Prenatal Lead Pb Exposure and Schizophrenia

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Prenatal Lead (Pb) Exposure and Schizophrenia
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Prenatal Exposures Schizophrenia

• Studies show that prenatal insults contribute to
  the risk of schizophrenia and schizophrenia
  spectrum disorders

• Infectious Agents Rubella, Influenza
• Nutritional Deficits lt4200 kJ/Day
• Advanced Paternal Age Risk for offspring
  w/fathers gt35
• Chemical Exposures No studies to date

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Lead and Neurodevelopment

• Oldest industrial toxin
• Lead is associated with cognitive and behavioral
  deficits
• Role in both pre- and postnatal development
• Long-term effects
• Decreased IQ
• Juvenile delinquency

Metallic Lead
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Hypothesis Goals

• Hypothesis Does high prenatal Pb exposure
  increase the risk of schizophrenia spectrum
  disorders?
• Develop and validate a method for testing
  maternal lead levels in prospectively collected
  biological samples
• Conduct study relate prenatal BPb to diagnosed
  schizophrenia spectrum disorder

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The Prenatal Determinants of Schizophrenia Study
(PDS)

• The PDS (Susser et al.) is a birth cohort with
  archived maternal serum drawn at each trimester
• Pregnancies via Kaiser Permanente clinics between
  1959-1966
• Obstetric Records
• Maternal Serum

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PDS Cohort
CHDS Cohort Liveborn N19,044
Eligible for Membership In Cohort N12,567
Infant/Child Deaths Adoptions
PDS Cohort N12,094
No documented health Plan contact gt Age 10
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Selection of Cases

• Computerized registries
• Inpatient
• Outpatient
• Pharmacy
• Record abstracted, reviewed
• Subjects interviewed face-to-face
• Reviewed by a team of 3 psychiatrists
• Consensus Diagnosis

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Nested Case-Control Study

• 71 cases of schizophrenia and related disorders
• 1-2 controls per case, matched on date of birth,
  gender, dates of enrollment in cohort, number of
  available sera samples, timing of 1st blood draw

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Expected Blood Pb in Individuals

• 1967 Red Bluff, CA
• Small town, 7,000
• Male residents, age 25-55 Mean7.7 ug/dL
• 1966 L.A. Study
• Proximity to freeways
• Women, ages 17-79
• Near Freeway
• Mean16.7 ug/dL
• Not Near Freeway Mean9.9 ug/dL

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Lead in Serum?

• While Pb is typically measured in whole blood
  (RBCs)
• No blood samples available in the PDS, only serum

Basophilic Stippling due to Pb poisoning
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Ambient Pb Exposure
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-Aminolevulinic Acid

• Biological Marker of Pb Exposure
• Typically measured in urine, plasma and in serum

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(No Transcript)
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d-ALA levels increase
Pb
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Measuring ? -Aminolevulinic Acid

• High pressure liquid chromatography
• Highly predictive at BPb gt15 ug/dL

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Main Study Summary

• 44 Cases Available, 75 Controls
• 2nd trimester sera

Crude OR 1.9, P0.09
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Adjusted Logistic Regression Model, Conditional
Method
Odds Ratio P-Value 95 Confidence
Interval 2.43 0.05 0.99-5.96
Conditional Model adjusted for categorized
Mothers Age
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Summary of Results

• Elevated blood lead during pregnancy is
  associated with an increased risk of
  schizophrenia and related diseases in offspring
• This finding is subject to a number of
  limitations (sample size is small) and is
  difficult to interpret without additional
  research
• A recently completed effort to enlarge the sample
  may help us better understand what is going on

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Replication Study of Pb/ d-ALA

• Samples from the New England/ NCPP Cohort
• A total of 27 samples from cases of schizophrenia
  and 2 controls per case.
• Pb exposure should be similar to that in Oakland,
  CA
• Additional research funded by NARSAD

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Combined California New England Sample
Adjusted Logistic Regression Model, Conditional
Method
Odds Ratio P-Value 95 Confidence
Interval 1.92 0.035 1.05-3.52
Generalized Linear and Mixed Model, adjusted
for categorized Mothers Age Education
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Current Pb Gasoline Use
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Conclusions

• Preliminary result
• Marginally significant
• d-ALA, not blood lead measured
• Only have 1 point estimate of blood lead for a
  specific point in pregnancy
• Replication studies underway

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Future Directions

• Future Research
• Replicating in New England Cohort
  (Boston/Providence NCPP), Buka et al.
• Role for Paternal Exposures?
• Exposure rarely limited only to mothers
• Paternal age example
• Animal studies proposed
• Expanding to work with Finnish Institute of
  Occupational Health, pending funding

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Acknowledgements

• The Individual Level
• M. Bresnahan, A. Brown, M. Desai, P.
  Factor-Litvak, J. Graziano, E. Susser, W. Zheng,
  B. Cohn
• The Population Level
• Columbia University, Depts. of Psychiatry,
  Epidemiology, Environmental Health Sciences
• Public Health Institute, Berkeley, CA

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Overview

• Schizophrenia related spectrum disorders are
  currently being investigated for developmental
  etiologies. Nutritional, infectious, and hypoxic
  stressors have all been shown to contribute to
  the risk of these disorders. However, no studies
  of environmentally relevant toxicants, such as Pb
  have been adequately performed.
• A combination of epidemiologic study design and
  toxicology is necessary to more accurately assess
  the role that Pb might play in psychiatric
  disorders. As most of the diagnoses for these
  disorders are made in adulthood, use of banked
  samples requires the development of more
  sensitive and specific methods of measurement
• The study described here uses a novel technique
  for determination of a biological marker of lead
  exposure in sera collected during the 2nd
  trimester of pregnancy.