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Does in-utero alcohol exposure impact on adverse outcomes in offspring? Rosa Alati NHMRC research fellow School of Population Health & Centre for Youth.

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Presentation on theme: "Does in-utero alcohol exposure impact on adverse outcomes in offspring? Rosa Alati NHMRC research fellow School of Population Health & Centre for Youth."— Presentation transcript:

1 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)

2 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

3 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

4 Physical Characteristics of FAS

5 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

6 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

7 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?

8 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

9 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.

10 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?

11 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

12 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)

13 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: Chotro MG, Arias C. Prenatal exposure to ethanol increases ethanol consumption: a conditioned response? Alcohol 2003;30: 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: 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: Evidence from animal studies

14 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

15 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

16 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: Disadvantages

17 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): 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: 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:

18 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):

19 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

20 MUSP Mater-University of Queensland Study of Pregnancy and its outcomes Brisbane Australia

21 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), 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)

22 Mater Misericordiae Hospital 1981

23

24 Brisbane City Council – MUSP 21 birthday 2004

25 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.

26 Summary of MUSP variables from the prenatal period to 21 years

27 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 Socio economic / hereditary Biological Parental modelling

28 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)

29 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)

30 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)

31 Sample by early and late onset of alcohol disorders (DSM-IV) N % No diagnosis Early onset (< 18 yrs) Late onset (18 + yrs) Total

32 Alcohol exposure over the life course N % Always < 3 glasses in early pregnancy in late pregnancy only after pregnancy (not during) pregnancy before and after (not during) pregnancy Total

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

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

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

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

37 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

38 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

39 Strengths Longitudinal Population sample Considered biological, environmental and family factors simultaneously R. Alati, AA Mamun, GM Williams, M OCallaghan, JM Najman, W. Bor (2006). Does in utero alcohol exposure predict alcohol disorders in early adulthood? A birth cohort study. Archives of General Psychiatry

40 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 OCallaghan, 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?

41 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?

42 The ALSPAC study (Children of the 90s) 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.

43 Is intrauterine exposure to alcohol and tobacco use associated with IQ in childhood? Childs 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.

44 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 (-0.11, 1.20)1.38 (0.94, 1.81)0.005 Model (0.03, 1.33)1.17 (0.74, 1.60)0.08 Model (-0.46, 0.74)0.41 (0.00, 0.81)0.43 Model (-0.46, 0.75)0.41 (0.00, 0.82)0.43 Model (-0.58, 0.65) 0.40 (-0.01, 0.82) 0.43 Drinking frequency of 4 + units Model (-2.53, -0.67)0.16 (-0.33, 0.66)0.001 Model (-2.02, -0.18)0.04 (-0.45, 0.53)0.03 Model (-1.26, 0.45)0.07 (-0.39, 0.52)0.38 Model (-1.28, 0.44)0.06 (-0.40, 0.52)0.38 Model (-1.32, 0.43) 0.10 (-0.36, 0.56) 0.38 Adjustments: Sex and other parents alcohol consumption, + maternal age, parity, ethnicity; SEP; + maternal and paternal education; + maternal and paternal smoking

45 Effects of maternal and paternal binge drinking during pregnancy on offspring IQ in childhood – age 8

46 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):

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


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