Neonatal Screening for Prenatal Alcohol Exposure - Update

1. Neonatal Screening for Prenatal Alcohol Exposure - Update Joey Gareri HBSc., MSc. Motherisk Laboratory Division of Clinical Pharmacology & Toxicology, Hospital for Sick Children Department of Pharmacology, University of Toronto

2. FASD Diagnosis:Canadian Guidelines (2005) (Chudley et al. 2005)

3. FASD Diagnosis METHODS: 1) Cranio-facial features 2) Confirmation of in utero alcohol exposure -maternal self-reporting -maternal biomarkers of alcoholism *The use of any single or multiple maternal markers is not very effective in the identification of a drinking mother (Stoler et al., 1998) BIOMARKER SPECIFIC TO PREGNANCY

4. Detecting Alcohol Abuse • One standard drink (Canadian definition) • 13.6 grams of ethanol • 12 oz. beer (5%) • 5 oz. wine (12-15%) • 1.5 oz. liquor (40%) • Alcohol Elimination Rate: ~7 g per hour • e.g. 5 drinks in 1 hour (i.e. binge episode) • 0 BAC within 10 hours • 0 UAC within 12 hours

5. Ethanol Metabolism & Elimination

6. FAEE production Oxidative ACETALDEHYDE ADH and Microsomal Oxidation (e.g. CYP 2E1) FATTY ACYL CoA ETHANOL Acyl-coenzyme A:ethanol O-acyltransferase (AEAT) FAEE FATTY ACIDS FAEE Synthases POTENTIAL BIOLOGICAL MARKERS Non-Oxidative

7. The Matrices:FAEE Analysis • Neonatal Meconium • 2nd & 3rd trimester prenatal ethanol exposure • Neonatal Hair • 3rd trimester prenatal ethanol exposure Chan et al. 2004: FAEE do not cross placenta neonatal FAEE = fetal exposure • Maternal Hair • < 6 month history of general drinking behaviour

8. Meconium FAEE • Meconium analysis • Begins formation at ~13 weeks of pregnancy • 2nd & 3rd trimester exposure • Available within 72 hours of birth • Discarded material

9. Meconium FAEE:Maternal Alcohol Consumption • Bearer et al. 1999: Prospective Study (United States) • Ethyl linolate; > 1 drink/week • N = 248 • n = 39 confirmed drinkers • Sensitivity 72%; Specificity 51% • Klein et al. 1999: Case report (Canada) • High [FAEE] in meconium w/reported prenatal ethanol consumption • [FAEE] 34-fold higher than non-drinking control group

10. Meconium FAEE:Maternal Alcohol Consumption • Bearer et al. 2003: Prospective study (South Africa) • Ethyl oleate; > 1.5 oz. ethanol/drinking day • N = 27 • n = 21 confirmed drinkers • Sensitivity 84.2%; Specificity 83.3% • Chan et al. 2003: Prospective study (Canada, Israel) • Meconium [FAEE] baseline = < 2.00 nmol/gram • n = 206 • n = 84 non-drinkers; Toronto • n = 99 non-drinkers; Jerusalem • n = 17 social drinkers; Toronto • n = 6 confirmed drinkers; Toronto • Sensitivity 100%; Specificity 98.4%

11. Meconium FAEE:Population-Based Studies • Chan et al. 2003 (Canada) • N = 142 meconium samples with suspicion of prenatal exposure • 71% samples positive for at least one illicit drug • 14% samples positive for FAEE > 2.0 nmol/gram • Moore et al. 2003 (United States) • 2 hospitals: Utah, Hawaii • Universal anonymous screening • N = 725 • 4th quartile = meconium [FAEE] > 10,000 ng/g

12. Meconium FAEE:Population-Based Studies • Gareri et al. in progress (Canada) • 5 hospitals: Grey Bruce Region, ON • Universal anonymous screening • N = 683 • 2.5 - 3.5% prevalence of fetal alcohol exposure • Meconium [FAEE] > 2.0 nmol/g • 5-fold > than clinical reporting • Hutson et al. in progress (Uruguay) • Prospective study; One hospital serving low SES population • N ~900 • Preliminary results • > 30.0% prevalence of fetal alcohol exposure • Meconium [FAEE] > 2.0 nmol/g • Neonatal outcomes available for comparison

13. Meconium FAEE:FASD Outcomes • Derauf et al. 2003 (United States) • Lower one-minute Apgar scores (p = 0.003) • [ethyl oleate] assoc. w/low birth weight (p = 0.006) • N = 422 • Noland et al. 2003 (United States) • Decreased score on executive functioning task • Tapping inhibition (age 4 years) • Lower birth weight, length, head circumference • N = 316 • Peterson et al. 2005 (United States) • Decreased psychomotor performance (age 2 years; P < 0.04) • N = 202

14. Meconium FAEE:FASD Outcomes • Jacobson et al. 2006 (South Africa) • ↑ [ethyl oleate] in FAS or pFAS diagnosed children • (age 5 years; p < 0.005) • [ethyl oleate] > maternal self-report correlates to: • Recognition memory, Processing speed, Complexity of symbolic play • N = 55 • Brien et al. 2006 (Canada) • Animal study: guinea pig • ↑ Meconium [FAEE] = ↓ neonatal brain weight • N = 51 • n = 25 ethanol-exposed • n = 23 pair-fed control • n = 3 water control

15. Hair FAEE • Neonatal Hair • Begins formation at ~20 weeks of pregnancy • 3rd trimester exposure • Available for up to 3 months after birth • Small quantities available • Maternal Hair • Grows at ~1.0 cm/month • Contains history of substance use

16. Hair FAEE & Maternal Alcohol Consumption • Pragst et al. 2001; Wurst et al. 2004 • < 6 cm hair analysis = maximum 6 mos. History • [FAEE] > 1.0 ng/mg • 75% sensitivity; 100% specificity • [FAEE] > 0.5 ng/mg • 90% sensitivity; 90% specificity • Kulaga et al. 2006 • Comparison of animal (guinea pig) vs. human data • FAEE incorporation in hair 11-fold higher in humans • [ethyl oleate] correlates with total systemic ethanol exposure

17. Hair FAEE:Neonatal Validation • Caprara et al. 2005 • Animal Study (guinea pig) • Neonatal [FAEE] 10-fold higher in ethanol-exposed litters • Caprara et al. 2005 • Pilot Study; baseline establishment • Community-based pediatric clinic • N = 56 • n = 33 non-drinkers • n = 23 social drinkers (≤ 2 drinks per week) • Range [FAEE] = 0.00 – 2.95 pmol/mg • Mean [FAEE] = 0.32 pmol/mg • Median [FAEE] = 0.008 pmol/mg

18. Future Directions • Complete validation of neonatal hair analysis for FAEE • Baseline establishment in large population • Determine predictive value between [FAEE] and FASD

19. Acknowledgements Canadian Institute for Health Research Dr. Gideon Koren Dr. James Brien Janine Hutson Susan Santiago Dr. Bhushan Kapur THANK YOU  THE END

20. Portrait of the Addicted Mother • Unemployed (93%) • Annual Income < $15,000/yr (CAD) (96%) • Grade 12 education or less (92%) • Single/Divorced/Separated (74%) • No permanent residence (23%) • Multiple pregnancies (87%) • Apprehended children (25%) • Children living with other family members (74%) • Abused by partner (60%) • Depressed (78%) • Suicidal thinking (25%)

21. PROS maximize diagnosis/intervention across socioeconomic lines opportunity to initiate therapy at earliest possible time in development (improved prognosis for outcome) avoids marginalization of high-risk women (as opposed to targeted screening) birth provides a window of opportunity in engaging high-risk women optimal intervention timing for behaviour changes in mother can provide adoptive parents with valuable background information enormous research potential in engaging an elusive study population CONS potential labeling/stigmatization of mother and child potential for conflict due to perceived or potential implications of a positive test low disease specificity associated with alcohol exposure (<60% unaffected) not diagnostic for specific treatment intensive follow-up required, high cost can potentially decrease the likelihood of adoption for exposed infants OVERVIEWNeonatal Screening for Fetal Alcohol Exposure

22. Prevention by Intervention NEONATAL INTERVENTION CANNOT PREVENT PRIMARY ALCOHOL-INDUCED DAMAGE • Mothers of alcohol-affected children are significantly more likely to produce subsequent alcohol affected children • Substance-addicted women have an 85% incidence of multiple pregnancies (average = 4) and 25% incidence of child apprehension by social services • EARLY MATERNAL INTERVENTION (e.g. 1st pregnancy) can potentially prevent future cases of FASD

23. Prevention by Intervention • In FASD • 50-70% incidence of substance addiction • 50% incidence of inappropriate or promiscuous sexual behaviour • FASD INTERVENTION is capable of alleviating secondary disabilities which perpetuate FASD