Two Decades of Research on FAS and FASD in the Western Cape
Philip A. May, Ph.D. Research Professor
Nutrition Research Institute Gillings School of Global Public Health
University of North Carolina at Chapel Hill, USA
“Shoe-Leather” Epidemiology
• A colloquial term: “Gathering of information for epidemiologic studies by direct inquiry among the people.”
• For example: walking from door to door and asking questions (wearing out shoe leather in the process).
• “Getting out in the field, towns, and communities, and immersing oneself in the setting. ”
• In the Western Cape: taking a team of clinical specialists to schools to assess and diagnose FASD.
Source: Last, J.M. (ed.) A Dictionary of Epidemiology, 4th edition, 2001.
FASD is Medical Diagnosis
• The diagnosis is best made by a pediatrician who is trained in diagnosis of a variety of birth defects (Hoyme, et al., 2015):
– Medical genetics.
– Teratology.
• The diagnosis involves three specific domains:
– Physical growth and development and dysmorphology.
– Cognition and behavior.
– Maternal risk factors.
Terminology for Fetal Alcohol Spectrum Disorders (FASD)
• U.S. Institute of Medicine (IOM) Recommended Terminology (Stratton, et al., 1996):
• FAS – fetal alcohol syndrome
• PFAS – partial fetal alcohol syndrome
• ARND – alcohol-related neurodevelopmental deficits
• ARBD – alcohol-related birth defects
Organization of the Talk
1.) Epi of FASD in South Africa.
2.) Prevalence of FASD in Various Countries with New Estimates.
3.) Implications for Prevention.
4.) Current initiatives in South Africa.
(1.) Epidemiology of FASD in South Africa
(SA Sample IV) 2008 - 2010
Studies in South Africa: Why?
Two children of the same age in
1st grade: 50th vs. 1st
centile 1. Population is
purely alcohol exposed.
2. Binge drinking pattern is very regular.
3. FASD rates among the Coloured population are extremely high.
Two Diagnostic Conundrums in FASD
• Inaccurate reports of maternal drinking, especially in first world countries:
• Denial of any drinking in the prenatal period.
• Misrepresentation/Underreporting of the QFT.
• Extreme variation in cognitive and behavioral outcomes.
• Within diagnostic groups (FAS, PFAS, ARND).
• Among/Between diagnostic groups.
FASER- SA History (cont.)
• Epidemiological studies of the prevalence and characteristics of FAS, and in the latter studies, PFAS, and ARND were completed via NIAAA supplemental grants and later large RO1/UO1 grants.
• Each covered all three domains of FASD research: Child physical characteristics and prevalence Maternal risk factors Cognitive and behavioral characteristics
• The studies: Wellington 1 - 6– 1997, 1999, 2002, 2008, 2010, 2014. BRAM 1 - 3 – 2009, 2011, 2016.
The bi-national diagnostic and research team in S.A., 1999.
Overview of In-school Study Design Tier ITier I Tier IITier II Tier IIITier III Final DiagnosisFinal Diagnosis
Height, Weight
and
Occipitofrontal
Circumference
Measured for all
children
Physical Growth
and Development
and
Dysmorphology
Exam
Maternal
Interviews
Neuropsychology
and Psychological
Development
Testing
CASE
CONFERENCE
Interdisciplinary
review for
each child:
Physical growth &
dysmorphology
Psychological &
behavioral testing
Maternal risk
factors
Final Diagnosis
with IOM
categories:
Not FAS
FAS
PFAS
ARND
ARBD
Sources: Multiple
Cut off: < 10th or 25th
centile
Randomly Selected Controls
Women working #30
1 bottle spirits (750ml)
1 bottle wine (750ml)
The number of standard drinks in commonly purchased quantities of alcohol
1/2 bottle spirits (375ml)
1 quart beer/cider
Double measure spirits (50ml)
R4-00 jar R2-00 jar R1-00 jar
Isiqatha or injemane
30 6 16 2 2 2 1 1/2
1 bottle beer/cider (330ml)
1 can beer/cider (330ml)
1 carton ijuba (1L)
1 glass wine (125ml)
Quantities of different drinks that are the same as ONE standard drink
R2-00 jar isiqatha/injemane
1 single measure spirits (25ml)
One South African rolled cigarette = I gram of tobacco
The Severity and Appearance of the Physical Phenotype of FASD and Normal Varies Within as Well as Between Each Group
Variable
All
Children1
(n=747)
Children
with FAS
(n=68)
Children
with Partial
FAS
(n=52)
Children
with
ARND
(n=35)
Exposed
R-S
Controls
(n=38)
Unexposed
R-S
Controls
(n=90)
Statistical
Test P
Sex (%)
Males 49 50 48.1 51.4 50 54.4 X2 = 0.64 0.958
Females 51 50 51.9 48.6 50 45.6
Age (months) – Mean (SD)
81.4 (7.1) 85.4 (8.7) 81.4 (9.5) 84.0 (7.9) 80.7 (6.7) 80.0(6.2) F = 5.57 <.001
Height (cm) – Mean (SD)
115.8 (5.9) 111.9 (5.5)
114.8 (7.5) 113.5 (4.9) 115.6 (5.5) 116.3 (6.3) F = 5.50 <.001
Weight (kg) – Mean (SD)
20.7 (3.6) 17.7 (2.1) 20.0 (3.1) 18.9 (1.9) 20.5 (2.7) 21.1 (3.5) F = 15.83 <.001
Child’s BMI – Mean (SD)
15.3 (1.6) 14.2 (1.1) 15.0 (1.0) 14.6 (1.2) 15.3 (1.1) 15.4 (1.8) F = 9.24 <.001
BMI Percentile – Mean (SD)
42.9 (27.5) 16.5
(16.9) 37.0 (21.2) 27.8 (25.3) 43.6 (25.0) 47.4 (24.9) F = 20.49 <.001
Head Circumference (OFC; in cm) Mean (SD)
50.9 (2.4) 48.6 (1.3) 50.0 (1.3) 49.4 (0.8) 51.1 (1.2) 51.1 (1.5) F = 42.69 <.001
Table 1. SA IV Children’s Demographic, Growth, and Dysmorphology
Variable Children with FAS
(n=68)
Children with Partial
FAS (n=52)
Children with
ARND (n=35)
Exposed R-S
Controls (n=38)
Unexposed R-S
Controls (n=90)
Statistical Test
P
Palpebral Fissure Length (cm) Mean (SD)
2.31 (0.2) 2.35 (0.1) 2.39 (0.1) 2.43 (0.1) 2.45 (0.1) F = 17.80 < .001
Percent Palpebral Fissure Length (%) is of Inner Canthal Distance
83.1 (9.7) 82.7 (10.2) 87.8 (7.9) 87.4 (9.6) 85.7 (9.7) F = 2.87 0.024
Maxillary Arc (cm)
23.2 (0.8) 23.8 (1.0) 23.5 (1.1) 24.1 (0.9) 23.8 (2.6) F = 2.59 0.037
Mandibular Arc (cm)
23.9 (0.9) 24.7 (1.2) 24.4 (1.1) 25.1 (1.1) 25.1 (0.9) F = 15.28 < .001
SA IV Children’s Demographic, Growth, and Dysmorphology
Variable
All
Children
(n=747)
Children
with FAS
(n=68)
Children
with
Partial
FAS
(n=52)
Children
with ARND
(n=35)
Exposed
R-S
Controls
(n=38)
Unexposed
R-S
Controls
(n=90)
Statistical
Test P
Short Inner Pupilary Distance (%)
-- 60.6 36.5 51.4 28.9 12.2 X2 = 44.22 <.001
Hypoplastic Midface (%)
-- 82.4 71.72 62.9 50 42.2 X2 = 30.54 <.001
Smooth Philtrum (%)
-- 80.9 80.8 22.9 31.6 22.5 X2 = 87.93 <.001
Narrow Vermillion Border (%)
-- 89.7 94.2 25.7 42.1 28.1 X2 =
106.69 <.001
“Railroad Track” Ears (%)
-- 10.3 5.8 5.7 10.5 5.6 X2 = 2.16 0.706
Ptosis (%) -- 14.7 7.7 0 0 5.6 X2 = 12.40 0.015
Epicanthal Folds (%)
-- 63.2 63.5 80 52.6 39.3 X2 = 21.04 <.001
Table 1 (cont.) SA IV Children’s Demographic, Growth, and Dysmorphology
Variable
All
Children
(n=747)
Children
with FAS
(n=68)
Children
with Partial
FAS
(n=52)
Children
with
ARND
(n=35)
Exposed
R-S
Controls
(n=38)
Unexposed
R-S
Controls
(n=90)
Statistical
Test P
Clinodactyly (%) -- 60.3 63.5 48.6 57.9 65.2 X2 = 3.20 0.525
Camptodactyly (%)
-- 27.9 23.1 11.4 10.5 6.7 X2 = 16.25 0.003
Palmar Crease Alteration (%)
-- 48.5 28.8 37.1 39.5 21.3 X2 = 14.07 0.007
Total Dysmorphology Score Mean (SD)
-- 18.9 (3.9) 14.3 (3.1) 12.2 (3.3) 8.2 (3.6) 7.1(3.6) F = 123.43 <.001
Table 1 (cont.) SA IV Children’s Demographic, Growth, and Dysmorphology
Source: May et al., ACER, 2013
TABLE 2. Mean Developmental and Behavioral Indicators1 of Children with
Specific FASD Diagnoses vs. Normal Controls: SA IV (n = 272)
Child Variables FAS (SD) PFAS (SD)
Children
with ARND
(SD)
Exposed R-S
Controls (SD)
Unexposed
R-S Controls
(SD)
Test
Score P
(n =66) (n = 51) (n = 35) (n = 38) (n= 87)
Developmental Traits
Verbal IQa 5.1 (7.6) 5.7 (10.2) 5.2 (7.5) 8.2 (7.9) 13.4 (18.2) F = 5.85 <.001
Non-verbal IQb 8.9 (7.2) 14.4 (12.1) 7.7 (4.5) 17.8 (10.9) 22.2 (18.1) F = 14.23 <.001
WISC-IV Digit-
Span Scaled
Score
4.4 (2.6) 5.1 (2.8) 4.7 (2.7) 6.8 (3.5) 6.7 (3.3) F = 8.07 <.001
Achenbach
Teacher Report
Form
50.2 (42.6) 45.1 (42.2) 58.3 (33.7) 35.8 (35.5) 29.1 (29.1) F = 5.63 <.001
Source: May et al., ACER, 2013
Simple View of Causation: Severity of Damage
• An individual child’s traits of FASD are influenced totally by:
Quantity (amount) of alcohol consumed by mother
during pregnancy.
Frequency (how often) that a mother drinks.
Timing of the drinking during gestation of the fetus.
Source: May, 1995; Stratton, et al, 1996.
TABLE 3. Substance Use By Mothers of Children with FASD and Controls: SA IV
Maternal Variables Mothers of
Children with FAS
Mothers of
Children with
Partial FAS
Mothers of
Children with
ARND
Mothers of R-S
Exposed Control
Children
Mothers of
R-S
Unexposed
Control
Children
Statistical
Test df P
(n = 68) (n = 52) (n = 35) (n =38) (n = 90)
Drinking Indicators
overall reported
drinking during
pregnancy (%)
91.4 89.1 96.8 100 -- X2 = 201.97 df = 4 <.001
Average No. drinks per
week (during
pregnancy)
13.4 (14.0) 13.1 (16.1) 13.0 (15.0) 5.6 (5.3) 0.0 (0.0) F = 16.43 df =
4/207 <.001
Consumed 3 drinks or
more per occasion
during pregnancy (%)
78.8 74.4 80.8 70.6 0 X2 =117.22 df = 4 <.001
Consumed 5 drinks or
more per occasion
during pregnancy (%)
59.6 53.8 61.5 41.2 0 X2 =69.92 df = 4 <.001
Current drinker in last
year (%) 100 96.9 100 92.3 46 X2 = 57.70 df = 4 <.001
1. Dunnett's C post hoc analyses show that FAS and Unexposed Controls differ at the P = .05 level.
Source: May et al., ACER, 2013
Mean Number of Standard Drinks per Week During
Pregnancy by Diagnostic Group
Diagnostic Group
Error bars = 95% Confidence Interval
Diagnostic Group
Mean Number of Drinks Consumed per Drinking Day During
Pregnancy by Diagnostic Group
Error bars = 95% Confidence Interval
Mean Peak BAC (at least one time during pregnancy)
by Diagnostic Group
Diagnostic Group
Ove
rall
Pe
ak B
AC
M
ean
.000
.050
.100
.150
.200
.250
.300
.350
FAS PFAS ARND Exposed Controls UnexposedControls
Error bars = + one Standard Deviation (SD)
Mean Drinks per Drinking Day (DDD) by Trimester and Diagnostic Group
Diagnostic Group
Me
an D
rin
ks p
er
Dri
nki
ng
Day
Error bars = + one Standard Error
Diagnostic Group
Mean Drinks per Drinking Day (DDD) by Trimester and
Diagnostic Group (with Standard Deviations to emphasize Individual variation)
Me
an D
rin
ks p
er
Dri
nki
ng
Day
Error bars = + one Standard Deviation (SD)
Frequency: Drinking Days per Week During Pregnancy (SA IV)
Maternal Variable
Mothers of
Children with
FAS
Mothers of
Children
with PFAS
Mothers of
Children
with ARND
Mothers of
Exposed
Controls
Mothers of
Unexposed
Controls
F P
Mean Number of Drinking Days per Week
2.27 (1.2)
1.75 (1.1)
1.88 (1.1)
1.02 (0.6)
0.00
5.29
.002
TABLE 4. Pearson Correlation Coefficients for Developmental1 and Physical Dysmorphology
vs. Selected Maternal Drinking Measures During Pregnancy: South Africa Wave IV
Trait
Reported
Drinking During
Pregnancy
Drinks Per
Month Drinks Per Day
3 Drinks Per
Occasion
5 Drinks Per
Occasion
(N = 339) (n = 302) (n = 302) (n = 302) (n =302)
Verbal abilitya -.253*** -.170** -.174** -.190** -.158**
Non-verbal
abilityb -.265*** -.194** -.209*** -.218*** -.210***
Behaviorc .203*** .172** .232*** .237*** .233***
Dysmorphology
score .431*** .353*** .378*** .467*** .384***
1 All scores standardized for age of child at time of testing.
a. Tests of the Reception of Grammar (TROG).
b. Raven Colored Progressive Matrices. c. Personal Behavior Checklist (PBCL-36).
*p <.05; **p <.01; ***p <.001
Source: May et al., ACER, 2013
Drinking Behavior
p
Odds Ratio
95% CI for Odds Ratio
Nagelkerke
R2 Lower Upper
First trimester only vs. no drinking <.001* 12.15 4.13 35.8 .27
First and second trimesters only vs.
no drinking <.001* 60.76 12.68 291.36 .50
All trimesters vs. no drinking <.001* 64.81 23.33 180.11 .65
Third trimester only vs. no drinking .212 6.08 0.36 103.31 .28
First and second trimesters vs. first trimester only .066 5.00 0.91 27.74 .14
All trimesters vs. first trimester only .008 5.33 1.55 18.33 .13
All trimesters vs. first and second trimesters only .940 1.07 0.20 5.71 .00
*p < .007
note: no cases for T2 and T3 but not T1 Source: May et al., DAD, 2013
From Maternal QFT of Drinking Study:
Comparisons of Odds of FASD for Mothers' Drinking Behavior over Pregnancy
Trimesters
TABLE 5. Prevalence Rates (per 1,000) of Individual Diagnoses and
Total FASD: South African Community, Wave IV
Diagnosis n Enrolled rate1 (n=1147) Consented rate2 (n=747)
FAS 68 59.3 91.0
PFAS 52 45.3 69.6
ARND 35 30.5 46.8
Total FASD 155 135.1 (13.5%) 207.5 (20.7%)
1. Denominator is all children attending first grade in local schools.
2. Denominator is the total number of child with consent to participate in this study. Source: May et al., ACER, 2013
Wellington IV R
ate
per
1,0
00
Oversample of Small Children (< 25th centile on height, weight, and head circumference) and Case from the
Randomly-Selected Children
Simple Random Sample for Entry into Study
Error bars = 95% confidence intervals
Oversample of Small Children (< 25th centile on height, weight, and head circumference) and Case from the
Randomly-Selected Children
Simple Random Sample for Entry into Study
BRAM I R
ate
per
1,0
00
Error bars = 95% confidence intervals
4.58* (.58)
9.64* (.51)
1.12* (.38)
0.52* (.52) -0.12*
(-.12)
0.87* (.23)
0.46* (.46)
-0.14 n.s. (.61)
2.26* (.62)
1.00 (.62)
-1.47* (-.80)
0.27* (.92)
0.06* (.48)
0.24 n.s. (.06)
2.67* (.82)
0.30* (.60)
-0.54* (-.44)
-0.36* (-.36)
3.73* (.57)
1.39* (.95)
1.27* (.96)
-0.69* (-.89)
0.33* (-.71)
0.41* (.84)
-0.75* (-.97)
0.38* (.83)
0.47* (.47)
Multiple Maternal Characteristics Predicting Child Dysmorphology And Diagnosis South Africa waves I, II, and III (combined)
R2 = 62.0% Source: May, et al., DAD, 2013.
Maternal Drinking Characteristics Predicting I.Q. and Problem Behavior: SA, waves I, II, and III
(Total Variance explained - R2 = 17.3%)
Source: May et al., JDBP, 2013
-0.57* (-.69)
0.31* (.68)
0.69* (-.89)
0.34* (.70)
0.41* (.83)
-0.74* (-.97)
3.10* (.42)
0.39* (.83)
1.00 (.67)
1.52* (.83)
-0.60* (-.53)
1.00 (.91)
Multiple Maternal Predictors of a Child’s Neuro-Psychological Characteristics: South Africa, waves I, II, and III combined.
Total variance explained: R2 = 55.3%
Source, May et al., JDBP, 2013
4.66* (.59) 8.40*
(.45)
1.31* (.43)
2.62* (.91)
0.30* (.60)
-0.56* (.43)
3.73* (.57)
0.51* (.51)
-0.36* (.36)
1.39* (.95)
1.27* (.96)
.47* (.47)
-.54* (-.69)
0.29* (.68)
-0.69* (-.89)
0.32* (.70)
0.41* (.83)
-0.75* (-.97)
0.38* (.83)
1.00 (.67)
-0.59* (-.54)
1.44* (.81)
1.00 (.69)
0.48* (.48)
2.70* (.36)
3.83* (.52)
0.52 n.s.
(.07)
-0.19 n.s.
(-.01)
-0.13* (.13)
2.) Review of Prevalence Findings from
In-School Studies of FASD
Our In-School Studies Funded by:
• NIH/ National Institute on Alcohol Abuse and Alcoholism (NIAAA).
• Thanks to: Jan Howard, Ph.D., Patricia Mail, Ph.D., and Marcia Scott, Ph.D.
• A very special thanks to:
Kenneth Warren,
Ph.D.
Faye Calhoun,
Ph.D.
Ting Kai Li,
M.D.
Enoch Gordis,
M.D.
United States (4)
Italy (2)
South Africa (7)
Location of FASER In-School Samples
FASER Research Teams: 1997 -2013 New Mexico: 2013 South Africa: 2013
South Dakota: 2012
South Africa: 2009
Italy: 2006
Summary Rates of FAS by Country for In-School Studies (avg. per 1,000)
Various sources
Current High Estimate:
3 per 1,000
(5 studies) (2 studies)
(3 pilot studies)
(1 study)
Summary Rates of FASD by Country for In-School Studies (avg. per 1,000)
43.5
69.7 78.6
30.4 18.5
28.6
88
40.8
171.3
0
25
50
75
100
125
150
175
200
South Africa Italy USA-RockyMountain
USA- Midwest City
Avg. R
ate
Per
1,0
00
Source: May et al., DDRR, 2009; and unpublished data.
Current Estimate:
9.1
(5 studies) (2 studies)
(3 pilot studies)
(1 study)
New General Population Prevalence Estimates of FASD: In-School Studies
Estimates per 1,000:
Old New - In-school
FAS 0.5 – 3.0 2.0 – 7.0
FASD 9.1 (1%) 20 – 50 (2-5%)
Source: May et al., DDRR, 2009.
Source: May et al., DDRR, 2009.
(Rates per 1,000)
The FASD Iceberg Analogy
Above water:
Only some FAS and
PFAS children w/
manifest problems and
classic dysmorphology
will reach tertiary clinics
for diagnosis.
Below water:
Many children with
FAS, PFAS, and
ARND who can be
found in a general
population.
3.) Implications for Prevention
• All of our research in the Western Cape is undertaken under an umbrella of Prevention.
• Primary/universal via abstinence from alcohol:
– entire prenatal period and when breastfeeding
• Secondary via antenatal clinics.
• Tertiary (case management of mothers) or Intervention for those born with an FASD is very promising.
Comprehensive Prevention of FASD: IOM, 1996
* Intervention: Educational Nutritional
(100% preventable) (100% Irreversible)
Early diagnosis leads to better life chances.
0
5
10
15
20
25
30
T1 - T2 T2 - T3
LLT
FASD-C
NONEXP-C
Mean change in all PAELT scores for Language and Literacy Therapy
Participants, FASD-Controls and NONEXP-Control groups of 8 to 10 year olds after 9 and 18 months LLT intervention: South Africa
Me
an PA
ELT score
chan
ge
T1 - T2 = Baseline to 9 months T2 - T3 = 9 months to 18 months
* P < .000 LLT vs FASD-Change
* P < .000 LLT vs NONEXP-Change
*
PAELT = Phonological awareness and early literacy test.
Source: Adnams, et al.,
Alcohol, 2009.
4.) Current FASD Epidemiology Research in South Africa
(FASER-SA)
FASER- SA History (cont.)
• Grant was brought to Stellenbosch University, Faculty of Health Sciences for what has become a “very successful collaboration” and completion of all activities.
Field Offices for FASER-SA
2006-present
Robertson Wellington
Specific Aims of the Current (Second Major) Grant for FASER-SA
2013-2018
Specific Aims of the Current Grant: “Trajectory of FASD Across the Lifespan”
1.) Initiate early intervention/remediation research for development of children with FASD from 12 months of age forward through:
• nutritional and
• cognitive/behavioral enhancement
Specific Aims of the Current Grant: “Trajectory of FASD Across the Lifespan”
2.) Continue a detailed longitudinal study of the physical and cognitive/behavioral developmental trajectory of children from the newborn period to seven years of age.
• to characterize FASD traits in this early period • to finalize universal diagnostic protocols for FASD in the earliest months of life.
Specific Aims of the Current Grant: “Trajectory of FASD Across the Lifespan”
3.) Initiate an efficacy study of biomarkers to detect alcohol consumption in the prenatal period:
a.) ethyl glucaronide (EtG) and b.) phosphatidyl ethanol (PEtH)
•We facilitate this new aim by continuing selected prevention of FASD in antenatal clinics.
Specific Aims of the Current Grant: “Trajectory of FASD Across the Lifespan”
4.) Initiate new methodology to study the nutrition of pregnant women via a survey of all major vitamins, minerals, and micro nutrients through 24-hour dietary recall and genetic influences on metabolism of selected key nutritients. •We facilitate this new aim by continuing secondary and tertiary prevention trials via the treble approach in case management.
Specific Aims of the Current Grant: “Trajectory of FASD Across the Lifespan”
5.) Evaluate the impact of nine years of IOM-recommended comprehensive prevention efforts with:
• a third, random survey of the community on Knowledge, Attitudes, Beliefs, and Behaviors (KABB) and
• final repetition of local in-school studies of the prevalence and characteristics of FASD
• Wellington 6 and Robertson and Ashton 3.
The USA and ZA team members: 2011
The Quest Continues….
