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

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

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

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

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

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.

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

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

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

What are the FASD Research Challenges for the Future

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.

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

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.

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.

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

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)

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

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

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)

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)

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

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

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.

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 –

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