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Maternal-fetal biomarkers of prenatal exposure to ethanol Simona Pichini National Observatory on Alcohol, tobacco, smoking, doping and gambling Istituto Superiore di Sanità Rome, Italy

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  • Maternal-fetal biomarkers of

    prenatal exposure to ethanol

    Simona Pichini

    National Observatory on Alcohol, tobacco,

    smoking, doping and gambling

    Istituto Superiore di Sanit

    Rome, Italy

  • Indirect Maternal biomarkers of gestational ethanol consumption

    -Interview with the mother (the most used,

    the most unreliable!)

    -Ethanol concentrations in expired air, blood

    and urine (very rare)

    - Glutamyltransferase (GGT)

    -Aspartate aminotransferase (AST)

    -Mean corpuscular volume (MCV)

    -N-Acetyl--Hexosaminidase (Beta-Hex)

    -apolipoprotein J

    -Total sialic acid

    -Hydroxytryptophol 5-(5-HTOL)

    -Phosphatidyl Ethanol (PEth)

    -Carbohydrate Deficient Transferrin (CDT)

  • ACUTE RECENT CHRONIC

    DA

    YS

    Indirect

    direct

    MARKERS OF ALCOHOL ABUSE

  • FAEEs (EtOH + fatty acids Synthetase FAEEs)

    O

    O

    CH3CH3

    O

    O

    CH3CH3

    O

    O

    CH3CH3

    O

    O

    CH3CH3

    O

    O

    CH3CH3

    O

    O

    CH3CH3

    O

    O

    CH3CH3

    ethyl palmitate

    ethyl palmitoleate

    ethyl stearate

    ethyl oleate

    ethyl linoleate

    ethyl linolenate

    ethyl arachinodate

  • Ethylglucuronide and Ethylsulfate

    EtOH

    CH3

    O

    HOH

    HH

    H

    H

    OOH

    OH

    COOH

    UDP-glucuronosyltransferase

    -D-ethylglucuronide (EtG)

    C8H14O7 (222.1945)

    S OH

    O

    O

    OCH3

    sulfotransferase

    ethylsulfate (EtS)

    C2H6O4S (126.1313)

    Alcohol dehydrogenase

    aldehyde dehydrogenase acetic acid Krebs cycle

    Accounting for 0.1% ingested ethanol

  • Placenta

    Fetus

    ABSORPTION

    DISTRIBUTION

    /

    METABOLISM

    EXCRETION

    cord

    blood

    meconium

    Newborn

    breast milk

    hair

    Drug

    Drug/Metabolites

    Blood/Plasma

    Gastrointestinal Tract

    faeces

    Skin and Lungs

    bronchial

    secretions/

    expired air

    Liver

    bile

    Lungs

    Extra-cellular fluids

    and matrices:

    tears, nails,

    cerebrospinal fluid,

    interstitial fluid,

    seminal fluid,

    vitreous humour,

    pericardial fluid,

    saliva, sweat, hair

    amniotic fluid

    Kidney

    urine

    Metabolites

    D/M

    D/M D/M

    D/M

    D/M

    D/M

    D/M

    D/M

    D/M Urine

    D/M

  • Direct ethanol metabolites in maternal biological

    matrices

    Fatty acid ethyl esters (FAEEs).

    - FAEEs in blood account for acute consumption.

    - FAEEs in hair account for chronic consumption as

    a function of hair length and segmental analysis

    (performed only in two labs worldwide).

    Ethyl glucuronide (EtG) and Ethyl sulfate (EtS).

    - EtG and EtS in blood account for recent

    consumption.

    - EtG and EtS in urine increase the window of

    detection to the previous 3-4 days.

    - EtG and EtS in hair account for chronic

    consumption as a function of hair length and

    segmental analysis

  • Biological Matrices

    related to gestation-

    delivery-neonatal

    period

    Amniotic Fluid

    Placenta

    Fetal hair

    Meconium

    Cord blood

    Neonatal urine

  • Ethyl glucuronide and ethyl sulfate in placenta and fetal tissues

    by LC-MS/MS: biomarkers of placental ethanol transport

    Luca Morini*1, Maria Falcn2, Simona Pichini3, Oscar Garcia-

    Algar4, Paolo Danesino1, Angelo Groppi1 and Aurelio Luna2

    1Department of Legal Medicine, Forensic and Pharmaco-Toxicological Science, University of Pavia, Italy; 2Deparment of Legal Medicine, Universidad de Murcia, Murcia, Spain; 3Istituto Superiore di Sanit, Rome, Italy; 4Unitat de Recerca Infancia i Entorn (URIE), Institut Municipal dInvestigaci Mdica-Hospital del Mar, Barcelona, Spain.

    http://milano.blogosfere.it/images/ecografia01.jpg

  • Real samples

    EtG EtS Placenta

    ng/g

    Fetal Tissues

    ng/g

    Hair

    pg/g

    Placenta

    ng/g

    Fetal Tissues

    ng/g

    S 1-S5

  • Similarly to amniotic fluid and

    placenta, cord blood objectively

    assess the acute exposure, which

    occurs at the end of the

    pregnancy.

    Cord blood is obtained during

    delivery and thus provides

    information on the last days

    before it.

    Neonatal urine is obtained the first

    day(s) of life and can account

    for the previous 60-72 hours.

  • As previously

    reported, meconium

    and fetal hair

    objectively assess a

    chronic exposure to

    drugs during fetal life,

    starting from second

    trimester of pregnancy

    in case of meconium

    whereas hair grows

    only during the third

    trimester of

    pregnancy.

  • FAEEs in neonatal hair

    Caprara DL, Klein J, Koren G.

    Baseline measures of fatty acid etil esters in hair of

    neonates born to abstaining or mild social drinking

    mothers.

    Ther Drug Monit. 2005 Dec;27(6):811-5.

    hair samples of infants born to women with problems of

    excessive alcohol consumption should be analyzed to

    check the possible difference in the concentrations of

    FAEEs

    AN IMPORTANT LIMITATION IS THE AMOUNT OF

    NEONATAL HAIR WHICH CAN BE COLLECTED (< 10

    mg)

    EtG and EtS in neonatal hair?

    All hair samples from newborns tested < LLOQ for HEtG.

    Morini L, Marchei E, Vagnarelli F, Garcia Algar O, Groppi A, Mastrobattista L, Pichini S.

    Ethyl glucuronide and ethyl sulfate in meconium and hair-potential biomarkers of intrauterine exposure to ethanol.

    Forensic Sci Int. 2010 Mar 20;196(1-3):74-7. Epub 2010 Jan 8.

    http://www.ncbi.nlm.nih.gov/pubmed/16306859?ordinalpos=8&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSumhttp://www.ncbi.nlm.nih.gov/pubmed/16306859?ordinalpos=8&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSumhttp://www.ncbi.nlm.nih.gov/pubmed/16306859?ordinalpos=8&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSumhttp://www.ncbi.nlm.nih.gov/pubmed/16306859?ordinalpos=8&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSumhttp://www.ncbi.nlm.nih.gov/pubmed/16306859?ordinalpos=8&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSumhttp://www.ncbi.nlm.nih.gov/pubmed/16306859?ordinalpos=8&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSumhttp://www.ncbi.nlm.nih.gov/pubmed/16306859?ordinalpos=8&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSumhttp://www.ncbi.nlm.nih.gov/pubmed/20060246http://www.ncbi.nlm.nih.gov/pubmed/20060246http://www.ncbi.nlm.nih.gov/pubmed/20060246http://www.ncbi.nlm.nih.gov/pubmed/20060246http://www.ncbi.nlm.nih.gov/pubmed/20060246http://www.ncbi.nlm.nih.gov/pubmed/20060246

  • The first bowel movement a baby has is called meconium.

    Meconium is composed of amniotic fluid, mucus, lanugo

    (the fine hair that covers the baby's body), bile, and cells

    that have been shed from the skin and the intestinal tract.

    Meconium is thick, greenish black, sticky and sterile.

  • The Meconium Project: An Italian-Spanish

    Joint Study to Assess Exposure to Illicit Drugs

    During Pregnancy and Birth Outcomes in a

    mediterranean city (2004-2008)

    Istituto Superiore di Sanit, Roma, Italy

    IMIM- Hospital del Mar, Barcelona, Spain

    We found in 1209 meconium samples of mother-infant dyads attending the

    Hospital during 2002-2004 a prevalence of prenatal exposure to 2.6%

    Cocaine, 4.7% heroin and 5.3% cannabis and.

    45% daily maternal ethanol measured by FAEEs in

    meconium

  • Chan et al., JPET 2004

    Fatty acid ethyl esters (FAEEs) in meconium

    Positive cut-off:

    7 FAEEs> 2 nmol/g meconium

  • Are there EtG + EtS in meconium?

  • 2007-2009

    MECONIUM SAMPLES OBTAINED FROM

    Similar sociodemographic (Urban) and ethnic (Caucasians with 40%

    immigrants from North Africa, South America and Asia)

    characteristics

    BARCELONA, SPAIN

    BCN

    REGGIO EMILIA, ITALY

    RE

  • Meconium

    Samples Statistics

    EtG

    (nmol/g) EtS

    (nmol/g)

    FAEEs > 2

    nmol/g

    (n=44)

    Mean 2.04 0.14

    SD 3.92 0.61

    Min 0.11 0.01

    Max 21.94 3.47

    Median 0.21 0.02

    FAEEs < 2

    nmol/g

    (n=133)

    Mean 0.63 0.02

    SD 1.19 0.03

    Min 0.02 1.01

    Max 7.11 0.2

    Median 0.06 0.01

    P value* 0.0002 0.009

    * In relation to samples FAEE >2

    EtS

    Measurable

    in 52%

    samples

    EtG

    Measurable

    in 84%

    samples

  • Comparison of EtG and EtS levels in meconium

    0

    1

    2

    3

    4

    5

    6

    7

    1 3 5 7 9 11 13 15 17 19 21 23 25 27 29 31 33 35 37 39 41 43 45 47 49 51 53 55 57 59 61 63 65 67 69 71 73 75 77 79 81 83 85 87 89 91 93 95 97 99

    Co

    nc

    en

    tra

    tio

    ns