Early-Life Predictors of Fetal Alcohol Spectrum Disorders Wendy O. Kalberg, MA, LED,a Philip A. May, PhD,a,b,c David Buckley, MA,a Julie M. Hasken, MPH,b Anna-Susan Marais, B Cur Nursing,c Marlene M. De Vries, MSW,c Heidre Bezuidenhout, MBChB, DCH, MSc,d Melanie A. Manning, MD,e Luther K. Robinson, MD,f Margaret P. Adam, MD,g Derek B. Hoyme, MD,h Charles D.H. Parry, PhD,c,i Soraya Seedat, MBChB, MMed, FC Psych, PhD,c Amy J. Elliott, PhD,j,k H. Eugene Hoyme, MDc,k,l,m

BACKGROUND AND OBJECTIVES: Fetal alcohol spectrum disorders (FASD) comprise the continuum of abstract disabilities associated with prenatal alcohol exposure. Although infancy remains the most effective time for initiation of intervention services, current diagnostic schemes demonstrate the greatest confidence, accuracy, and reliability in school-aged children. Our aims for the current study were to identify growth, dysmorphology, and neurodevelopmental features in infants that were most predictive of FASD at age 5, thereby improving the timeliness of diagnoses. METHODS: A cohort of pregnant South African women attending primary health care clinics or giving birth in provincial hospitals was enrolled in the project. Children were followed longitudinally from birth to 60 months to determine their physical and developmental trajectories (N = 155). Standardized protocols were used to assess growth, dysmorphology, and development at 6 weeks and at 9, 18, 42, and 60 months. A structured maternal interview, including estimation of prenatal alcohol intake, was administered at 42 or 60 months. RESULTS: Growth restriction and total dysmorphology scores differentiated among children with and without FASD as early as 9 months (area under the receiver operating characteristic curve = 0.777; P , .001; 95% confidence interval: 0.705–0.849), although children who were severely affected could be identified earlier. Assessment of developmental milestones revealed significant developmental differences emerging among children with and without FASD between 18 and 42 months. Mothers of children with FASD were significantly smaller, with lower BMIs and higher alcohol intake during pregnancy, than mothers of children without FASD. CONCLUSIONS: Assessment of a combination of growth, dysmorphology, and neurobehavioral characteristics allows for accurate identification of most children with FASD as early as 9 to 18 months.

WHAT’S KNOWN ON THIS SUBJECT: Drinking during pregnancy results in aCenter on Alcoholism, Substance Abuse, and Addictions, University of New Mexico, Albuquerque, New Mexico; b d a continuum of disabilities in exposed offspring, fetal alcohol spectrum Nutrition Research Institute, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina; Division of fl c disorders. Although early infant intervention positively in uences long-term Molecular Biology and Human Genetics, Departments of Biomedical Sciences and Psychiatry, Faculty of Medicine developmental outcome of at-risk children, current diagnostic criteria e and Health Sciences, Stellenbosch University, Stellenbosch, South Africa; Departments of Pathology and reveal highest accuracy and reliability in school-aged children. Pediatrics, School of Medicine, Stanford University, Stanford, California; fDepartment of Pediatrics, School of Medicine, State University of New York at Buffalo, Buffalo, New York; gDepartment of Pediatrics, School of WHAT THIS STUDY ADDS: Growth, dysmorphic features, and Medicine, University of Washington, Seattle, Washington; hDepartment of Pediatrics, School of Medicine and neurobehavioral characteristics in infancy can predict which children are at Public Health, University of Wisconsin–Madison, Madison, Wisconsin; iAlcohol, Tobacco, and Other Drug Research greatest risk of being assigned fetal alcohol spectrum disorder diagnoses Unit, South African Medical Research Council, Cape Town, South Africa; jAvera Research Institute Center for at age 5, thereby aiding in timely diagnosis and initiation of intervention Pediatric and Community Research, Sioux Falls, South Dakota; kDepartment of Pediatrics, Sanford School of services in early life. Medicine, University of South Dakota, Sioux Falls, South Dakota; lSanford Children’s Genomic Medicine Consortium, Sanford Health, Sioux Falls, South Dakota; and mDepartments of Pediatrics and Medicine, College of To cite: Kalberg WO, May PA, Buckley D, et al. Early-Life Medicine, University of Arizona, Tucson, Arizona Predictors of Fetal Alcohol Spectrum Disorders. Pediatrics. 2019;144(6):e20182141

Downloaded from www.aappublications.org/news by guest on September 28, 2021 PEDIATRICS Volume 144, number 6, December 2019:e20182141 ARTICLE Fetal alcohol spectrum disorders confidence, accuracy, and reliability of collection tools. As an incentive and (FASD) encompass a range of diagnoses in school-aged reimbursement for their time, – deleterious effects of maternal children.9,10,14 17 participating women and children alcohol consumption during received a grocery store voucher at In the current study, we seek to pregnancy. Together, they comprise each clinic visit. identify discriminating features of the most common environmentally FASD in early life, which will lead to induced category of intellectual improved timeliness of diagnosis. Our disability in the world, potentially Screening for Prenatal Alcohol aims for the study include comparing Exposure and Selection of affecting 1% to 6.5% of school-aged and contrasting young children with Participants children (10–65 per 1000) in the FASD with typically developing United States.1–4 Although the most Trained research staff recruited children on (1) growth patterns, (2) severe end of the FASD continuum pregnant women and their index dysmorphic features, and (3) (fetal alcohol syndrome [FAS]) occurs study children from primary health measures of temperament and in 0.2% to 0.9% of live births (2–9 care clinics and hospitals, explained development, thereby identifying per 1000) in the United States,3 it is the study to prospective participants, features in infants that can most much more common elsewhere.5 For and, after obtaining consent, accurately predict a diagnosis of example, in some communities in the conducted screening interviews that FASD at age 5. Western Cape Province of South included the 10-item Alcohol Use Africa, 9.3% to 12.8% of children Disorders Test (AUDIT).25,26 Women (93–128 per 1000) have documented METHODS with a history of drinking within the FAS, whereas the full gamut of FASD An international multidisciplinary last year were advised about the affects 18.2% to 25.9% of children team of experienced investigators led dangers of drinking during pregnancy 6,7 (182–259 per 1000). the study, which was conducted over and counseled to stop drinking. The – screened women reported the Although several diagnostic schemes an 8-year period (2008 2015). complete gamut of drinking behavior, are used to assign diagnoses in the Dysmorphology and developmental ranging from abstinence to heavy FASD continuum, the parameters set assessments were completed on each drinking. The modal pattern of forth by the Institute of Medicine study child at 6 weeks (time point 1 drinking occurred in binges of $3 have been employed most extensively [T1]) and at 9 (time point 2 [T2]), 18 standard drinks per day (14 g of in international population-based (time point 3 [T3]), 42 (time point 4 absolute alcohol) on weekends. studies.8,9 These diagnostic guidelines [T4]) and 60 months of age (time Initially, any woman who visited recently were updated as the point 5 [T5]). a primary health care clinic for Collaboration on Fetal Alcohol Two regional communities in the antenatal care and who agreed to Spectrum Disorder Prevalence Western Cape Province of South participate was recruited. After (CoFASP) Consensus Clinical Africa with a high prevalence of delivery, the children of enrolled Diagnostic Guidelines for FASD10 documented FASD (comprising 5 women were evaluated at T1, T2, and (Table 1). towns and their surrounding rural – T3. Once several hundred children areas) housed the project.6,7,18 21 The Many consequences of FASD are were recruited and had been followed province’s population encompasses lifelong, and behavioral and learning through T3, a subset for the a diverse racial makeup (mixed race, difficulties constitute a significant longitudinal study was selected. The 50%; black, 33%; white, 16%; and burden. Neuroscience has revealed criteria for inclusion in the Indian or Asian, 1%).22 The that the neural plasticity of young longitudinal cohort included proportion of women who drink brains is positively enhanced by completion of testing at all 3 time heavily during pregnancy in the 2 intervention through early infant periods and maternal AUDIT scores rural agricultural study communities stimulation and augmented .8or,7. Of the 199 children is 23.7%.23 By 20 weeks’ gestation, nutrition.11,12 Although identification initially enrolled in the study, mothers 52.5% of pregnant women receive and referral of at-risk children within of 105 reported AUDIT scores .8 prenatal care, and most women the first few months of life may be (52.8%), and mothers of 94 (47.2%) schedule their first antenatal visit in crucial for initiating effective early reported AUDIT scores ,7. Of the the second trimester.24 intervention services, diagnosis of the women whose AUDIT scores were continuum of FASD in infants is rarely The Faculty of Medicine and Health .8, 44 (42%) scored between 8 and attempted. Such diagnostic Sciences Research Ethics Committees 14, and 61 (58%) scored .15. Of the inattention may be explained by at Stellenbosch University and the women whose AUDIT scores were a lack of phenotypic specificity in the University of New Mexico approved ,7, 52 (55%) scored 0, and 42 (45%) newborn13 and by the higher all study procedures and data scored between 1 and 7. Therefore,

Downloaded from www.aappublications.org/news by guest on September 28, 2021 2 KALBERG et al TABLE 1 Updated Diagnostic Guidelines for FASD CoFASP Consensus Clinical Diagnostic Guidelines for FASD Prenatal Alcohol Exposure FAS Facial Growth Restrictionb Deficient Brain Neurobehavioral Neurobehavioral Structural Featuresa Growthc Impairment Impairment Birth (,3y)d (.3y)e Defectsf FAS With confirmed or XX X X X— unconfirmed alcohol exposure PFAS With confirmed alcohol X —— XX— exposure With unconfirmed alcohol X X (or deficient brain X (or deficient height XX— exposure growth) and/or weight) ARNDg With confirmed alcohol —— — N/A X — exposure Alcohol-related birth defects With confirmed alcohol —— — — — X exposure Adapted from Hoyme HE, Kalberg WO, Elliott AJ, et al. Updated clinical guidelines for diagnosing fetal alcohol spectrum disorders. Pediatrics. 2016;138(2):e20154256. N/A, not applicable; X, required; —, not required. a The characteristic pattern of facial anomalies is defined by the presence of $2 of the following: (1) short palpebral fissures (#10th percentile), (2) thin vermilion border (rank of 4 or 5 on racially normed lip-philtrum guide), and (3) smooth philtrum (rank of 4 or 5 on racially normed lip-philtrum guide). b Prenatal and/or postnatal growth deficiency: height and/or weight #10th percentile on sex-specific population-normed growth curves. c Deficient brain growth, morphogenesis, and/or neurophysiology is characterized by $1 of the following: (1) OFC #10th percentile, (2) structural brain abnormalities, and (3) recurrent nonfebrile seizures. d Affected children must display evidence of developmental delay $1.5 SD below the mean. e Children should be assessed for global, cognitive, and behavioral deficits. Global impairment: general conceptual ability, performance IQ, visual IQ, or spatial IQ $1.5 SD below the mean; cognitive deficit: $1.5 SD below the mean in 1 domain (executive function, specific learning impairment, memory impairment, or visual spatial impairment); behavioral impairment without cognitive impairment: behavioral deficit in 1 domain $1.5 SD below the mean in areas of self-regulation (mood or behavioral regulation impairment, attention deficit, or impulse control). f One or more major malformations demonstrated in animal models and human studies to be related to prenatal alcohol exposure, including cardiac defects (eg, atrial septal defects, ventricular septal defects, aberrant great vessels, conotruncal heart defects), musculoskeletal defects (eg, radioulnar synostosis, vertebral segmentation defects, large joint con- tractures, scoliosis), renal anomalies (eg, aplastic, hypoplastic, or dysplastic kidneys; “horseshoe” kidneys; ureteral duplications), eye anomalies (eg, strabismus, ptosis, retinal vascular anomalies, optic nerve hypoplasia), and/or hearing impairment (eg, conductive or neurosensory hearing loss). g For ARND, 2 domains of impairment are required for either cognitive deficit without behavioral impairment or behavioral impairment without cognitive deficit. the cohort reflected a representative whom were last evaluated at T3. development. A structured maternal range of maternal drinking by design. There were no statistically significant interview was also performed on all differences (on t tests, P , .05) participants. After completion of the Comparison of Excluded Subjects between the 44 children with study, data were analyzed to and Study Participants insufficient data and those with determine which morphometric One mother-child dyad dropped out complete data sets when compared measures, dysmorphic features, immediately (before T1), and an on height, weight, occipitofrontal developmental skills, or combination additional 44 were later excluded (head) circumference (OFC), total thereof was most predictive of from analysis because of insufficient dysmorphology score, or Bayley adefinitive FASD diagnosis at age 5. data. Of the 44 children who were Scales of Infant Development, Third Maternal Interviews excluded from the study, 23 were Edition (BSID-III) cognitive percentile discussed at a case conference after at T3, T4, or T5. A total of 155 Structured maternal interviews were T5 and were found to have children completed the entire used to gather information about insufficient data for inclusion: 18 protocol with a complete data set and maternal age, ethnicity, physical traits because of lack of developmental are included in this analysis. Because (height, weight, OFC, BMI), gravidity, testing and 5 because both testing of the complexity of the project, the parity, time of pregnancy recognition, and prenatal alcohol exposure data number of children seen at each time and drinking before and during were missing. An additional 21 period was variable (Fig 1). pregnancy by trimester. children were not available and were therefore not examined by the The children were assessed on 3 Dysmorphology Assessments dysmorphologists at T5, 9 of whom domains: (1) growth (height, weight, Expert US clinical geneticists and were last examined at T4 and 12 of and OFC), (2) dysmorphology, and (3) dysmorphologists assigned diagnoses

Downloaded from www.aappublications.org/news by guest on September 28, 2021 PEDIATRICS Volume 144, number 6, December 2019 3 FIGURE 1 Consolidated Standards of Reporting Trials chart for the longitudinal study. aAfter 44 subjects were excluded because of incomplete data, 155 children completed the entire battery. using the CoFASP diagnostic scheme and weighted numerical exposed to alcohol. Dysmorphology guidelines for FASD.10 The guidelines scoring system for quantifying examinations adhered to set forth a structured, empirically growth restriction and minor a standardized protocol at each age based dysmorphology assessment anomalies common among children interval (T1–T5). US or South African

Downloaded from www.aappublications.org/news by guest on September 28, 2021 4 KALBERG et al dysmorphologists, pediatricians, or processing index (MPI) that de- diagnoses assigned. Categorical specially trained research staff emphasizes acquired knowledge, diagnoses assigned at case conducted the examinations. All staff instead focusing on sequential and conferences included FAS, partial were trained in the CoFASP simultaneous processing, learning fetal alcohol syndrome (PFAS), diagnostic methodology10 by the ability, and planning ability. The alcohol-related neurodevelopmental expert US dysmorphologists. KABC-II was chosen because it has disorder (ARND), or not FASD. No Examiners were blinded to each been validated for use in previous children met diagnostic criteria for child’s prenatal alcohol exposure South African and other African alcohol-related birth defects.9,10 No history and to the results of any research initiatives.31,32 Two other genetic or malformation previous study assessments at each Afrikaans-speaking clinical syndromes were identified. Final time interval. psychologists who were blinded to diagnoses were assigned by the US alcohol exposure history dysmorphologists in Developmental Assessments: Birth administered the assessment. a multidisciplinary case conference to 42 Months on the basis of the data gathered at Specially trained research staff Data Collection T5 (psychological and behavioral administered the Brazelton Neonatal During the initial clinical assessment assessments, growth, and Behavioral Assessment Scale (BNBAS- at T1, a dysmorphology examination, dysmorphology examinations) and on 3). Assessment of each infant’s ability BNBAS-3 assessment, and BSID-III the basis of alcohol exposure to regulate his or her state was testing were completed. The BSID-III information obtained from the a focus of this study.27 Self-regulation was administered at assessment questionnaire responses provided at (including general irritability, ability points T1 to T4, and the KABC-II was both the initial screening and from to maintain attention, and general completed at T5. US the full maternal interview completed state maintenance) was hypothesized dysmorphologists provided 2 physical at either T4 or T5. At the time of fi to be more difficult for children who examinations, 1 at T4 and 1 at T5. assignment of the nal diagnosis, were prenatally exposed to alcohol. Children who were born before 36 diagnosticians were blinded to any Specific items on the BNBAS-3 weeks’ gestation were considered other data previously gathered or to explored aspects of the child’s state, pre-term, and all developmental preliminary diagnoses assigned at affect, and temperament.28 testing was scored on the basis of the earlier time points. child’s adjusted age for prematurity 33 Sanctioned trainers instructed staff SPSS was used for all data analyses. until 24 months. Interexaminer members on administration of the A repeated-measure ANOVA was used reliability data are not available for BSID-III. The BSID-III,29 designed to to measure differences between the present investigation but have track attainment of developmental related population means over time been sound in previous studies that milestones and abilities, was used to because the primary longitudinal were conducted by using this assess infant and toddler study aim was to identify factors methodology.18,19 ’ development from 1 to 42 months of early in a child s life that would age across 5 domains (cognitive, All dysmorphology data were predict a later FASD diagnosis. In language, motor, social-emotional, systematically collected and recorded addition, a receiver operating and adaptive abilities). Cognitive, on a standard dysmorphology characteristic (ROC) analysis was fi language, and motor skills were checklist,9,10 and developmental employed to strictly de ne the time assessed directly with the child, testing followed standardized period when diagnostic prediction, by whereas social-emotional skills were procedures. After the data were using the dysmorphology score, fi derived from responses of the collected, they were entered into achieved signi cance. The null primary caregiver to a questionnaire. Excel databases, quality assured, and hypothesis was that the means of Composite standard scores were exported into a master database in FASD groups and the children derived for cognitive, language, SPSS (version 22; IBM SPSS Statistics, without FASD would be equal motor, and social-emotional skills.29 IBM Corporation, Armonk, NY]).33 over time.

Assessment Tool Used for Children at Data Analysis RESULTS 60 Months of Age Data from the 155 children diagnosed The Kaufman Assessment Battery for produced a data set for Maternal Characteristics Children, Second Edition (KABC-II)30 multiple–repeated-measures analysis In Table 2, the following are was used to measure processing and of variance (ANOVA) to compare compared between mothers who gave cognitive abilities of children at T5. changes in scores over the 5 time birth to children with FASD and those This tool provides a mental points on the basis of the final who did not: (1) age, (2) growth

Downloaded from www.aappublications.org/news by guest on September 28, 2021 PEDIATRICS Volume 144, number 6, December 2019 5 parameters, (3) educational level, (4) TABLE 2 Maternal Characteristics race, (5) gravidity, (6) parity, (7) and Mothers of Children Mothers of Children P self-reported drinking behavior With FASD Without FASD before and during pregnancy.34,35 (n = 79) (n = 76) Mothers of children diagnosed with Age at interview, y, mean (SD) 32.5 (7.9) 29.3 (7.1) .01 FASD at age 5 demonstrated Height, cm, mean (SD) 154.5 (5.7) 158.7 (7.6) ,.001 , significantly higher gravidity (3.5 vs Weight, kg, mean (SD) 55.4 (15.8) 70.2 (19.2) .001 OFC, cm, mean (SD) 54.2 (2.4) 55.2 (2.3) .010 2.6) than did mothers of children BMI, mean (SD) 22.9 (5.8) 27.7 (7.6) ,.001 without FASD. Self-reported drinking Number of years of school, mean (SD)a 8.2 (2.1) 9.8 (2.2) .001 before and during pregnancy Race, % revealed significant differences in Mixed race 97.5 90.8 — — drinking during pregnancy (especially Black 2.5 9.2 White 0.0 0.0 .07 in the second and third trimesters) Gravidity, mean (SD) 3.5 (1.6) 2.6 (1.6) .002 between mothers who had children Parity, mean (SD) 3.2 (1.7) 2.4 (1.3) .003 with FASD and those who did not. By Spontaneous abortions, mean (SD) 0.3 (0.6) 0.2 (0.5) .25 FASD diagnosis, the percentages of Induced abortions, mean (SD) 0.0 (0.1) 0.1 (0.2) .17 women who reported drinking during Stillbirths, mean (SD) 0.1 (0.2) 0.0 (0.3) .55 Week of pregnancy recognition, mean 12.6 (5.4) 12.8 (6.2) .81 pregnancy were 90% for FAS, 100% (SD) for PFAS, 100% for ARND, and 51.4% Drinking during pregnancy, % yes 94.9 51.4 ,.001 for non-FASD. A comparison of other Usual number of drinks per drinking day, traits between mothers who drank mean (SD) First trimesterb 8.3 (9.3) 5.9 (4.9) .14 during pregnancy and those who did b fi Second trimester 7.4 (10.0) 3.8 (4.4) .04 not revealed signi cant differences in Third trimesterb 5.3 (10.4) 1.8 (3.9) .02 height (P , .001), weight (P = .006), — P P , not applicable. OFC ( = .010), BMI ( = .024), a FASD: n = 50; not FASD: n = 42. number of years of education (P , b Among drinkers only in the specific time period. .001), gravidity (P = .002), and parity (P = .003). The mothers of children and many cognitive and behavioral decisions. In the children included exposed to alcohol were significantly characteristics display moderate to in the final analysis, all other shorter and lighter, had smaller OFCs high degrees of heritability, when apparent diagnoses, genetic or and BMIs, and demonstrated higher such information was available about otherwise, were ruled out on the gravidity and parity. the family, these data were basis of the clinical impression of considered in final diagnostic the dysmorphologists. Dysmorphology Table 3 presents a comparison of TABLE 3 Child Age, Sex, Growth, and Dysmorphology Comparisons study children at age 5 who were a diagnosed with FASD with those FASD Not FASD P (n = 79) (n = 76) children who were not. Children ’ diagnosed with FAS, PFAS, or ARND Weeks gestation at birth, mean (SD) 38.0 (2.7) 37.8 (3.4) .70 ’ b fi Childs age at T5, mo, mean (SD) 58.8 (7.3) 56.4 (6.5) .03 demonstrated signi cantly higher Sex, % male 40.5 43.4 .71 total dysmorphology scores than Height percentile at T5, mean (SD)c 14.3 (17.0) 34.4 (26.6) ,.001 those without FASD. No significant Height z score at T5, mean (SD) 20.4 (0.7) 0.4 (1.1) ,.001 difference was observed between the Weight percentile at T5, mean (SD)c 10.4 (16.2) 33.5 (30.1) ,.001 2 , FASD and non-FASD groups on length of Weight z score at T5, mean (SD) 0.4 (0.6) 0.5 (1.2) .001 BMI percentile at T5, mean (SD)c 23.4 (25.8) 41.4 (31.3) ,.001 gestation, sex, or age at the Bonferroni- BMI z score at T5, mean (SD) 20.3 (0.9) 0.3 (1.1) ,.001 adjusted value of 0.005 at age 5. OFC percentile at T5, mean (SD)c 8.8 (15.4) 30.2 (26.4) ,.001 OFC z score at T5, mean (SD) 20.5 (0.7) 0.5 (1.1) ,.001 As is the case with any medical PFL percentile at T5, mean (SD)c 11.4 (12.4) 26.5 (15.7) ,.001 condition, sound clinical judgment PFL z score at T5, mean (SD) 235 (0.8) 0.4 (1.0) ,.001 was exercised in assigning diagnoses Philtrum ranking at T5, mean (SD) 3.5 (0.9) 2.8 (0.7) ,.001 in the FASD continuum. Among the Vermilion ranking at T5, mean (SD) 3.6 (0.9) 2.9 (0.8) ,.001 , differential diagnoses considered Total dysmorphology score at T5, mean (SD) 14.2 (5.0) 7.0 (3.8) .001 were genetic disorders or conditions PFL, palpebral fissure length. a Bonferroni-adjusted significance level = 0.005. arising from other teratogens. b Senior dysmorphologist examinations used for analysis. Additionally, because OFC, growth, c Centers for Disease Control and Prevention percentiles.

Downloaded from www.aappublications.org/news by guest on September 28, 2021 6 KALBERG et al TABLE 4 Dysmorphology Scoring System (a Weighted Score Based on Analysis of the Frequency of Growth Restriction and Minor Anomalies in 370 Children With FAS) Feature Score OFC #10% 3 Growth deficiency Height #10% 2 Weight #10% 1 Short PFL (#10%) 3 Smooth philtrum 3 Thin vermilion 3 Hypoplastic midface 2 Epicanthal folds 2 Decreased IPD or ICD (#25%) 2 Flat nasal bridge 2 Altered palmar crease 2 Fifth-finger clinodactyly 2 Long philtrum ($90%) 2 Anteverted nares 2 Camptodactyly 2 Ptosis 1 “Railroad track” ears 1 Heart murmur or confirmed CHD 1 Strabismus 1 Limited elbow supination 1 Hypoplastic nails 1 Prognathism 1 Hypertrichosis 1 Total possible score 41 Adapted from Hoyme HE, Kalberg WO, Elliott AJ, et al. Updated clinical guidelines for diagnosing fetal alcohol spectrum disorders. Pediatrics. 2016;138(2):e20154256. CHD, congenital heart disease; ICD, intercanthal distance; IPD, interpupillary distance; PFL, palpebral fissure length.

The total dysmorphology score has proven to be a useful and discriminating tool in evaluating individuals for potential FASD (Table 4). Figure 2 reveals the FIGURE 2 trajectories of weight, OFC, and Weight, OFC, and total dysmorphology score over time. dysmorphology scores for children with FASD and those without FASD at age 5. Children with FASD weighed less and demonstrated smaller OFCs T1 (95% confidence interval [CI]: specific FASD diagnoses at all time points. The children with 0.695–0.848), 0.777 at T2 (see independently are illustrated in Fig 4. FASD at age 5 also displayed below), and 0.839 at T3 (95% CI: This classification reveals that the significantly higher dysmorphology 0.705–0.849), each of which was dysmorphology score clearly scores throughout early life compared statistically significant (P , .001). discriminates between children with with those children without FASD. The ROC value at 9 months (T2) is FASD and those without FASD at ROC analysis was performed to illustrated in Fig 3, and the AUC of 9 months of age because each of the quantify the level of discrimination 0.777 (P , .001; 95% CI: specific FASD diagnostic group lines provided by the dysmorphology score 0.705–0.849) is both statistically become separated by total by time period. The analysis revealed significant and robust in light of other dysmorphology score alone. that the area under the curve (AUC) findings at T2 and later time periods. Moreover, the total dysmorphology (discrimination value) was 0.772 at Data used to classify each of the score was also highly discriminating

Downloaded from www.aappublications.org/news by guest on September 28, 2021 PEDIATRICS Volume 144, number 6, December 2019 7 emotional response variable between children who were exposed to alcohol during the first trimester of pregnancy and those who were not exposed. There was also a significant difference between the children who were exposed and the children who were unexposed on the cost of attention and examiner facilitation variables only (Supplemental Table 7).

Scores From the BSID-III and the KABC-II Cognitive scores from the BSID-III were analyzed on the basis of the assigned FASD diagnostic categories at T5; they began to differentiate among the groups between 9 and 18 months of age (Fig 5), especially those with FAS. The BSID-III did not discriminate among specific FASD diagnostic groups in a clinically interpretable way at any age (although the ROC analysis revealed significant discrimination [P = .003] of FASD versus non-FASD at 18 months [AUC = 0.628; 95% CI: 0.544–0.711]). By T5, when assessed by using the KABC-II, the various FASD groups continued to show increasing decline in overall cognitive abilities, as would be expected. The FIGURE 3 children with FAS were the most ROC analysis: AUC for accuracy of the total dysmorphology score in discriminating children with FASD from children without FASD at T2 (9 months of age) evaluation. different from subjects without FASD (Table 5). Additional BSID-III testing between children diagnosed with FAS from those without FASD. Finally, the results are presented in Supplemental and those without FASD from T1 to post hoc analysis (Supplemental Table 8 for all testing domains at each T5 (Fig 4, Supplemental Table 6). Table 6) reveals that the differences time period by diagnostic category. fi These data indicate that making any between each of the specific FASD Signi cant differences among diagnosis of FASD versus non-FASD diagnoses are significant at T5 diagnostic categories began to at 9 months of age through (60 months). emerge over T3 (18 months) and T4 dysmorphology score alone is more (42 months). strongly supported than doing so at BNBAS-3 Results KABC-II Scores Compared by an earlier age. Additionally, data from BNBAS-3 data at 6 weeks were Diagnostic Categories at 60 Months the post hoc analysis in Supplemental explored to see if self-regulation The KABC-II overall MPI global Table 6 also support this finding. At would be lower for infants exposed to scores, the simultaneous visual T3 (18 months), children with FAS alcohol during pregnancy. Infants processing scores, and the learning fi are signi cantly discriminated from whose mothers were abstinent during scores were significantly lower for both those without FASD and those pregnancy were compared with children with FAS, PFAS, and ARND with ARND on the dysmorphology infants whose mothers drank during when compared by ANOVA with score. Furthermore, at T4 (42 the first trimester of pregnancy. This those for the children who did not months), the dysmorphology score comparison revealed significant have FASD (Table 5). Pairwise also discriminated children with PFAS differences on the examiner’s differences (individual diagnostic

Downloaded from www.aappublications.org/news by guest on September 28, 2021 8 KALBERG et al potential, especially when coupled with expert dysmorphology evaluations, for guiding surveillance of children who maybeatriskforaspecificFASD diagnosis because of prenatal alcohol exposure.

Our data indicate that dysmorphic features differentiate between children with FASD and unaffected children as early as 9 months of age, although children with FAS who are severely affected can be identified earlier with a significant degree of probability.36,37 Data from the dysmorphology examinations reveal that the specificity of facial features observed in FAS and PFAS begins to differentiate among diagnostic categories within the FASD continuum at 9 months but do so most clearly from 18 months onward. Growth restriction, a clear criterion needed for a diagnosis of FAS, is evident at 9 months as well, if not before.

Assessment of early behavioral and FIGURE 4 Total dysmorphology score over time by diagnosis at 60 months (5 years); error bars: 6 1 SE; N =94 developmental milestones and ROC (total number of children seen at all 5 time points); repeated measures analysis, within subjects analysis revealed significant effect, time: F = 24.263, P , .001; repeated measures analysis, within subjects effect, time 3 group: developmental differences between F = 2.370, P , .002; repeated measures analysis, between subjects effect, group: F = 21.338, P , children with FASD and those without .001; Mauchly’s test of Sphericity has been violated: x2(9) = 17.118, P = .047. FASD between 18 and 42 months of age. The results of the BNBAS-3 at T1 revealed that infants prenatally groups), were also significantly lower however, the short-term memory exposed to alcohol have significantly for each of the 3 FASD diagnostic scores were not significantly different more difficulty maintaining a state of groups than for those without FASD between children who were affected attention (cost of attention). Infants for global, simultaneous visual and those who were not. who are frailer or those who have processing, and learning percentile a known developmental issue may ranks. Any percentile score equal to have greater difficulty maintaining or less than the eighth percentile DISCUSSION a state of attention.29 When an infant ’ $ would place the child s skills 1.5 This study reveals the accuracy of has such difficulty, the clinician may SDs from the mean. All global and using dysmorphology assessments for observe shallow or irregular . visual processing scores fell 1.5 SDs FASD diagnostic purposes in children breathing; motor disorganization and below the mean. The percentile-rank under the age of 3, especially in exhaustion displayed by flailing, mean scores on the MPI and visual conjunction with appropriate hyper- or hypotonicity, jerkiness, or processing subtests range from 2.5% behavioral evaluations. Such complete shut down into a sleeping to 6.2%, which fall in the borderline assessments progressively discriminate state; or state overload displayed by range of ability for children diagnosed among specificFASDdiagnosticgroups, crying, hiccups, yawns, regurgitating, with FAS, PFAS, and ARND. The from 18 to 60 months (when the or gagging. When an infant exhibits learning domain scores were also KABC-II can discriminate each of the these traits, the examination becomes significantly lower for children with FASD diagnostic groups from one more difficult to complete or facilitate FASD, although the percentile scores another). These early signs from (examiner facilitation), and the fell in the average range. Interestingly, behavioral testing reveal significant examiner may experience more stress

Downloaded from www.aappublications.org/news by guest on September 28, 2021 PEDIATRICS Volume 144, number 6, December 2019 9 Attrition of 44 children because of incomplete data (of 199 entering the evaluation protocol) did not skew the results. There were no statistical differences (P , .05) in height, weight, OFC, total dysmorphology score, or BSID-III cognitive percentile at T3, T4, or T5 among those with a diagnosis of FASD or non-FASD who were discussed at case conference and those excluded because of insufficient data or not being assessed at T5. Of the 44 children who were excluded from analysis, 23 were discussed in detail at a multidisciplinary case conference at 60 months of age and determined to have insufficient data for final analysis in the study. Eighteen were determined to have insufficient data because of the lack of testing (KABC- II), and none were found to have insufficient data because of a lack of alcohol exposure information. Five had insufficient data because both testing and alcohol exposure information were missing. Twenty- FIGURE 5 one individuals were not evaluated by Cognitive percentile scores over time; error bars: 6 1 SE; the BSID-III was used in T1 to T4; the KABC- II was used in T5; N = 57 (total number of children seen at all 4 time points); repeated measures the dysmorphologists at T5. Of the 21 analysis, within subjects effect, time: F = 8.687, P , .001; repeated measures analysis, within subjects not evaluated at T5, 9 were last effect, time 3 group: F = 1.340, P = .198; repeated measures analysis, between subjects effect, group: F = assessed at T4, and 12 were last ’ x2 , 0.174, P = .971; Mauchlys test of Sphericity has been violated: (5) = 22.736, P .001. assessed at T3.

Other investigators previously have when conducting the assessment subtests. Conceptual thinking and attempted to determine features in (examiner’s emotional response). overall cognitive deficits were reported early infancy that are most predictive in the earliest studies of children with Children who were prenatally of FASD as the child with alcohol 38,39 exposed to alcohol did not score as FASD. Although children who were exposure grows older. Coles et al40 highly on the KABC-II (MPI global affected scored significantly lower on used neonatal microcephaly (OFC less score) at 60 months and had the most the learning cluster, their scores were than the fifth percentile), pre- or difficulty in the visual processing still in the average range. postnatal growth deficiency, and level

TABLE 5 KABC-II Global Percentile Rank, KABC-II Simultaneous or GV Percentile Rank, and KABC Sequential Number Recall or GSM Perentile Rank Compared by Diagnostic Groups FAS PFAS ARND Not FASD P (n = 34) (n = 13) (n = 18) (n = 64) Mean (SD) Mean (SD) Mean (SD) Mean (SD) KABC-II global percentile rank 4.6 (4.8) 6.2 (10.2) 6.0 (6.6) 19.1 (18.5) ,.001a,b,c KABC-II simultaneous or GV percentile rank 2.5 (3.8) 5.1 (9.7) 2.7 (3.0) 16.0 (20.7) ,.001a,b,c KABC-II sequential or GSM percentile rank 15.9 (17.6) 20.5 (18.7) 18.4 (16.0) 25.6 (22.0) .12 KABC-II learning or GLR (Atlantis) percentile rank 29.2 (26.1) 23.1 (19.7) 30.7 (22.4) 50.4 (26.3) ,.001a,b,c GLR, long-term storage and retrieval; GSM, short term memory; GV, visual processing. a Post hoc comparisons are significantly different between FAS and not FASD. b Post hoc comparisons are significantly different between PFAS and not FASD. c Post hoc comparisons are significantly different between ARND and not FASD.

Downloaded from www.aappublications.org/news by guest on September 28, 2021 10 KALBERG et al of self-reported maternal alcohol use straightforward way to determine features, and neurobehavioral during pregnancy to predict which individual risk for later characteristics allows for accurate infants at 6 or 12 months would be at developmental delay. identification of most children with highest risk for developmental delay. FASD as early as 9 to 18 months. Stoler and Holmes41 employed Although diagnoses at the more severe end of the FASD continuum a standardized facial assessment may be suspected in early infancy, no scale to attempt to differentiate ABBREVIATIONS accepted diagnostic criteria for newborns exposed to alcohol from infants and preschool-aged children ANOVA: analysis of variance newborns not exposed to alcohol in with FASD currently exist. Thus, such ARND: alcohol-related a blinded fashion. The facial diagnoses are, by definition, neurodevelopmental disorder assessment differentiated the groups preliminary until more AUC: area under thecurve to some extent; however, individual comprehensive neurobehavioral AUDIT: Alcohol Use Disorders Test diagnoses were not assigned and testing can be accomplished when BNBAS-3: Brazelton Neonatal developmental follow-up was not children reach school age. However, Behavioral Assessment attempted. Thus, the predictive value lack of defined and accepted Scale of their facial assessment scale in diagnostic criteria for FASD in infancy BSID-III: Bayley Scales of Infant terms of developmental outcome in should not deter referral of infants Development, Third individual children with alcohol exposed to alcohol for appropriate Edition exposure was not evaluated. Carter fi diagnostic services. Children with CI: con dence interval et al42 demonstrated that growth prenatal alcohol exposure (especially CoFASP: Collaboration on Fetal trajectory in infancy and childhood is those demonstrating developmental Alcohol Spectrum a marker of which heavily alcohol- delay or behavioral concerns or those Disorder Prevalence exposed infants are at greatest risk of who are in foster care) should be FAS: fetal alcohol syndrome cognitive developmental deficits, with evaluated at any age. Even without FASD: fetal alcohol spectrum those displaying prenatal growth adefinitive FASD diagnosis, such disorder restriction, persistent postnatally, at children may benefit from specific KABC-II: Kaufman Assessment greatest risk. Mesa et al43 recently interventions and therapies. Battery for Children, published results of a study in which Second Edition cardiac-orienting responses were MPI: mental processing index used as an early scalable biomarker of OFC: occipitofrontal (head) CONCLUSIONS alcohol-related neurodevelopmental circumference impairment. The study revealed that Although any child with prenatal PFAS: partial fetal alcohol the cardiac-orienting response at alcohol exposure falls into an at-risk syndrome 6 months was more predictive of category for developmental ROC: receiver operating developmental delay on the 12-month disabilities, in the current study, we characteristic BSID-III testing than the 6-month have established that determination T1: time point 1 BSID-III score.43 Although further of a diagnosis within the FASD T2: time point 2 work is needed to determine the continuum is possible earlier in T3: time point 3 long-term predictive accuracy of this childhood than has previously been T4: time point 4 technique, cardiac-orienting appreciated. Assessment of T5: time point 5 responses may be an early and a combination of growth, dysmorphic

Ms Kalberg is a co–principal investigator for the Oxnard Foundation–funded portion of this project and conceptualized and designed the study, helped design the neurodevelopmental assessment protocol for enrolled infants and children, drafted the initial manuscript, and serves as the first author; Dr May is the principal investigator of the National Institute on Alcohol Abuse and Alcoholism–funded studies in South Africa on which this article is based and substantially contributed to the conception and design of the study as well as to the analysis and interpretation of data gathered and revised the manuscript critically for important intellectual content, including all statistical analyses and epidemiological designs and analyses; Mr Buckley and Ms Hasken make up the data analysis group for the fetal alcohol spectrum disorders team collaboration and supervised the acquisition, storing, and analysis of sensitive subject data, produced the tables and figures for the manuscript, and revised the manuscript critically for important intellectual content; Ms Marais and Ms De Vries are the local South African project managers of the present longitudinal cohort study and substantially contributed to the conception and design of the study as well as to the acquisition, analysis, and interpretation of data and revised the article critically for important intellectual content; Drs Bezuidenhout, Manning, Robinson, Adam, and Derek B. Hoyme substantially aided in the conception and design of the study, extensively contributed to data acquisition by providing dysmorphology examinations of all children in the current study, extensively contributed to the analysis and interpretation of data by assigning final diagnoses to all subjects in multidisciplinary case

Downloaded from www.aappublications.org/news by guest on September 28, 2021 PEDIATRICS Volume 144, number 6, December 2019 11 conferences throughout the project, and revised the article critically for important intellectual content; Drs Parry and Seedat are the South African coinvestigators of the National Institute on Alcohol Abuse and Alcoholism–funded studies on which this article is based and actively participated in the conception and design of the study (including providing critical input about and liaison with the local South African communities in which subjects were recruited), participated in the vital analysis and interpretation of data, and revised the article critically for important intellectual content; Dr Elliott assisted with the design of the current investigation (specifically with substantial planning of the neurodevelopmental assessment protocol for infants and children in the study), trained the South African staff in the administration of the neurodevelopmental tests performed, participated in the analysis and interpretation of the neurodevelopmental data gathered, and critically revised the manuscript for important intellectual content; Dr H. Eugene Hoyme is a coprincipal investigator for the Oxnard Foundation–funded portion of the current study and conceptualized and designed the study, analyzed and interpreted the growth and dysmorphology data acquired, reviewed the manuscript critically for important intellectual content, and performed the final edits of the manuscript; and all authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. DOI: https://doi.org/10.1542/peds.2018-2141 Accepted for publication Sep 12, 2019 Address correspondence to H. Eugene Hoyme, MD, Sanford Children’s Genomic Medicine Consortium, Sanford Health, 1305 W 18th St, Route 6744, Sioux Falls, SD 57117-5039. E-mail: [email protected] PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275). Copyright © 2019 by the American Academy of Pediatrics FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose. FUNDING: Funded by National Institute on Alcohol Abuse and Alcoholism grants R01 AA11685 and R01/UO1 AA01115134. Funding was also provided by the Oxnard Foundation (Newport Beach, CA). Funded by the National Institutes of Health (NIH). POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose.

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Downloaded from www.aappublications.org/news by guest on September 28, 2021 PEDIATRICS Volume 144, number 6, December 2019 13 Early-Life Predictors of Fetal Alcohol Spectrum Disorders Wendy O. Kalberg, Philip A. May, David Buckley, Julie M. Hasken, Anna-Susan Marais, Marlene M. De Vries, Heidre Bezuidenhout, Melanie A. Manning, Luther K. Robinson, Margaret P. Adam, Derek B. Hoyme, Charles D.H. Parry, Soraya Seedat, Amy J. Elliott and H. Eugene Hoyme Pediatrics originally published online November 19, 2019;

Updated Information & including high resolution figures, can be found at: Services http://pediatrics.aappublications.org/content/early/2019/11/15/peds.2 018-2141 References This article cites 32 articles, 6 of which you can access for free at: http://pediatrics.aappublications.org/content/early/2019/11/15/peds.2 018-2141#BIBL Subspecialty Collections This article, along with others on similar topics, appears in the following collection(s): Fetus/Newborn Infant http://www.aappublications.org/cgi/collection/fetus:newborn_infant_ sub Birth Defects http://www.aappublications.org/cgi/collection/birth_defects_sub Genetics http://www.aappublications.org/cgi/collection/genetics_sub Dysmorphology http://www.aappublications.org/cgi/collection/dysmorphology_sub Permissions & Licensing Information about reproducing this article in parts (figures, tables) or in its entirety can be found online at: http://www.aappublications.org/site/misc/Permissions.xhtml Reprints Information about ordering reprints can be found online: http://www.aappublications.org/site/misc/reprints.xhtml

Downloaded from www.aappublications.org/news by guest on September 28, 2021 Early-Life Predictors of Fetal Alcohol Spectrum Disorders Wendy O. Kalberg, Philip A. May, David Buckley, Julie M. Hasken, Anna-Susan Marais, Marlene M. De Vries, Heidre Bezuidenhout, Melanie A. Manning, Luther K. Robinson, Margaret P. Adam, Derek B. Hoyme, Charles D.H. Parry, Soraya Seedat, Amy J. Elliott and H. Eugene Hoyme Pediatrics originally published online November 19, 2019;

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