What’s New in FASD

Dr. Ana Hanlon-Dearman

Developmental Paediatrician

Section Head Developmental Paediatrics

Associate Professor Paediatrics & Child Health

University of Manitoba

Canada

FASD

FAS

• Growth retardation

• Facial features

• Brain effects

Partial FAS

• Facial features

• Brain effects

ARND • Brain effects

FASD

FAS

• Growth retardation

• Facial features

• Brain effects

Partial FAS

• Facial features

• Brain effects

ARND • Brain effects

Sentinel Physical Features

No Sentinel Physical Features

In Practice….

• Identification of alcohol affected individuals is not simple

– spectrum of effects

– complexity of exposure/exposures

• Must consider

– evidence of prenatal exposure

– influence of postnatal caring environments

– co-occuring conditions and differential diagnosis

Differential Diagnosis FASD (Liebson, Chudley et al, 2014)

“There is … a wide range of minor anomalies and malformations that can result from PAE. Hence in most affected individuals FASD is a diagnosis of exclusion. … most common alternate diagnosis was a chromosome anomaly (8.75%)

See p.e27 Comparative Table of Morphology

p.e3

Risk to Fetus Depends on: •amount of alcohol consumed •when during the pregnancy •pattern •maternal and fetal metabolism

Complicated by: •poor nutrition •multiple drug use •stress: physical, emotional, obstetric •genetic susceptibility •paternal alcohol consumption

Drugs and Alcohol

• determining the additional harm from polydrug use is challenging – differences in drug absorption, metabolism, distribution

• additive and synergistic effects – eg. aspirin, Tagamet (cimetidine) and Zantac (ranitidine)

can increase blood alcohol – smoking/nicotine has been shown to reduce blood alcohol

-- but may lead to increased use of alcohol with accumulation of active alcohol metabolite (acetaldehyde)

– cocaine has synergistic effect on alcohol – toxic metabolite cocaethylene

ACEs and Alcohol Use in Pregnancy

• Adverse Childhood Experiences (ACEs) (CDC/Kaiser Permanente)

– disrupt childhood development – increase susceptibility to stressors – increase reactivity to adult stress – highly interconnected – ACEs are strong risk factors for

pregnancy risk behaviors such as alcohol use (Chung et al., 2010; Roberts et al., 2013; Nelson et al., 2010)

• ACEs may contribute to use of alcohol in pregnancy (Choi, 2014)

ACEs and Alcohol Use in Pregnancy

Methods • Data from Nevada’s 2010

Behavioral Risk Factor Surveillance System (BRFSS)

• Outcome: Alcohol use during pregnancy – “Upon learning you were

pregnant, about how many days per week did you have at least one drink of any alcoholic beverage?”

• Exposure: ACEs – BRFSS ACEs module

• Covariates: SES, depression, smoking, prepreg ETOH use

BRFSS ACEs Module

Frankenburger et al. Women's Health

Issues xxx-xx (2015) 1–8

ACEs and Alcohol Use in Pregnancy

Results: 1. Strong relationship between

pre- pregnancy alcohol consumption and alcohol use during pregnancy – Adj OR 11.95 (95% CI 5.02,

28.43)

2. Graded dose–response relationship between ACEs and alcohol use during pregnancy -- even after controlling for pre-pregnancy alcohol use and other covariates

Frankenburger et al. Women's Health

Issues xxx-xx (2015) 1–8

ACEs and Alcohol Use in Pregnancy

• Routine ACEs screening among women of childbearing age as well as pregnant women may be an effective way to identify and address many of the emotional, behavioral, and physical sequelae of childhood adversity

• Screening for ACEs could identify women who may benefit from stress management programs & trauma- focused interventions

Frankenburger et al. Women's Health

Issues xxx-xx (2015) 1–8

Stress vulnerability in PAE

• PAE causes dysregulation of HPA axis (Weinberg et al., 2008)

• PAE infants show altered basal and post-stress cortisol levels (Haley, Handmaker, &

Lowe, 2006; Jacobson, Bihun, & Chiodo, 1999; Oberlander et al., 2010; Ramsay, Bendersky, & Lewis, 1996)

Glaser & Kiecolt-Glaser Nature Reviews Immunology 5, 243-251 (March 2005)

Identification of FASD

Craniofacial features Key:

• A: FASD features

• B: mouse with gestational day 7 alcohol exposure

• C: Zebrafish with embryonic alcohol exposure on the left

Murawski et al. Alcohol Res. 2015; 37(1): 97–108.

Biomarkers of Alcohol Metabolism • most sensitive and specific measures

for detecting drinking are the presence of alcohol in body fluids or exhaled breath or the presence of acetaldehyde in blood – BUT: short half life

• Other metabolites: – Fatty Acid Ethyl Esters (FAEE) – Ethyl glucuronide – Ethyl sulphate – Alcohol-derived phospholipid

phosphatidylethanol

• each is limited by how long after alcohol exposure they are detectable

http://pubs.niaaa.nih.gov/publications/arh341/56-63.htm

Biomarkers

Biomarkers and Timing Consider:

• Biomarkers in Maternal and Newborn Hair:

– Hair FAEE: 90-100 sensitivity/90% specificity

– BUT: very low FAEE concentrations can be detected even among strict abstainers – false positives can be related to use of cosmetics, endogenous alcohol (Pragst and Yegles 2008)

Murawski et al. Alcohol Res. 2015; 37(1): 97–108. http://pubs.niaaa.nih.gov/publications/arh341/56-63.htm

Micro RNA (miRNA)

• non-coding areas of the RNA that play a critical role in regulation of target gene expression

• lead to either expression or suppression of the protein in question through degradation or translation interruption of mRNAs leading to cell type change

• looking for altered miRNA expression allows for:

– differentiating normal from affected tissues, possibly even subtyping

– early detection by looking for circulating blood miRNA

miRNA as Biomarkers MicroRNAs (miRNAs) may serve as potential biomarkers

miR-9 (and others: -15b, -19b, and -20a) may be indicative of alcohol exposure in the mother, but also may serve as a marker of alcohol-induced injury in the neonate

Murawski et al. Alcohol Res. 2015; 37(1): 97–108.

FASD Screening Ethics (Racine & Bell)

• Key Issues: – Population based/universal

screening

– Consent and Stigma

– Cost effectiveness

– False Results

– Confidentiality and Follow-up

– Criminal Prosecution

What’s New in FASD Diagnosis

• 3-D Facial Modeling

• fMRI

• eye-tracking

Facial Analysis

• Surface-based morphometry – characteristic features

– builds computational models of face-shape variation

Douglas, 2011

3-D facial imaging & computer based dense surface modeling • Hammond compared 3-D modeling with a standard dysmorphology exam --high degree of agreement (Suttie et al. 2013)

• Heavily exposed (HE) children with FAS-like faces performed like the FAS group on neurobehavioral tests

• relationships between facial measurements and brain structure (Moore

2014): •shorter PF -- predicts volume reductions in the bilateral ventral diencephalon

•smoothness of the philtrum predicts volumetric reductions in the thalamus and the left pallidum

•Facial measures also predict brain maturation patterns

•greater facial dysmorphia displayed a linear pattern of cerebral cortex growth, at least from childhood through adolescence, rather than the developmentally appropriate inverted U-shaped trajectory

Murawski et al. Alcohol Res. 2015; 37(1): 97–108.

MRI FASD: Timing of exposure • timing of alcohol administration produces differing patterns of brain malformations – outcome variability:

•GD7 medial forebrain

•GD 8 volume reductions in the olfactory bulbs, hippocampus, and cerebellum

•GD 9 cerebellar volume, ventricle enlargement, and shape deviations in the cerebral cortex, hippocampus, and right striatum

•interaction of alcohol with specific genes involved in brain development may affect the FASD phenotype:

• zebrafish studies of platelet-derived growth factor receptor alpha (Pdgfra) responsible for cellular migration of neural crest cells -- pdgfra interacts with alcohol to protect against severe craniofacial defects

•replicated in human studies (McCarthy et al. 2013)

Saccadic Eye Movements and FASD

Children with FASD have saccades of lower velocity and duration

• Show deficits in eye movement control and sensory- motor integration

• implicates impairment in cerebellar and/or brain stem circuits

NeuroDevNet: “Eye movement control tasks were directly related to measures of psychometric tests for both working memory and visuospatial processing.”

“There is potential for practitioners to use eye movement control tasks as a first screening step for FASD diagnosis.”

Abstracts / Paolozza, Int. J. Devl Neuroscience 47 (2015) 1–131 57

ARND vs ADHD

Limited activation patterns in ARND

• problems in information processing along the ventral frontoparietal attention pathway

• Poor integrity of the inferior longitudinal fasciculus (ILF) in ARND

– may compromise the ventral attention pathway and may require subjects to less efficient dorsal pathway

fMRI activation maps

Carrie R O’Conaill, et al. J Neurodev Disord. 2015;7(1):10.

ARND vs ADHD

• compared on cognitive and behavioral measures for four groups of children: FASD, ADHD, FASD + ADHD, and other neuropsychological disorders

• Children with FASD were found to perform significantly worse than ADHD on:

– externalizing problems, Full-Scale IQ, and indices of Verbal Comprehension, Perceptual Reasoning, and Working Memory

– significantly higher levels of atypicality and aggression relative to ADHD

• WISC-IV and the BASC-2 -- discriminate between FASD, ADHD, or other type of neuropsychological compromise

Raldiris et al J Atten Disord 2014 Dec 18

Epigenetics

• the study of heritable changes in genome function that occur without a change in DNA sequence

• “Epigenetics has always been all the weird and wonderful things that can’t be explained by genetics.”Denise Barlow (Scientist, Vienna,

Austria)

January 2012

FASD and Epigenetics

Epigenetics and FASD

• Environmental factors can cause changes in chromatin state

• Chromatin, which is comprised primarily of DNA spooled around histone proteins, is located in the cell nucleus

• Local state of chromatin influences gene expression

• Ethanol may disrupt the homocysteine-methionine cycle, resulting in a decrease in the levels of S-adenosyl methionine, which acts as a methyl donor for DNA and histone methylation.

from: Michael S. Kobor, et al. Alcohol Res Health. 2011;34(1):29-37.

FASD Model: Continuum of Epigenetic and Genetic Events (Kleiber 2014)

from: Kleiber et al, Front Genet. 2014; 5: 161.

DNA methylation changes in FASD

• NeuroDevNet – how genetic and environmental factors interact with gestational alcohol exposure to produce neurobehavioural and neurobiological deficits in children – epigenetic cohort – methylation changes in miRNA and genes

associated with FASD/NDD

– identified 34 genes that are targeted by the deregulated miRNAs

– “Both voluntary chronic exposure and binge injections at different developmental time points cause long-lasting changes in miRNA and gene expression” (Laufer et al 2013)

(Kobor et al, 2015)

Permissive and Protective Factors (May, 2011/Abel & Harrington, 1995)

• Blue circles: sociobehavioural permissive factors

• Purple squares: biological provocative factors

• Orange lines: associations among various environmental, demographic, and behavioral variables; can be bidirectional

• Blue lines: physiological pathways

Factors Associated with Improved Outcomes (A.

Streissguth)

• Stable home: >72% of child’s life, >2.8 years in each placement

• Good quality home environment

• Basic needs met for at least 13% of life

• Early diagnosis

• No experience of personal/family violence

• Recognized disabilities

Genetic Protective Factors (Dodge et al 2014)

• Alcohol dehydrogenase-ADH1B*3 allele

• Unique to individuals of African descent

• Associated with more rapid alcohol metabolism leading to a reduction of the peak blood alcohol concentration than the more prevalent ADH1B*1 allele

• Continues to be evident during adolescence

What’s New in FASD Treatment

• Evidence supporting intervention programs to improve neuropsychological deficits in children with FASD

– Behavioural: Strongest Families (Reynolds et al), GoFAR (Coles et al)

– Physical

– Nutritional: iron, choline

Exercise and Cognitive Stimulation: Hamilton et al (2014)

• Rat studies – high binge like exposure produces significant and long

lasting damage to neurons

– exercise is good, but not good enough to overcome the decreases in adult neurogenesis in alcohol exposure

– treatment: exercise + environmental complexity

– a ‘‘super-intervention’’ in the form of exercise followed by complex environmental exposure is sufficient to successfully enhance brain plasticity and recovery of behavioral function.

Reduced Stress with Physical Activity

• Physical activity (Salmon, 2001; Tsatsoulis & Fountoulakis, 2006, Campeau

et al., 2010; Droste, Chandramohan, Hill, Linthorst, & Reul, 2007 , Nyhuis, Masini, Sasse, Day, & Campeau, 2010; Sasse et al., 2008)

– decreased sensitivity to stress

– improved cognitive function

– improved sleep

– stress resiliency through attenuated HPA dysregulation

Strongest Families (Turner et al, 2015)

• Adapted from the Strongest Families "Parenting the Active Child" program

• Internet-based application (strongestfamilies.ca) in conjunction with 11 telephone coaching sessions

• ClinicalTrials.gov NCT02210455

GoFAR (Coles et al, 2015)

• “A Metacognitive Strategy to Reduce Disruptive Behaviour”

• computer game

• learning strategy:

F: Focus and make a plan

A: Act out the plan

R: Reflect on the plan

GoFAR Game Screen “Miles, the space alien, is required to overcome a series of obstacles to secure the key and open the door behind which he will find his lost cat, Junior. In order to do this, he has to carry out the FAR steps” Parents receive 5 individual training therapy sessions with techniques to support regulation of child’s behaviour. 1. How PAE contributes to problems

with arousal and behavioral regulation and how to use the FAR strategy

2. How to recognize their child’s level of arousal, what are the triggers, and how to teach them in a calm, alert state.

3. How to modify the home environment to promote the child’s success, using various positive behavioral support techniques

4. how to apply FAR methodology to improving the child’s adaptive living skills and how to deal with negative behaviors

5. Steps needed to help their child learn a specific adaptive living skill

Coles et al, 2015

Nutrition: Dietary requirements (Fuglestad et al, 2013)

• children with FASD had lower intakes of saturated fat, vitamin D, and calcium

• majority (>50%) of children with FASD did not meet the Recommended Dietary Allowance (RDA) or Adequate Intake (AI) for fiber, n-3 fatty acids, vitamin D, vitamin E, vitamin K, choline, and calcium

Nutrition: Iron (Rufer et al 2012)

• Maternal iron status has a unique influence upon FASD outcome

• Iron deficiency (ID)-alcohol interaction likely represents a significant portion of FASD diagnoses because ID is common in alcohol-abusing pregnancies

• Iron status may also underlie the associations between FASD and parity or socioeconomic status

Cholecalciferol (vitamin D3) (Idrus et al, 2013)

• Rat study

• cholecalciferol given before, during, and after 3rd trimester alcohol exposure

• reduced perseverative behavior that is associated with developmental alcohol exposure in a spatial discrimination task in a dose-dependent manner

Omega-3 Fatty Acids (Patten et al 2013)

• Rat study

• postnatal diet enriched with omega-3 fatty acids

• Omega-3 FA rescued synaptic plasticity in dentate gyrus

• Omega-3 FA also reduce oxidative stress and enhance antioxidant protection (2012)

Omega-3 Fatty Acid

• polyunsaturated fatty acids

• found in high concentrations in neuron membranes; important for building cell membranes in the brain, and also for blood clotting

• ALAs – soybean oil, flaxseed, walnuts, brussel sprouts, kale, spinach, salad greens

• EPA, DHA – fatty fish like salmon

Omega-3 Fatty Acid

• in healthy brains, omega-3 supplementation reduces oxidative stress, inhibits cell death (apoptosis), and enhances membrane fluidity

• can improve plasticity in other disease and injury models

Choline

• essential nutrient, usually classified with B complex • natural amine found in lipids of cell membranes and neurotransmitter (ACh)

• involved in:

– acetylcholine (neurotransmitter) synthesis – phosphatidylcholine and sphingomyelin synthesis – control of phospholipid concentration in liver and blood – synthesis of internal cell messengers – methyl group donor/trimethylglycine

• works with folate to help promote brain and memory development (hippocampus) in developing fetus – Prenatally, choline affects neurogenesis, thereby contributing to increased cell proliferation and decreased

apoptosis in the hip- pocampus – Postnatal choline may affect synaptogenesis as well as continued hippocampal growth,rapid during the first

2-4 years of life and slower thereafter – (Wozniak, 2015)

• found in eggs and fatty meats like liver, soy lecithin granules, wheat germ

Choline must be consumed in diet

However….

The adequate intake is 200mg for ages 1–3 years and

250mg for ages 4–8y(National Academy Press, 1998)

Choline Supplementation (Wozniak et al, 2013)

• preclinical studies, choline partially ameliorates memory and learning deficits from prenatal alcohol exposure

• choline supplementation at 500 mg/d for 9 months in children aged 2 to 5 years

• feasible and has high tolerability

Nutrition: Choline (Wozniak et al, 2015)

• RCT N=60 (choline 31, placebo 29), 2-5 year olds

• Intervention:

– Rx: 500 mg choline (1.25 g choline bitartrate) • “500 mg dose was selected to bring all participants to sufficiency,

to provide supplementation, and to keep amounts in the tolerable range of 1000 mg/d”

– Supplied in a coded light-blocking foil packets that contained a powdered, fruit-flavored drink mix

– Given: 1 dose/d by mixing it with 4 fl oz (118.3 mL) H2O

Nutrition: Choline (Wozniak et al, 2015)

• Age-dependent improvements were seen on a hippocampus-dependent memory task (important because of choline’s presumed effects on hippocampal development) – younger participants 2.5- to <4.0- year olds) showed greater

improvement than older participants (>4.0–5.0 year olds) --

– improvement has implications for future cognitive ability

Nutrition: Choline 2 (Coles et al CIFASD, 2015 epub ahead of print)

• RCT: OMNI-Net sites in Western Ukraine that included high and low risk individuals

• Randomized to one of three multivitamin/mineral supplement groups: none, multivitamins/minerals (MVM), and multivitamin/minerals plus choline.

• Children (N = 367)

• Outcomes: Bayley Scales of Infant Development

Nutrition: Choline 2 (Coles et al CIFASD, 2015 epub ahead of print)

• Results:

– MDI was significantly impacted by peri-conceptual alcohol dose (p < .001) -- more alcohol associated with lower scores and males more negatively affected than females

– Micronutrient supplementation had a protective effect: those receiving supplements performed better (p < .005)

Nutrition: Choline 2 (Kable et al CIFASD, 2015)

• Clinical trial conducted in Ukraine • Cardiac orienting responses (ORs) during a

habituation/dishabituation learning paradigm were obtained from 6 to 12 month-olds to assess neurophysiological encoding and memory.

• Changes in maternal nutrient status suggested that one mechanism by which choline supplementation may positively impact brain development is through prevention of fetal alcohol-related depletion of DMG, a metabolic nutrient that can protect against overproduction of glycine, during critical periods of neurogenesis

Conclusions

• FASD expanding field in understanding pathology, promoting and alleviating factors, treatments

• Canadian print media themes (Aspler et al, 2015):

1. descriptions of FASD (e.g., primary and secondary disabilities, severity)

2. systemic concerns (e.g., inadequate social services, inadequate criminal justice accommodation)

3. medical concerns (e.g., access to, and efficacy of, diagnoses, preventions, treatments)

4. social concerns (e.g., criminality, stigma, race and class myths)

Conclusions

• Media still reports wide variability in reported safe amounts of alcohol while pregnant and descriptions of FASD (Aspler et al, 2015)

• Discourse needs to be grounded in evidence and supportive of affected individuals and their families