Presentation on theme: "Rosa Alati NHMRC research fellow School of Population Health &"— Presentation transcript:
1Does in-utero alcohol exposure impact on adverse outcomes in offspring? Rosa AlatiNHMRC research fellowSchool of Population Health &Centre for Youth Substance Abuse Research (CYSAR)University of Queensland (Australia)In collaboration withQueensland Alcohol and Drug Research and Education Centre (Qadrec)
2FETAL 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 documentedprenatal and postnatal growth retardation,characteristic facial features,central nervous system problems, andprenatal exposure to alcohol
3Prenatal and postnatal growth retardation Below average height, weight or bothPhysical Characteristics of FASSmall head circumferenceSmall eye openingsSmooth, wide philtrumThin upper lip
5Central nervous system problems Can be assessed in three areasStructuralMicrocephalyNeurologicalepilepsy /seizure disorderssofter signsbroader, nonspecific neurological symptoms: impaired motor skills, clumsiness, poor eye-hand coordinationFunctionalbehavior or cognitive abnormalities
6Secondary disabilities Primary disabilitiesCognition — Mental retardation, slower cognitive processingAchievement — Learning disabilitiesAdaptive behavior — developmental delaysAttention — Attention-Deficit/Hyperactivity Disorder (ADHD),Executive functioningSecondary disabilitiesMental health problemsDisrupted school experienceTrouble with the lawConfinementInappropriate sexual behaviorAlcohol and drug problems
7Prenatal exposure to alcohol How much is too much?Heavy consumption of alcohol or binge-type patterns of drinkingBUTHow about low levels of consumption in pregnancy?How much reason for concern?
8Australian 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 weekMaternal 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.
9Australian Guidelines TO REDUCE HEALTH RISKS from Drinking Alcohol Revision of the new alcohol guidelines 2009:PRECAUTIONARY APPROACHFor 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.
10Two 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?
11Challenges Retrospective surveys Pre-birth cohort studies CONFOUNDING Recall biasPre-birth cohort studieslong term follow-up of mothers and their childrenCONFOUNDINGTake into account additional influencesalso associated with these outcomes and may be the true causeSEP, education, timing of alcohol use
12Two 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)
13Is there a role for a developmental origin of alcohol problems? Evidence from animal studiesNizhnikov 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: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:
14Is there a role for a developmental origin of alcohol problems? Animal studiesAssociation between in-utero alcohol exposure and the development of early uptake of and greater alcohol consumption in adolescent animals.More severe effectswhen alcohol is administered all at once rather than gradually,The effect holds even for small quantities of injected ethanol
15Evidence from animal studies AdvantagesThe use of animal models permitsAccuracy of alcohol intake (eg grams)Control for environmental factorsControl for maternal exposure at other time periodsIsolate the influence of alcohol use by othersExplore effects at critical periodsTiming of the exposure
16Evidence from animal studies DisadvantagesCan findings be generalised to humans?Animals differ from humans intheir level of susceptibility to substances andin 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.
17Is there a role for a developmental origin of alcohol disorders? Seattle Longitudinal Study of Alcohol and PregnancyMaternal 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 25Baer 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:
18Is 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):
19Issues related to human studies Familial history of alcohol problemsPaternal alcohol useMaternal use of other substance use in pregnancyTobacco particularlyMaternal alcohol use at other time periodsModelling influenceSiblings alcohol useTiming of the exposureFirst, second or third semester?How to disentangle timing
20MUSP Mater-University of Queensland Study of Pregnancy and its outcomes 1981-2004 Brisbane Australia
21Mater-University Study of Pregnancy (MUSP) Pregnancy/birth cohort study of mothers and children7,223 live singleton babies52% males (n=3758) and 48% females (n=3465)Enrolled at first clinic visit at the Mater Misericordiae Hospital (Brisbane, Australia),Follow-up3-5 days6 months5 and 14 years after the birth21 years after the birth 2555 participants completed the alcohol modules of the Composite International Diagnostic Interview – computerised version (CIDI-Auto)
25Content of MUSP Socio-demographics Age, marital status, income, religiosity, employment status, marital status changes, number of children in household, etc.LifestyleTobacco, alcohol, illicit drugs, breastfeeding duration, patterns of child care, feelings about child, physical activity, diet (FFQ), TV watching, delinquency.
26Summary of MUSP variables from the prenatal period to 21 years
27Socio economic / hereditary Child cognitive functioning BiologicalBiologicalSocio economic / hereditaryParental modellingOnset alcohol abuse/dependence at age 21Alcohol exposureAlcohol exposureAlcohol exposureAlcohol exposureEarly pregnancyAfter pregnancy(At 5 / 14 yrs)Before pregnancyLate pregnancyEarly adulthoodSmokingSmokingSmokingSmokingDespite 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 functioningSES - Maternal education & age, income, marital status, birth weight, gestation
28MeasuresOutcomeLifetime diagnosis of alcohol abuse and dependence (DSM-IV)Time of onset< 18 years18 + yearsAlcohol abuse: A destructive pattern of alcohol use, leading to significant social, occupational, or medical impairmentAlcohol dependence (must have three or more of the following):Alcohol toleranceAlcohol withdrawal symptoms: EitherTwo or more withdrawal symptoms orAlcohol is taken to relieve or avoid withdrawal symptomsDiagnostic and Statistical Manual of Mental Disorders DSM-IV-TR,American Psychiatric Association, 2000the Composite International Diagnostic Interview – computerised version (CIDI-Auto)
29Measures Main predictor and main confounder Other confounders Alcohol composite measureRepeated measures of number of glasses per drinking occasion< 3 glasses3 + glassesTiming of the exposurepre-pregnancyearly pregnancylate pregnancyat 5 years and14 yearsTobacco composite measureRepeated measure of smoking/no smoking statusOther confoundersBirth weight, gestational age, maternal education, age, marital status, family income, maternal anxiety and depressionMediatorsChild behaviour (YSR) Cognitive function at age 5 (Peabody)Paternal/ siblings alcohol problems (In sensitivity analysis at age 14)
30Data analysis Age adjusted multinomial logistic regression with a 3-level categorical end pointReference category “No Disorder”,“Early onset (< 18 yrs) ”“Late onset (18 + yrs) ”
31Sample by early and late onset of alcohol disorders (DSM-IV) %No diagnosis191575.0Early onset (< 18 yrs)33313.0Late onset (18 + yrs)307Total2555100
32Alcohol exposure over the life course N%Always < 3 glasses224349.83 + in early pregnancy2495.53 + in late pregnancy1633.63 + only after pregnancy (not during) pregnancy84118.73 + before and after (not during) pregnancy100522.3Total4501100.0
33Alcohol exposure of 3 + glasses over the life course and early onset of alcohol disorders Unadjusted OR (95%CI)Life course exposure
34Alcohol exposure of 3 + glasses over the life course and early onset of alcohol disorders Adjusted OR (95%CI)Life course exposure
35Alcohol exposure of 3 + glasses over the life course and late onset of alcohol disorders Unadjusted OR (95%CI)Life course exposure
36Alcohol exposure of 3 + glasses over the life course and late onset of alcohol disorders Adjusted OR (95%CI)Life course exposure
37Main findingExposure to relatively moderate alcohol use in early pregnancy is an independent predictor of alcohol disorders in early adulthoodEarly onsetAlcohol use in early pregnancy predicted early onset alcohol disorders. The effect was only partly accounted for by maternal smoking during pregnancyLate onsetAlcohol use in early pregnancy may predict late onset alcohol disordersMaternal drinking at other time periods was also associated with late onset
38Possible mechanisms for the association Exposure during pregnancy may act by modifying the natural reward circuitry of the brainThis circuit involves the mesolimbic dopamine system, with dopamine-producing neuronsLong-term effects on the hypothalamus and/or pituitary adrenal axis,lead to increased alcohol intake in adult offspring
39Strengths Longitudinal Population sample Considered biological, environmental and family factors simultaneouslyR. 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
40Limitations Attrition Combination of multiple imputation and IPWNo follow-up data available between 5 and 14 years of ageCONFOUNDINGUnable to assess all potentially important factorsPeer influencesPaternal alcohol useIs 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
41A better approach to confounding Mendelian randomisationSibling pair approachPaternal and maternal comparisons of alcohol use in pregnancy with outcomes in childhoodAre these different?
42The 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.
43Is 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)Confoundersmarital status, occupational social class, home ownership, crowding condition of the household, ethnicity, gender, maternal parity, education.
44Mean change in offspring IQ per increase in maternal alcohol category Mean change in offspring IQ per increase in maternal alcohol categoryMean change in offspring IQ per increase in paternal alcohol categoryp-value for difference between maternal and paternal associationsComplete case analyses (n=4,332)Amount of alcohol in first 3 months of pregnancyModel 10.55 (-0.11, 1.20)1.38 (0.94, 1.81)0.005Model 20.68 (0.03, 1.33)1.17 (0.74, 1.60)0.08Model 30.14 (-0.46, 0.74)0.41 (0.00, 0.81)0.43Model 40.15 (-0.46, 0.75)0.41 (0.00, 0.82)Model 50.03 (-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
45Effects of maternal and paternal ‘binge’ drinking during pregnancy on offspring IQ in childhood – age 8
46Is 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):