Drugs_ Booze and Heavy Metal in Pregnancy_ Causes of

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					Drugs, booze and heavy metal in pregnancy:
 Causes of childhood asthma and allergy?

                Seif Shaheen
      Professor of Respiratory Epidemiology
     Centre for Primary Care and Public Health
                   Blizard Institute
          Barts and The London School of
               Medicine and Dentistry

       Hunting for the causes of asthma

Primary prevention Secondary prevention
in utero   infancy childhood adolescenc   adulthood
        Does asthma begin in utero?
• Early presentation
• Prenatal risk factors
  – Maternal smoking in pregnancy
  – Antibiotic use in pregnancy
  – Infections in pregnancy
  – Complications of pregnancy
  – Mode of delivery
  – Gestational age at birth
  – Anthropometry at birth
                                             H       C
                                                 N       CH3


                            Cytochrome P450

              O                                      O
      H       C                                      C
          N       CH3                            N       CH3

          OH                                     O
Glutathione conjugate                      N-Acetyl-p-
   Importance of the prenatal environment

“The only clever thing I did was to remember
  that life begins at conception, not at birth….”

                                 Alice Stewart
  Avon Longitudinal Study of
Parents and Children (ALSPAC)
 Paracetamol use in late pregnancy and risk of
           wheezing at 3.5 years
             (Thorax 2002; 57: 958-63)

                       Adj OR (95% CI)
Paracetamol use
Never                  1.00
Sometimes              1.12 (0.98, 1.28)
Most days/daily        2.10 (1.30, 3.41)*

      Paracetamol use in late pregnancy and
              asthma and total IgE
           (Clin Exp Allergy 2005; 35: 18-25)
              Asthma@6yrs           Total IgE@7yrs
              Adj OR (95% CI)       Adj GMR (95% CI)
of use
Never           1.00                 1.00
Sometimes       1.22 (1.06, 1.41)    1.14 (1.03, 1.26)
Most days/
  daily         1.62 (0.86, 3.04)    1.52 (0.98, 2.38)

P trend:          0.0037                   0.0034
    Further evidence against confounding
                 IJE 2010; 39: 790-4

• Effects on Total IgE of prenatal exposure
  – Maternal prenatal 1.21 (1.09, 1.33) 0.00024
  – Maternal postnatal 0.95 (0.85, 1.06) 0.35
  – Partner postnatal 1.00 (0.86, 1.16) 0.98

• Confounding by unmeasured behavioural factors
  linked to paracetamol usage unlikely
       Gene by environment interaction

• Strengthening causal inference
  – Biological plausibility
     • modification of paracetamol effect by gene variants
       influencing toxicity
  – Glutathione-S-transferase
     • GSTT1, GSTM1, GSTP1
     • conjugates NAPQI with glutathione
  – Nrf2
     • Nrf2 knockout mice sensitive to paracetamol toxicity
     • Disruption of Nrf2 leads to increased allergic
       inflammation in a mouse model of asthma
    Paracetamol use in early pregnancy and asthma
            risk stratified by maternal Nrf2
               (JACI 2010; 126: 1141-8)

                        Adj OR*            95% CI         P

C:C (n=3754)                0.99          0.81 to 1.21   0.91

T:C/T:T (n=1137) 1.73                     1.22 to 2.45   0.002

                                          Interaction    0.02
*Per category of exposure

No interaction with child Nrf2 genotype
              Of mice and men
• A mouse model of asthma (Clare Lloyd)
• Prenatal intervention
  – Outcome: allergic airway inflammation
  Could prenatal alcohol be a risk factor?

• Danish studies
  – Associated with raised cord IgE and infant
    eczema, but not hospitalisation for asthma
  – Intake tends to be under-reported
  – Confounding a big problem
             Mendelian randomisation:
                increasing rigour

ALCOHOL                 Acetaldehyde                 Acetic acid

 Alcohol dehydrogenase             Aldehyde dehydrogenase
        ADH1B*                             ALDH2

 *Carriers of A allele metabolise faster and drink less

• Funding
  – Asthma UK and British Lung Foundation

• Colleagues
  – Jean Golding, John Henderson, Sue Ring,
    George Davey Smith (Bristol University)
  – John Holloway (Southampton University)
  – Roger Newson (Imperial College)

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