Does in-utero alcohol exposure impact on adverse

outcomes in offspring?Rosa Alati

NHMRC research fellowSchool 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

– Mental health problems– Disrupted school experience– Trouble with the law– Confinement– Inappropriate sexual behavior– Alcohol and drug problems

Secondary disabilities

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 GuidelinesTO 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 GuidelinesTO 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?

• 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.

• Evidence from animal studies

Is there a role for a developmental origin of alcohol problems?

• 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

Animal studies

Evidence from animal studies

• 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

Advantages

Evidence from animal studies

• 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.

Disadvantages

Is there a role for a developmental origin of alcohol disorders?

• 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

Seattle Longitudinal Study of Alcohol and Pregnancy

• 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

MUSPMater-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) Sample size Children (C) n=7223 n=7223 n=6720 n=5259

n=5172 n=5172

n=4100 n=3910

Alcohol use M M M M MC MC Tobacco/ illicit substance use M M M M MC MC SES - Education

Income, Marital status M M

M

M

M

C M

MC MC

Stress Depression / anxiety

M M

M M

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 WRAT/Ravens SPM C

C 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

Onset alcohol abuse/

dependence at age 21

SES - Maternal education & age, income, marital status, birth weight, gestation

Early pregnancy

Smoking

After pregnancy

(At 5 / 14 yrs)

Early adulthood

Smoking

Child cognitive

functioning

Alcohol exposure

Before pregnancy

Smoking

Alcohol exposure

Smoking

Late pregnancy

Alcohol exposure

Alcohol exposure

Socio economic / hereditary

Biological Biological Parental modelling

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   %

No diagnosis 1915 75.0

Early onset (< 18 yrs) 333 13.0

Late onset (18 + yrs) 307 13.0

Total 2555 100

Alcohol exposure over the life course

N   %

Always < 3 glasses 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

Alcohol exposure of 3 + glasses over the life course and early onset of alcohol disorders

Unadjusted OR (95%CI)

Life course exposure

3.22

1.591.31

0.96

0.00

1.00

2.00

3.00

4.00

5.00

2.43

1.191.04

0.71

1.671.50

0.00

1.00

2.00

3.00

4.00

5.00

Alcohol exposure of 3 + glasses over the life course and early onset of alcohol disorders

Life course exposure

Adjusted OR (95%CI)

2.68

1.661.48 1.44

0.00

1.00

2.00

3.00

4.00

5.00

Alcohol exposure of 3 + glasses over the life course and late onset of alcohol disorders

Life course exposure

Unadjusted OR (95%CI)

Alcohol exposure of 3 + glasses over the life course and late onset of alcohol disorders

Life course exposure

Adjusted OR (95%CI)

2.68

1.54 1.45 1.44

1.120.83

0.00

1.00

2.00

3.00

4.00

5.00

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

• 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

• CONFOUNDING• Unable to assess all potentially important

factors– Peer influences– Paternal alcohol use– Is assessment of time of exposure a robust approach?

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 (WISC-

III)

– 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

Model 5   -0.45 (-1.32, 0.43) 0.10 (-0.36, 0.56) 0.38

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

Mothers Fathers-1.5

-1

-0.5

0

0.5

1

F= 0.38

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 Parental-Offspring Comparison within the Avon Longitudinal Study of Parents and Children. Pediatric Research. 2008;64(6):659-66.

Acknowledgements

The ALSPAC participantsThe ALSPAC Team

The MUSP participantsThe MUSP Team

Principal Investigators Research Fellows

International collaborators Project Managers