Two Decades of Research on FAS and FASD in the Western Cape

Transcription

1 Two Decades of Research on FAS and FASD in the Western Cape Philip A. May, Ph.D. Research Professor Nutrition Research Institute Gillings School of Global Public Health University of North Carolina at Chapel Hill, USA

2 Shoe-Leather Epidemiology A colloquial term: Gathering of information for epidemiologic studies by direct inquiry among the people. For example: walking from door to door and asking questions (wearing out shoe leather in the process). Getting out in the field, towns, and communities, and immersing oneself in the setting. In the Western Cape: taking a team of clinical specialists to schools to assess and diagnose FASD. Source: Last, J.M. (ed.) A Dictionary of Epidemiology, 4 th edition, 2001.

3 FASD is Medical Diagnosis The diagnosis is best made by a pediatrician who is trained in diagnosis of a variety of birth defects (Hoyme, et al., 2015): Medical genetics. Teratology. The diagnosis involves three specific domains: Physical growth and development and dysmorphology. Cognition and behavior. Maternal risk factors.

4 Terminology for Fetal Alcohol Spectrum Disorders (FASD) U.S. Institute of Medicine (IOM) Recommended Terminology (Stratton, et al., 1996): FAS fetal alcohol syndrome PFAS partial fetal alcohol syndrome ARND alcohol-related neurodevelopmental deficits ARBD alcohol-related birth defects

5 Organization of the Talk 1.) Epi of FASD in South Africa. 2.) Prevalence of FASD in Various Countries with New Estimates. 3.) Implications for Prevention. 4.) Current initiatives in South Africa.

6 (1.) Epidemiology of FASD in South Africa (SA Sample IV)

7 Studies in South Africa: Why?

8 Two children of the same age in 1 st grade: 50 th vs. 1 st centile 1. Population is purely alcohol exposed. 2. Binge drinking pattern is very regular. 3. FASD rates among the Coloured population are extremely high.

9 Two Diagnostic Conundrums in FASD Inaccurate reports of maternal drinking, especially in first world countries: Denial of any drinking in the prenatal period. Misrepresentation/Underreporting of the QFT. Extreme variation in cognitive and behavioral outcomes. Within diagnostic groups (FAS, PFAS, ARND). Among/Between diagnostic groups.

10 FASER- SA History (cont.) Epidemiological studies of the prevalence and characteristics of FAS, and in the latter studies, PFAS, and ARND were completed via NIAAA supplemental grants and later large RO1/UO1 grants. Each covered all three domains of FASD research: Child physical characteristics and prevalence Maternal risk factors Cognitive and behavioral characteristics The studies: Wellington , 1999, 2002, 2008, 2010, BRAM , 2011, 2016.

11 The bi-national diagnostic and research team in S.A., 1999.

12 Overview of In-school Study Design Tier I Tier II Tier III Final Diagnosis Randomly Selected Controls Height, Weight and Occipitofrontal Circumference Measured for all children Cut off: < 10 th or 25 th centile Physical Growth and Development and Dysmorphology Exam Maternal Interviews Neuropsychology and Psychological Development Testing CASE CONFERENCE Interdisciplinary review for each child: Physical growth & dysmorphology Psychological & behavioral testing Maternal risk factors Final Diagnosis with IOM categories: Not FAS FAS PFAS ARND ARBD Sources: Multiple

13 Women working #30

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15 Quantities of different drinks that are the same as ONE standard drink 1 glass wine (125ml) 1 single measure spirits (25ml) 1 bottle beer/cider (330ml) 1 can beer/cider (330ml) 1 carton ijuba (1L) R2-00 jar isiqatha/injemane The number of standard drinks in commonly purchased quantities of alcohol 1 bottle spirits (750ml) 1 bottle wine (750ml) 1/2 bottle spirits (375ml) 1 quart beer/cider Double measure spirits (50ml) Isiqatha or injemane R4-00 jar R2-00 jar R1-00 jar /2

16 One South African rolled cigarette = I gram of tobacco

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19 The Severity and Appearance of the Physical Phenotype of FASD and Normal Varies Within as Well as Between Each Group

20 Variable Sex (%) Table 1. SA IV Children s Demographic, Growth, and Dysmorphology All Children 1 (n=747) Children with FAS (n=68) Children with Partial FAS (n=52) Children with ARND (n=35) Exposed R-S Controls (n=38) Unexposed R-S Controls (n=90) Males Females Statistical Test P X 2 = Age (months) Mean (SD) 81.4 (7.1) 85.4 (8.7) 81.4 (9.5) 84.0 (7.9) 80.7 (6.7) 80.0(6.2) F = 5.57 <.001 Height (cm) (5.9) Mean (SD) (5.5) (7.5) (4.9) (5.5) (6.3) F = 5.50 <.001 Weight (kg) Mean (SD) 20.7 (3.6) 17.7 (2.1) 20.0 (3.1) 18.9 (1.9) 20.5 (2.7) 21.1 (3.5) F = <.001 Child s BMI Mean (SD) 15.3 (1.6) 14.2 (1.1) 15.0 (1.0) 14.6 (1.2) 15.3 (1.1) 15.4 (1.8) F = 9.24 <.001 BMI Percentile (27.5) Mean (SD) (16.9) 37.0 (21.2) 27.8 (25.3) 43.6 (25.0) 47.4 (24.9) F = <.001 Head Circumference 50.9 (2.4) 48.6 (1.3) (OFC; in cm) 50.0 (1.3) 49.4 (0.8) 51.1 (1.2) 51.1 (1.5) F = <.001 Mean (SD)

21 SA IV Children s Demographic, Growth, and Dysmorphology Variable Palpebral Fissure Length (cm) Mean (SD) Percent Palpebral Fissure Length (%) is of Inner Canthal Distance Maxillary Arc (cm) Mandibular Arc (cm) Children with FAS (n=68) Children with Partial FAS (n=52) Children with ARND (n=35) Exposed R-S Controls (n=38) Unexposed R-S Controls (n=90) Statistical Test 2.31 (0.2) 2.35 (0.1) 2.39 (0.1) 2.43 (0.1) 2.45 (0.1) F = < (9.7) 82.7 (10.2) 87.8 (7.9) 87.4 (9.6) 85.7 (9.7) F = (0.8) 23.8 (1.0) 23.5 (1.1) 24.1 (0.9) 23.8 (2.6) F = (0.9) 24.7 (1.2) 24.4 (1.1) 25.1 (1.1) 25.1 (0.9) F = <.001 P

22 Table 1 (cont.) SA IV Children s Demographic, Growth, and Dysmorphology Variable Short Inner Pupilary Distance (%) Hypoplastic Midface (%) Smooth Philtrum (%) Narrow Vermillion Border (%) All Children (n=747) Children with FAS (n=68) Children with Partial FAS (n=52) Children with ARND (n=35) Exposed R-S Controls (n=38) Unexposed R-S Controls (n=90) Statistical Test X 2 = < X 2 = < X 2 = < X 2 = P <.001 Railroad Track Ears (%) X 2 = Ptosis (%) X 2 = Epicanthal Folds (%) X 2 = <.001

23 Table 1 (cont.) SA IV Children s Demographic, Growth, and Dysmorphology Variable All Children (n=747) Children with FAS (n=68) Children with Partial FAS (n=52) Children with ARND (n=35) Exposed R-S Controls (n=38) Unexposed R-S Controls (n=90) Statistical Test P Clinodactyly (%) X 2 = Camptodactyly (%) Palmar Crease Alteration (%) Total Dysmorphology Score Mean (SD) X 2 = X 2 = (3.9) 14.3 (3.1) 12.2 (3.3) 8.2 (3.6) 7.1(3.6) F = <.001 Source: May et al., ACER, 2013

24 TABLE 2. Mean Developmental and Behavioral Indicators 1 of Children with Specific FASD Diagnoses vs. Normal Controls: SA IV (n = 272) Child Variables FAS (SD) PFAS (SD) Developmental Traits Children with ARND (SD) Exposed R-S Controls (SD) Unexposed R-S Controls (SD) (n =66) (n = 51) (n = 35) (n = 38) (n= 87) Test Score P Verbal IQ a 5.1 (7.6) 5.7 (10.2) 5.2 (7.5) 8.2 (7.9) 13.4 (18.2) F = 5.85 <.001 Non-verbal IQ b 8.9 (7.2) 14.4 (12.1) 7.7 (4.5) 17.8 (10.9) 22.2 (18.1) F = <.001 WISC-IV Digit- Span Scaled Score Achenbach Teacher Report Form 4.4 (2.6) 5.1 (2.8) 4.7 (2.7) 6.8 (3.5) 6.7 (3.3) F = 8.07 < (42.6) 45.1 (42.2) 58.3 (33.7) 35.8 (35.5) 29.1 (29.1) F = 5.63 <.001 Source: May et al., ACER, 2013

25 Simple View of Causation: Severity of Damage An individual child s traits of FASD are influenced totally by: Quantity (amount) of alcohol consumed by mother during pregnancy. Frequency (how often) that a mother drinks. Timing of the drinking during gestation of the fetus. Source: May, 1995; Stratton, et al, 1996.

26 TABLE 3. Substance Use By Mothers of Children with FASD and Controls: SA IV Maternal Variables Mothers of Children with FAS Mothers of Children with Partial FAS Mothers of Children with ARND Mothers of R-S Exposed Control Children Mothers of R-S Unexposed Control Children Statistical Test df P Drinking Indicators overall reported drinking during pregnancy (%) Average No. drinks per week (during pregnancy) Consumed 3 drinks or more per occasion during pregnancy (%) Consumed 5 drinks or more per occasion during pregnancy (%) Current drinker in last year (%) (n = 68) (n = 52) (n = 35) (n =38) (n = 90) X 2 = df = 4 < (14.0) 13.1 (16.1) 13.0 (15.0) 5.6 (5.3) 0.0 (0.0) F = df = 4/207 < X 2 = df = 4 < X 2 =69.92 df = 4 < X 2 = df = 4 < Dunnett's C post hoc analyses show that FAS and Unexposed Controls differ at the P =.05 level. Source: May et al., ACER, 2013

27 Mean Number of Standard Drinks per Week During Pregnancy by Diagnostic Group Error bars = 95% Confidence Interval Diagnostic Group

28 Mean Number of Drinks Consumed per Drinking Day During Pregnancy by Diagnostic Group Error bars = 95% Confidence Interval Diagnostic Group

29 Overall Peak BAC Mean Mean Peak BAC (at least one time during pregnancy) by Diagnostic Group Error bars = + one Standard Deviation (SD) FAS PFAS ARND Exposed Controls Unexposed Controls Diagnostic Group

30 Mean Drinks per Drinking Day Mean Drinks per Drinking Day (DDD) by Trimester and Diagnostic Group Error bars = + one Standard Error Diagnostic Group

31 Mean Drinks per Drinking Day Mean Drinks per Drinking Day (DDD) by Trimester and Diagnostic Group (with Standard Deviations to emphasize Individual variation) Error bars = + one Standard Deviation (SD) Diagnostic Group

32 Frequency: Drinking Days per Week During Pregnancy (SA IV) Maternal Variable Mean Number of Drinking Days per Week Mothers of Children with FAS 2.27 (1.2) Mothers of Children with PFAS 1.75 (1.1) Mothers of Children with ARND 1.88 (1.1) Mothers of Exposed Controls 1.02 (0.6) Mothers of Unexposed Controls F P

33 TABLE 4. Pearson Correlation Coefficients for Developmental 1 and Physical Dysmorphology vs. Selected Maternal Drinking Measures During Pregnancy: South Africa Wave IV Trait Reported Drinking During Pregnancy Drinks Per Month Drinks Per Day 3 Drinks Per Occasion 5 Drinks Per Occasion (N = 339) (n = 302) (n = 302) (n = 302) (n =302) Verbal ability a *** ** ** ** ** Non-verbal ability b *** ** *** *** *** Behavior c.203 ***.172 **.232 ***.237 ***.233 *** Dysmorphology score.431 ***.353 ***.378 ***.467 ***.384 *** 1 All scores standardized for age of child at time of testing. a. Tests of the Reception of Grammar (TROG). Source: May et al., ACER, 2013 b. Raven Colored Progressive Matrices. c. Personal Behavior Checklist (PBCL-36). *p <.05; **p <.01; ***p <.001

34 From Maternal QFT of Drinking Study: Comparisons of Odds of FASD for Mothers' Drinking Behavior over Pregnancy Trimesters 95% CI for Odds Ratio Drinking Behavior p Odds Ratio Lower Upper Nagelkerke R 2 First trimester only vs. no drinking <.001* First and second trimesters only vs. no drinking <.001* All trimesters vs. no drinking <.001* Third trimester only vs. no drinking First and second trimesters vs. first trimester only All trimesters vs. first trimester only All trimesters vs. first and second trimesters only *p <.007 note: no cases for T2 and T3 but not T1 Source: May et al., DAD, 2013

35 TABLE 5. Prevalence Rates (per 1,000) of Individual Diagnoses and Total FASD: South African Community, Wave IV Diagnosis n Enrolled rate 1 (n=1147) Consented rate 2 (n=747) FAS PFAS ARND Total FASD (13.5%) (20.7%) 1. Denominator is all children attending first grade in local schools. 2. Denominator is the total number of child with consent to participate in this study. Source: May et al., ACER, 2013

36 Rate per 1,000 Wellington IV Oversample of Small Children (< 25 th centile on height, weight, and head circumference) and Case from the Randomly-Selected Children Simple Random Sample for Entry into Study Error bars = 95% confidence intervals

37 Rate per 1,000 BRAM I Oversample of Small Children (< 25 th centile on height, weight, and head circumference) and Case from the Randomly-Selected Children Simple Random Sample for Entry into Study Error bars = 95% confidence intervals

38 Multiple Maternal Characteristics Predicting Child Dysmorphology And Diagnosis South Africa waves I, II, and III (combined) 9.64* (.51) 1.12* (.38) 2.67* (.82) 0.30* (.60) -0.54* (-.44) 3.73* (.57) 1.39* (.95) 4.58* (.58) 0.52* (.52) -0.12* (-.12) -0.36* (-.36) 0.46* (.46) 0.47* (.47) 0.87* (.23) n.s. (.61) 2.26* (.62) 0.24 n.s. (.06) -1.47* (-.80) 0.06* (.48) 0.27* (.92) R 2 = 62.0% 1.27* (.96) -0.69* (-.89) 1.00 (.62) Source: May, et al., DAD, * (-.71) 0.41* (.84) -0.75* (-.97) 0.38* (.83)

39 Maternal Drinking Characteristics Predicting I.Q. and Problem Behavior: SA, waves I, II, and III (Total Variance explained - R 2 = 17.3%) 0.69* (-.89) 0.34* (.70) 0.31* (.68) 0.41* (.83) -0.74* (-.97) -0.57* (-.69) 0.39* (.83) 3.10* (.42) 1.00 (.67) -0.60* (-.53) 1.52* (.83) 1.00 (.91) Source: May et al., JDBP, 2013

40 Multiple Maternal Predictors of a Child s Neuro- Psychological Characteristics: South Africa, waves I, II, and III combined. Total variance explained: R 2 = 55.3% 8.40* (.45) 1.31* (.43) 2.62* (.91) 0.30* (.60) -0.56* (.43) 3.73* (.57) 1.39* (.95) 0.29* (.68) 1.27* (.96) -0.69* (-.89) -.54* (-.69) 4.66* (.59) 0.51* (.51) -0.36* (.36) 0.32* (.70) 0.41* (.83) -0.13* (.13).47* (.47) 0.38* (.83) 0.48* (.48) -0.75* (-.97) 2.70* (.36) 3.83* (.52) 0.52 n.s. (.07) n.s. (-.01) 1.00 (.67) 1.00 (.69) 1.44* (.81) -0.59* (-.54) Source, May et al., JDBP, 2013

41 2.) Review of Prevalence Findings from In-School Studies of FASD

42 Our In-School Studies Funded by: NIH/ National Institute on Alcohol Abuse and Alcoholism (NIAAA). Thanks to: Jan Howard, Ph.D., Patricia Mail, Ph.D., and Marcia Scott, Ph.D. A very special thanks to: Kenneth Warren, Ph.D. Faye Calhoun, Ph.D. Ting Kai Li, M.D. Enoch Gordis, M.D.

43 Location of FASER In-School Samples United States (4) Italy (2) South Africa (7)

44 FASER Research Teams: New Mexico: 2013 South Africa: 2013 South Dakota: 2012 South Africa: 2009 Italy: 2006

45 Summary Rates of FAS by Country for In-School Studies (avg. per 1,000) Current High Estimate: 3 per 1,000 (5 studies) (2 studies) (3 pilot studies) (1 study) Various sources

46 Avg. Rate Per 1,000 Summary Rates of FASD by Country for In-School Studies (avg. per 1,000) South Africa Italy USA-Rocky (5 studies) (2 studies) Mountain (3 pilot studies) 28.6 Current Estimate: 9.1 USA- Midwest City (1 study) Source: May et al., DDRR, 2009; and unpublished data.

47 New General Population Prevalence Estimates of FASD: In-School Studies Estimates per 1,000: Old New - In-school FAS FASD 9.1 (1%) (2-5%) Source: May et al., DDRR, 2009.

48 (Rates per 1,000) Source: May et al., DDRR, 2009.

49 The FASD Iceberg Analogy Above water: Only some FAS and PFAS children w/ manifest problems and classic dysmorphology will reach tertiary clinics for diagnosis. Below water: Many children with FAS, PFAS, and ARND who can be found in a general population.

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52 3.) Implications for Prevention All of our research in the Western Cape is undertaken under an umbrella of Prevention. Primary/universal via abstinence from alcohol: entire prenatal period and when breastfeeding Secondary via antenatal clinics. Tertiary (case management of mothers) or Intervention for those born with an FASD is very promising.

53 * Intervention: Educational Nutritional Comprehensive Prevention of FASD: IOM, 1996

54 (100% preventable) (100% Irreversible)

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56 Early diagnosis leads to better life chances.

57 Mean change in all PAELT scores for Language and Literacy Therapy Participants, FASD-Controls and NONEXP-Control groups of 8 to 10 year olds after 9 and 18 months LLT intervention: South Africa Mean PAELT score change * LLT FASD-C NONEXP-C 5 0 T1 - T2 T1 - T2 = Baseline to 9 months * P <.000 LLT vs FASD-Change * P <.000 LLT vs NONEXP-Change T2 - T3 Source: Adnams, et al., Alcohol, T2 - T3 = 9 months to 18 months PAELT = Phonological awareness and early literacy test.

58 4.) Current FASD Epidemiology Research in South Africa (FASER-SA)

59 FASER- SA History (cont.) Grant was brought to Stellenbosch University, Faculty of Health Sciences for what has become a very successful collaboration and completion of all activities.

60 Field Offices for FASER-SA 2006-present Wellington Robertson

61 Specific Aims of the Current (Second Major) Grant for FASER-SA

62 Specific Aims of the Current Grant: Trajectory of FASD Across the Lifespan 1.) Initiate early intervention/remediation research for development of children with FASD from 12 months of age forward through: nutritional and cognitive/behavioral enhancement

63 Specific Aims of the Current Grant: Trajectory of FASD Across the Lifespan 2.) Continue a detailed longitudinal study of the physical and cognitive/behavioral developmental trajectory of children from the newborn period to seven years of age. to characterize FASD traits in this early period to finalize universal diagnostic protocols for FASD in the earliest months of life.

64 Specific Aims of the Current Grant: Trajectory of FASD Across the Lifespan 3.) Initiate an efficacy study of biomarkers to detect alcohol consumption in the prenatal period: a.) ethyl glucaronide (EtG) and b.) phosphatidyl ethanol (PEtH) We facilitate this new aim by continuing selected prevention of FASD in antenatal clinics.

65 Specific Aims of the Current Grant: Trajectory of FASD Across the Lifespan 4.) Initiate new methodology to study the nutrition of pregnant women via a survey of all major vitamins, minerals, and micro nutrients through 24-hour dietary recall and genetic influences on metabolism of selected key nutritients. We facilitate this new aim by continuing secondary and tertiary prevention trials via the treble approach in case management.

66 Specific Aims of the Current Grant: Trajectory of FASD Across the Lifespan 5.) Evaluate the impact of nine years of IOMrecommended comprehensive prevention efforts with: a third, random survey of the community on Knowledge, Attitudes, Beliefs, and Behaviors (KABB) and final repetition of local in-school studies of the prevalence and characteristics of FASD Wellington 6 and Robertson and Ashton 3.

67 The USA and ZA team members: 2011

68 The Quest Continues.