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Prenatal Lead Pb Exposure and Schizophrenia

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Title: Prenatal Lead Pb Exposure and Schizophrenia


1
Prenatal Lead (Pb) Exposure and Schizophrenia
2
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

3
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
4
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

5
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

6
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
7
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

8
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

9
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

10
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
11
Ambient Pb Exposure
12
-Aminolevulinic Acid
  • Biological Marker of Pb Exposure
  • Typically measured in urine, plasma and in serum

13
(No Transcript)
14
d-ALA levels increase
Pb
15
Measuring ? -Aminolevulinic Acid
  • High pressure liquid chromatography
  • Highly predictive at BPb gt15 ug/dL

16
Main Study Summary
  • 44 Cases Available, 75 Controls
  • 2nd trimester sera

Crude OR 1.9, P0.09
17
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
18
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

19
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

20
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
21
Current Pb Gasoline Use
22
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

23
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

24
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

25
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.
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