1. Questions of Ethics: Neonatal Screening for Prenatal Alcohol Exposure Joey Gareri HBSc. Division of Clinical Pharmacology and Toxicology Hospital for Sick Children, Toronto Department of Pharmacology University of Toronto Dr. Gideon Koren MD, FRCPC

2. INTRODUCTION Challenges of Diagnosis Full blown FAS (severe neurodevelopmental delay) Indinstinct philtrum Intrauterine growth retardation Short palpebral fissures Less apparent forms of FASD, such as Alcohol Related Neurodevelopmental Disorder (ARND) are difficult to diagnose ARND is associated with non-pathognomonic features Confirmed maternal drinking history in pregnancy required for diagnosis Delayed diagnosis and intervention further increases the risk of secondary disabilities

3. INTRODUCTION Diagnostic Tools Questionnaires T-ACE TWEAK Biomarkers Liver enzymes Ethyl glucuronide Fatty Acid Ethyl Esters (FAEE)

4. INTRODUCTION The Questions of Ethics Analysis of the Ethical Aspects of the Screen (Hermerin et al., 1999) Purpose Informed Consent Access to Information Cost Effectiveness Assessment of the Quality of the Screening Method (Loeber et al., 1999) Coverage Sample Quality Demographic Data Collected Epidemiological Evaluation Proposed Follow-up

5. INTRODUCTION Neonatal Screening for Fetal Alcohol Exposure 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 address potential alcohol withdrawal in the neonate 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

6. The Questions of Ethics Analysis of the Ethical Aspects of the Screen Purpose Informed Consent Access to Information Cost Effectiveness Assessment of the Quality of the Screening Method Coverage Sample Quality Demographic Data Collected Epidemiological Evaluation Proposed Follow-up

7. PURPOSE… Prevalence Drinking in pregnancy About 50% of women of reproductive age admitted to drinking regularly (CDC 2002, Health Canada 2002) Use of alcohol in pregnancy ranges from 3.5% to 9.9% (CDC 2004) Rates of binge (>5 drinks/ occasion) and frequent (>7 drinks/ week) drinking ~3% (CDC 1997 & 2002) Prevalence of heavy drinking in pregnancy (>14 drinks/ week) is about 0.1% to 0.3% (CDC 1997 & 2002) FASD in the general neonatal population FASD ~1% (9.1/1000 live births) Compare currently screened disorders… phenylketonuria: 1/15,000 congenital hypothyroidism: 1/4,000 Full-blown FAS ~0.1% (0.3-1.5/1000 live births)

8. PURPOSE… Health Outcomes CHILD In FAS, the primary neurological insult results in severe mental retardation In FASD, the primary neurological insult results in a complex pattern of behavioral or cognitive abnormalities 95% incidence of mental health problems* 50-70% incidence of substance addiction* ADDICTED MOTHER 78% incidence of depression** 30% incidence of eating disorders** 25% incidence of suicidal thinking** * statistics provided by FASworld Canada ** statistics provided by Breaking The Cycle 1995-2000 Evaluation Report

9. PURPOSE… Social Outcomes CHILD Secondary Disabilities resulting from alcohol-induced damage : 60% incidence of “disrupted school experience” and “trouble with the law”* 55% incidence of institutionalization/incarceration* 70-82% incidence of unemployment/ dependent living* 50% incidence of inappropriate or promiscuous sexual behaviour* ADDICTED MOTHER 93% incidence of unemployment** 60% incidence of current partner abuse** 50% incidence of recent partner abuse** 96% income <$15,000/yr CAD** 23% incidence of homelessness** * statistics provided by FASworld Canada ** statistics provided by Breaking The Cycle 1995-2000 Evaluation Report

10. The Questions of Ethics Analysis of the Ethical Aspects of the Screen Purpose Informed Consent Access to Information Cost Effectiveness Assessment of the Quality of the Screening Method Coverage Sample Quality Demographic Data Collected Epidemiological Evaluation Proposed Follow-up

11. INFORMED CONSENT... Required PROS Potential to facilitate follow-up engagement Addresses legal concerns Provides mothers with choice  improve retention CONS Potential to alienate target population

12. INFORMED CONSENT… Not Required PROS Maximum coverage CONS Uncertain legality (mother vs. child) Potential conflict on follow-up engagement Increased danger to child

13. The Questions of Ethics Analysis of the Ethical Aspects of the Screen Purpose Informed Consent Access to Information Cost Effectiveness Assessment of the Quality of the Screening Method Coverage Sample Quality Epidemiological Evaluation Proposed Follow-up

14. The Biomarker MECONIUM baby’s first bowel movements (i.e. first few stools) A matrix unique to the developing fetus that is already commonly used in neonatal drug screening Superior to blood and urine Discarded material Collection is easy and non-invasive Wide window of opportunity Accumulation from 13 th week gestation until birth FATTY ACID ETHYL ESTERS Ethanol metabolites present in both maternal and fetal tissues (Bearer et al. 1992) Cohort studies in drinking and non-drinking women showed accumulation of FAEE in the meconium of neonates exposed to alcohol with some evidence of overlap (Mac et al. 1994; Bearer et al. 1996, 1997, 1999, 2003; Klein et al. 1999) Do not cross the placenta, thus indicating FAEE in meconium are the result of ONLY fetal metabolism of ethanol (Chan et al., 2004) Positive cut-off = 2.0 nmol total FAEE/g meconium (ethyl palmitate, palmitoleate, stearate, oleate, linoleate, linolenate, and arachidonate (Chan et al., 2003)

15. FAEE 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 POTENTIAL BIOLOGICAL MARKERS

16. Quality Assessment… COVERAGE Preliminary analysis of our ongoing regional prevalence study demonstrates a coverage rate of 87.07%. EPIDEMIOLOGICAL EVALUATION Sensitivity/Specificity Baseline study carried out in a population of 183 non-drinkers, 17 social drinkers (~2 dks/month), and 6 confirmed heavy drinkers ( > 14 dks/wk, > 5 dks/occasion) yielded a sensitivity of 100% and a specificity of 98.4%  *note: the FAEE test cannot detect exposure to mild/social drinking levels of alcohol Predictive Value This has not yet been determined at this stage of development of the FAEE test Maximum efficacy of the FAEE test would theoretically provide a predictive value of 40%. For reasons unknown, 60% of the children born to heavy- drinkers are not alcohol-affected

17. Quality Assessment… SAMPLE QUALITY Assessment of sample quality is relatively simple and objective Issues of sample quality Non-sufficient quantity (<0.5 grams) Feces; can be determined by odour, texture, colour, and chromatographic character Ideally the designated biomarker would be used in conjunction with an accepted questionnaire such as the T-ACE or TWEAK

18. The Questions of Ethics Analysis of the Ethical Aspects of the Screen Purpose Informed Consent Access to Information Cost Effectiveness Assessment of the Quality of the Screening Method Coverage Sample Quality Epidemiological Evaluation Proposed Follow-up

19. PROPOSED FOLLOW-UP… PRELIMINARY ASSESSMENT There must be a preliminary assessment to determine whether or not social services will be involved; i.e. determine whether the child is in immediate danger The preliminary assessment must be carried out by a health care worker as this is primarily a health-care issue Public Health Nurse  a PHN is likely the ideal liaison to carry out the initial assessment  Currently PHN visits are voluntary ENGAGEMENT If mother is deemed to require intervention, she must then be engaged into an easily accessible, “one-stop”, integrated treatment program Outreach worker Family doctor Monitoring of the child’s development should involve co-ordination with the pediatrician

20. PROPOSED FOLLOW-UP… CHILD (diagnostic) 18 months; post-natal growth retardation, microcephaly, craniofacial assessment, Bayley’s test (“developmental adequacy”) 3½-4 years; speech delay, fine motor skills, cognitive assertion CHILD (therapeutic) Treatment initiated before 6 years of age is maximally effective Enriched learning environments can be very beneficial early in development Treatment may vary with the specific needs of the affected individual; i.e. attention deficit, speech, cognitive therapy… e.g. SCREAMS model of intervention* Structure, Cues, Role models, Environment, Attitude, Medication, Supervision

21. PROPOSED FOLLOW-UP… MOTHER Multi-faceted intervention strategy addressing addiction, mental health, social support, family functioning, self-efficacy, and general well-being via… Home visits/intensive case management  Involves all members of family and includes positive action of male partner Motivational interviewing  Enables free choice and change through a process of self- actualizations  This intervention strategy has had proven results when implemented in several locations across North America

22. PROPOSED FOLLOW-UP… MOTHER One-stop-shop approach Addiction counselling Child development services Health/Medical/Psychiatric care Parenting support services Basic needs services

23. FOLLOW-UP… Model Integrated Programs Breaking the Cycle (Toronto, Ontario) Improved developmental scores in children Lower rates of apprehension by social services Sheway (Vancouver, British Columbia) 1993-1998 50% reduction apprehension by social services over first five years 20% increase in babies with healthy birth weights. And 61 per cent more women were connected to a midwife or doctor by the time they delivered their babies. Four-State FAS consortium (North Dakota, South Dakota, Montana, Minnesota) Preliminary results show statistically significant improvement in 14/16 areas of therapy

24. FOLLOW-UP… Barriers/Gaps in Treatment Adult FASD assessment Culture gaps between aboriginal women and primary health care providers Affordable Housing Greater income security/social assistance Significant partnership between all involved professionals (MDs, PHNs, outreach workers, etc.)

25. The Questions of Ethics Analysis of the Ethical Aspects of the Screen Purpose Informed Consent Access to Information Cost Effectiveness Assessment of the Quality of the Screening Method Coverage Sample Quality Epidemiological Evaluation Proposed Follow-up

26. ACCESS TO INFORMATION… Necessary Diagnosis and follow up Agencies responsible for follow-up and/or post-natal medical care require knowledge of a positive result Pediatrician/Family Doctor Public Health Nurse Social Services (if involved) Adoption Agencies/Adoptive Parents

27. ACCESS TO INFORMATION Beneficial Research purposes Access to population data for an elusive study population Birth weight, Head circumference, Body length, Gestational age, Maternal age, Gravida and Para status Research Ethics Boards Charged with maintenance of ethical standards in all research undertakings Individual data Would require consent under guidance of REBs Potential to isolate susceptible genotypes 60% alcohol-exposed neonates unaffected FAS mothers significantly more likely to produce subsequent FAS children

28. 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. 1 st pregnancy) can potentially prevent future cases of FASD 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

29. The Questions of Ethics Analysis of the Ethical Aspects of the Screen Purpose Informed Consent Access to Information Cost Effectiveness Assessment of the Quality of the Screening Method Coverage Sample Quality Epidemiological Evaluation Proposed Follow-up

30. COST EFFECTIVENESS PREVENTION Reduced disease prevalence in the future can potentially off-set the immediate costs of implementing a mother/child support system. The lifetime cost of FASD per affected individual has been estimated to be as high as $1,400,000.00 (USD)* Potential long-term savings in the justice system; FASD prevalence in corrections has been estimated at rates of 25% up to 50%*. Treatment could significantly reduce burden in the criminal justice system

31. COST EFFECTIVENESS Questionnaire-based… cheaper Underreporting is common due to embarrassment, guilt, and fear of punitive action  Not specific to gestational alcohol consumption Biomarkers… objective (upon sufficient validation) Maternal biomarkers for alcohol consumption Traditional markers of alcoholism (e.g. HAA, CDT, MCV, GGT)  Not specific to gestational alcohol consumption FAEE Not fully validated  Specific to gestational alcohol consumption

32. THANK YOU Acknowledgements Canadian Institute for Health Research Daphne Chan Julia Klein Dr. Irena Nulman Dr. Joanne Rovet Dr. Cindy Woodland Margaret Leslie Gina DeMarchi Nerina Chiodo