Schizophrenia: Prenatal and Perinatal Complications

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Schizophrenia Prenatal and Perinatal
Complications

• Michelle Carruthers and
• Jennifer Wood

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Overview

• Neurodevelopmental Hypothesis
• Risk Factors
• Impact on the real world

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Neurodevelopmental Hypothesis

• Idea that brain abnormalities are inherited or
  sustained early in life, but are not fully
  expressed until early adulthood
• Disruption in programmed maturation of the brain
  in prenatal and early neonatal life

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Contd

• A causal relationship between prenatal and
  perinatal factors in schizophrenia is hard to
  directly establish
• Due to time spread between the damage and the
  diagnosis of the illness

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Evidence for the Neurodevelopmental Hypothesis

• Children destined to develop schizophrenia many
  years later tend to have mild impairments on
  tests of neurocognition, behaviour and subtle
  signs of neuromotor dysfunction
• Increase in severity of minor physical anomalies,
  most prominently in the craniofacial area, known
  to result from in utero insults (ex. viral
  infections)

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Contd.

• Abnormalities in the brain
• Enlarged cerebral ventricles
• Diminished hippocampal volume
• Demonstrated in patients during their 1st episode
  of schizophrenia
• Suggesting that these anomalies were present
  before the illness onset

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Major Risk Factors

• Exposure to infection
• Maternal stress
• Nutritional deprivation
• Prenatal concentration of sex hormones
• Traumatic delivery
• Limbic system abnormalities

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More Risk Factors

• Mothers weight
• Diabetes during pregnancy
• Uterine atony (weak contractions during labour)
• Preterm rupture of the membranes
• Vacuum extraction
• Twin birth
• Toxins and Drugs (i.e. cocaine exposure)

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More Risk Factors

• Small or large for gestational age
• Low birth weight
• Small head circumference
• Asphyxia (not direct association usually occurs
  in pregnancies with placental complications or
  retarded intrauterine growth)
• Neonatal jaundice

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More Risk Factors

• Depression during pregnancy
• Maternal separation (isolation rearing) ??
  inconclusive evidence
• Increase in age of father
• Bleeding during pregnancy ( sign of placental
  insufficiency which is associated with
  retardation of intrauterine growth)
• Radiation (shown to lead to decreased volume in
  the thalamus in rhesus monkeys)

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1. Exposure to Infection

• Some conflicting findings classification
  differences?
• Evidence comes from
• Many winter and early spring cases (infections
  peak times)
• Birth in urban areas increase risk (crowding
  facilitates transmission of infection)
• The magnitiude of the association, following
  adjustment for potential confounds
• Neurobiological plausibility of infection as a
  cause of schizophrenia

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Infection

• Causes release of cytokines (involved in CNS
  development) by cells from the immune system
• Infection also causes an increase in cortisone
  (rats)
• Human schizophrenics have also been shown to have
  increased levels of cytokines and cortisol

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Infection

• Cytokines have been found to detrimentally effect
  hippocampal neurons
• If administered causes
• Characteristic maturational delay of the disorder
• Mimics the cognitive, and neurochemical
  abnormalities of the disorder

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Infection

• Leads to an increase in dopaminergic function
  (increase release in the striatum of DA)
• Proof - the effectiveness of atypical and typical
  antipsychotics to correct this abnormality
• Abnormalities in the basal ganglia, limbic
  system, nucleus accumbens

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Prenatal Rubella

• Effect is strongest following exposure in the
  first 2 months of gestation
• Possibility that rubella induces inhibition of
  mitosis, resulting in diminished brain growth.
• Retardation of myelination due to inhibited
  replication of oligodendrocytes (glial cells)
• Evidence from rats
• decreased prefrontal thickness
• increased behavioral deficits mediated by
  corticostriatal circuits and sensorimotor gating
  abnormalities
• Enlargement of ventricles and diminished cortical
  gray matter
• Same in humans?

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Maternal Respiratory Infection (MRI)

• MRI leads to marked behavioral and
  pharmacological abnormalities in the offspring
  that are relevant to schizophrenia
• Significant association between 2nd trimester MRI
  and risk for schizophrenia, even when adjusting
  for maternal smoking, education and race
• No association between MRI and 1st and 3rd
  trimesters
• Direct effect- (crosses the placenta and into
  fetal brain)
• Indirect effect- maternal hyperthermia, cold and
  flu medications, or excessive cytokine response
  to infection

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Influenza

• Maternal infection with influenza virus in the
  2nd trimester of pregnancy is linked to inability
  to gate out sensory and cognitive information
  in animal models, which is similar to what is
  seen in schizophrenics
• Alterations in the basal ganglia is associated to
  sensorimotor gating circuitry and to some extent
  resemble those described in schizophrenics

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2. Maternal Stress

• Evidence from both human and animal studies that
  prenatal stress can affect postnatal behavior and
  brain chemistry
• People with schizophrenia are more likely to have
  been in utero (2nd trimester) when mothers were
  exposed to stressful events

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Stress

• Common mechanism of many risk factors
• Stress response during 2nd trimester may effect
  brain development
• High glucocorticoid levels increase risk
• Enhances responsiveness of childs HPA axis to
  acute stress during adulthood, therefore leading
  to diminished ability to inhibit stress-induced
  gluccocorticoid secretion

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Contd.

• Dexamethasone test
• shows impaired negative feedback in HPA axis
  (animal models)
• Humans also reported to have diminished feedback
  regulation and abnormalities in the HPA axis
• Increased glucocorticoids is associated with
• Impaired cognitive capacity
• Decrease hippocampal volume
• Also shown in humans

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Contd.

• HPA axis is associated with disruption in
  cognitive abilities and severity of symptoms
• Stress reduction effects relapse rate
• Prenatal glucocorticoid effects on NTs
• Dopamine
• Norepinephrine
• Seretonin

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3. Nutritional Deprivation

• Evidence from studying people who were in utero
  during the Dutch Hunger Winter reveal that 1st
  trimester famine exposure increases the risk of
  schizophrenia
• Various evidence comes from postmortem,
  neuroimaging and cytoarchitectonic studies

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Factors Involved

• Folate
• Zinc
• B12
• Factors that still need more empirical evidence
• Thiamine
• Vitamin D
• Iron
• Copper

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Folate Deficiency

• Folate plays a role in
• Neurogenesis
• Cell growth
• Myelination
• Folate deficiency causes
• Decreased rate of DNA synthesis
• Decreased cell division
• All things needed for proper development

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Prenatal Protein-Calorie Malnutrition (PCM)

• Disrupts morphology of the denate gyrus (a key
  hippocampal structure)
• Increases inhibition activity of the denate
  granual cells which has effects on learning,
  memory and gating of incoming information
• Leads to enhanced release and turnover of DA and
  5-HT( this decreases the of binding sites in
  the striatum)

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Contd

• Indirect effects of PCM on brain development
• Compromises immune system- leading to increased
  vulnerability to infections
• Prenatal famine and other specific nutritional
  deficiencies are associated with perinatal
  complications (ex. Traumatic delivery)
• Can lead to behavioural and cognitive
  abnormalities

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Evidence

• Adverse effects on brain development
• General malnutrition results in neuropathological
  anomalies of the brain regions implicated in
  schizophrenia
• Prenatal malnutrition effects maternal systems
  critical to the development of fetal nervous
  system

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4. Prenatal Concentration of Sex Hormones

• Intrauterine hormones may be a factor which helps
  induce expression of a genetic vulnerability
• Higher morbid risk for DZ twins than for siblings
  
• Progesterone
• Thyroid Hormone and Gonadal Steroids

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5. Traumatic Delivery

• Subtle alterations in birth procedure can produce
  long-lasting increases in dopamine-mediated
  behaviour (such as caesarian section with general
  anesthesia)
• This gives support to the role of birth
  complications in the development of schizophrenia

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6. Limbic System Abnormalities

• Limbic damage in early development (2nd
  trimester) can cause abnormalities in structures
  involved in schizophrenia
• Smaller amygdalae, hippocampi and frontal lobes
• Enlarged ventricles
• Elevated levels of DA or DA receptors

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Contd

• Early hippocampal damage causes an increased
  response to stress and effects DA
• Variation in mesolimbic temperature control
  system has also been shown to render this system
  susceptible to changes producing psychosis
• Evidence of temperature involvement?

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NOTE

• We have been talking about environmental factors
  for schizophrenia, but there are also significant
  genetic factors
• Schizophrenia develops as a result of an
  interaction between genetic, developmental and
  environmental factors

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The Impact in the Real World

• All of the work done on prenatal and perinatal
  risk factors for schizophrenia has implications
  for public mental health, as it may lead to new
  measures aimed at the primary prevention of
  schizophrenia
• Also, the identification of the risk factors for
  schizophrenia may translate into new insights for
  the treatment for this devastating disorder