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 prenatal and postnatal growth retardation, characteristic facial features, central nervous system problems, and prenatal exposure to alcohol

Prenatal and postnatal growth retardation Below average height, weight or both Physical Characteristics of FAS Small head circumference Small eye openings Smooth, wide philtrum Thin upper lip

Physical Characteristics of FAS

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

Secondary disabilities 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

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 Maternal alcohol consumption can result in a spectrum of harms to the fetus. Although the risk of birth defects is greatest with high, frequent maternal alcohol intake during the first trimester or throughout pregnancy may have consequences for development of the fetal brain. The guidelines recognises that ‘heavy’ drinking poses the greatest risk; that the timing of exposure is important; and that not all ‘heavy’ drinkers will have an affected child. The previous alcohol guidelines published by NHMRC in 2005 allowed occasional alcohol use during pregnancy.

Australian Guidelines TO REDUCE HEALTH RISKS from Drinking Alcohol Revision of the new alcohol guidelines 2009: PRECAUTIONARY APPROACH For women who are pregnant or planning a pregnancy, not drinking is the safest option. The new guidelines take the view that limitations in the available evidence make it impossible to set a ‘safe’ drinking level for pregnant women. A precautionary approach has been taken in recommending that ‘not drinking alcohol is the safest option’ for pregnant women and women planning a pregnancy. This decision was not based on the fact that substantial new evidence had emerged since the previous guidelines were published, but on limitations of the existing evidence. Women who drank alcohol before they knew they were pregnant or during their pregnancy should be reassured that risk to the fetus from low level drinking is likely to be low. Women who find it difficult to decrease their alcohol intake will require support and treatment.

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 Pre-birth cohort studies CONFOUNDING 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

Socio economic / hereditary Child cognitive functioning Biological Biological Socio economic / hereditary Parental modelling Onset alcohol abuse/ dependence at age 21 Alcohol exposure Alcohol exposure Alcohol exposure Alcohol exposure Early pregnancy After pregnancy (At 5 / 14 yrs) Before pregnancy Late pregnancy Early adulthood Smoking Smoking Smoking Smoking Despite a wealth of research conducted on factors predicting alcohol problems in high-risk populations, little is known about life course predictors of these problems amongst youth. We know for example that events occurring in-utero are associated with a variety of health and mental problems. There is almost no evidence, however, on whether birth or early infant factors predict problematic drinking in early adulthood. Other periods may also be important for the development of alcohol problems. Familial influences, permissive environment, early deviant behaviour in childhood appear to predict alcohol initiation in the late teens, but less is known about childhood predictors of continuation of drinking into early adulthood. To date, the available evidence suggests that early signs of psychopathology, behaviour problems in adolescence, and family structure and other influences are important factors for the development of alcohol problems amongst young adults. Child cognitive functioning SES - Maternal education & age, income, marital status, birth weight, gestation

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 Other confounders 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 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)   % No diagnosis 1915 75.0 Early onset (< 18 yrs) 333 13.0 Late onset (18 + yrs) 307 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

Alcohol exposure of 3 + glasses over the life course and early onset of alcohol disorders Adjusted OR (95%CI) Life course exposure

Alcohol exposure of 3 + glasses over the life course and late onset of alcohol disorders Unadjusted OR (95%CI) Life course exposure

Alcohol exposure of 3 + glasses over the life course and late onset of alcohol disorders Adjusted OR (95%CI) Life course exposure

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 (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 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) Model 5 0.03 (-0.58, 0.65) 0.40 (-0.01, 0.82) Drinking frequency of 4 + units -1.60 (-2.53, -0.67) 0.16 (-0.33, 0.66) 0.001 -1.10 (-2.02, -0.18) 0.04 (-0.45, 0.53) 0.03 -0.41 (-1.26, 0.45) 0.07 (-0.39, 0.52) 0.38 -0.42 (-1.28, 0.44) 0.06 (-0.40, 0.52) -0.45 (-1.32, 0.43) 0.10 (-0.36, 0.56) 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

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.

The ALSPAC participants Acknowledgements The ALSPAC participants The ALSPAC Team The MUSP participants The MUSP Team Principal Investigators Research Fellows International collaborators Project Managers