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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
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Page 1: Alcohol and Pregnancy: What Have We Learned in 37 Years? · 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.

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

Page 2: Alcohol and Pregnancy: What Have We Learned in 37 Years? · 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.

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

Page 3: Alcohol and Pregnancy: What Have We Learned in 37 Years? · 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.

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

Page 4: Alcohol and Pregnancy: What Have We Learned in 37 Years? · 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.
Page 5: Alcohol and Pregnancy: What Have We Learned in 37 Years? · 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.

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

Page 6: Alcohol and Pregnancy: What Have We Learned in 37 Years? · 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.

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

Page 7: Alcohol and Pregnancy: What Have We Learned in 37 Years? · 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.

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

Page 8: Alcohol and Pregnancy: What Have We Learned in 37 Years? · 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.

Palpebral Fissure Length (PFL) Measurement

►Document measurement from inner to outer canthus in millimeters

►Use hard, clear plastic ruler

►Follow curve of the face

Page 9: Alcohol and Pregnancy: What Have We Learned in 37 Years? · 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.

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

Page 10: Alcohol and Pregnancy: What Have We Learned in 37 Years? · 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.
Page 11: Alcohol and Pregnancy: What Have We Learned in 37 Years? · 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.

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

Page 12: Alcohol and Pregnancy: What Have We Learned in 37 Years? · 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.

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

Page 13: Alcohol and Pregnancy: What Have We Learned in 37 Years? · 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.
Page 14: Alcohol and Pregnancy: What Have We Learned in 37 Years? · 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.

IOM works outside the Federal Government to provide unbiased, evidence-based and authoritative information and advice concerning health and science policy to policy-makers, professional leaders in every sector of society and the public at large.

Page 15: Alcohol and Pregnancy: What Have We Learned in 37 Years? · 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.

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)

Page 16: Alcohol and Pregnancy: What Have We Learned in 37 Years? · 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.

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

Page 17: Alcohol and Pregnancy: What Have We Learned in 37 Years? · 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.

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.

Page 18: Alcohol and Pregnancy: What Have We Learned in 37 Years? · 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.

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)

Page 19: Alcohol and Pregnancy: What Have We Learned in 37 Years? · 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.

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

Page 20: Alcohol and Pregnancy: What Have We Learned in 37 Years? · 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.

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.

Page 21: Alcohol and Pregnancy: What Have We Learned in 37 Years? · 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.

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.

Page 22: Alcohol and Pregnancy: What Have We Learned in 37 Years? · 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.
Page 23: Alcohol and Pregnancy: What Have We Learned in 37 Years? · 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.

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.

Page 24: Alcohol and Pregnancy: What Have We Learned in 37 Years? · 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.

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.

Page 25: Alcohol and Pregnancy: What Have We Learned in 37 Years? · 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.
Page 26: Alcohol and Pregnancy: What Have We Learned in 37 Years? · 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.

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

Page 27: Alcohol and Pregnancy: What Have We Learned in 37 Years? · 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.
Page 28: Alcohol and Pregnancy: What Have We Learned in 37 Years? · 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.

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

Page 29: Alcohol and Pregnancy: What Have We Learned in 37 Years? · 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.

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

Page 30: Alcohol and Pregnancy: What Have We Learned in 37 Years? · 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.

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

Page 31: Alcohol and Pregnancy: What Have We Learned in 37 Years? · 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.

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.

Page 32: Alcohol and Pregnancy: What Have We Learned in 37 Years? · 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.

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

Page 33: Alcohol and Pregnancy: What Have We Learned in 37 Years? · 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.

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)

Page 34: Alcohol and Pregnancy: What Have We Learned in 37 Years? · 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.

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)

Page 35: Alcohol and Pregnancy: What Have We Learned in 37 Years? · 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.

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)

Page 36: Alcohol and Pregnancy: What Have We Learned in 37 Years? · 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.

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

Page 37: Alcohol and Pregnancy: What Have We Learned in 37 Years? · 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.
Page 38: Alcohol and Pregnancy: What Have We Learned in 37 Years? · 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.

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%)

Page 39: Alcohol and Pregnancy: What Have We Learned in 37 Years? · 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.
Page 40: Alcohol and Pregnancy: What Have We Learned in 37 Years? · 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.

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


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