Blomstrom et al., 2016; Brown & Derkits, 2010).
However, other work suggests that infections during childhood do appear to increase the risk of later development of schizophrenia, even aer controlling for the
eects of low parental socioeconomic status and childhood adversity (Debost et al.,
2019). In addition, mid- trimester maternal inuenza infections have been associated with an increased risk of schizophrenia in the ospring, and maternal infection from a variety of other infectious diseases including herpes simplex virus,
rubella, and Toxoplasma gondii also have been associated with an elevated risk of
schizophrenia in the ospring. Maternal genital infections also appear to increase
the likelihood of schizophrenia in the ospring (Babulas et al., 2006; Brown &
Meyer, 2018). Based on data from the Child Health and Development Study, Brown
and Patterson (2011) found that the population attributable risk for schizophrenia
from maternal exposure to Toxoplasma gondii, inuenza, and maternal genital in-
fections was 30 percent, meaning that if the relationships are causal approximately
a third of the cases of schizophrenia could be prevented if maternal exposure to
Toxoplasma gondii, inuenza, and genital infections was eliminated. Based on data
from the Child Health and Developmental study linked with Kaiser Permanente
Medical Care Plan registries, Babulas et al. (2006) found that maternal cervicitis,
Infectious Diseases and Development 451
condylomata, endometriosis, gonorrhea, pelvic inammatory disease, vaginitis,
sexually transmitted diseases including syphilis during the time from 30 days before the last menstrual period to 30 days aer the last menstrual period were associated with a ve- times greater risk of schizophrenia and schizophrenia spectrum
disorders in the ospring. However, there were no associations with maternal genital and other reproductive infections during the rst, second, and third trimesters
and schizophrenia and schizophrenia spectrum disorders. Children of women infected with inuenza during the rst half of pregnancy have a threefold increased
risk of developing schizophrenia, and children of women infected with inuenza
during the rst trimester of pregnancy have a sevenfold increase in schizophrenia,
although there were no associations between infection with inuenza in the second
half of pregnancy and elevated risk of schizophrenia (Brown & Derkits, 2010).
While Blomstrom et al. (2016) using a large Swedish database did not nd an association between maternal gestational infection and psychosis in the ospring even
aer accounting for whether the maternal infection was viral or bacterial, they did
observe that the combination of maternal gestational infection and maternal psychosis acted synergistically to increase the risk of the ospring having a psychotic
disorder. ey also found evidence that maternal gestational infection increased
the likelihood of infections in their ospring, the combination of which also increased the risk of psychosis in the ospring. Findings from the same large longitudinal birth cohort in England that found associations between childhood infections
and depression in adolescence also found an association between the number of
common childhood infections between ages 1.5 and 7.5 years and symptoms of
psychosis at age 12 years but not at ages 18 and 19 years. Although attrition of study
participants could have aected associations at ages 18 and 19 years, these results
suggest that exposure to commonly encountered infections during childhood
could be associated with psychotic symptoms in adolescence (Chaplin et al., 2022).
While it appears that a variety of maternal infectious diseases are associated with
the later occurrence of schizophrenia in the ospring and there might be common
mechanisms in how infectious diseases elevate the risk of schizophrenia in the ospring, there also may be some dierences in the mechanisms by which maternal infection elevates the risk of schizophrenia in the ospring between viral and bacterial
infections (Brown & Meyer, 2018).
How exposure to infectious diseases in childhood is associated with later mental
illness is unclear, although several potential mechanisms exist. Clearly, however, not
all maternal infections during pregnancy or all infections during childhood are associated with neuropsychiatric disorders. In their study of maternal infections during
pregnancy and autism spectrum disorders in the ospring, Zerbo et al. (2015) found
that 50 percent of all women experienced an infection during pregnancy, a rate far
higher than the prevalence of autism spectrum disorders in the general population.
Although the individual risk for maternal infection resulting in neuropsychiatric
disease in the ospring is likely small, the population eects of maternal infection
could be substantial (al- Haddad et al., 2019a).
Infectious Disease and Neurocognition
While it is possible that the infectious diseases are causing the mental illness,
possibly either directly or via inammation, it is also feasible that underlying genetic, immunologic (Estes & McAllister, 2016), or socioeconomic factors are associated with both mental illness and susceptibility to infectious diseases (Green et al.,
2021). Maternal immune activation could interact with susceptibility genes to increase the risk of neuropsychiatric disease in the ospring (Brown & Derkits, 2010;
Brown & Meyer, 2018). Underlying genetic susceptibilities or socioeconomic vulnerabilities to both mental illness and infections and infectious disease directly or
indirectly possibly through the immune system could aect brain function. In addition, maternal inammatory cytokines released in response to infection can pass
through the placental and fetal blood– brain barrier and aect prenatal brain development (Brown & Patterson, 2011). In a study of maternal inammatory markers
and behavior in the ospring, elevated maternal interleukin 8 in the rst trimester
of pregnancy was associated with externalizing symptoms (e.g., impulsivity, aggression, acting out, antisocial behavior) in children at ages 9– 11 years, and elevated
maternal interleukin- 1 receptor antagonist in the second trimester was associated
with internalizing symptoms (e.g., anxiousness, somatization, withdrawal) in girls
at ages 9– 11 years. Contextualizing these ndings, the authors note that childhood
internalizing and externalizing symptoms are associated with a range of later psychopathology (Mac Giollabhui et al., 2019). Findings from animal models show
that maternal immune activation can interact with genetic variants to aect behavior (Brown & Meyer, 2018). Oxidative stress from infection also could be involved
(Waldorf & McAdams, 2013).
A variety of factors likely contributes to how maternal infection can lead to adverse neuropsychiatric outcomes in the ospring. e type of infectious disease, its
timing during fetal development, maternal and fetal inammatory responses, maternal and fetal genetics, and interactions with other environmental factors, as well
as many other factors (al- Haddad et al., 2019a) including direct neuronal injury
from an infectious pathogen, placental inammation from infection, disruption of
neurotransmitters from infection, and microglial and astrocyte activation as a result
in infection (al- Haddad et al., 2019b) can aect fetal brain development and require
additional research to better characterize their roles in modifying associations between maternal infection and inammation and neurocognitive and neuropsychiatric outcomes in the ospring.
Animal models of ospring of mothers exposed to infectious diseases have shown
changes in brain function that are highly relevant to pathophysiological ndings associated with schizophrenia in humans (Brown & Derkits, 2010). According to ndings from animal models, a two- hit model for some infectious diseases also could be
involved in how maternal infectious diseases elevate the risk for psychopathology in
the ospring, wherein maternal immune activation from an infectious disease is the
rst hit followed by later stress or biological insult, which is the second hit (Brown
& Meyer, 2018; Estes & McAllister, 2016), a mechanism that appears relevant to humans (Brown & Meyer, 2018) and that would involve not only infectious diseases
Infectious Diseases and Development 453
but that could include a range psychosocial stresses such as neglect and exposure to
poverty during development. While pointing out that most maternal infections do
not result in schizophrenia or autism spectrum disorders in the ospring, Estes and
McAllister (2016) argue that maternal immune activation from a variety of sources
including infectious diseases could make the brain more susceptible to other developmental insults to result in a range of brain disorders. is gateway eect of maternal and possibly childhood infections leading to neuropsychiatric disease in adult
ospring could be an important factor driving the incidence of neuropsychiatric
disease.
Infections associated with poverty that can aect
brain development and influence cognitive and
neuropsychiatric outcome
Although infectious diseases can aect people at all socioeconomic levels, people
including children living in poverty are at increased risk for exposure to a variety of
infectious diseases, increasing the likelihood of their exposure to infectious diseases
that have been associated with abnormal brain and child development (Waldorf &
McAdams, 2013). Although data are limited, children living in low- and middleincome countries are at higher risk for having disorders of neurodevelopment than
are children from regions with higher incomes, a relationship to which exposures
to infectious diseases likely contributes (Krebs et al., 2017). Risk factors for many
of the parasites that that can have brain involvement include poverty and living in
tropical areas (Finsterer & Auer, 2013). Among the diseases disproportionately affecting people living in poverty are the neglected tropical diseases, a group of infectious diseases estimated to aect approximately 1 billion people worldwide (Hotez,
2014). While disproportionately aecting people living in poverty including many in
subtropical regions, the neglected tropical diseases are not necessarily restricted to
tropical regions but can aect people living in temperate regions. In this regard, the
neglected parasitic infectious diseases Chagas disease, toxoplasmosis, toxocariasis,
and cysticercosis, can aect people living in the southern United States, where poor
sanitation and environmental contamination are thought to be the main drivers of
exposure to infectious diseases (Hotez, 2014). An array of other parasites that are
associated with low- income regions, poverty, and tropical areas also can aect the
brain. e list of these parasites is long but includes cestodes, nematodes, trematodes, and protozoa. In addition to their associations with poverty, many of these
infectious diseases have been associated with adverse cognitive or neuropsychiatric
outcomes (Finsterer & Auer, 2013; Hotez, 2014).
Chagas disease or American trypanosomiasis is caused by the protozoan parasite
Trypanosomiasis cruzi. Associated with cardiomyopathy and a variety of other health
problems (Hotez, 2014), Chagas disease has also been associated with adverse neuropsychiatric and cognitive outcomes (Finsterer & Auer, 2013). Another protozoal
Infectious Disease and Neurocognition
disease, toxoplasmosis, caused by the protozoal parasite Toxoplasma gondii, has been
associated with schizophrenia, bipolar, disorder, suicide attempts (Hotez, 2014), epilepsy, obsessive– compulsive disorder, decreased cognitive function, and changes in
brain volume (Erickson et al., 2021; Flegr et al., 2014; Gale et al., 2020; Mendy et al.,
2015; Palmer, 2007). Caused by Toxocara canis or Toxocara cati from eggs in con-
taminated soil, toxocariasis is a helminthic parasite (Hotez, 2014) more likely to infect people in areas with a low human development index (Rostami et al., 2019) and
that also has been associated with decreased cognitive function in children (Walsh
& Haseeb, 2012), middle- aged adults, and older adults (Gale & Hedges, 2020).
e cause of cysticercosis is Taenia solium, the pig tapeworm. Human can acquire
cysticercosis when the parasite forms cysts in brain tissue, which can result in epilepsy and other neurological diseases (Garcia et al., 2020). Another example of an infectious disease associated with both socioeconomic factors and brain development
is cytomegalovirus. Cytomegalovirus is an infectious disease that while occurring
across all socioeconomic levels is associated with socioeconomic factors such as
crowded living conditions (Adler & Reddehase, 2019). Cytomegalovirus is also associated with cognitive delay (Elliott, 2011) and with autism spectrum disorders in
people with tuberous sclerosis (Yang et al., 2022). Infecting a high percentage of the
world’s population, the bacterium Helicobacter pylori, too, is associated with poverty,
an association that could strengthen with climate change (Khalifa et al., 2010).
An emerging infectious disease threat that has the potential to adversely aect
cognitive and brain function in vulnerable children (Otto et al., 2019) as well as
in at- risk adults is the increasing incidence of fungal infections including among
many others Cryptococcus neoformans and Candida auris, both of which can invade the central nervous system (World Health Organization, 2022). While limited
data about persistent cognitive and neuropsychiatric eects from brain fungal infections are available, the increasing incidence and geographical range of invasive
fungal infections, part of which could be related to climate change (World Health
Organization, 2022), requires further research into how fungal infections aect
childhood and brain development.
Implications for public health
Associations between maternal and childhood infections and the later occurrence
of neuropsychiatric disease in the ospring are highly relevant for public health
policies and practice. Prevention is paramount (al- Haddad et al., 2019b). In many
cases, however, limited overall awareness of the eects of infectious diseases on cognitive, neurological, and psychiatric health can impede eorts to prevent exposure
to infectious diseases that can aect brain development and cognition (Hotez, 2014).
Many maternal infections are in principle treatable (Brown & Derkits, 2010; Brown
& Patterson, 2011) or preventable (al- Haddad et al., 2019a) or potentially preventable via vaccines, surveillance, treatment of maternal infections (Babulas et al., 2006;
Infectious Diseases and Development 455
Brown & Patterson, 2011), vector control (Wheeler et al., 2020), and other public
health measures such as improved sanitation such as, for example, with preventing
Toxoplasma gondii (Brown & Derkits, 2010; Brown & Patterson, 2011) and measures designed to decrease sexually transmitted diseases (Brown & Meyer, 2018).
Particularly in the case of maternal vaccination, additional research evaluating the
risks and benets of maternal vaccination on a variety of maternal and child outcomes including schizophrenia (Brown & Patterson, 2011) and other neuropsychiatric and cognitive outcomes is needed. Additional research about how maternal
antibiotic treatment aects infectious and inammatory outcomes in a fetal brain is
required (al- Haddad et al., 2019b).
Conclusion
Maternal and childhood infection likely accounts for some of the incidence and
prevalence of neuropsychiatric diseases (al- Haddad et al., 2019b). Prenatal and
childhood exposure to some infectious diseases such as inuenza, Toxoplasma
gondii, and herpesvirus 2 (Brown & Derkits, 2010) appears to alter fetal and child
brain development as shown by associations between some childhood infections and
later occurrence of schizophrenia and psychosis and between some maternal infections and the subsequent development of neuropsychiatric disease in the ospring.
Maternal gestational infections and inammation, therefore, likely contribute to the
overall burden of neuropsychiatric disease and suggest fetal origins of some neuropsychiatric disease (al- Haddad et al., 2019b). Additional research further exploring
the eects of gestational infections, and infections acquired early in life, and inammation on brain development and neuropsychiatric diseases including cognitive
dysfunction is necessary, keeping in mind the caveat that some fetal brain injuries
associated with maternal infection and inammation might not become apparent
for many years aer birth (al- Haddad et al., 2019a). Because many infectious diseases are potentially preventable or treatable, in principle it is possible to prevent
some cases of psychosis and schizophrenia through public health measures to improve sanitation, vaccination, and treatment. In fact, targeting the maternal infectious diseases that have been associated with schizophrenia in the ospring would
possibly substantially decrease the incidence of schizophrenia in part because the
maternal infectious diseases associated with ospring schizophrenia are common
(Brown & Patterson, 2011). Similarly, preventing maternal and childhood infectious
diseases associated with neurocognitive dysfunction could reduce the substantial
burden of atypical brain development and cognitive impairment.
Many of the infectious diseases associated with abnormal child and brain development preferentially aect children and adults in impoverished regions and in
low- and middle- income nations where public health and prenatal and pediatric resources are limited, resulting in dierential exposure to infectious diseases associated with abnormal child and brain development, adding to a range of other adverse
Infectious Disease and Neurocognition
eects on developing brain in these already vulnerable populations. As Paul Farmer
observed, “one nds little evidence that the non- poor ever faced the same risks as
the poor— whether we’re speaking of risk of infection or of poor outcomes once infected” (Farmer, 2020, pp. 298– 299). Research involving the eects of public health
measures including the prevention and treatment of infectious diseases including
maternal infections on the overall burden of neurocognitive and neuropsychiatric
diseases in impoverished and low- income regions is sorely needed.
Maternal infectious diseases and inammation appear to contribute to neuropsychiatric disease in the ospring and to the overall burden of neuropsychiatric and
neurocognitive disease. Treatment and prevention of maternal infectious diseases
provide potentially eective methods of reducing the overall burden of neuropsychiatric and neurocognitive disease.
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