Questions of Ethics:Neonatal Screening for

Prenatal Alcohol Exposure

Joey Gareri HBSc.Division of Clinical Pharmacology and Toxicology

Hospital for Sick Children, TorontoDepartment of Pharmacology

University of Toronto

Dr. Gideon Koren MD, FRCPC

INTRODUCTION Challenges of Diagnosis

Full blown FAS (severe neurodevelopmental delay) Indinstinct philtrum Intrauterine growth retardationShort 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

INTRODUCTIONDiagnostic Tools

Questionnaires T-ACE TWEAK

Biomarkers Liver enzymes Ethyl glucuronide

Fatty Acid Ethyl Esters (FAEE)

INTRODUCTIONThe 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

INTRODUCTIONNeonatal 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

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

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)

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

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

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

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

INFORMED CONSENT…Not Required

PROS Maximum coverage

CONS Uncertain legality

(mother vs. child) Potential conflict on

follow-up engagement Increased danger to

child

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

CoverageSample QualityEpidemiological Evaluation Proposed Follow-up

The BiomarkerMECONIUM 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 13th 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)

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

POTENTIALBIOLOGICAL

MARKERS

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

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

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

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

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

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

PROPOSED FOLLOW-UP…

MOTHER One-stop-shop approach

Addiction counselling Child development services Health/Medical/Psychiatric care Parenting support services Basic needs services

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

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.)

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

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

ACCESS TO INFORMATIONBeneficial

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

Prevention by InterventionNEONATAL 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

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

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

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

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

THANK YOUAcknowledgements

Canadian Institute for Health ResearchDaphne Chan

Julia Klein Dr. Irena NulmanDr. Joanne Rovet

Dr. Cindy Woodland Margaret LeslieGina DeMarchiNerina Chiodo