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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
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
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
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
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
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
Palpebral Fissure Length (PFL) Measurement
►Document measurement from inner to outer canthus in millimeters
►Use hard, clear plastic ruler
►Follow curve of the face
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
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
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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FASD Phenotype Institute of Medicine
1996 1. 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
2. FAS without confirmed maternal alcohol exposure.
3. Partial FAS with confirmed maternal alcohol exposure
4. Alcohol-related birth defects (ARBD)
5. Alcohol-related neuro-developmental disorder (ARND)
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
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.
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)
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
Feature N (%) p-value*
Railroad Track Ears FAS Deferred No FAS
29 (11.8) 12 (4.9) 6 (1.8)
<0.001
Ptosis FAS Deferred No FAS
30 (12.2) 11 (4.5) 4 (1.2)
<0.001
Heart Murmur FAS Deferred No FAS
25 (10.2) 5 (2.0) 5 (1.5)
<0.001
Decreased elbow pronation/supination FAS Deferred No FAS
36 (14.7) 13 (5.3) 4 (1.2)
<0.001
Incomplete extension of digits FAS Deferred No FAS
90 (36.7) 43 (17.6) 21 (6.1)
<0.001
Other joint contractures FAS Deferred No FAS
6 (2.4) 2 (0.8) 1 (0.3)
0.0373
Hockey Stick crease FAS Deferred No FAS
53 (21.6) 28 (11.5) 18 (5.3)
<0.001
Other palmar crease abnormalities FAS Deferred No FAS
38 (15.5) 20 (8.2) 13 (3.8)
<0.001
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.
Feature N (%) p-value*
Railroad Track Ears FAS Deferred No FAS
29 (11.8) 12 (4.9) 6 (1.8)
<0.001
Ptosis FAS Deferred No FAS
30 (12.2) 11 (4.5) 4 (1.2)
<0.001
Heart Murmur FAS Deferred No FAS
25 (10.2) 5 (2.0) 5 (1.5)
<0.001
Decreased elbow pronation/supination FAS Deferred No FAS
36 (14.7) 13 (5.3) 4 (1.2)
<0.001
Incomplete extension of digits FAS Deferred No FAS
90 (36.7) 43 (17.6) 21 (6.1)
<0.001
Other joint contractures FAS Deferred No FAS
6 (2.4) 2 (0.8) 1 (0.3)
0.0373
Hockey Stick crease FAS Deferred No FAS
53 (21.6) 28 (11.5) 18 (5.3)
<0.001
Other palmar crease abnormalities FAS Deferred No FAS
38 (15.5) 20 (8.2) 13 (3.8)
<0.001
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.
Feature N (%) p-value*
Railroad Track Ears FAS Deferred No FAS
29 (11.8) 12 (4.9) 6 (1.8)
<0.001
Ptosis FAS Deferred No FAS
30 (12.2) 11 (4.5) 4 (1.2)
<0.001
Heart Murmur FAS Deferred No FAS
25 (10.2) 5 (2.0) 5 (1.5)
<0.001
Decreased elbow pronation/supination FAS Deferred No FAS
36 (14.7) 13 (5.3) 4 (1.2)
<0.001
Incomplete extension of digits FAS Deferred No FAS
90 (36.7) 43 (17.6) 21 (6.1)
<0.001
Other joint contractures FAS Deferred No FAS
6 (2.4) 2 (0.8) 1 (0.3)
0.0373
Hockey Stick crease FAS Deferred No FAS
53 (21.6) 28 (11.5) 18 (5.3)
<0.001
Other palmar crease abnormalities FAS Deferred No FAS
38 (15.5) 20 (8.2) 13 (3.8)
<0.001
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.
Feature N (%) p-value*
Railroad Track Ears FAS Deferred No FAS
29 (11.8) 12 (4.9) 6 (1.8)
<0.001
Ptosis FAS Deferred No FAS
30 (12.2) 11 (4.5) 4 (1.2)
<0.001
Heart Murmur FAS Deferred No FAS
25 (10.2) 5 (2.0) 5 (1.5)
<0.001
Decreased elbow pronation/supination FAS Deferred No FAS
36 (14.7) 13 (5.3) 4 (1.2)
<0.001
Incomplete extension of digits FAS Deferred No FAS
90 (36.7) 43 (17.6) 21 (6.1)
<0.001
Other joint contractures FAS Deferred No FAS
6 (2.4) 2 (0.8) 1 (0.3)
0.0373
Hockey Stick crease FAS Deferred No FAS
53 (21.6) 28 (11.5) 18 (5.3)
<0.001
Other palmar crease abnormalities FAS Deferred No FAS
38 (15.5) 20 (8.2) 13 (3.8)
<0.001
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.
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
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
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
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
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.
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
Prevalence of Fetal Alcohol Syndrome Western Cape Province, South Africa - Wave 3
Category Number of Children
Total in 1st grade 1,013
Screened for growth (Tier 1) 818
Dysmorphology exam (Tier 2) 244 + 62
Preliminary diagnosis 30 FAS+78 Deferred
Final diagnosis 55 FAS+18 FASD
Rate 68.0 - 89.2/1,000
May PA et al Drug and Alcohol Dependence 88:259-71 (2007)
Prevalence of Fetal Alcohol Syndrome Lazio Province, Italy
Category Number of Children
Total N in 1st grade 1,086
Total evaluated (Tier 1) 543
Total dysmorphology exam (Tier 2)
230
Final diagnosis 4 FAS + 17 FASD + 1 ARND
Rates 3.7 - 7.4 per 1,000 FAS 20.3 - 40.5 per 1,000 FASD
May PA Alcoholism Clin Exp Res 30:1562-75 (2006)
Fetal Alcohol Syndrome in Boarding Schools and Orphanages in Moscow
Facility
Total Number Children
Children
Examined
Preliminary Diagnosis
FAS
Confirmed Diagnosis
FAS
Boarding Schools for Children Mental Deficiency N = 5
760 574 (76%) 35 27 (6.1%)
Orphanages for Children with Mental Deficiency N = 7
648 561 (87%) 71 69 (12.3%)
Orphanages for Normal or Mildly Delayed Children N = 3
218 190 (76%) 17 17 (8.9%)
Marintcheva G et al Soc Clin Psychiatry 3:17-22 (2003)
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
Moderate Alcohol Consumption
Alcohol Consumed
Evidence of Prenatal Effect
Alcohol
Normal 2 or more ounces of
absolute alcohol (n=16)
3/16 (19%)
13/16 (81%)
1-2 ounces absolute alcohol
(n=54)
6/54 (11%)
48/54 (89%)
Less than 1 ounce absolute alcohol
(n=93)
2/93 (2%)
91/93 (98%)
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