Updated Clinical Guidelines

for Diagnosing Fetal Alcohol

Spectrum Disorders
H. Eugene Hoyme, MD,a,b Wendy O. Kalberg, MA, LED,c Amy J. Elliott, PhD,a Jason Blankenship, PhD,c,†
David Buckley, MA,c Anna-Susan Marais, B Cur Nursing,d Melanie A. Manning, MD,e Luther K. Robinson, MD,f Margaret P.
Adam, MD,g Omar Abdul-Rahman, MD,h Tamison Jewett, MD,i Claire D. Coles, PhD, j
Christina Chambers, PhD, MPH,k Kenneth L. Jones, MD,k Colleen M. Adnams, MBChB,l Prachi E. Shah, MD,m
Edward P. Riley, PhD,n Michael E. Charness, MD,o Kenneth R. Warren, PhD,p Philip A. May, PhDa,c,q

The adverse effects of prenatal alcohol exposure constitute a continuum of abstract

disabilities (fetal alcohol spectrum disorders [FASD]). In 1996, the Institute
NIH
of Medicine established diagnostic categories delineating the spectrum
but not specifying clinical criteria by which diagnoses could be assigned.
In 2005, the authors published practical guidelines operationalizing the Disclaimer: The guidelines/recommendations
in this article are not American Academy of
Institute of Medicine categories, allowing for standardization of FASD Pediatrics policy, and publication herein does
diagnoses in clinical settings. The purpose of the current report is to present not imply endorsement.
updated diagnostic guidelines based on a thorough review of the literature
aSanford Research and Department of Pediatrics, Sanford
and the authors’ combined expertise based on the evaluation of >10 000 School of Medicine, University of South Dakota, Sioux Falls,
children for potential FASD in clinical settings and in epidemiologic studies South Dakota; bCenter for Applied Genetics and Genomic
in conjunction with National Institute on Alcohol Abuse and Alcoholism– Medicine and Department of Pediatrics, University of Arizona
College of Medicine, Tucson, Arizona; cCenter on Alcoholism,
funded studies, the Collaborative Initiative on Fetal Alcohol Spectrum Substance Abuse and Addictions, University of New
Disorders, and the Collaboration on FASD Prevalence. The guidelines Mexico, Albuquerque, New Mexico; dStellenbosch University
Faculty of Medicine and Health Sciences, Stellenbosch,
were formulated through conference calls and meetings held at National South Africa; Departments of ePathology and Pediatrics,
Institute on Alcohol Abuse and Alcoholism offices in Rockville, MD. Specific Stanford University School of Medicine, Stanford, California;
fDepartment of Pediatrics, State University of New York
areas addressed include the following: precise definition of documented at Buffalo School of Medicine and Biomedical Sciences,
prenatal alcohol exposure; neurobehavioral criteria for diagnosis of fetal Buffalo, New York; gDepartment of Pediatrics, University
of Washington School of Medicine, Seattle, Washington;
alcohol syndrome, partial fetal alcohol syndrome, and alcohol-related hDepartment of Pediatrics, University of Mississippi School

neurodevelopmental disorder; revised diagnostic criteria for alcohol- of Medicine, Jackson, Mississippi; iDepartment of Pediatrics,
related birth defects; an updated comprehensive research dysmorphology Wake Forest University School of Medicine, Winston-
Salem, North Carolina; jDepartment of Psychiatry and
scoring system; and a new lip/philtrum guide for the white population, Behavioral Sciences, Emory University School of Medicine,
incorporating a 45-degree view. The guidelines reflect consensus among Atlanta, Georgia; kDepartment of Pediatrics, University of
California, San Diego School of Medicine, La Jolla, California;
a large and experienced cadre of FASD investigators in the fields of lDepartment of Psychiatry and Mental Health, University of

dysmorphology, epidemiology, neurology, psychology, developmental/ Cape Town Faculty of Health Sciences, Cape Town, South
Africa; mDepartment of Pediatrics and Communicable
behavioral pediatrics, and educational diagnostics. Their improved clarity Diseases, University of Michigan Medical School, Ann Arbor,
and specificity will guide clinicians in accurate diagnosis of infants and Michigan; nDepartment of Psychology, San Diego State
University, San Diego, California; oVA Boston Healthcare
children prenatally exposed to alcohol. System, Department of Neurology, Harvard Medical School,
and Department of Neurology, Boston University School of
Medicine, Boston, Massachusetts; pNational Institute on
Alcohol Abuse and Alcoholism, Bethesda, Maryland; and
The adverse effects of alcohol on fetal alcohol syndrome (FAS).2 As qDepartment of Nutrition, Gillings School of Global Public

the developing fetus were described pediatricians became more familiar Health, Nutrition Research Institute, University of North
Carolina at Chapel Hill, Chapel Hill, North Carolina
independently by Lemoine et al in with the clinical presentation of children
19681 and by Jones et al in 1973.2 As prenatally exposed to alcohol, it became
with most malformation syndromes, clear that the associated disabilities To cite: Hoyme HE, Kalberg WO, Elliott AJ, et al.
the most severely affected children represent a spectrum, from mild to Updated Clinical Guidelines for Diagnosing Fetal
Alcohol Spectrum Disorders. Pediatrics. 2016;
were described first, with the associated severe (fetal alcohol spectrum disorders
138(2):e20154256
pattern of malformation termed or FASD). In 1996, the Institute of

PEDIATRICS Volume 138, number 2, August 2016:e20154256 SPECIAL ARTICLE

Medicine (IOM) described 4 distinct disabilities in the world. Recent meetings at the offices of NIAAA
diagnostic categories within FASD: FAS, school-based studies in the United in Rockville, MD. The following
partial fetal alcohol syndrome (PFAS), States estimate the prevalence working subgroups of investigators
alcohol-related neurodevelopmental of FASD to be much higher than were organized to revisit diagnostic
disorder (ARND), and alcohol-related previously thought. May et al13 criteria: dysmorphology evaluation,
birth defects (ARBD).3 However, the recently recorded combined rates neurobehavioral assessment, and
task force did not specify the clinical of FAS and PFAS of 10.9 to 25.2 definition of significant documented
process by which individual children per 1000 (1.1%–2.5%) in a Rocky prenatal alcohol exposure.
could be assigned to the groups. Since Mountain community, whereas Recommendations from the working
that time, a number of diagnostic the complete continuum of FASD committees were brought back to
systems have been proposed.4–10 In (including ARND) was observed to be the larger group for discussion and
2005, Hoyme et al4 described specific 24 to 48 per 1000 (2.4%–4.8%) in a revision. The guidelines presented
clinical guidelines that allowed for community in the Northern Plains.14 herein are the result of a thorough
assigning diagnoses within the 1996 In the mixed race population of the review of the literature and the
IOM classification. Western Cape Province in South longstanding collective expertise
Subsequently, the authors have Africa, the highest prevalence rates of the authors. The updated clinical
evaluated >10 000 children for of FASD in the world have been guidelines for diagnosis of FASD are
potential FASD in clinical settings documented, 135.1 to 207.5 per 1000 set forth in Table 1.
and epidemiologic studies as part of (13.5%–20.8%).15 The World Health
National Institute on Alcohol Abuse Organization (WHO) is currently
APPLICATION OF THE GUIDELINES IN
and Alcoholism (NIAAA) supported planning prevalence studies in
THE DIAGNOSIS OF FASD
studies, the Collaborative Initiative several countries in Europe, Asia,
Africa, and North America, which An FASD diagnostic algorithm
on Fetal Alcohol Spectrum Disorders
should lead to global data about incorporating the updated diagnostic
(CIFASD), and the Collaboration on
the frequency of this continuum of guidelines is depicted in Fig 1.
FASD Prevalence (CoFASP). CIFASD
was established by NIAAA in 2003 to disabilities.16
investigate data-driven methods for The high prevalence of FASD Optimal Diagnostic Setting and the
complete diagnosis of the continuum produces an immense burden to Role of the Pediatrician
of FASD, prevention of the adverse society in financial terms, unrealized
Assignment of an FASD diagnosis
effects of prenatal alcohol exposure, productivity, and human suffering.
is a complex medical diagnostic
and effective interventions for In the United States, annual cost
process best accomplished through
affected individuals.11,12 CoFASP estimates have ranged from $74.6
a structured multidisciplinary
seeks to establish the prevalence of million in 198417 to $4.0 billion in
approach by a clinical team
FASD among school-age children 1998.18 In 2007, the estimated annual
comprising members with varied
in US communities by using active cost of FASD in Canada was CAD $5.3
but complementary experience,
case ascertainment methodology.12 billion.19
qualifications, and skills. The
Based on this broad multidisciplinary The soaring prevalence and burden assessment of individuals prenatally
experience, the purpose of this of FASD in children recently led the exposed to alcohol requires a medical
special article is to propose updated American Academy of Pediatrics to assessment and team leadership by
clinical guidelines for diagnosing stress the following: no amount of a pediatrician or clinical geneticist/
FASD that clarify and expand on alcohol intake during pregnancy can dysmorphologist with expertise in
the original 2005 guidelines. These be considered safe; there is no safe the full range of human malformation
updated diagnostic criteria have been trimester to drink alcohol; all forms syndromes and the dysmorphology
formulated, reviewed, and accepted of alcohol pose a similar risk; and evaluation of children with FASD.
by the investigators and collaborating binge drinking poses a dose-related In addition, exposed children
sites of CoFASP and the administrative risk to the fetus.20 should have expert psychological/
core of CIFASD. They do not
neuropsychological assessment,
necessarily represent the policy of the
and a skilled interviewer should
American Academy of Pediatrics. PREPARATION OF UPDATED
evaluate prenatal maternal alcohol
DIAGNOSTIC GUIDELINES
intake. Other team members may
BACKGROUND AND SCOPE OF THE These guidelines were formulated include developmental behavioral
PROBLEM by the authors over a 12-month pediatricians, psychiatrists, speech
FASDs are the leading cause period, through a series of pathologists, occupational therapists,
of preventable developmental conference calls and face-to-face physical therapists, special

2 HOYME et al
TABLE 1 Updated Criteria for the Diagnosis of FASD
Diagnostic Categories
(See Table 2 for definition of documented prenatal alcohol exposure)
I. FAS
(With or without documented prenatal alcohol exposure)
A diagnosis of FAS requires all features, A–D:
A. A characteristic pattern of minor facial anomalies, including ≥2 of the following:
1. Short palpebral fissures (≤10th centile)
2. Thin vermilion border of the upper lip (rank 4 or 5 on a racially normed lip/philtrum guide, if available)
3. Smooth philtrum (rank 4 or 5 on a racially normed lip/philtrum guide, if available)
B. Prenatal and/or postnatal growth deficiency
1. Height and/or weight ≤10th centile (plotted on a racially or ethnically appropriate growth curve, if available)
C. Deficient brain growth, abnormal morphogenesis, or abnormal neurophysiology, including ≥1 of the following:
1. Head circumference ≤10th percentile
2. Structural brain anomalies
3. Recurrent nonfebrile seizures (other causes of seizures having been ruled out)
D. Neurobehavioral impairmenta
1. For children ≥3 y of age (a or b):
a. WITH COGNITIVE IMPAIRMENT:
−Evidence of global impairment (general conceptual ability ≥1.5 SD below the mean, or performance IQ or verbal IQ or spatial IQ ≥1.5 SD below the mean)
OR
−Cognitive deficit in at least 1 neurobehavioral domain ≥1.5 SD below the mean (executive functioning, specific learning impairment, memory impairment or
visual-spatial impairment)
b. WITH BEHAVIORAL IMPAIRMENT WITHOUT COGNITIVE IMPAIRMENT:
−Evidence of behavioral deficit in at least 1 domain ≥1.5 SD below the mean in impairments of self-regulation (mood or behavioral regulation impairment,
attention deficit, or impulse control)
2. For children <3 y of age:
−Evidence of developmental delay ≥1.5 SD below the mean
II. PFAS
-For children with documented prenatal alcohol exposure, a diagnosis of PFAS requires features A and B:
A. A characteristic pattern of minor facial anomalies, including ≥2 of the following:
1. Short palpebral fissures (≤10th centile)
2. Thin vermilion border of the upper lip (rank 4 or 5 on a racially normed lip/philtrum guide, if available)
3. Smooth philtrum (rank 4 or 5 on a racially normed lip/philtrum guide, if available)
B. Neurobehavioral impairmenta
1. For children ≥3 y of age (a or b):
a. WITH COGNITIVE IMPAIRMENT:
−Evidence of global impairment (general conceptual ability ≥1.5 SD below the mean, or performance IQ or verbal IQ or spatial IQ ≥1.5 SD below the mean)
OR
−Cognitive deficit in at least 1 neurobehavioral domain ≥1.5 SD below the mean (executive functioning, specific learning impairment, memory impairment or
visual-spatial impairment)
b. WITH BEHAVIORAL IMPAIRMENT WITHOUT COGNITIVE IMPAIRMENT:
−Evidence of behavioral deficit in at least 1 domain ≥1.5 SD below the mean in impairments of self-regulation (mood or behavioral regulation impairment,
attention deficit, or impulse control)
2. For children <3 y of age:
−Evidence of developmental delay ≥1.5 SD below the mean
-For children without documented prenatal alcohol exposure, a diagnosis of PFAS requires all features, A–C:
A. A characteristic pattern of minor facial anomalies, including ≥2 of the following:
1. Short palpebral fissures (≤10th centile)
2. Thin vermilion border of the upper lip (rank 4 or 5 on a racially normed lip/philtrum guide, if available)
3. Smooth philtrum (rank 4 or 5 on a racially normed lip/philtrum guide, if available)
B. Growth deficiency or deficient brain growth, abnormal morphogenesis, or abnormal neurophysiology
1. Height and/or weight ≤10th centile (plotted on a racially or ethnically appropriate growth curve, if available), or:
2. Deficient brain growth, abnormal morphogenesis or neurophysiology, including ≥1 of the following:
a. Head circumference ≤10th percentile
b. Structural brain anomalies
c. Recurrent nonfebrile seizures (other causes of seizures having been ruled out)
C. Neurobehavioral impairmenta
1. For children ≥3 y of age (a or b):
a. WITH COGNITIVE IMPAIRMENT:
−Evidence of global impairment (general conceptual ability ≥1.5 SD below the mean, or performance IQ or verbal IQ or spatial IQ ≥1.5 SD below the mean)
OR
−Cognitive deficit in at least 1 neurobehavioral domain ≥1.5 SD below the mean (executive functioning, specific learning impairment, memory impairment, or
visual-spatial impairment)

PEDIATRICS Volume 138, number 2, August 2016 3

TABLE 1 Continued
Diagnostic Categories
b. WITH BEHAVIORAL IMPAIRMENT WITHOUT COGNITIVE IMPAIRMENT:
−Evidence of behavioral deficit in at least 1 domain ≥1.5 SD below the mean in impairments of self-regulation (mood or behavioral regulation impairment,
attention deficit, or impulse control)
2. For children <3 y of age:
−Evidence of developmental delay ≥1.5 SD below the mean
III. ARND
Requires features A and B (this diagnosis cannot be made definitively in children <3 y of age):
A. Documented prenatal alcohol exposure
B. Neurobehavioral impairmenta
For children ≥3 y of age (a or b):
a. WITH COGNITIVE IMPAIRMENT:
−Evidence of global impairment (general conceptual ability ≥1.5 SD below the mean, or performance IQ or verbal IQ or spatial IQ ≥1.5 SD)
OR
−Cognitive deficit in at least 2 neurobehavioral domains ≥1.5 SD below the mean (executive functioning, specific learning impairment, memory impairment or
visual-spatial impairment)
b. WITH BEHAVIORAL IMPAIRMENT WITHOUT COGNITIVE IMPAIRMENT:
−Evidence of behavioral deficit in at least 2 domains ≥1.5 SD below the mean in impairments of self-regulation (mood or behavioral regulation impairment,
attention deficit, or impulse control)
IV. ARBD
Requires features A and B:
A. Documented prenatal alcohol exposure
B. One or more specific major malformations demonstrated in animal models and human studies to be the result of prenatal alcohol exposure: cardiac:
atrial septal defects, aberrant great vessels, ventricular septal defects, conotruncal heart defects; skeletal: radioulnar synostosis, vertebral segmentation
defects, large joint contractures, scoliosis; renal: aplastic/hypoplastic/dysplastic kidneys, “horseshoe” kidneys/ureteral duplications; eyes: strabismus,
ptosis, retinal vascular anomalies, optic nerve hypoplasia; ears: conductive hearing loss, neurosensory hearing loss
Diagnostic Caveats: The assignment of an FASD is a complex medical diagnostic process best accomplished through a multidisciplinary approach. As is the case with many medical
conditions, sound clinical judgment must be used. Differential diagnoses should always include genetic disorders or conditions arising from other teratogens. Additionally, because head
circumference, growth, and many cognitive and behavioral characteristics have moderate to high degrees of heritability, when information is available about the biological parents, these
data should be considered in the final diagnostic decision.
a Adaptive skills should be assessed, but such deficits cannot stand alone for diagnosis.

FIGURE 1
FASD diagnostic algorithm. See text for complete discussion. A positive dysmorphology facial evaluation requires 2 of the 3 cardinal facial features of
FASD (short palpebral fissures, smooth philtrum, and this vermilion border of the upper lip). Cutoffs for neuropsychological testing are –1.5 SD. Cutoffs
for stature, weight, and head circumference are at the 10th percentile.

4 HOYME et al
TABLE 2 Definition of Documented Prenatal Alcohol Exposure (as Applied to the Diagnostic Categories Set Forth in Table 1)
One or more of the following conditions must be met to constitute documented prenatal alcohol exposure during pregnancy (including drinking levels reported
by the mother 3 mo before her report of pregnancy recognition or a positive pregnancy test documented in the medical record). The information must be
obtained from the biological mother or a reliable collateral source (eg, family member, social service agency, or medical record):
− ≥6 drinks/wk for ≥2 wk during pregnancya
− ≥3 drinks per occasion on ≥2 occasions during pregnancya
− Documentation of alcohol-related social or legal problems in proximity to (before or during) the index pregnancy (eg, history of citation[s] for driving while
intoxicated or history of treatment of an alcohol-related condition)
− Documentation of intoxication during pregnancy by blood, breath, or urine alcohol content testing
− Positive testing with established alcohol-exposure biomarker(s) during pregnancy or at birth (eg, analysis of fatty acid ethyl esters, phosphatidylethanol, and/
or ethyl glucuronide in maternal hair, fingernails, urine, or blood, or placenta, or meconium)50–55
− Increased prenatal risk associated with drinking during pregnancy as assessed by a validated screening tool of, for example, T-ACE (tolerance, annoyance, cut
down, eye-opener) or AUDIT (alcohol use disorders identification test)56
Assignment of documented prenatal alcohol exposure to any individual case requires the sound judgment of an experienced clinician.
a These criteria for maternal drinking are based on large epidemiologic studies that demonstrate adverse fetal effects from ≥3 drinks per occasion26,57 and others that indicate 1 drink/

day as a threshold measure for FASD.58–60

educators, audiologists, and/or during gestation, because timing be asked in a timeline followback
ophthalmologists.10,21–23 of significant exposure (even in manner,39,40 progressing from the
the early weeks of pregnancy) can broader context of health history
The essential role of the pediatrician
produce different physical and (childbearing, general illness,
in the identification and care of
neurobehavioral phenotypes.26–30 nutrition, and dietary intake26,41,42)
children with FASD cannot be
Binge drinking (3–5 drinks or more to the more sensitive alcohol use
overstated. Pediatricians are
per occasion) has been shown questions. It is important to also
among the most likely practitioners
in animal and human studies to consider the overall drinking pattern
to first encounter children with
immediately before pregnancy
prenatal alcohol exposure who are be the most detrimental to fetal
recognition, as it is common for the
potentially at risk for FASD. Jones development.26,31 Asking about
drinking pattern of 3 months before
et al24 demonstrated the accuracy use of other potential teratogens
pregnancy to persist into early
of pediatricians in recognizing FAS during pregnancy is also important
pregnancy.13,14,43–49
on the basis of physical and other because, in addition to their own
common associated features after a potential teratogenicity, women A consensus definition of significant
relatively short training session. In who abuse drugs are more likely to prenatal alcohol exposure is set
addition, once a diagnosis is use alcohol during pregnancy.13,14,32 forth in Table 2. Note that although
assigned, pediatricians are called Because in many populations it is certain circumstances permit the
on to provide a medical home for likely that prenatal alcohol use will be diagnosis of FAS or PFAS without
affected children, coordinate mental firm documentation of gestational
denied completely or be significantly
health services, and manage other alcohol use (Table 1), positive
underreported,13,14,33–35 biomarkers
comorbid mental health disorders. confirmation of alcohol exposure
can assist in documenting prenatal
Pediatricians also play an important must be available for the
alcohol exposure. Most frequently,
role in the prevention of future diagnosis of ARND or ARBD to
alcohol-exposed pregnancies through alcohol exposure information is be assigned.
counseling women with affected collected retrospectively. It is
children.25 well documented that accurate Dysmorphology Evaluation
information on a particular
Documentation of Significant After assessing prenatal alcohol
pregnancy can be obtained from
Prenatal Alcohol Exposure exposure, the presence or absence
a willing respondent years after
of the characteristic structural
Assessment of maternal prenatal the birth of a child36–38 or from the
features of FASD must be
alcohol intake is an essential part medical or social service records or evaluated. For the dysmorphology
of the diagnostic process and is a collateral informant (eg, spouse, examination, height, weight, and
the first step in the diagnostic close relative, or friend) who had head circumference should first
algorithm outlined in Fig 1. It regular contact with the mother be measured and plotted by using
is best measured by quantity of during pregnancy.15,26 population-specific growth curves.
alcohol consumed per occasion In maternal interviews, because of In the United States, the authors
(standard drinks per drinking day), potential stigmatization associated advise following the Centers for
frequency that it is consumed (eg, with prenatal alcohol use, and Disease Control and Prevention
daily, times per week), and timing for accuracy, questions should (CDC) recommendations: use the

PEDIATRICS Volume 138, number 2, August 2016 5

 smaller than those measured live.
Similarly, Astley67 found the norm
for palpebral fissures measured from
2-dimensional photographic software
to fall 1.6 SDs below the mean on a
palpebral fissure chart derived from
live examinations. Figure 3 A and
B depicts the technique for direct
measurement of palpebral fissure
length, and Fig 3C demonstrates why,
in our experience, 2-dimensional
photographic assessment of
palpebral fissure length is prone to
inaccuracy because of individual
variation in the zygomatic angle that
cannot be corrected for by a single
mathematical adjustment. However,
FIGURE 2 it should be noted that investigators
Typical child with FAS. The 3 cardinal facial features are evident: short palpebral fissures, smooth disagree on the method that results
philtrum, and relatively thin vermilion border of the upper lip. Midface hypoplasia is also apparent.
in the most accurate measurement
of palpebral fissure length.67–69 The
WHO growth charts for children population-based norms. For the
morphology of the philtrum and the
from birth to 2 years to assess purposes of these guidelines, a
vermilion border of the upper lip are
height and weight. (The WHO small head circumference is defined
objectively scored by comparison
growth standards for children as ≤10th centile.4,8
with a racially normed lip/philtrum
younger than 2 years have been guide (Fig 4).70,71 Scores of 4 or 5
The presence or absence of the
adapted for use in the United 3 cardinal facial characteristics are consistent with the effects of
States.) Use the CDC growth of FASD must next be objectively prenatal alcohol exposure. If 2 of the
charts for children and teenagers assessed: short palpebral fissures, 3 cardinal facial characteristics are
aged 2 to 19 years.61 In other smooth philtrum, and thin vermilion present (short palpebral fissures,
countries, we recommend using border of the upper lip (Fig 2). smooth philtrum, and/or thin
more-specific population-normed Although other investigators have vermilion border of the upper lip) the
charts, if available. If growth curves advocated for measurement of facial child is classified as having a positive
specific to the population studied anthropometry from 2-dimensional dysmorphology facial evaluation for
are not available, we endorse the photography, we feel that direct FASD.
recommendations of the CDC for examinations are more practical
US children.61 Prenatal growth in an office setting. Here we define Neurodevelopmental Assessment
restriction can be determined short palpebral fissures as ≤10th and Neuropsychology Evaluation
from reference data published by centile.4,8 Palpebral fissure length Because the primary manifestations
Oken et al62 by gestational age. centiles can be estimated from a of the teratogenic effects of alcohol
In these diagnostic guidelines, number of published norms; we are demonstrated by changes in
we define growth deficiency as have used the curves derived from brain structure and/or function,
≤10th centile.4,8 Prenatal growth direct examination of children comprehensive neurodevelopmental
restriction should be exhibited, published by Thomas et al.64 If facial assessment is essential. Although the
or a pattern of postnatal growth anthropometry is measured live, dysmorphology assessment of infants
deficiency should be documented palpebral fissure norms derived and small children for the growth
if possible (decreased height and/ from live examinations must be and facial characteristics of FASD is
or weight on >1 occasion over 12 used. (If palpebral fissure lengths feasible, a comprehensive cognitive/
months, and unrelated to postnatal are measured from photographs, developmental evaluation may not
environmental deprivation). With published norms obtained from be possible by using conventional
respect to determination of head 2-dimensional photography are assessment tools until after age
circumference centiles, we have available.65) Similar to the experience 3 years.72 However, the cognitive
used the head circumference of the authors, Avner et al66 found and neurobehavioral phenotype of
growth charts from Nellhaus63 in all palpebral fissure lengths measured affected children evolves predictably
populations, in lieu of more-specific from photographs to be consistently over time73–76 and can be correlated

6 HOYME et al
FIGURE 3
A, Technique for measuring palpebral fissure length. A small plastic ruler is used to measure the distance between the endocanthion (where the eyelids
meet medially) and the exocanthion (where the eyelids meet laterally). Subject and examiner should be seated at the same level opposite from one
another. Keeping the chin level, the subject is asked to look up, allowing the examiner to bring the ruler as close to the eye as possible (without touching
the lashes). The ruler can be rested on the cheek for stability while recording the measurement. B, Note that the ruler is angled slightly to follow the
curve of the zygoma. C, The correct length of the palpebral fissure is depicted here as measurement “C.” This highlights the difficulty of 2-dimensional
photographic measurement, because “B” is highly variable among individuals, leading to differences in the zygomatic angle (the angle between line
segments B and C).

with areas of brain vulnerability Therefore, physicians should use a within the continuum of FASD
(Table 3). low threshold for ordering additional remain the most apt descriptors of
genetic testing of children with the range of disabilities observed.
The authors promote the use
potential FASD. A chromosome These longstanding categories
of standardized tests that were
microarray has been shown to be the have heretofore been accepted by
developed by using normative
highest-yield diagnostic test when a many of the diagnostic systems,4,8,9
groups that are representative of the
genetic phenocopy of FASD is being and we see no need to introduce
population being tested. Therefore,
considered.77,78 additional confusion into a field
in the updated guidelines, ≥1.5 SD
in which diagnostic consensus is
below the mean refers to the mean
critical. In addition, classification
of the normative group on which the
DISCUSSION of individuals into 1 of the existing
tests were standardized. Therefore,
specific IOM categories allows for
both groups (alcohol-exposed In the decade since the original
determination of prognosis and
children as well as unexposed operationalized IOM diagnostic
treatment planning. We also assert
children) are tested by using the same criteria4 were published, extensive
that the category of ARBDs, although
well-normed testing battery, thereby international research on the
uncommon, remains necessary,
making the comparisons appropriate. teratogenic effects of alcohol and the
especially in epidemiologic
authors’ broad clinical experience
Multidisciplinary Case Conference studies.82,83 Our extensive database
have allowed for the development
of alcohol-exposed children reveals
Once the prenatal exposure history, of further clarity and specificity in
many examples of affected children
dysmorphology assessment, and the diagnostic guidelines presented
not fitting into 1 of the other
neuropsychological testing have in this article. However, it should be
categories who display 1 of the
been obtained, a multidisciplinary noted that agreement on a universal
major malformations set forth in
case conference offers the best diagnostic system for FASD is lacking
Table 1 and whose mothers binged
opportunity for full discussion of the among investigators in the field of
during the embryonic stage critical
case before assignment of an FASD or FASD, especially concerning some
to the developmental pathology of
other diagnosis (Fig 1). of the features of the diagnostic
the malformation.
guidelines set forth in Table 1. A
Phenocopies of FASD discussion of the debated elements It should be noted that the Canadian
Clinicians should be aware that the follows. diagnostic guideline for FASD
facial phenotype of FAS, although recently was updated, collapsing
Diagnostic Categories Within the
most commonly associated with the diagnostic categories under the
Continuum of FASD
prenatal alcohol exposure, is also diagnosis of “fetal alcohol spectrum
observed in a variety of genetic and It is the authors’ assertion that the 4 disorder” to 2: FASD with sentinel
teratogenic conditions (Table 4). original IOM diagnostic categories3 facial features and FASD without

PEDIATRICS Volume 138, number 2, August 2016 7

sentinel facial features.10 Whether
this simplified diagnostic scheme
will result in practical improvements
in the clinical care of affected
individuals and more accurate
epidemiologic studies estimating the
prevalence of FASD remains to be
demonstrated.

Sensitivity Versus Specificity in

Clinical Diagnosis
Similar to others, our goals in the
formulation of FASD diagnostic
guidelines have been improved
sensitivity and greater inclusion of
children in the complete continuum
of FASD4,8; thus, we have set cutoff
levels for growth deficiency, head
circumference, and palpebral
fissure length at ≤10th centile and
required 2, rather than 3, cardinal
facial features for a diagnosis
of FAS and PFAS. Because we
advocate for a structured expert-
led multidisciplinary diagnostic
approach to the diagnosis of FASD,
casting a broad net early in the
diagnostic process and later using the
case conference to carefully assign
diagnoses has been our standard.
Other diagnostic systems advocate
for more stringent cutoffs: growth
deficiency, head circumference,
and palpebral fissure length less
than or equal to the third centile
and requiring all 3 of the cardinal
facial features for alcohol-related
diagnoses.5,9,10 Sensitivity and
specificity are 2 sides of a diagnostic
coin. Theoretically, the guidelines
presented here demonstrating
increased sensitivity could lead to
overdiagnosis; thus, our advocacy for
a structured expert multidisciplinary
approach. On the other hand,
strict diagnostic cutoffs associated
with increased specificity could
lead to underdiagnosis of affected
children. Children with FASD
are subject to a host of societal,
educational, health, and judicial
problems, all of which are affected
by the time of diagnosis.84,85 Because
early diagnosis and initiation of
intervention should be of paramount

8 HOYME et al
importance, the authors assert that universal part of other diagnostic diagnoses (with the exception of
improved, sensitive, and inclusive systems.6–8 those with ARBD) must display
diagnostic criteria for FASD should neurobehavioral impairment
continue to be imperatives in the Other Minor Anomalies in Children (cognitive impairment or behavioral
diagnostic process. With FASD impairment without cognitive
In dysmorphology, clinical diagnoses impairment). The original guidelines
Deficient Brain Growth, Abnormal are based on recognizable patterns of allowed for children with the
Morphogenesis, or Abnormal major and minor anomalies. Although requisite facial features, growth
Neurophysiology the dysmorphology contribution restriction, and/or microcephaly
to FASD diagnoses is derived from to be assigned an FASD diagnosis
In the updated criteria, we have
objective evaluation of the face, a in the absence of significant
added documentation of recurrent
number of other minor anomalies neurobehavioral impairment.
nonfebrile seizures to the potential
have been observed consistently However, because neurocognitive
assignment of children to the
and more commonly in children impairment and abnormal behavior
diagnostic categories of FAS or PFAS.
prenatally exposed to alcohol than in are the principal sources of disability
A child with FAS must now exhibit
nonexposed controls.4,13,14,92,93 The in FASD, assignment of children
deficient brain growth, structure, or
clinical assessment of the presence or with prenatal alcohol exposure
neurophysiology. This modification
absence of these features should be into an FASD category without
was prompted by a growing body of
part of the dysmorphology evaluation neurobehavioral impairment has no
research that indicates that epilepsy
of children with potential FASD. The practical utility for either the child or
is a frequent accompaniment of
overall dysmorphic variation in any the child’s family.
FASD.86,87 More commonly observed
individual child can be quantified
in children with FASD, a small head The definition of neurobehavioral
by calculation of a dysmorphology
circumference is a reliable, easily impairment in FASD has become more
score (an updated dysmorphology
obtained proxy for decreased brain specific over the past decade.36,72–76
scoring system based on objective
volume.88,89 Finally, a number of The original 1996 IOM criteria
observations of growth and minor
structural brain anomalies have and the 2005 guidelines defined
anomalies in 370 children with
been observed in imaging studies neurobehavioral impairment as
FAS is presented in Table 5). The
in animals and human subjects with “evidence of a complex pattern of
dysmorphology score allows for
FASD. Although no specific anatomic behavioral or cognitive abnormalities
objective comparison among groups
region of the brain is preferentially inconsistent with developmental
of children with FASD and has proven
affected, malformations resulting level that cannot be explained
to be a valuable research tool. It is
from migration abnormalities, by genetic predisposition, family
also a useful instrument to review
changes in size and shape of the background, or environment alone.”3,4
as part of the differential diagnostic
corpus callosum, cerebellar vermis Although the 2005 criteria outlined
process when assessing features
hypoplasia, and hypoplasia of the areas of marked neurobehavioral
of genetic or other teratogenic
basal ganglia and hippocampus have impairment, levels of deficit and
disorders that may mimic FASD
been documented.90,91 affected functional domains were not
(Table 4). The score has been
clearly articulated. The guidelines
The 4-digit diagnostic code5 assesses observed to correlate significantly
set forth in Table 1 clearly delineate
these features as “structural evidence with prenatal maternal alcohol
domains of functioning to be assessed
of central nervous system damage,” intake, as well as with the cognitive
and levels of deficit to be reached to
and the updated Canadian guideline and neurobehavioral characteristics
meet the diagnostic criteria for FAS,
for diagnosis of FASD10 includes of the affected child.26,94
PFAS, and ARND.
a similar category (abnormal
neuroanatomy/neurophysiology) as Specificity of Neurobehavioral The domains of function outlined
Impairment in the updated criteria encompass
1 of the 10 central nervous system
domains that may be impaired, The updated guidelines now require the following: (1) global intellectual
although this category is not a that all children assigned FASD ability (full-scale, verbal,
performance, or spatial IQ), (2)
cognition (executive functioning,
FIGURE 4 Continued learning, memory, and visual-
FIGURE 4 spatial skills), (3) behavior and
Lip/philtrum guide for the white population, incorporating a 45-degree view. This guide was self-regulation (mood, behavioral
produced by analysis of photographs of >800 white children from school-based studies in the United
States.13,14 Scores are assessed separately for the philtrum and vermilion border; scores of 4 or 5 regulation, attention, and impulse
are compatible with FAS or PFAS. control), and (4) adaptive skills.

PEDIATRICS Volume 138, number 2, August 2016 9

10

TABLE 3 Developmental Emergence of Neurocognitive and Behavioral Deficits Associated With FASD
Infancy: 0–2 y
Areas of Brain Vulnerability in FASD Neurocognitive/Behavioral Deficits Associated With Developmental Stage
• Cortical synaptogenesis Neurocognitive • Delayed cognitive development or global developmental delay
• Development of cortical gray matter
• Myelination of sensory pathways Self-Regulation • Tremulousness, increased jitteriness
• Maturation of the limbic system • Difficulty with self-soothing, and being soothed
• Emotional withdrawal, decreased infant affective functioning
• Impaired stress reactivity; deficits in pain regulation
• Less complex play
• Myelination of motor pathways Adaptive • Delayed gross and fine motor milestones
• Poor feeding: poor sucking. Easily fatigued
Toddler/Preschool: 3–5 y
Areas of Brain Vulnerability in FASD Neurocognitive/Behavioral Deficits Associated With Developmental Stage
• Synaptogenesis Neurocognitive • Delayed cognitive development or global developmental delay
• Development of cortical gray matter
• Development of prefrontal cortex Self-Regulation • Attention: difficulties with attention regulation; hyperactivity and impulsivity; difficulty shifting attention; impaired
visual and auditory attention; difficulty with sustained attention
• Executive function: difficulty encoding information; difficulty with multistep directions; difficulty with planning and
organization; poor understanding of consequences
• Development of temporal lobes • Sleep deficits: shortened sleep duration; increased sleep anxiety; parasomnias
• Sensory processing: difficulty modulating sensory input; sensory seeking
• Development of dorsal motor cortex Adaptive • Delayed gross motor function: balance, coordination problems; “clumsiness”
• Poor fine motor skills: difficulty with writing/drawing; poor dexterity; visual-spatial deficits; impaired visual-motor
coordination
• Development of temporal lobes • Delayed auditory processing: central auditory delay
• Speech and language deficits: difficulties with language acquisition; receptive, expressive language delays; deficits
in word processing/word recognition; articulation errors; deficits in social pragmatics
• Memory deficits: difficulty remembering things previously learned
School-age: 6–12 y
Areas of Brain Vulnerability in FASD Neurocognitive/Behavioral Deficits Associated With Developmental Stage
• Decreased intracranial volume: Neurocognitive • Lower intellectual quotient
• Decreased volume of parietal and temporal lobes • Learning disabilities
• White matter abnormalities • Deficits in mathematics (numerical operations/global mathematics skills)
• Prefrontal cortex Self-Regulation • Executive function deficits: decreased working memory, decreased verbal fluency, poorer planning, sequencing,
organization
• Attention deficits: hyperactivity; impulsivity
• Temporal lobe Adaptive • Language: deficits in higher order language processing
• Social pragmatics: deficits in social cognition: inappropriate social initiation/social interaction; inappropriate
sexual behaviors
• Memory: difficulty encoding/consolidating new memory
• Parietal lobe • Language processing: impaired gestural communication; deficits in social perception
• Visual-spatial: deficits in spatial processing; poor handwriting; impaired visual-motor integration
Adolescence: 13–21 y
Areas of Brain Vulnerability in FASD Neurocognitive/Behavioral Deficits Associated With Developmental Stage
• Decreased intracranial volume: Neurocognitive • Lower intellectual quotient
HOYME et al

• Decreased volume of parietal and temporal lobes • Learning disabilities

• White matter abnormalities • Deficits in mathematics skills (numerical operations/global mathematics skills)
 These functional domains were the mean on a standardized measure
• Executive function deficits: decreased verbal fluency, poorer planning, sequencing, organization; slow processing;

selected based on the empirical of developmental trajectory. However,

• Social pragmatics: deficits in social cognition: inappropriate social initiation/social interaction; inappropriate evidence of deficits in children for ARND, a definitive diagnosis
prenatally exposed to alcohol and/or cannot be made before 3 years of age.
who have been given a diagnosis of The neurobehavioral criteria
• Visual-spatial: deficits in spatial processing; poor handwriting; impaired visual-motor integration FASD.32,95–107 for diagnoses within the FASD
For children >3 years of age, continuum differ from those
diagnoses of FAS or PFAS require proposed by other investigators5,9,10
evidence of global cognitive (our guidelines require: cutoffs
• Working memory: difficulty encoding new memories; difficulty with memory recall

impairment (reflected in a deficit of –1.5 SDs rather than –2 SDs, for

of ≥1.5 SDs below the mean on a neurobehavioral assessment and
measure of global intelligence [full- less stringent neurobehavioral
scale IQ score] or performance, criteria for those affected
verbal, or visual/spatial IQ) or children who demonstrate the
evidence of behavioral deficit ≥1.5 requisite dysmorphology allowing
• Language: deficits in higher order language processing

SDs below the mean in ≥1 domain in classification into the categories

impairments of self-regulation (mood of FAS and PFAS). Our previously
• Language processing: deficits in social perception

or behavioral regulation impairment, published data confirm that because

attention deficit, or impulse control). the dysmorphology score has the
deficits in judgment and metacognition

A diagnosis of ARND can be made highest correlation with confirmed

only if there is confirmed prenatal diagnoses in the FASD continuum,
alcohol exposure and global confidence in an FAS or PFAS
• Attention deficits: inattention

cognitive impairment, reflected diagnosis can be ensured with

in a deficit of ≥1.5 SDs below impairment in fewer neurobehavioral
domains.26,94
sexual behaviors

the mean on a measure of global

intelligence (full-scale IQ score)
or performance, verbal, or visual/ Differentiation Between ARND and
spatial IQ. If cognitive impairment Neurobehavioral Disorder With
is not present (often the case with Prenatal Alcohol Exposure
individuals prenatally exposed to These updated criteria continue
Self-Regulation

alcohol), cognitive deficits in at to include ARND as a necessary

Adaptive

least 2 additional neurobehavioral diagnostic category. With the

domains (executive functioning, introduction of Neurobehavioral
specific learning, memory, or visual- Disorder with Prenatal Alcohol
spatial) are required at ≥1.5 SDs Exposure (ND-PAE) into the
below the mean. Additionally, the Diagnostic and Statistical Manual
new guidelines provide for an ARND of Mental Disorders, Fifth Edition
diagnosis based on behavioral as a “condition in need of further
impairment without cognitive study,”7 there has been significant
• Development of connections between PFC and basal ganglia

impairment, as evidenced by deficits confusion about the necessity of

at ≥1.5 SDs below the mean in at retaining both ARND and ND-PAE as
least 2 behavioral domains: mood diagnostic entities. To be clear, ARND
or behavioral regulation, attention is a complex medical diagnosis, best
deficit, or impulse control. Adaptive assigned as part of a multidisciplinary
skills also should be assessed.108–110
• Myelination of prefrontal cortex (PFC)

team evaluation for FASD. It has

The adaptive scores can be used to been widely applied in epidemiologic
assist with the diagnosis; however, studies14,93 and in clinical settings and
specific cutoffs and adaptive behavior has been found to accurately describe
requirements are not included in the the end of the continuum of FASD
TABLE 3 Continued

diagnostic criteria. without dysmorphology.111,112 In

• Temporal lobe

For children who are ≤3 years of contrast, ND-PAE is an experimental

• Parietal lobe

age, a diagnosis of FAS and PFAS mental health diagnostic code that
can be made if there is evidence of is intended to be used in clinical
developmental delay ≥1.5 SDs below settings by clinicians from a variety

PEDIATRICS Volume 138, number 2, August 2016 11

TABLE 4 Genetic and Teratogenic Conditions to Be Considered in the Differential Diagnosis of FASD79–81
Malformation Syndrome Etiology
Cornelia deLange Syndrome OMIM 122470 Autosomal dominant (Mutations in NIPBL, 60%)
Velocardiofacial Syndrome (del 22q11.2 Syndrome) OMIM Chromosome microdeletion (del 22q11.2)
#188400
Duplication 15q Syndrome OMIM 608636 Chromosome partial duplication (dup 15q)
Dubowitz Syndrome OMIM 223370 Autosomal recessive
Noonan Syndrome OMIM 163950 Autosomal dominant (Mutations in RAS-MAPK signal transduction pathway genes, PTPN11, SOS1,
KRAS, NRAS, and others)
Williams Syndrome OMIM 194050 Chromosome microdeletion (del 7q11.23, a contiguous gene syndrome incorporating the elastin
gene)
Fetal Hydantoin Syndrome Teratogenic effects of hydantoin exposure during gestation
Fetal Valproate Syndrome Teratogenic effects of valproic acid exposure during gestation
Maternal Phenlyketonuria Effects Teratogenic effects of high levels of phenylalanine, accompanying poorly controlled maternal
phenylketonuria
Toluene Embryopathy Teratogenic effects of maternal solvent exposure during pregnancy
This list is not comprehensive. OMIM, Online Mendelian Inheritance in Man.56

TABLE 5 Revised Dysmorphology Scoring System (Based on Quantitative Analysis of Growth

of theoretical orientations, including
Restriction and Minor Anomalies in 370 Children With FAS) psychiatrists (and other physicians),
psychologists, social workers, nurses,
Feature No. Affected Score
occupational and rehabilitation
OFC ≤10% 354 3
therapists, and counselors. This
Growth deficiency
Height ≤10% 327 2 code triggers payment for services
Weight ≤10% 322 1 related to the condition as well as
Short PFL (≤10%) 313 3 helps individuals access needed
Smooth philtrum 307 3 interventions and treatments.113
Thin vermilion 293 3
Hypoplastic midface 216 2
According to the Diagnostic and
Epicanthal folds 204 2 Statistical Manual of Mental Disorders,
Decreased IPD/ICD (≤25%) 202/104 2 Fifth Edition, ND-PAE requires ≥1
Flat nasal bridge 179 2 deficits in neurocognition and in
Altered palmar crease 173 2
self-regulation plus ≥2 deficits
5th finger clinodactyly 149 2
Long philtrum (≥90%) 122 2 in adaptive functioning (with at
Anteverted nares 118 2 least 1 in communication or social
Camptodactyly 114 2 communication and interaction).99,114
Ptosis 64 1 An ARND diagnosis can be made
“Railroad track” ears 57 1
Heart murmur/confirmed CHD 50/6 1
based on global cognitive deficits
Strabismus 35 1 alone without the behavioral issues
Limited elbow supination 31 1 that fall into the psychiatric realm.
Hypoplastic nails 23 1 ARND also can be diagnosed if there
Prognathism 21 1
is evidence of behavioral deficits in
Hypertrichosis 19 1
Total possible score 41 at least 2 behavioral domains in the
CHD, congenital heart disease; ICD, intercanthal distance; IPD, interpupillary distance; OFC, occipitofrontal (head)
absence of cognitive deficits. Whether
circumference; PFL, palpebral fissure length. in the long run they will merge into a
The Revised Dysmorphology Score was derived from analysis of growth and structural data from 370 children with single entity will depend on further
full-blown FAS. The subjects were among the international cohort of children examined by the dysmorphology experts
(HEH, MAM, LKR, MPA, OAR, TJ, KLJ) involved in NIAAA-supported CIFASD and CoFASP studies. The children were examined study and refinement of both ARND
blindly by the investigators as part of school-based epidemiology studies of children in grade 1 (ages 5–8). Interexaminer and ND-PAE as they are applied in
agreement on anthropometric measures was high (Cronbach’s α scores ranged from 0.975 to 0.855 for craniofacial practice.
assessment items).
The cardinal diagnostic features (small head circumference, growth restriction [height and weight combined], short
palpebral fissures, smooth philtrum, and thin vermilion border of the upper lip) were assigned a score of 3. Other features Future Directions
observed in ≥100 children were assigned a score of 2. Features observed in <100 children received a score of 1. The score
provides an objective method of quantifying dysmorphic features and comparing the structural phenotype of FASD among
The guidelines presented here are
affected children; it is not used in assigning FASD diagnoses. However, compilation of the minor anomalies cataloged in the based on the most recent FASD
score is useful in differentiating children with FASD from genetic and teratogenic phenocopies (Table 5). research and clinical data. However,
This supplants the original scoring system that was based on the authors’ subjective analysis of the frequency of minor
anomalies associated with FASD.4
their accuracy will need to be
reevaluated over time as their validity
is more extensively assessed. Among

12 HOYME et al
areas in need of further study are the challenge. The first step in
following: potential use of improved
ABBREVIATIONS
addressing this dilemma is to
and more practical 3-dimensional recognize the magnitude of the ARBD: alcohol-related birth
photographic imaging as an accurate problem through careful case defects
proxy for live facial anthropometric definition. Since the authors’ ARND: alcohol-related neurode-
measurements115; improved diagnostic guidelines were published velopmental disorder
noninvasive biomarkers for alcohol in 2005, considerable progress has CDC: Centers for Disease Control
exposure throughout pregnancy been made in further specifying and Prevention
and postnatally50–55; postnatal the anatomic and neurobehavioral CIFASD: Collaborative Initiative
epigenetic markers as a proxy for characteristics of FASD. These on Fetal Alcohol
documentation of prenatal maternal updated guidelines reflect consensus Spectrum Disorders
alcohol intake116–118; improved among a large and experienced CoFASP: Collaboration on Fetal
definition of which fetal and postnatal cadre of FASD investigators in Alcohol Spectrum
growth patterns are most consistent the fields of dysmorphology, Disorders Prevalence
with the teratogenic effects of alcohol; epidemiology, neurology, FAS: fetal alcohol syndrome
and a more precise definition of psychology, developmental/ FASD: fetal alcohol spectrum
what constitutes minimal criteria for behavioral pediatrics, and disorders
adverse fetal alcohol exposure during educational diagnostics. They IOM: Institute of Medicine
gestation. Finally, other diagnostic ND-PAE: Neurobehavioral
do not necessarily represent the
approaches to FASD that can be Disorder with Prenatal
policy of the American Academy of
readily applied in resource-poor Alcohol Exposure
Pediatrics. The improved specificity
settings should be explored. NIAAA: National Institute on
of these guidelines will aid clinicians
Alcohol Abuse and
in assignment of more accurate
Alcoholism
diagnoses of alcohol-exposed infants
CONCLUSIONS PFAS: partial fetal alcohol
and children, thereby leading to
syndrome
FASD continues to represent a more widespread early intervention
WHO: World Health Organization
pressing global public health and improved prevention efforts.

Dr Hoyme was the first author of the original diagnostic guidelines for fetal alcohol spectrum disorders (FASD) published in Pediatrics in 2005, conceptualized
and designed the study, and drafted the initial document; Ms Kalberg with Dr Coles formulated the psychological testing battery used for the subjects and
assisted in assignment of FASD diagnoses, along with Drs Elliott and Coles she was charged with clarifying the definition of alcohol-related neurodevelopmental
disorder, and she revised the document; Dr Elliott assisted with assignment of FASD diagnoses, along with Ms Kalberg and Dr Coles she was charged with
clarifying the definition of alcohol-related neurodevelopmental disorder, and she revised the document; Dr Blankenship and Mr Buckley comprised the data
analysis group for the FASD team collaboration, they oversaw the gathering, storing, and analysis of sensitive subject data, and produced tables and figures for
the manuscript; Dr Blankenship died before submission of the paper; Mr Buckley revised the document; Ms Marais coordinated the multidisciplinary diagnostic
case conferences on the children from whom the data for this report were collected and revised the document; Drs Manning, Robinson, Adam, Abdul-Rahman,
Jewett, and Jones examined all of the children in the studies on which the updated criteria are based, assigned diagnostic categories to the subjects, aided
in crafting the definitions of the updated diagnostic criteria, and revised the document; Dr Coles contributed significantly to the clarification of alcohol-related
neurodevelopmental disorder and revised the manuscript; Dr Chambers contributed significantly to the development of the overall diagnostic scheme for FASD
and revised the manuscript; Dr Adnams developed the psychological and neuropsychological testing battery and oversaw the testing of the large South African
cohort of children examined over the past decade, participated in developing the neuropsychological criteria set forth in the article, and revised the document;
Dr Shah authored the sections on the natural history of the neurobehavioral phenotype of FASD over the life span, and revised the document; Drs Riley and
Charness added significantly to the formulation of the specific revised diagnostic guidelines and revised the document; Dr Warren is the driving force behind the
epidemiological investigations that form the basis of the revised guidelines, participated in formulating the specific guidelines, and edited the document; Dr May
is principal investigator of the school-based population studies in South Africa, Italy, and the United States on which this manuscript is based, and revised the
document; and all authors agree to be accountable for all aspects of the work and approved the final manuscript as submitted.
†Deceased.

DOI: 10.1542/peds.2015-4256
Accepted for publication Apr 27, 2016
Address correspondence to H. Eugene Hoyme, MD, Chief, Genetics and Genomic Medicine, Sanford Health, PO Box 5039, Sioux Falls, SD 57117-5039. E-mail: gene.
[email protected]
PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275).
Copyright © 2016 by the American Academy of Pediatrics
FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose.

PEDIATRICS Volume 138, number 2, August 2016 13

FUNDING: This project was funded by the National Institutes of Health (NIH): National Institute on Alcohol Abuse and Alcoholism grants R01 AA11685, RO1/UO1
AA01115134, and U01 AA019879-01/NIH-NIAAA (Collaboration on Fetal Alcohol Spectrum Disorders Prevalence); and 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.

REFERENCES
1. Lemoine P, Harousseau H, Borteyru JP, Committee on Fetal Alcohol Spectrum incidence of FAS and its economic
Menuet JC. Les enfants des parents Disorder. Fetal alcohol spectrum impact. Alcohol Clin Exp Res.
alcoholiques: anomolies observees disorder: Canadian guidelines for 1991;15(3):514–524
a propos de 127 cas [The children diagnosis. CMAJ. 2005;172(suppl
18. Harwood H. Updating Estimates of the
of alcoholic parents: anomalies 5):S1–S21
Economic Costs of Alcohol Abuse in
observed in 127 cases]. Quest Medical.
10. Cook JL, Green CR, Lilley CM, et al. Fetal the United States: Estimates, Updated
1968;25:476–482
alcohol spectrum disorder: a guideline Methods and Data. Report Prepared
2. Jones KL, Smith DW, Ulleland for diagnosis across the lifespan. by the Lewin Group. Bethesda, MD:
CN, Streissguth P. Pattern of CMAJ. 2015;188(3):191–197 National Institute on Alcohol Abuse and
malformation in offspring of Alcoholism; 2000
11. Mattson SN, Foroud T, Sowell ER,
chronic alcoholic mothers. Lancet. et al; CIFASD. Collaborative initiative 19. Stade B, Ali A, Bennett D, et al.
1973;1(7815):1267–1271 on fetal alcohol spectrum disorders: The burden of prenatal exposure
3. Stratton K, Howe C, Battaglia F, eds. methodology of clinical projects. to alcohol: revised measurement
Institute of Medicine. Fetal Alcohol Alcohol. 2010;44(7-8):635–641 of cost. Can J Clin Pharmacol.
Syndrome: Diagnosis, Epidemiology, 12. National Institute on Alcohol Abuse 2009;16(1):e91–e102
Prevention, and Treatment. and Alcoholism. Major initiatives. Fetal 20. Williams JF, Smith VC; Committee
Washington, DC: National Academies alcohol spectrum disorders. Available on Substance Abuse. Fetal alcohol
Press; 1996 at: www.niaaa.nih.gov/research/major- spectrum disorders. Pediatrics.
initiatives/fetal-alcohol-spectrum- 2015;136(5). Available at: www.
4. Hoyme HE, May PA, Kalberg WO,
disorders. Accessed March 29, 2016 pediatrics.org/cgi/content/full/136/5/
et al. A practical clinical approach to
13. May PA, Keaster C, Bozeman R, et al. e1395
diagnosis of fetal alcohol spectrum
disorders: clarification of the Prevalence and characteristics of fetal 21. Clarren SK, Lutke J, Sherbuck M.
1996 Institute of Medicine criteria. alcohol syndrome and partial fetal The Canadian guidelines and the
Pediatrics. 2005;115(1):39–47 alcohol syndrome in a Rocky Mountain interdisciplinary clinical capacity
Region City. Drug Alcohol Depend. of Canada to diagnose fetal alcohol
5. Astley SJ, Clarren SK. Diagnosing 2015;155:118–127 spectrum disorder. J Popul Ther Clin
the full spectrum of fetal alcohol-
14. May PA, Baete A, Russo J, et al. Pharmacol. 2011;18(3):e494–e499
exposed individuals: introducing
the 4-digit diagnostic code. Alcohol. Prevalence and characteristics of 22. Grundfast KM. The role of the
2000;35(4):400–410 fetal alcohol spectrum disorders. audiologist and otologist in the
Pediatrics. 2014;134(5):855–866 identification of the dysmorphic child.
6. World Health Organization. The ICD-10 Ear Hear. 1983;4(1):24–30
15. May PA, Blankenship J, Marais AS,
Classification of Mental and Behavioral
et al. Approaching the prevalence 23. Strömland K. Visual impairment and
Disorders: Clinical Descriptions
of the full spectrum of fetal alcohol ocular abnormalities in children with
and Diagnostic Guidelines. Geneva,
spectrum disorders in a South African fetal alcohol syndrome. Addict Biol.
Switzerland: World Health Organization;
population-based study. Alcohol Clin 2004;9(2):153–157, discussion
1992
Exp Res. 2013;37(5):818–830 159–160
7. American Psychiatric Association.
16. Centre for Addiction and Mental 24. Jones KL, Robinson LK, Bakhireva
Diagnostic and Statistical Manual
Health. Fetal alcohol spectrum LN, et al. Accuracy of the diagnosis
of Mental Disorders, Fifth Edition.
disorders: How widespread are they of physical features of fetal alcohol
Arlington, VA: American Psychiatric
in Canada? Available at: www.camh.ca/ syndrome by pediatricians after
Publishing; 2013:798–801
en/hospital/about_camh/newsroom/ specialized training. Pediatrics.
8. Centers for Disease Control and news_releases_media_advisories_ 2006;118(6). Available at: www.
Prevention. Fetal Alcohol Spectrum and_backgrounders/current_year/ pediatrics.org/cgi/content/full/118/6/
Disorders: Guidelines for Referral and Pages/Fetal-Alcohol-Spectrum- e1734
Diagnosis. Atlanta, GA: Centers for Disorders-How-Widespread-Are-They-
in-Canada.aspx. Accessed March 29, 25. Gahagan S, Sharpe TT, Brimacombe
Disease Control and Prevention; 2004
2016 M, et al. Pediatricians’ knowledge,
9. Chudley AE, Conry J, Cook JL, Loock training, and experience in the care of
C, Rosales T, LeBlanc N; Public Health 17. Abel EL, Sokol RJ. A revised children with fetal alcohol syndrome.
Agency of Canada’s National Advisory conservative estimate of the Pediatrics. 2006;118(3). Available at:

14 HOYME et al
 www.pediatrics.org/cgi/content/full/ in Prince Edward Island: a population- New Zealand women. Drug Alcohol Rev.
118/3/e657 based descriptive study. CMAJ Open. 2013;32(4):389–397
26. May PA, Blankenship J, Marais AS, 2014;2(2):E121–E126 46. Parackal SM, Parackal MK, Harraway
et al. Maternal alcohol consumption 36. Hannigan JH, Chiodo LM, Sokol RJ, JA. Prevalence and correlates of
producing fetal alcohol spectrum et al. A 14-year retrospective maternal drinking in early pregnancy among
disorders (FASD): quantity, frequency, report of alcohol consumption in women who stopped drinking on
and timing of drinking. Drug Alcohol pregnancy predicts pregnancy pregnancy recognition. Matern Child
Depend. 2013;133(2):502–512 and teen outcomes. Alcohol. Health J. 2013;17(3):520–529
27. Sulik KK. Fetal alcohol spectrum 2010;44(7-8):583–594 47. Russell M, Czarnecki DM, Cowan R,
disorder: pathogenesis and 37. Czarnecki DM, Russell M, Cooper ML, McPherson E, Mudar PJ. Measures
mechanisms. Handb Clin Neurol. Salter D. Five-year reliability of self- of maternal alcohol use as
2014;125:463–475 reported alcohol consumption. J Stud predictors of development in early
28. Lipinski RJ, Hammond P, O’Leary- Alcohol. 1990;51(1):68–76 childhood. Alcohol Clin Exp Res.
Moore SK, et al. Ethanol-induced 1991;15(6):991–1000
38. Alvik A, Haldorsen T, Groholt B,
face-brain dysmorphology patterns Lindemann R. Alcohol consumption 48. Skagerström J, Alehagen S,
are correlative and exposure-stage before and during pregnancy Häggström-Nordin E, Årestedt K, Nilsen
dependent. PLoS One. 2012;7(8):e43067 comparing concurrent and P. Prevalence of alcohol use before
29. Parnell SE, Holloway HE, Baker LK, retrospective reports. Alcohol Clin Exp and during pregnancy and predictors
Styner MA, Sulik KK. Dysmorphogenic Res. 2006;30(3):510–515 of drinking during pregnancy: a cross
effects of first trimester-equivalent sectional study in Sweden. BMC Public
39. Sobell LC, Agrawal S, Annis H, et al.
ethanol exposure in mice: a Health. 2013;13:780
Cross-cultural evaluation of two
magnetic resonance microscopy- drinking assessment instruments: 49. Alvik A, Haldorsen T, Lindemann R.
based study. Alcohol Clin Exp Res. alcohol timeline followback and Consistency of reported alcohol use by
2014;38(7):2008–2014 inventory of drinking situations. Subst pregnant women: anonymous versus
30. Schambra UB, Goldsmith J, Nunley K, Use Misuse. 2001;36(3):313–331 confidential questionnaires with item
Liu Y, Harirforoosh S, Schambra HM. nonresponse differences. Alcohol Clin
40. Sobell LC, Sobell MB, Leo GI, Cancilla
Low and moderate prenatal ethanol Exp Res. 2005;29(8):1444–1449
A. Reliability of a timeline method:
exposures of mice during gastrulation assessing normal drinkers’ reports 50. Ostrea EM Jr. Testing for exposure
or neurulation delays neurobehavioral of recent drinking and a comparative to illicit drugs and other agents in
development. Neurotoxicol Teratol. evaluation across several populations. the neonate: a review of laboratory
2015;51:1–11 Br J Addict. 1988;83(4):393–402 methods and the role of meconium
31. Maier SE, West JR. Drinking patterns analysis. Curr Probl Pediatr.
41. King AC. Enhancing the self-report of
and alcohol-related birth defects. 1999;29(2):37–56
alcohol consumption in the community:
Alcohol Res Health. 2001;25(3):168–174 two questionnaire formats. Am J 51. Bearer CF, Jacobson JL, Jacobson SW,
32. Ceccanti M, Fiorentino D, Coriale G, Public Health. 1994;84(2):294–296 et al. Validation of a new biomarker
et al. Maternal risk factors for fetal of fetal exposure to alcohol. J Pediatr.
42. May PA, Gossage JP, Brooke LE, et
alcohol spectrum disorders in a 2003;143(4):463–469
al. Maternal risk factors for fetal
province in Italy. Drug Alcohol Depend. alcohol syndrome in the Western cape 52. Soderberg BL, Salem RO, Best CA,
2014;145:201–208 province of South Africa: a population- Cluette-Brown JE, Laposata M. Fatty
33. Manich A, Velasco M, Joya X, based study. Am J Public Health. acid ethyl esters. Ethanol metabolites
et al. Validity of a maternal alcohol 2005;95(7):1190–1199 that reflect ethanol intake. Am J Clin
consumption questionnaire in Pathol. 2003;119(suppl):S94–S99
43. Floyd RL, Decouflé P, Hungerford
detecting prenatal exposure DW. Alcohol use prior to pregnancy 53. Kulaga V, Pragst F, Fulga N, Koren
[in Spanish]. An Pediatr (Barc). recognition. Am J Prev Med. G. Hair analysis of fatty acid ethyl
2012;76(6):324–328 1999;17(2):101–107 esters in the detection of excessive
34. Wurst FM, Kelso E, Weinmann W, Pragst drinking in the context of fetal alcohol
44. Tan CH, Denny CH, Cheal NE, Sniezek
F, Yegles M, Sundström Poromaa spectrum disorders. Ther Drug Monit.
JE, Kanny D. Alcohol use and
I. Measurement of direct ethanol 2009;31(2):261–266
binge drinking among women of
metabolites suggests higher rate of childbearing age - United States, 2011- 54. Pichini S, Marchei E, Vagnarelli F,
alcohol use among pregnant women 2013. MMWR Morb Mortal Wkly Rep. et al. Assessment of prenatal
than found with the AUDIT—a pilot 2015;64(37):1042–1046 exposure to ethanol by meconium
study in a population-based sample of analysis: results of an Italian
45. Mallard SR, Connor JL, Houghton LA.
Swedish women. Am J Obstet Gynecol. multicenter study. Alcohol Clin Exp Res.
Maternal factors associated with
2008;198(4):407.e1–407.e5 2012;36(3):417–424
heavy periconceptional alcohol intake
35. Bryanton J, Gareri J, Boswall D, et al. and drinking following pregnancy 55. Morini L, Marchei E, Tarani L, et al.
Incidence of prenatal alcohol exposure recognition: a post-partum survey of Testing ethylglucuronide in maternal

PEDIATRICS Volume 138, number 2, August 2016 15

 hair and nails for the assessment of school age children. Can J Clin 76. Howell KK, Lynch ME, Platzman KA,
fetal exposure to alcohol: comparison Pharmacol. 2010;17(1):e67–e78 Smith GH, Coles CD. Prenatal alcohol
with meconium testing. Ther Drug 66. Avner M, Henning P, Koren G, Nulman exposure and ability, academic
Monit. 2013;35(3):402–407 I. Validation of the facial photographic achievement, and school functioning in
56. Allen JP, Wilson VB. Assessing alcohol in fetal alcohol spectrum disorder adolescence: a longitudinal follow-up. J
problems: a guide for clinicians and screening and diagnosis. J Popul Ther Pediatr Psychol. 2006;31(1):116–126
researchers. 2nd ed. NIH publication Clin Pharmacol. 2014;21(1):e106–e113 77. Douzgou S, Breen C, Crow YJ, et al.
No. 03-3745; revised 2003. Available at: 67. Astley SJ. Canadian palpebral fissure Diagnosing fetal alcohol syndrome:
http://pubs.niaaa.nih.gov/publications/ length growth charts reflect a good fit new insights from newer genetic
AssessingAlcohol/index.htm. Accessed for two school and FASD clinic-based technologies. Arch Dis Child.
March 29, 2016 U.S. populations. J Popul Ther Clin 2012;97(9):812–817
57. May PA, Gossage JP, Marais AS, et Pharmacol. 2011;18(2):e231–e241 78. Abdelmalik N, van Haelst M, Mancini
al. Maternal risk factors for fetal 68. Cranston ME, Mhanni AA, Marles SL, G, et al. Diagnostic outcomes of 27
alcohol syndrome and partial fetal Chudley AE. Concordance of three children referred by pediatricians to
alcohol syndrome in South Africa: methods for palpebral fissure length a genetics clinic in the Netherlands
a third study. Alcohol Clin Exp Res. measurement in the assessment of with suspicion of fetal alcohol
2008;32(5):738–753 fetal alcohol spectrum disorder. spectrum disorders. Am J Med Genet
58. Day NL, Robles N, Richardson G, et al. Can J Clin Pharmacol. 2009;16(1): A. 2013;161A(2):254–260
The effects of prenatal alcohol use e234–e241 79. Leibson T, Neuman G, Chudley AE,
on the growth of children at three 69. Astley SJ. Palpebral fissure length Koren G. The differential diagnosis
years of age. Alcohol Clin Exp Res. measurement: accuracy of the of fetal alcohol spectrum disorder.
1991;15(1):67–71 FAS facial photographic analysis J Popul Ther Clin Pharmacol.
59. Robles N, Day NL. Recall of alcohol software and inaccuracy of the 2014;21(1):e1–e30
consumption during pregnancy. J Stud ruler. J Popul Ther Clin Pharmacol. 80. Jones KL, Jones MC, del Campo
Alcohol. 1990;51(5):403–407 2015;22(1):e9–e26 M. Smith’s Recognizable Patterns
60. Larkby CA, Goldschmidt L, Hanusa BH, 70. Astley S. FAS Diagnostic and Prevention of Human Malformation. 7th ed.
Day NL. Prenatal alcohol exposure is Network. Available at: http://depts. Philadelphia, PA: Elsevier Saunders;
associated with conduct disorder in washington.edu/fasdpn/htmls/lip- 2013
adolescence: findings from a birth philtrum-guides.htm. Accessed March 81. OMIM (Online Mendelian Inheritance
cohort. J Am Acad Child Adolesc 29, 2016 in Man). An online catalog of human
Psychiatry. 2011;50(3):262–271 71. Hoyme HE, Hoyme DB, Elliott AJ, et al. genes and genetic disorders. Updated
61. Use and interpretation of the WHO and A South African mixed race lip/ November 13, 2015. Available at: www.
CDC growth charts for children from philtrum guide for diagnosis of fetal omim.org/. Accessed March 29, 2016
birth to 20 years in the United States. alcohol spectrum disorders. Am J Med 82. Hofer R, Burd L. Review of published
Available at: www.cdc.gov/nccdphp/ Genet A. 2015;167A(4):752–755 studies of kidney, liver, and
dnpa/growthcharts/resources/ 72. Olson HC, Jirikowic T, Kartin D, Astley gastrointestinal birth defects in
growthchart.pdf. Accessed March 29, SJ. Responding to the challenge of fetal alcohol spectrum disorders.
2016 early intervention for fetal alcohol Birth Defects Res A Clin Mol Teratol.
62. Oken E, Kleinman KP, Rich-Edwards spectrum disorders. Infants Young 2009;85(3):179–183
J, Gillman MW. A nearly continuous Child. 2007;20(2):172–189 83. O’Leary CM, Nassar N, Kurinczuk
measure of birth weight for 73. Coles CD, Smith I, Fernhoff PM, JJ, et al. Prenatal alcohol exposure
gestational age using a United States Falek A. Neonatal neurobehavioral and risk of birth defects. Pediatrics.
national reference. BMC Pediatr. characteristics as correlates of 2010;126(4). Available at: www.
2003;3:6 maternal alcohol use during gestation. pediatrics.org/cgi/content/full/126/4/
63. Nellhaus G. Head circumference Alcohol Clin Exp Res. 1985;9(5):454–460 e843
from birth to eighteen years. 74. Coles CD, Brown RT, Smith IE, Platzman 84. Salmon J. Fetal alcohol spectrum
Practical composite international KA, Erickson S, Falek A. Effects disorder: New Zealand birth mothers’
and interracial graphs. Pediatrics. of prenatal alcohol exposure at experiences. Can J Clin Pharmacol.
1968;41(1):106–114 school age. I. Physical and cognitive 2008;15(2):e191–e213
64. Thomas IT, Gaitantzis YA, Frias JL. development. Neurotoxicol Teratol. 85. Salmon JV, Buetow SA. An exploration
Palpebral fissure length from 29 1991;13(4):357–367 of the experiences and perspectives
weeks gestation to 14 years. J Pediatr. 75. Brown RT, Coles CD, Smith IE, et al. of New Zealanders with fetal alcohol
1987;111(2):267–268 Effects of prenatal alcohol exposure spectrum disorder. J Popul Ther Clin
65. Clarren SK, Chudley AE, Wong L, Friesen at school age. II. Attention and Pharmacol. 2012;19(1):e41–e50
J, Brant R. Normal distribution of behavior. Neurotoxicol Teratol. 86. Bell SH, Stade B, Reynolds JN, et al.
palpebral fissure lengths in Canadian 1991;13(4):369–376 The remarkably high prevalence of

16 HOYME et al
 epilepsy and seizure history in fetal memory in children with fetal alcohol (CIFASD). Toward a neurobehavioral
alcohol spectrum disorders. Alcohol syndrome. Alcohol Clin Exp Res. profile of fetal alcohol spectrum
Clin Exp Res. 2010;34(6):1084–1089 1996;20(5):810–816 disorders. Alcohol Clin Exp Res.
87. Nicita F, Verrotti A, Pruna D, et al. 97. Willoughby KA, Sheard ED, Nash 2010;34(9):1640–1650
Seizures in fetal alcohol spectrum K, Rovet J. Effects of prenatal 107. Mattson SN, Roesch SC, Glass L,
disorders: evaluation of clinical, alcohol exposure on hippocampal et al; CIFASD. Further development of a
electroencephalographic, and volume, verbal learning, and neurobehavioral profile of fetal alcohol
neuroradiologic features in a verbal and spatial recall in late spectrum disorders. Alcohol Clin Exp
pediatric case series. Epilepsia. childhood. J Int Neuropsychol Soc. Res. 2013;37:517–528
2014;55(6):e60–e66 2008;14(6):1022–1033 108. Whaley SE, O’Connor And MJ,
88. Bartholomeusz HH, Courchesne E, 98. Coles CD, Lynch ME, Kable JA, Johnson Gunderson B. Comparison of the
Karns CM. Relationship between KC, Goldstein FC. Verbal and nonverbal adaptive functioning of children
head circumference and brain memory in adults prenatally exposed prenatally exposed to alcohol to a
volume in healthy normal toddlers, to alcohol. Alcohol Clin Exp Res. nonexposed clinical sample. Alcohol
children, and adults. Neuropediatrics. 2010;34(5):897–906 Clin Exp Res. 2001;25(7):1018–1024
2002;33(5):239–241 99. Connor PD, Sampson PD, Bookstein FL, 109. Crocker N, Vaurio L, Riley EP, Mattson
89. Treit S, Zhou D, Andrew G, Chudley Barr HM, Streissguth AP. Direct and SN. Comparison of adaptive behavior
A, Beaulieu C. Abstract. Is head indirect effects of prenatal alcohol in children with heavy prenatal
circumference an accurate proxy for damage on executive function. Dev alcohol exposure or attention-deficit/
brain volume in individuals with fetal Neuropsychol. 2000;18(3):331–354 hyperactivity disorder. Alcohol Clin Exp
alcohol spectrum disorders? Int J Dev 100. Kodituwakku PW, Kalberg W, May Res. 2009;33(11):2015–2023
Neurosci. 2015;47:84–85 PA. The effects of prenatal alcohol 110. Jirikowic T, Kartin D, Olson HC.
90. Mattson SN, Schoenfeld AM, Riley EP. exposure on executive functioning. Children with fetal alcohol spectrum
Teratogenic effects of alcohol on brain Alcohol Res Health. 2001;25(3):192–198 disorders: a descriptive profile of
and behavior. Alcohol Res Health. 101. Aragón AS, Kalberg WO, Buckley D, adaptive function. Can J Occup Ther.
2001;25(3):185–191 Barela-Scott LM, Tabachnick BG, 2008;75(4):238–248
91. Spadoni AD, McGee CL, Fryer SL, May PA. Neuropsychological study of 111. Consensus statement on recognizing
Riley EP. Neuroimaging and fetal FASD in a sample of American Indian alcohol-related neurodevelopmental
alcohol spectrum disorders. Neurosci children: processing simple versus disorder (ARND) in primary health care
Biobehav Rev. 2007;31(2):239–245 complex information. Alcohol Clin Exp of children. Interagency Coordinating
92. Jones KL, Hoyme HE, Robinson Res. 2008;32(12):2136–2148 Committee on Fetal Alcohol Spectrum
LK, et al. Fetal alcohol spectrum 102. Coles CD, Platzman KA, Lynch ME, Disorders (ICCFASD). Joseph F. Hagan,
disorders: extending the range of Freides D. Auditory and visual Jr., M.D., Conference Panel Chair.
structural defects. Am J Med Genet A. sustained attention in adolescents Available at: http://niaaa.nih.gov/sites/
2010;152A(11):2731–2735 prenatally exposed to alcohol. Alcohol default/files/ARNDConferenceCon
Clin Exp Res. 2002;26(2):263–271 sensusStatementBooklet_Complete.
93. May PA, Gossage JP, Marais AS, pdf. Accessed March 29, 2016
et al. The epidemiology of fetal alcohol 103. Coles CD, Platzman KA, Raskind-Hood
syndrome and partial FAS in a South CL, Brown RT, Falek A, Smith IE. A 112. AAP Division of Children with Special
African community. Drug Alcohol comparison of children affected Needs. AAP endorses statement on
Depend. 2007;88(2-3):259–271 by prenatal alcohol exposure and alcohol-related neurodevelopmental
attention deficit, hyperactivity disabilities. AAP News. 2012;33:18
94. May PA, Tabachnick BG, Gossage JP,
et al. Maternal risk factors predicting disorder. Alcohol Clin Exp Res. 113. American Psychiatric Association.
child physical characteristics and 1997;21(1):150–161
Diagnostic and Statistical Manual of
dysmorphology in fetal alcohol 104. Kodituwakku PW. Neurocognitive Mental Disorders (DSM). Available at:
syndrome and partial fetal alcohol profile in children with fetal alcohol www.psychiatry.org/psychiatrists/
syndrome. Drug Alcohol Depend. spectrum disorders. Dev Disabil Res practice/dsm. Accessed March 29,
2011;119(1-2):18–27 Rev. 2009;15(3):218–224
2016
95. Streissguth AP. The behavioral 105. Ware AL, O’Brien JW, Crocker N,
114. Doyle LR, Mattson SN. Neurobehavioral
teratology of alcohol: performance, et al; CIFASD. The effects of prenatal
behavioral and intellectual deficits in alcohol exposure and attention- disorder associated with prenatal
prenatally exposed children. In: West deficit/hyperactivity disorder on alcohol exposure (ND-PAE): review
J, ed. Alcohol and Brain Development. psychopathology and behavior. Alcohol of evidence and guidelines for
New York, NY: Oxford University Press; Clin Exp Res. 2013;37(3):507–516 assessment. Curr Dev Disord Rep.
1986:3–44 106. Mattson SN, Roesch SC, Fagerlund 2015;2(3):175–186
96. Mattson SN, Riley EP, Delis DC, Stern A, et al; Collaborative Initiative on 115. Suttie M, Foroud T, Wetherill L,
C, Jones KL. Verbal learning and Fetal Alcohol Spectrum Disorders et al. Facial dysmorphism across the

PEDIATRICS Volume 138, number 2, August 2016 17

 fetal alcohol spectrum. Pediatrics. of exposure and correlate with exposure: a model for fetal alcohol
2013;131(3). Available at: www. fetal alcohol syndrome birth spectrum disorders. Front Genet.
pediatrics.org/cgi/content/full/131/3/ defects. Epigenetics Chromatin. 2014;5:161
e779 2015;8:39 118. Mead EA, Sarkar DK. Fetal alcohol
116. Veazey KJ, Parnell SE, Miranda RC, 117. Kleiber ML, Diehl EJ, Laufer BI, spectrum disorders and their
Golding MC. Dose-dependent alcohol- et al. Long-term genomic and transmission through genetic and
induced alterations in chromatin epigenomic dysregulation as a epigenetic mechanisms. Front Genet.
structure persist beyond the window consequence of prenatal alcohol 2014;5:154

18 HOYME et al