Transcript Document

Does in-utero alcohol
exposure impact on adverse
outcomes in offspring?
Rosa Alati
NHMRC research fellow
School of Population Health &
Centre for Youth Substance Abuse Research (CYSAR)
University of Queensland (Australia)
In collaboration with
Queensland Alcohol and Drug Research and Education Centre (Qadrec)
FETAL ALCOHOL SYNDROME
(FAS)
FAS is the term coined in the United States in 1973 by Dr.
Kenneth Jones and Dr. David Smith at the University of
Washington to describe individuals with documented
1. prenatal and postnatal growth retardation,
2. characteristic facial features,
3. central nervous system problems, and
4. prenatal exposure to alcohol
1. Prenatal and postnatal growth
retardation
• Below average height, weight or both
2. Physical Characteristics of FAS
•
•
•
•
Small head circumference
Small eye openings
Smooth, wide philtrum
Thin upper lip
Physical Characteristics of FAS
3. Central nervous system problems
• Can be assessed in three areas
– Structural
• Microcephaly
– Neurological
• epilepsy /seizure disorders
• softer signs
– broader, nonspecific neurological symptoms: impaired motor
skills, clumsiness, poor eye-hand coordination
– Functional
• behavior or cognitive abnormalities
Primary disabilities
–
–
–
–
–
Cognition — Mental retardation, slower cognitive processing
Achievement — Learning disabilities
Adaptive behavior — developmental delays
Attention — Attention-Deficit/Hyperactivity Disorder (ADHD),
Executive functioning
Secondary disabilities
–
–
–
–
–
–
Mental health problems
Disrupted school experience
Trouble with the law
Confinement
Inappropriate sexual behavior
Alcohol and drug problems
4. Prenatal exposure to
alcohol
• How much is too much?
– Heavy consumption of alcohol or binge-type
patterns of drinking
BUT
– How about low levels of consumption in pregnancy?
– How much reason for concern?
Australian Guidelines
TO REDUCE HEALTH RISKS
from Drinking Alcohol
• Maternal alcohol consumption can harm the
developing fetus or breastfeeding baby.
• Is there a ‘safe’ level of alcohol consumption
in pregnancy?
– previous Guidelines would allow 1/2 units of
alcohol a couple of days a week
Australian Guidelines
TO REDUCE HEALTH RISKS
from Drinking Alcohol
• Revision of the new alcohol guidelines 2009:
• PRECAUTIONARY APPROACH
A. For women who are pregnant or planning a
pregnancy, not drinking is the safest option.
Two disabilities: Intelligence (measured by
IQ) and alcohol disorders
• Is intrauterine exposure to alcohol use
associated with IQ in childhood?
• Is there a role for a developmental origin
of alcohol problems?
Challenges
• Retrospective surveys
– Recall bias
• Pre-birth cohort studies
– long term follow-up of mothers and their
children
• CONFOUNDING
– Take into account additional influences
• also associated with these outcomes and
may be the true cause
– SEP, education, timing of alcohol use
Two internationally well reputed
longitudinal studies
• The Mater University Study of Pregnancy
and its outcomes (MUSP) (Australia)
• The Avon Longitudinal Study of Parents and
Children (ALSPAC) (UK)
Is there a role for a developmental
origin of alcohol problems?
•Evidence from animal studies
•
Nizhnikov ME, Molina JC, Varlinskaya EI, Spear NE. Prenatal Ethanol
Exposure Increases Ethanol Reinforcement in Neonatal Rats.
Alcoholism: Clinical and Experimental Research 2006;30:34-45.
•
Chotro MG, Arias C. Prenatal exposure to ethanol increases ethanol
consumption: a conditioned response? Alcohol 2003;30:19-28.
•
Spear NE, Molina JC. Fetal or infantile exposure to ethanol promotes
ethanol ingestion in adolescence and adulthood: A theoretical review.
Alcoholism-Clinical and Experimental Research 2005;29:909-929.
•
Arias C, Chotro MG. Increased preference for ethanol in the infant rat
after prenatal ethanol exposure, expressed on intake and taste reactivity
tests. Alcoholism-Clinical and Experimental Research 2005;29:337-346.
Is there a role for a developmental
origin of alcohol problems?
Animal studies
• Association between in-utero alcohol
exposure and the development of early
uptake of and greater alcohol consumption in
adolescent animals.
• More severe effects
– when alcohol is administered all at once rather
than gradually,
– The effect holds even for small quantities of
injected ethanol
Evidence from animal studies
Advantages
• The use of animal models permits
– Accuracy of alcohol intake (eg grams)
– Control for environmental factors
• Control for maternal exposure at other time periods
• Isolate the influence of alcohol use by others
– Explore effects at critical periods
• Timing of the exposure
Evidence from animal studies
Disadvantages
• Can findings be generalised to humans?
– Animals differ from humans in
• their level of susceptibility to substances and
• in the timing and stages of brain development during pregnancy
and at the time of birth.
• Huizink AC, Mulder EJH. Maternal smoking, drinking or cannabis use
during pregnancy and neurobehavioral and cognitive functioning in human
offspring. Neuroscience & Biobehavioral Reviews 2006;30:24-41.
Is there a role for a developmental
origin of alcohol disorders?
Seattle Longitudinal Study of Alcohol and Pregnancy
• Maternal drinking in mid-pregnancy was
independently associated with the excessive drinking
at age 14, with problems drinking at age 21 and with
alcohol disorders at age 25
•
Baer JS, Barr HM, Bookstein FL, Sampson PD, Streissguth AP. Prenatal alcohol exposure and
family history of alcoholism in the etiology of adolescent alcohol problems. Journal of Studies on
Alcohol 1998;59(5):533-543.
•
Baer JS, Sampson PD, Barr HM, Connor PD, Streissguth AP. A 21-year longitudinal analysis of
the effects of prenatal alcohol exposure on young adult drinking. Archives of General Psychiatry
2003;60:377-385.
•
Barr HM, Bookstein FL, O'Malley KD, Connor PD, Huggins JE, Streissguth AP. Binge drinking
during pregnancy as a predictor of psychiatric disorders on the Structured Clinical Interview for
DSM-IV in young adult offspring. American Journal of Psychiatry 2006;163:1061-5.
Is there a role for a developmental
origin of alcohol addiction?
• Baer JS, Sampson PD, Barr HM, Connor PD,
Streissguth AP. A 21-year longitudinal analysis
of the effects of prenatal alcohol exposure on
young adult drinking. Archives of General
Psychiatry 2003;60(4):377-385.
Issues related to human studies
• Familial history of alcohol problems
– Paternal alcohol use
• Maternal use of other substance use in pregnancy
• Tobacco particularly
• Maternal alcohol use at other time periods
• Modelling influence
• Siblings alcohol use
• Timing of the exposure
• First, second or third semester?
• How to disentangle timing
MUSP
Mater-University of Queensland Study of
Pregnancy and its outcomes
1981-2004
Brisbane Australia
Mater-University Study of
Pregnancy (MUSP)
• Pregnancy/birth cohort study of mothers and children
• 7,223 live singleton babies
– 52% males (n=3758) and 48% females (n=3465)
• Enrolled at first clinic visit at the Mater Misericordiae
Hospital (Brisbane, Australia), 1981-1984
• Follow-up
– 3-5 days
– 6 months
– 5 and 14 years after the birth
– 21 years after the birth 2555 participants completed the alcohol
modules of the Composite International Diagnostic Interview –
computerised version (CIDI-Auto)
Mater Misericordiae Hospital 1981
Brisbane City Council – MUSP 21 birthday
2004
Content of MUSP
Socio-demographics
Age, marital status, income, religiosity, employment status,
marital status changes, number of children in household, etc.
Lifestyle
Tobacco, alcohol, illicit drugs, breastfeeding duration,
patterns of child care, feelings about child, physical activity,
diet (FFQ), TV watching, delinquency.
Summary of MUSP variables from the prenatal period
to 21 years
Phases of the study*
Item
1
2
3
4
5
6
Sample size Mothers (M)
n=5172
n=4100
Sample size Children (C)
n=7223 n=7223 n=6720 n=5259 n=5172
n=3910
Alcohol use
M
M
M
M
MC
MC
Tobacco/ illicit substance use
M
M
M
M
MC
MC
SES - Education
M
C
MC
Income, Marital status
M
M
M
M
M
MC
Stress
M
M
M
M
Depression / anxiety
M
M
M
M
M
MC
Life events
M
M
M
M
M
Marital satisfaction / QOL
M
M
M
M
MC
Interpersonal violence
M
MC
Obstetric/biological/physical
M
MC
C
C
MC
Behaviour /ADHD
M
MC
MC
School achievement
MC
MC
Cognition PPVT
C
C
WRAT/Ravens SPM
C
Child health status
M
MC
MC
Familial and peer alcohol use
MC
MC
* 1= pre-pregnancy/pregnancy; 2= birth; 3= 6 months; 4= 5 yrs; 5=14 yrs; 6=21 yrs
Socio
economic /
hereditary
Alcohol
exposure
Before
pregnancy
Smoking
Biological
Alcohol
exposure
Early
pregnancy
Smoking
Biological
Alcohol
exposure
Late
pregnancy
Smoking
SES - Maternal education & age, income,
marital status, birth weight, gestation
Parental
modelling
Alcohol
exposure
After
pregnancy
(At 5 / 14 yrs)
Smoking
Child
cognitive
functioning
Onset alcohol
abuse/
dependence
at age 21
Early
adulthood
Measures
• Outcome
– Lifetime diagnosis of alcohol abuse and dependence (DSM-IV)
• Time of onset
– < 18 years
– 18 + years
– Alcohol abuse: A destructive pattern of alcohol use, leading to
significant social, occupational, or medical impairment
– Alcohol dependence (must have three or more of the following):
• Alcohol tolerance
• Alcohol withdrawal symptoms: Either
• Two or more withdrawal symptoms or
• Alcohol is taken to relieve or avoid withdrawal symptoms
Diagnostic and Statistical Manual of Mental Disorders DSM-IV-TR,
American Psychiatric Association, 2000
– the Composite International Diagnostic Interview –
computerised version (CIDI-Auto)
Measures
• Main predictor and main confounder
– Alcohol composite measure
• Repeated measures of number of glasses per drinking occasion
– < 3 glasses
– 3 + glasses
• Timing of the exposure
–
–
–
–
–
pre-pregnancy
early pregnancy
late pregnancy
at 5 years and
14 years
– Tobacco composite measure
• Repeated measure of smoking/no smoking status
• Timing of the exposure
• Other confounders
– Birth weight, gestational age, maternal education, age, marital status,
family income, maternal anxiety and depression
• Mediators
– Child behaviour (YSR) Cognitive function at age 5 (Peabody)
– Paternal/ siblings alcohol problems (In sensitivity analysis at age 14)
Data analysis
• Age adjusted multinomial logistic regression
– with a 3-level categorical end point
– Reference category “No Disorder”,
• “Early onset (< 18 yrs) ”
• “Late onset (18 + yrs) ”
Sample by early and late onset of alcohol disorders
(DSM-IV)
N
%
1915
75.0
Early onset (< 18 yrs)
333
13.0
Late onset (18 + yrs)
307
13.0
2555
100
No diagnosis
Total
Alcohol exposure over the life course
N
%
2243
49.8
3 + in early pregnancy
249
5.5
3 + in late pregnancy
163
3.6
3 + only after pregnancy (not during) pregnancy
841
18.7
3 + before and after (not during) pregnancy
1005
22.3
Total
4501
100.0
Always < 3 glasses
Alcohol exposure of 3 + glasses over the life course
and early onset of alcohol disorders
Unadjusted OR (95%CI)
5.00
4.00
3.00
3.22
2.00
1.59
1.31
1.00
0.96
0.00
y
nc
a
n
eg
r
yp
l
r
ea
In
lat
n
I
y
nc
a
n
eg
r
ep
l
on
fte
a
y
y
nc
a
n
eg
r
rp
Life course exposure
e
aft
/
e
for
e
b
y
nc
a
n
reg
p
r
Alcohol exposure of 3 + glasses over the life course
and early onset of alcohol disorders
Adjusted OR (95%CI)
5.00
4.00
3.00
2.43
2.00
1.67
1.19
1.00
1.50
1.04
0.71
0.00
e
In
reg
p
y
ar l
y
nc
a
n
In
r eg
p
e
lat
n
na
cy
on
ly
e
aft
reg
p
r
y
nc
a
n
fo
be
re
te
/af
reg
p
r
y
nc
a
n
o
sm
kin
n
gi
p
n
na
g
re
cy
o
sm
g
kin
at
es
it m
er
h
t
o
Alcohol exposure of 3 + glasses over the life
course and late onset of alcohol disorders
Unadjusted OR (95%CI)
5.00
4.00
3.00
2.68
2.00
1.66
1.48
1.44
1.00
0.00
y
nc
a
n
reg
p
y
arl
e
In
y
nc
a
n
reg
p
e
lat
In
e
aft
y
l
on
y
nc
a
n
reg
p
r
Life course exposure
fte
a
/
e
for
e
b
y
nc
a
n
reg
p
r
Alcohol exposure of 3 + glasses over the life
course and late onset of alcohol disorders
Adjusted OR (95%CI)
5.00
4.00
3.00
2.68
2.00
1.54
1.45
1.44
1.12
1.00
0.83
0.00
y
nc
a
n
eg
r
p
rly
a
e
In
lat
In
y
nc
a
n
eg
r
ep
l
on
fte
ya
y
nc
a
n
eg
r
rp
fte
a
/
e
for
e
b
y
nc
a
n
eg
r
rp
in
g
n
i
ok
m
s
Life course exposure
y
nc
a
n
eg
r
p
kin
o
sm
to
a
g
tim
r
the
es
Main finding
• Exposure to relatively moderate alcohol use in early
pregnancy is an independent predictor of alcohol
disorders in early adulthood
– Early onset
• Alcohol use in early pregnancy predicted early onset alcohol
disorders. The effect was only partly accounted for by maternal
smoking during pregnancy
– Late onset
• Alcohol use in early pregnancy may predict late onset alcohol
disorders
• Maternal drinking at other time periods was also
associated with late onset
Possible mechanisms for the
association
• Exposure during pregnancy may act by
modifying the natural reward circuitry of
the brain
– This circuit involves the mesolimbic dopamine
system, with dopamine-producing neurons
• Long-term effects on the hypothalamus
and/or pituitary adrenal axis,
– lead to increased alcohol intake in adult
offspring
Strengths
• Longitudinal
• Population sample
• Considered biological, environmental and family
factors simultaneously
•R. Alati, AA Mamun, GM Williams, M O’Callaghan, JM Najman, W. Bor (2006). Does in
utero alcohol exposure predict alcohol disorders in early adulthood? A birth
cohort study. Archives of General Psychiatry
Limitations
• Attrition
– Combination of multiple imputation and IPW
• No follow-up data available between 5 and 14
years of age
• CONFOUNDING
• Unable to assess all potentially important
factors
– Peer influences
– Paternal alcohol use
– Is assessment of time of exposure a robust approach?
•R. Alati, AA Mamun, GM Williams, M O’Callaghan, JM Najman, W. Bor (2006). Does in
utero alcohol exposure predict alcohol disorders in early adulthood? A birth
cohort study. Archives of General Psychiatry
A better approach to
confounding
• Mendelian randomisation
• Sibling pair approach
• Paternal and maternal comparisons of
alcohol use in pregnancy with outcomes
in childhood
– Are these different?
The ALSPAC study (Children of the
90’s)
• More than 14,000 mothers enrolled during pregnancy
in 1991 and 1992, and the health and development of
their children has been followed in great detail ever
since.
Is intrauterine exposure to alcohol
and tobacco use associated with IQ
in childhood?
• Child’s IQ at age 8: the Weschler Intelligence Scale for Children (WISCIII)
– Maternal and paternal alcohol use in pregnancy at 8
weeks' gestation.
•
Two measures: daily drinking and ‘binge drinking’
–
–
•
how often they had drunk alcoholic drinks during the first 3 months of
pregnancy (Never, <1 glass a week, 1+ glass a week, 1+ glasses every day).
how many days in the previous month they had drunk 4+ standard drinks.
(Never, 1-4 days, 5-10 days, 10 + days)
Confounders
–
marital status, occupational social class, home ownership, crowding condition
of the household, ethnicity, gender, maternal parity, education.
Mean change in
offspring IQ per
increase in maternal
alcohol category
Mean change in
offspring IQ per
increase in paternal
alcohol category
p-value for
difference between
maternal and
paternal
associations
Complete case analyses (n=4,332)
Amount of alcohol in first 3 months of pregnancy
Model 1
0.55 (-0.11, 1.20)
1.38 (0.94, 1.81)
0.005
Model 2
0.68 (0.03, 1.33)
1.17 (0.74, 1.60)
0.08
Model 3
0.14 (-0.46, 0.74)
0.41 (0.00, 0.81)
0.43
Model 4
0.15 (-0.46, 0.75)
0.41 (0.00, 0.82)
0.43
Model 5
0.03 (-0.58, 0.65)
0.40 (-0.01, 0.82)
0.43
Drinking frequency of 4 + units
Model 1
-1.60 (-2.53, -0.67)
0.16 (-0.33, 0.66)
0.001
Model 2
-1.10 (-2.02, -0.18)
0.04 (-0.45, 0.53)
0.03
Model 3
-0.41 (-1.26, 0.45)
0.07 (-0.39, 0.52)
0.38
Model 4
-0.42 (-1.28, 0.44)
0.06 (-0.40, 0.52)
0.38
-0.45 (-1.32, 0.43)
0.10 (-0.36, 0.56)
0.38
Model 5
Adjustments:
Sex and other parent’s alcohol consumption, + maternal age, parity, ethnicity; SEP; + maternal and paternal
education; + maternal and paternal smoking
Effects of maternal and paternal ‘binge’ drinking during
pregnancy on offspring IQ in childhood – age 8
1
0.5
0.56
0.43
0.1
0
F= 0.38
-0.45
-0.5
-0.36
-1
-1.32
-1.5
Mothers
Fathers
Is intrauterine exposure to alcohol
use associated with IQ in
childhood?
• In unadjusted analyses greater frequency of drinking 4 or more units on a
single occasion by mothers was associated with lower scores on verbal
and total IQ scales in children.
• In adjusted analyses, however, we found no strong evidence of an
intrauterine effect effect of alcohol consumption in first 3 months of
pregnancy by mothers and variation in childhood mean IQ or prevalence of
low IQ.
• Parental educational attainment was strongly associated with offspring IQ.
Alati R, Macleod J, Hickman M, Sayal K, May M, Davey-Smith G, et al. Intrauterine
Exposure to Alcohol and Tobacco Use and Childhood IQ: Findings from a ParentalOffspring Comparison within the Avon Longitudinal Study of Parents and Children.
Pediatric Research. 2008;64(6):659-66.
Acknowledgements
The ALSPAC participants
The ALSPAC Team
The MUSP participants
The MUSP Team
Principal Investigators
Research Fellows
International collaborators
Project Managers