1. FETAL ALCOHOL SPECTRUM DISORDERS The Research Agenda
Kenneth R. Warren, PhD
Senior Advisor
National Institute on Alcohol Abuse and Alcoholism

2. What is Fetal Alcohol Syndrome?
It is a Neurodevelopmental Disorder caused by pre-natal alcohol and characterized by:
A specific pattern of facial features
Growth deficiency
And the presence of brain or neurobehavioral deficits – subsequently noted to fit a characteristic pattern
Photo courtesy of Teresa Kellerman

3. Face of Fetal Alcohol Syndrome
Cardinal Features
Associated Features
Short
palpebral fissure
Elongated & Hypoplastic philtrum
Thin upper
vermillion lip border
(hypoplastic “cupid’s bow”)
Epicanthal folds
Low nasal bridge
Minor ear anomalies
Micrognathia

4. …..and other minor abnormalities
Other Physical Features of FAS
Eyes/
Ears
Cardiac
Renal
Skeleton
…..and other minor abnormalities

5. CNS Deficits in FAS Physical and Neurophysiological:
Sm Head Circumference < 10th Structural Abnormalities
Hearing/Visual abnormalities Fine and Gross Motor Deficits
Cognitive:
Global Intellectual Impairment Learning Problems
Executive Functioning Deficits Math Deficits > Language
(Planning; Abstract reasoning) Memory Deficits
Poor Visual Spatial Abilities
Impaired Behavioral Regulation:
Impulse Control Problems Attention Problems
Mood or Behavioral Regulation Preserveration
Deficits in Adaptive Functioning:
Communication Issues Poor Social Skills
Problems with Daily Living Motor Challenges

6. From FAS to Fetal Alcohol Spectrum Disorders (FASD)
From early on in the FAS history researchers and clinicians noticed that there were children with a history of prenatal alcohol exposure who showed the neuro-behavioral deficits without having the facial features of FAS.
Several terms were proposed over the next years to refer to these individuals, such as, Partial FAS (pFAS) and Alcohol Related Neurobehavioral Disorder (ARND).
By the early 2000s, the term Fetal Alcohol Spectrum Disorders (FASD) to cover the full range of deficits arising from prenatal alcohol exposure.

7. Fetal Alcohol Spectrum Disorders (FASD) are not rare disorders!

8. Epidemiology: Current Evidence on the Prevalence of FAS and pFAS in Select Locations (Countries)
All obtained from In School Active Case Ascertainment
*IOM 1996 prevalence estimated in U.S. for FAS at 0.5 – 2 per 1000

9. Why FASD Remains an Important Public Health and Research Issue
We know that:
The agent responsible for FASD is alcohol
Alcohol has a diversity of toxic (teratologic) effects on the developing embryo and fetus, and these adverse effects can occur across the total embryonic and gestational course of pregnancy
Some of the most serious adverse effects can occur in the early phase of pregnancy often before a woman’s self-awareness that a pregnancy has commenced

10. What are the FASD Research Challenges for the Future

11. Research Challenge I Improve Diagnostic Capabilities to:
Identify Women and Children in Need of Care and Services , and
Determine the full Prevalence of all of the disorders that lie within the spectrum of FASD.

12. Obtaining the Most Accurate Understanding of FASD Prevalence
Even FAS and pFAS (no less ARND) remain under-diagnosed because:
facial features are subtle, particularly in newborns
The neurobehavioral deficits necessary for diagnosis may not be obvious <age 3 years
In epidemiology, one approach that has been used to obtain more accurate prevalence is Active Case Ascertainment
It involves assessment among an entire, or representative sample population such as all 1st grade school entry students
It is the most expensive in money and time – but it affords the most reliable prevalence rates – especially for FAS and pFAS

13. Research Challenge II
Prevention of drinking in pregnancy through detection of risk drinking:
Though self-reports of drinking can be informative – biomarkers of alcohol use disclose far greater levels of risk
Biomarkers that appear to be promising are the non- oxidative alcohol metabolites – ethyl glucuronide, ethyl sulfate, phosphatidyl ethanol, and fatty acid ethyl esters (FAEEs) some of which are obtained from newborn meconium
Research continues on other potential biomarkers including miRNA and altered epigenetic profiles (DNA and histone methylation, acetylation, etc.) which have the potential to reveal evidence of prenatal alcohol exposure in an individual long after birth.

14. Research Challenge III
Given the subtlety of FAS facial deficits – to improve the acumen for FAS facial recognition through 3-D photography and computer analysis
Advantages:
The 3-D image is suitable for telemedicine
Computer is free of human eye bias
“Machine learning” approach may be used where the computer on its own identifies key feature from known cases and controls
The computer may even )able to see more subtle facial feature signatures in FASD and when full FAS or partial (pFAS) is not present.

15. Mapping 3D images FACE SIGNATURE SIGNATURE GRAPH FAS - MALE
red-contracted
blue-expanded
FAS - MALE
SIGNATURE
GRAPH

16. Able to diagnose FAS/pFAS, but the affected, nondymorphic alcohol-exposed child is a problem (59 PAE children) HE
FAS-Like
Control-Like
Equal in performance on IQ, learning and memory to those with FAS/pFAS
Equal in performance on IQ, learning and memory to those with no exposure
(Suttie et al, Pediatrics, 2013)

17. Research Challenge IV
Refining our understand of the complexities in the neurobehavioral phenotype associated with FAS, pFAS and ARND (i.e. ND-PAE):
To help in differentiating from other developmental disorders
To use this knowledge in the pursuit of appropriate interventions to help those with prenatal alcohol deficits

18. Research Challenge V We can also ask the question:
We can ask: “Is the face as a window on brain structural deficits in FASD?”
Research is showing that the specific facial features in FAS correlate with structural deficits in the brain

19. Results: Correlations with PFL
With permission Lebel & Sowell
Roussotte et al., 2011
Positive correlations between brain volume and palpebral fissure length after controlling for scan location, age, sex, and ICV in subjects with FASD. (N = 52)

20. Results: Correlations with Lipometer Scores
Roussotte et al., 2011
With permission
Lebel & Sowell
Negative correlations between brain volume and lipometer scores after controlling for scan location, age, sex, and ICV in subjects with FASD. (N = 52)

21. Research Challenge VI: Etiology of FASD
Establishing the Mechanisms through
which alcohol causes FAS and FASD to be able to apply this knowledge to the Prevention and Treatment of these disorders.
Complication: Alcohol appears to have many distinct actions whereby it can elicit harm to the developing embryo and fetus

22. Etiology of FASD
The multiple sites of alcohol’s actions in FASD include:
Early Embryologic genes -Pax6, Otx 6, Sox 3 and NCAM, TBX5, VAX2
Oxidative stress
Altered apoptosis
Epigenetic Effects on histones and DNA – (e.g., HPA axis)
Impaired cell adhesion mechanisms, e.g., the L1 molecule and binding
Altered response to trophic factors: IGF, NGF, ADNF (SAL), and ADNP (NAP)
Neurotransmitter system: glutamate (NMDA); Serotonin; plus others
Impaired glia development and migration,
Impaired myelination

23. Other Research Challenges
Determining the most effective approaches to incorporate interventions for at-risk drinking into pre-pregnancy and prenatal care
Mounting health education efforts in the medical community, among public health officials, legislators and the public to inform them of the risks that that alcohol may cause to the embryo and fetus.

24. The Key Public Health Challenge
Recognizing that 50% of pregnancies are unplanned so that substantial prenatal alcohol exposure may have occurred before pregnancy recognition
Working to change the social norms surrounding drinking behavior whenever there is a risk of a pregnancy –

25. Thank You! Kenneth R. Warren, Ph.D. Senior Advisor
Former Deputy Director
And Former Acting Director
National Institute on Alcohol Abuse and Alcoholism