Alcohol and Pregnancy: What Have We Learned in 37 Years?

1. Alcohol and Pregnancy: What Have We Learned in 37 Years? Kenneth Lyons Jones, M.D. Professor of Pediatrics University of California, San Diego School of Medicine La Jolla, CA

2. Generalizations About Phenotype • The developing brain is structure most sensitive to prenatal effects of alcohol • Most of the features are secondary to the effect of alcohol on brain development • Many of the features seen in this disorder are difficult to recognize in newborns

3. Fetal Alcohol Syndrome • Growth • Prenatal Growth Deficiency • Postnatal Growth Deficiency • Microcephaly • Performance • Developmental Delay • Fine Motor Dysfunction • Face • Short Palpebral Fissures • Long, Smooth Philtrum • Thin Vermilion Border

5. Fetal Alcohol Syndrome • Growth • Prenatal Growth Deficiency • Postnatal Growth Deficiency • Microcephaly • Performance • Developmental Delay • Fine Motor Dysfunction • Face • Short Palpebral Fissures • Long, Smooth Philtrum • Thin Vermilion Border

6. Fetal Alcohol Syndrome Neurobehavioral Abnormalities • Problems with attention (sustained attention and shifting of attention) • Executive functioning deficits • e.g. Impaired planning, concept formation • Reduced IQ (average in low 70s) • Learning and memory deficits, including problems with habituation, spatial memory • Increased reactivity and activity • Perseverative (may repeat errors, have difficulty changing from doing things one way to another) • Poor fine and gross motor skills • Developmental delays • Feeding deficits • Hearing abnormalities • Poor state regulation • Immature social behaviors • Sensory integration problems

7. Fetal Alcohol Syndrome • Growth • Prenatal Growth Deficiency • Postnatal Growth Deficiency • Microcephaly • Performance • Developmental Delay • Fine Motor Dysfunction • Face • Short Palpebral Fissures • Long, Smooth Philtrum • Thin Vermilion Border

8. Palpebral Fissure Length (PFL) Measurement Document measurement from inner to outer canthus in millimeters Use hard, clear plastic ruler Follow curve of the face

9. Fetal Alcohol Syndrome • Growth • Prenatal Growth Deficiency • Postnatal Growth Deficiency • Microcephaly • Performance • Developmental Delay • Fine Motor Dysfunction • Face • Short Palpebral Fissures • Long, Smooth Philtrum • Thin Vermilion Border

11. Lip and Philtrum Assessment • Ensure the patient has a neutral expression • Smiling will falsely increase the score • Place guide alongside face • Score lip and philtrum separately • 4 or 5 is considered positive

12. Fetal Alcohol Syndrome • Growth • Prenatal Growth Deficiency • Postnatal Growth Deficiency • Microcephaly • Performance • Developmental Delay • Fine Motor Dysfunction • Face • Short Palpebral Fissures • Long, Smooth Philtrum • Thin Vermilion Border

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15. FASD Phenotype Institute of Medicine 1996 • FAS with confirmed maternal alcohol exposure. • A. Confirmed maternal alcohol exposure • B. Characteristic facial anomalies including short palpebral fissures and abnormalities of premaxillary zone. • C. Growth retardation • D. CNS neuro-developmental anomalies • FAS without confirmed maternal alcohol exposure. • Partial FAS with confirmed maternal alcohol exposure • Alcohol-related birth defects (ARBD) • Alcohol-related neuro-developmental disorder (ARND)

16. Alcohol Related Neurodevelopmental Disorder • Evidence of CNS neurodevelopmental abnormalities, as in any one of the following - decreased cranial size at birth - structural brain abnormalities (e.g. microcephaly, partial or complete agenesis of the corpus callosum, cerebellar hypoplasia) - neurological hard or soft signs, such as impaired fine motor skills, neurosensory hearing loss. Poor tandem gait, poor eye-hand coordination. and/or

17. Alcohol Related Neurodevelopmental Disorder(continued) • Evidence of a complex pattern of behavior or cognitive abnormalities that are inconsistent with developmental level and cannot be explained by familial background or environment alone, such as learning difficulties ; deficits in school performance; poor impulse control; problems in social perception; deficits in higher level receptive and expressive language; poor capacity for abstraction or metacognition; specific deficits in mathematical skills; or problems in memory, attention or judgment.

18. Looking at the broader spectrum of FAS and ARND • Population-based study in Seattle, WA measured rate of FAS at 3.1 per 1,000 but full spectrum of FASD was measured to be 9.1 per 1,000 or 3-9 x greater than rates of FAS alone. • The combined rate of FAS and ARND was thus almost one in every 100 livebirths. • Sampson et al Teratology; 56:317-26 (1997)

19. Questions to be Answered Regarding the Prenatal Effects of Alcohol as of May 2013 Spectrum of defects (FASD) Neurobehavioral phenotype Successful prevention strategy Successful intervention strategy Genetic Susceptibility Nutritional factors Prevalence in various populations throughout the world Incidence in offspring of women who drink various amounts of alcohol

20. Table 2. Prevalence of additional features by FAS diagnostic category Fetal Alcohol Spectrum Disorders: Establishing the Broad Range of Structural Defects Kenneth Lyons Jones, H. Eugene Hoyme, Luther K. Robinson, Miguel del Campo, Melanie A. Manning, Lela M. Prewitt, Christina D. Chambers.

21. Table 2. Prevalence of additional features by FAS diagnostic category Fetal Alcohol Spectrum Disorders: Establishing the Broad Range of Structural Defects Kenneth Lyons Jones, H. Eugene Hoyme, Luther K. Robinson, Miguel del Campo, Melanie A. Manning, Lela M. Prewitt, Christina D. Chambers.

23. Table 2. Prevalence of additional features by FAS diagnostic category Fetal Alcohol Spectrum Disorders: Establishing the Broad Range of Structural Defects Kenneth Lyons Jones, H. Eugene Hoyme, Luther K. Robinson, Miguel del Campo, Melanie A. Manning, Lela M. Prewitt, Christina D. Chambers.

24. Table 2. Prevalence of additional features by FAS diagnostic category Fetal Alcohol Spectrum Disorders: Establishing the Broad Range of Structural Defects Kenneth Lyons Jones, H. Eugene Hoyme, Luther K. Robinson, Miguel del Campo, Melanie A. Manning, Lela M. Prewitt, Christina D. Chambers.

26. Questions to be Answered Regarding the Prenatal Effects of Alcohol as of May 2013 Spectrum of defects (FASD) Neurobehavioral phenotype Successful prevention strategy Successful intervention strategy Genetic Susceptibility Nutritional factors Prevalence in various populations throughout the world Incidence in offspring of women who drink various amounts of alcohol

28. Russia/Ukraine CIFASD Clinical Project • Prospective cohort study involving 300 moderate to heavily exposed pregnant women recruited from Ladies Consultation Prenatal Care Centers and 300 low/unexposed comparison women

29. Specific Aim 1 • Measure incidence and spectrum of alcohol-related birth outcomes in relation to specific dose and timing of alcohol: • Standardized repeated in-person maternal interviews; supplemented by biomarkers of exposure • Standardized physical examinations by specially trained neonatologists/geneticists • Neurobehavioral testing at 6 m and 12 m with BSID II; infant stimulus response testing at 6 m

30. Specific Aim 2 Assess contribution of nutritional status and effect of nutritional intervention trial initiated in mid-pregnancy Blood samples taken at enrollment and third trimester - evaluated for vitamin and mineral status Multivitamin/mineral supplement provided for 50% of sample upon enrollment Additional choline supplement provided to 25% of sample upon enrollment

31. Specific Aim 2: Results Specific maternal micronutrient levels in pregnancy vary by maternal dose of alcohol. Specific maternal micronutrient levels in pregnancy are significantly correlated with cardinal facial features and growth in alcohol exposed/affected children. A MVM intervention initiated mid-gestation appears in preliminary analysis to have a protective effect on some alcohol-associated neurocognitive performance measures and growth in infants in the first year of life.

32. Questions to be Answered Regarding the Prenatal Effects of Alcohol as of May 2013 Spectrum of defects (FASD) Neurobehavioral phenotype Successful prevention strategy Successful intervention strategy Genetic Susceptibility Nutritional factors Prevalence in various populations throughout the world Incidence in offspring of women who drink various amounts of alcohol

33. Prevalence of Fetal Alcohol Syndrome Western Cape Province, South Africa - Wave 3 May PA et al Drug and Alcohol Dependence 88:259-71 (2007)

34. Prevalence of Fetal Alcohol SyndromeLazio Province, Italy May PA Alcoholism Clin Exp Res 30:1562-75 (2006)

35. Fetal Alcohol Syndrome in Boarding Schools and Orphanages in Moscow Marintcheva G et al Soc Clin Psychiatry 3:17-22 (2003)

36. Questions to be Answered Regarding the Prenatal Effects of Alcohol as of May 2013 Spectrum of defects (FASD) Neurobehavioral phenotype Successful prevention strategy Successful intervention strategy Genetic Susceptibility Nutritional factors Prevalence in various populations throughout the world Incidence in offspring of women who drink various amounts of alcohol

38. Moderate Alcohol Consumption

40. Conclusion and where from here? We can improve ability of clinicians to make a diagnosis We can move diagnosis to an earlier age Risk factors for FAS/D may vary by population and subgroup but heavy episodic drinking is the primary factor Prevention of prenatal alcohol exposure among risky drinkers should be the goal