Neonatal Screening for Prenatal Alcohol Exposure Update Joey

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

FASD Diagnosis: Canadian Guidelines (2005) (Chudley et al. 2005) A. Presence of the 3 characteristic facial features (short palpebral fissures, smooth or flattened philtrum, thin vermilion border). B. Evidence of significant prenatal exposure to alcohol at levels known to be associated with physical or developmental effects, or both. C. Presence of 1 or more facial features with growth deficits plus known or probable significant prenatal alcohol exposure. D. Presence of 1 or more facial features with 1 or more central nervous system deficits plus known or probable significant prenatal alcohol exposure. E. Presence of 1 or more facial features with pre- or postnatal growth deficits or both (at the 10 th percentile or below [1. 5 SD below the mean]) and 1 or more central nervous system deficits plus known or probable significant prenatal alcohol exposure.

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

Detecting Alcohol Abuse n One standard drink (Canadian definition) n 13. 6 grams of ethanol 12 oz. beer (5%) n 5 oz. wine (12 -15%) n 1. 5 oz. liquor (40%) n n Alcohol Elimination Rate: ~7 g per hour n e. g. 5 drinks in 1 hour (i. e. binge episode) 0 BAC within 10 hours n 0 UAC within 12 hours n

Ethanol Metabolism & Elimination

FAEE production Oxidative ACETALDEHYDE ADH and Microsomal Oxidation (e. g. CYP 2 E 1) ETHANOL FATTY ACYL Co. A Acyl-coenzyme A: ethanol O-acyltransferase (AEAT) FATTY ACIDS FAEE Synthases Non-Oxidative FAEE POTENTIAL BIOLOGICAL MARKERS

The Matrices: FAEE Analysis Neonatal Meconium 1) n 2 nd & 3 rd trimester prenatal ethanol exposure Neonatal Hair 2) n 3 rd trimester prenatal ethanol exposure Chan et al. 2004: FAEE do not cross placenta neonatal FAEE = fetal exposure Maternal Hair 3) n < 6 month history of general drinking behaviour

Meconium FAEE 1) Meconium analysis n n Begins formation at ~13 weeks of pregnancy 2 nd & 3 rd trimester exposure Available within 72 hours of birth Discarded material

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

Meconium FAEE: Maternal Alcohol Consumption n Bearer et al. 2003: Prospective study (South Africa) n n Ethyl oleate; > 1. 5 oz. ethanol/drinking day N = 27 n n = 21 confirmed drinkers Sensitivity 84. 2%; Specificity 83. 3% Chan et al. 2003: Prospective study (Canada, Israel) n n Meconium [FAEE] baseline = < 2. 00 nmol/gram n = 206 n n 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%

Meconium FAEE: Population-Based Studies n Chan et al. 2003 (Canada) n N = 142 meconium samples with suspicion of prenatal exposure n n n 71% samples positive for at least one illicit drug 14% samples positive for FAEE > 2. 0 nmol/gram Moore et al. 2003 (United States) n n 2 hospitals: Utah, Hawaii Universal anonymous screening N = 725 4 th quartile = meconium [FAEE] > 10, 000 ng/g

Meconium FAEE: Population-Based Studies n Gareri et al. in progress (Canada) n n 5 hospitals: Grey Bruce Region, ON Universal anonymous screening N = 683 2. 5 - 3. 5% prevalence of fetal alcohol exposure n n n Meconium [FAEE] > 2. 0 nmol/g 5 -fold > than clinical reporting Hutson et al. in progress (Uruguay) n n n Prospective study; One hospital serving low SES population N ~900 Preliminary results n > 30. 0% prevalence of fetal alcohol exposure n n Meconium [FAEE] > 2. 0 nmol/g Neonatal outcomes available for comparison

Meconium FAEE: FASD Outcomes n Derauf et al. 2003 (United States) n n 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) n Decreased score on executive functioning task n n Tapping inhibition (age 4 years) Lower birth weight, length, head circumference N = 316 Peterson et al. 2005 (United States) n n Decreased psychomotor performance (age 2 years; P < 0. 04) N = 202

Meconium FAEE: FASD Outcomes n Jacobson et al. 2006 (South Africa) n ↑ [ethyl oleate] in FAS or p. FAS diagnosed children n n [ethyl oleate] > maternal self-report correlates to: n n n (age 5 years; p < 0. 005) Recognition memory, Processing speed, Complexity of symbolic play N = 55 Brien et al. 2006 (Canada) n n n Animal study: guinea pig ↑ Meconium [FAEE] = ↓ neonatal brain weight N = 51 n n = 25 ethanol-exposed n = 23 pair-fed control n = 3 water control

Hair FAEE 2) Neonatal Hair n n 3) Begins formation at ~20 weeks of pregnancy 3 rd trimester exposure Available for up to 3 months after birth Small quantities available Maternal Hair n n Grows at ~1. 0 cm/month Contains history of substance use

Hair FAEE & Maternal Alcohol Consumption n Pragst et al. 2001; Wurst et al. 2004 n n < 6 cm hair analysis = maximum 6 mos. History [FAEE] > 1. 0 ng/mg n n [FAEE] > 0. 5 ng/mg n n 75% sensitivity; 100% specificity 90% sensitivity; 90% specificity Kulaga et al. 2006 n n n 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

Hair FAEE: Neonatal Validation n Caprara et al. 2005 n n n Animal Study (guinea pig) Neonatal [FAEE] 10 -fold higher in ethanol-exposed litters Caprara et al. 2005 n n n Pilot Study; baseline establishment Community-based pediatric clinic N = 56 n n 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

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

Acknowledgements Canadian Institute for Health Research Dr. Gideon Koren Dr. James Brien Janine Hutson Susan Santiago Dr. Bhushan Kapur

Portrait of the Addicted Mother n n n 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%)

OVERVIEW Neonatal Screening for Fetal Alcohol Exposure PROS n n n n 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 n n n 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

Prevention by Intervention NEONATAL INTERVENTION CANNOT PREVENT PRIMARY ALCOHOL-INDUCED DAMAGE n n 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 n EARLY MATERNAL INTERVENTION (e. g. 1 st pregnancy) can potentially prevent future cases of FASD

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