neonatal screening for prenatal alcohol exposure - update joey gareri hbsc., msc. motherisk...
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Neonatal Screening Neonatal Screening for for
Prenatal Alcohol Exposure Prenatal Alcohol Exposure - -
UpdateUpdate Joey Gareri HBSc., MSc.Joey Gareri HBSc., MSc.
Motherisk LaboratoryMotherisk LaboratoryDivision of Clinical Pharmacology & Toxicology, Hospital for Sick ChildrenDivision of Clinical Pharmacology & Toxicology, Hospital for Sick Children
Department of Pharmacology, University of TorontoDepartment of Pharmacology, University of Toronto
FASD Diagnosis:FASD Diagnosis:Canadian Guidelines (2005)Canadian Guidelines (2005)
(Chudley (Chudley et al. et al. 2005)2005)
A.A. Presence of the 3 characteristic facial features (short palpebral fissures, smooth or Presence of the 3 characteristic facial features (short palpebral fissures, smooth or flattened philtrum, thin vermilion border).flattened philtrum, thin vermilion border).
B.B. Evidence of significant prenatal exposureEvidence of significant prenatal exposure to alcoholto alcohol at levels known to be at levels known to be associated with physical or developmental effects, or both.associated with physical or developmental effects, or both.
C.C. Presence of 1 or more facial features with growth deficits Presence of 1 or more facial features with growth deficits plus known or probable plus known or probable significant prenatal alcohol exposure.significant prenatal alcohol exposure.
D.D. Presence of 1 or more facial features with 1 or more central nervous system deficits Presence of 1 or more facial features with 1 or more central nervous system deficits plus known or probable significant prenatal alcohol exposure.plus known or probable significant prenatal alcohol exposure.
E.E. Presence of 1 or more facial features with pre- or postnatal growth deficits or both Presence of 1 or more facial features with pre- or postnatal growth deficits or both (at the 10th percentile or below [1.5 SD below the mean]) and 1 or more central (at the 10th percentile or below [1.5 SD below the mean]) and 1 or more central nervous system deficits nervous system deficits plus known or probable significant prenatal alcohol plus known or probable significant prenatal alcohol exposure.exposure.
FASD DiagnosisFASD Diagnosis
METHODS:METHODS:1)1) Cranio-facial featuresCranio-facial features2)2) Confirmation of Confirmation of in utero in utero alcohol exposurealcohol exposure
-maternal self-reporting-maternal self-reporting-maternal biomarkers of alcoholism -maternal biomarkers of alcoholism
**The use of any single or multiple maternal markers is not The use of any single or multiple maternal markers is not very effective in the identification of a drinking mother very effective in the identification of a drinking mother
(Stoler et al., 1998)(Stoler et al., 1998)
BIOMARKER SPECIFIC TO PREGNANCYBIOMARKER SPECIFIC TO PREGNANCY
Detecting Alcohol AbuseDetecting Alcohol Abuse
One standard drink One standard drink (Canadian definition)(Canadian definition)
13.6 grams of ethanol13.6 grams of ethanol 12 oz. beer (5%)12 oz. beer (5%) 5 oz. wine (12-15%)5 oz. wine (12-15%) 1.5 oz. liquor (40%)1.5 oz. liquor (40%)
Alcohol Elimination Rate: ~7 g per hourAlcohol Elimination Rate: ~7 g per hour e.g. 5 drinks in 1 hour e.g. 5 drinks in 1 hour (i.e. binge episode)(i.e. binge episode)
0 BAC within 10 hours0 BAC within 10 hours 0 UAC within 12 hours0 UAC within 12 hours
Ethanol Metabolism & EliminationEthanol Metabolism & Elimination
Oxidative Metabolism
Urine/Breath/Sweat
Non-oxidative Metabolism
FAEE productionFAEE production
ETHANOL
ADH and Microsomal Oxidation (e.g. CYP 2E1)ACETALDEHYDE
FAEE Synthases
FAEE
Non-Oxidative
FATTY ACIDS
Oxidative
Acyl-coenzyme A:ethanol O-acyltransferase (AEAT)
FATTY ACYL CoA
POTENTIALBIOLOGICAL
MARKERS
The Matrices:The Matrices:FAEE AnalysisFAEE Analysis
1)1) Neonatal MeconiumNeonatal Meconium 22ndnd & 3 & 3rdrd trimester prenatal ethanol exposure trimester prenatal ethanol exposure
2)2) Neonatal HairNeonatal Hair 33rdrd trimester prenatal ethanol exposure trimester prenatal ethanol exposure
Chan Chan et al. et al. 2004: 2004: FAEE do not cross placenta FAEE do not cross placenta
neonatal FAEE = fetal exposureneonatal FAEE = fetal exposure
3)3) Maternal HairMaternal Hair < 6 month history of general drinking behaviour< 6 month history of general drinking behaviour
Meconium FAEEMeconium FAEE
1)1) MeconiumMeconium analysis analysis Begins formation at ~13 weeks of pregnancyBegins formation at ~13 weeks of pregnancy 22ndnd & 3 & 3rdrd trimester exposure trimester exposure Available within 72 hours of birthAvailable within 72 hours of birth Discarded materialDiscarded material
Meconium FAEE:Meconium FAEE:Maternal Alcohol ConsumptionMaternal Alcohol Consumption
Bearer Bearer et al. et al. 1999: 1999: Prospective Study (United Prospective Study (United States)States) Ethyl linolate; Ethyl linolate; >> 1 drink/week 1 drink/week N = 248N = 248
n = 39 confirmed drinkersn = 39 confirmed drinkers Sensitivity 72%; Specificity 51%Sensitivity 72%; Specificity 51%
Klein Klein et al. et al. 1999: 1999: Case report (Canada)Case report (Canada) High [FAEE] in meconium w/reported prenatal ethanol High [FAEE] in meconium w/reported prenatal ethanol
consumptionconsumption [FAEE] 34-fold higher than non-drinking control group[FAEE] 34-fold higher than non-drinking control group
Meconium FAEE:Meconium FAEE:Maternal Alcohol ConsumptionMaternal Alcohol Consumption
Bearer Bearer et al. et al. 2003: 2003: Prospective study (South Africa)Prospective study (South Africa) Ethyl oleate; Ethyl oleate; >> 1.5 oz. ethanol/drinking day 1.5 oz. ethanol/drinking day N = 27N = 27
n = 21 confirmed drinkersn = 21 confirmed drinkers Sensitivity 84.2%; Specificity 83.3%Sensitivity 84.2%; Specificity 83.3%
Chan Chan et al. et al. 2003: 2003: Prospective study (Canada, Israel)Prospective study (Canada, Israel) Meconium [FAEE] baseline = < 2.00 nmol/gram Meconium [FAEE] baseline = < 2.00 nmol/gram n = 206n = 206
n = 84 non-drinkers; Toronton = 84 non-drinkers; Toronto n = 99 non-drinkers; Jerusalemn = 99 non-drinkers; Jerusalem n = 17 social drinkers; Toronton = 17 social drinkers; Toronto n = 6 confirmed drinkers; Toronton = 6 confirmed drinkers; Toronto
Sensitivity 100%; Specificity 98.4%Sensitivity 100%; Specificity 98.4%
Meconium FAEE:Meconium FAEE:Population-Based StudiesPopulation-Based Studies
Chan Chan et al. et al. 2003 2003 (Canada)(Canada) N = 142 meconium samples with suspicion of prenatal N = 142 meconium samples with suspicion of prenatal
exposure exposure 71% samples positive for at least one illicit drug71% samples positive for at least one illicit drug 14% samples positive for FAEE > 2.0 nmol/gram14% samples positive for FAEE > 2.0 nmol/gram
Moore Moore et alet al. 2003. 2003 (United States) (United States) 2 hospitals: Utah, Hawaii2 hospitals: Utah, Hawaii Universal anonymous screeningUniversal anonymous screening N = 725N = 725 44thth quartile = meconium [FAEE] > 10,000 ng/g quartile = meconium [FAEE] > 10,000 ng/g
Meconium FAEE:Meconium FAEE:Population-Based StudiesPopulation-Based Studies
Gareri Gareri et al. et al. in progressin progress (Canada) (Canada) 5 hospitals: Grey Bruce Region, ON5 hospitals: Grey Bruce Region, ON Universal anonymous screeningUniversal anonymous screening N = 683N = 683 2.5 - 3.5% prevalence of fetal alcohol exposure 2.5 - 3.5% prevalence of fetal alcohol exposure
Meconium [FAEE] > 2.0 nmol/gMeconium [FAEE] > 2.0 nmol/g 5-fold > than clinical reporting5-fold > than clinical reporting
Hutson Hutson et al. et al. in progressin progress (Uruguay) (Uruguay) Prospective study; One hospital serving low SES populationProspective study; One hospital serving low SES population N ~900N ~900 Preliminary resultsPreliminary results
> 30.0% prevalence of fetal alcohol exposure> 30.0% prevalence of fetal alcohol exposure Meconium [FAEE] > 2.0 nmol/gMeconium [FAEE] > 2.0 nmol/g
Neonatal outcomes available for comparisonNeonatal outcomes available for comparison
Meconium FAEE:Meconium FAEE:FASD OutcomesFASD Outcomes
Derauf Derauf et al. et al. 2003 2003 (United States)(United States) Lower one-minute Apgar scores (p = 0.003)Lower one-minute Apgar scores (p = 0.003) [ethyl oleate] assoc. w/low birth weight (p = 0.006)[ethyl oleate] assoc. w/low birth weight (p = 0.006) N = 422N = 422
Noland Noland et al. et al. 2003 2003 (United States)(United States) Decreased score on executive functioning taskDecreased score on executive functioning task
Tapping inhibition (age 4 years)Tapping inhibition (age 4 years) Lower birth weight, length, head circumferenceLower birth weight, length, head circumference N = 316N = 316
Peterson Peterson et al. et al. 2005 2005 (United States)(United States) Decreased psychomotor performance (age 2 years; P < 0.04)Decreased psychomotor performance (age 2 years; P < 0.04) N = 202N = 202
Meconium FAEE:Meconium FAEE:FASD OutcomesFASD Outcomes
Jacobson Jacobson et al. et al. 2006 2006 (South Africa)(South Africa) ↑ ↑ [ethyl oleate] in FAS or pFAS diagnosed children [ethyl oleate] in FAS or pFAS diagnosed children
(age 5 years; p < 0.005)(age 5 years; p < 0.005) [ethyl oleate] > maternal self-report correlates to:[ethyl oleate] > maternal self-report correlates to:
Recognition memory, Processing speed, Complexity of symbolic playRecognition memory, Processing speed, Complexity of symbolic play N = 55N = 55
Brien Brien et al. et al. 20062006 (Canada) (Canada) Animal study: guinea pigAnimal study: guinea pig ↑ ↑ Meconium [FAEE] = ↓ neonatal brain weightMeconium [FAEE] = ↓ neonatal brain weight N = 51N = 51
n = 25 ethanol-exposedn = 25 ethanol-exposed n = 23 pair-fed controln = 23 pair-fed control n = 3 water controln = 3 water control
Hair FAEEHair FAEE
2)2) Neonatal HairNeonatal Hair Begins formation at ~20 weeks of pregnancyBegins formation at ~20 weeks of pregnancy 33rdrd trimester exposure trimester exposure Available for up to 3 months after birthAvailable for up to 3 months after birth Small quantities availableSmall quantities available
3)3) Maternal HairMaternal Hair Grows at ~1.0 cm/monthGrows at ~1.0 cm/month Contains history of substance useContains history of substance use
Hair FAEE & Hair FAEE & Maternal Alcohol ConsumptionMaternal Alcohol Consumption
Pragst Pragst et al. et al. 2001; Wurst 2001; Wurst et al. et al. 20042004 < 6 cm hair analysis = maximum 6 mos. History< 6 cm hair analysis = maximum 6 mos. History [FAEE] > 1.0 ng/mg[FAEE] > 1.0 ng/mg
75% sensitivity; 100% specificity75% sensitivity; 100% specificity [FAEE] > 0.5 ng/mg[FAEE] > 0.5 ng/mg
90% sensitivity; 90% specificity90% sensitivity; 90% specificity
Kulaga Kulaga et al. et al. 20062006 Comparison of animal (guinea pig) vs. human dataComparison of animal (guinea pig) vs. human data FAEE incorporation in hair 11-fold higher in humansFAEE incorporation in hair 11-fold higher in humans [ethyl oleate] correlates with total systemic ethanol [ethyl oleate] correlates with total systemic ethanol
exposureexposure
Hair FAEE:Hair FAEE:Neonatal ValidationNeonatal Validation
Caprara Caprara et al. et al. 20052005 Animal Study (guinea pig)Animal Study (guinea pig) Neonatal [FAEE] 10-fold higher in ethanol-exposed littersNeonatal [FAEE] 10-fold higher in ethanol-exposed litters
Caprara Caprara et al. et al. 20052005 Pilot Study; baseline establishmentPilot Study; baseline establishment Community-based pediatric clinicCommunity-based pediatric clinic N = 56N = 56
n = 33 non-drinkersn = 33 non-drinkers n = 23 social drinkers (≤ 2 drinks per week)n = 23 social drinkers (≤ 2 drinks per week)
Range [FAEE] = 0.00 – 2.95 pmol/mgRange [FAEE] = 0.00 – 2.95 pmol/mg Mean [FAEE] = 0.32 pmol/mgMean [FAEE] = 0.32 pmol/mg Median [FAEE] = 0.008 pmol/mgMedian [FAEE] = 0.008 pmol/mg
Future DirectionsFuture Directions
Complete validation of neonatal hair analysis Complete validation of neonatal hair analysis for FAEEfor FAEE Baseline establishment in large populationBaseline establishment in large population
Determine predictive value between [FAEE] Determine predictive value between [FAEE] and FASDand FASD
AcknowledgementsAcknowledgements
Canadian Institute for Health ResearchCanadian Institute for Health Research
Dr. Gideon KorenDr. Gideon Koren
Dr. James BrienDr. James Brien
Janine HutsonJanine Hutson
Susan SantiagoSusan Santiago
Dr. Bhushan KapurDr. Bhushan Kapur
THANK YOU THANK YOU
THE ENDTHE END
Portrait of the Addicted MotherPortrait of the Addicted Mother Unemployed (93%)Unemployed (93%) Annual Income < $15,000/yr (CAD) (96%)Annual Income < $15,000/yr (CAD) (96%) Grade 12 education or less (92%)Grade 12 education or less (92%) Single/Divorced/Separated (74%)Single/Divorced/Separated (74%) No permanent residence (23%)No permanent residence (23%) Multiple pregnancies (87%)Multiple pregnancies (87%) Apprehended children (25%) Apprehended children (25%) Children living with other family members (74%)Children living with other family members (74%) Abused by partner (60%)Abused by partner (60%) Depressed (78%)Depressed (78%) Suicidal thinking (25%)Suicidal thinking (25%)
OVERVIEWOVERVIEWNeonatal Screening for Fetal Alcohol Neonatal Screening for Fetal Alcohol
ExposureExposurePROSPROS
maximize diagnosis/intervention maximize diagnosis/intervention across socioeconomic linesacross socioeconomic lines
opportunity to initiate therapy at opportunity to initiate therapy at earliest possible time in development earliest possible time in development (improved prognosis for outcome)(improved prognosis for outcome)
avoids marginalization of high-risk avoids marginalization of high-risk women (as opposed to targeted women (as opposed to targeted screening)screening)
birth provides a window of opportunity birth provides a window of opportunity in engaging high-risk womenin engaging high-risk women
optimal intervention timing for optimal intervention timing for behaviour changes in motherbehaviour changes in mother
can provide adoptive parents with can provide adoptive parents with valuable background informationvaluable background information
enormous research potential in enormous research potential in engaging an elusive study populationengaging an elusive study population
CONSCONS
potential labeling/stigmatization of potential labeling/stigmatization of mother and childmother and child
potential for conflict due to perceived potential for conflict due to perceived or potential implications of a positive or potential implications of a positive test test
low disease specificity associated with low disease specificity associated with alcohol exposure (<60% unaffected)alcohol exposure (<60% unaffected)
not diagnostic for specific treatmentnot diagnostic for specific treatment intensive follow-up required, high costintensive follow-up required, high cost
can potentially decrease the likelihood can potentially decrease the likelihood of adoption for exposed infantsof adoption for exposed infants
Prevention by InterventionPrevention by Intervention
NEONATAL INTERVENTION CANNOT PREVENT NEONATAL INTERVENTION CANNOT PREVENT PRIMARY ALCOHOL-INDUCED DAMAGEPRIMARY ALCOHOL-INDUCED DAMAGE
Mothers of alcohol-affected children are significantly more Mothers of alcohol-affected children are significantly more likely to likely to produce subsequentproduce subsequent alcohol affected children alcohol affected children
Substance-addicted women have an Substance-addicted women have an 85%85% incidence of incidence of multiple pregnancies (average = 4) and multiple pregnancies (average = 4) and 25%25% incidence of incidence of child apprehension by social serviceschild apprehension by social services
EARLY MATERNAL INTERVENTION (e.g. 1EARLY MATERNAL INTERVENTION (e.g. 1stst pregnancy) can pregnancy) can potentially prevent future cases of FASDpotentially prevent future cases of FASD
Prevention by InterventionPrevention by Intervention
In FASD In FASD 50-70% incidence of substance addiction50-70% incidence of substance addiction 50% incidence of inappropriate or promiscuous 50% incidence of inappropriate or promiscuous
sexual behavioursexual behaviour FASD INTERVENTION is capable of alleviating FASD INTERVENTION is capable of alleviating
secondary disabilities which perpetuate FASDsecondary disabilities which perpetuate FASD