INTRODUCTION — Prenatal exposure to alcohol is the leading preventable cause of birth defects and developmental disabilities. Fetal alcohol spectrum disorder (FASD) is a term that is used to describe the range of physical, behavioral, and neurodevelopmental effects that can occur in an individual who was prenatally exposed to alcohol and may have lifelong implications and high societal costs [1,2].
This topic will discuss the clinical features and diagnosis of FASD. The management, prognosis, and prevention of FASD and alcohol use in pregnancy are discussed separately. (See "Fetal alcohol spectrum disorder: Management and prognosis" and "Alcohol intake and pregnancy".)
TERMINOLOGY — FASD is an umbrella term that encompasses the range of physical, mental health, behavioral, and cognitive effects that can occur in individuals with prenatal alcohol exposure [3-5]. In most classification systems, FASD is not a diagnostic term but describes a group of specific conditions with mild to severe phenotypes; the conditions include (table 1) [6,7]:
●Fetal alcohol syndrome (FAS)
●Partial fetal alcohol syndrome (pFAS)
●Alcohol-related neurodevelopmental disorder (ARND)
●Neurobehavioral disorder associated with prenatal alcohol exposure (ND-PAE), sometimes called neurodevelopmental disorder associated with prenatal alcohol exposure
●Alcohol-related birth defects (ARBD)
The terminology for FASD continues to evolve within and between professional societies [3,8-14]. As an example, ND-PAE was introduced in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) [15]. ARND and ND-PAE describe the neurobehavioral effects of prenatal alcohol exposure without facial dysmorphology or growth abnormalities [9,13]. They are similar, but not completely overlapping (table 1) [9,16]; both are clinically useful. The 2015 Canadian Guidelines for diagnosis of FASD across the lifespan recognized FASD as a diagnostic term and introduced some new terminology and diagnostic criteria for FASD, including an "at risk" category (table 2) [8]. The 2016 Australian guidelines and the 2019 Scottish Intercollegiate Guidelines Network align with the 2015 Canadian guidelines and divide FASD into two subcategories: FASD with three sentinel facial features and FASD with less than three sentinel facial features [2,17]. The 2016 National Institute on Alcohol Abuse and Alcoholism (NIAAA) consensus guidelines retained the diagnostic categories established by the Institute of Medicine in 1996 (ie, FAS, pFAS, ARND, and ARBD) (table 1) [9]. (See 'Diagnostic criteria' below.)
Terms that have been used to describe clinical or neurodevelopmental effects of prenatal alcohol exposure in the past or are less commonly used include "fetal alcohol effects" and "neurodevelopmental disorder/alcohol-exposed" or "static encephalopathy/alcohol-exposed" [7,10].
PATHOGENESIS — Alcohol is a teratogen with irreversible central nervous system effects [18].
Neuroimaging and pathologic studies in humans and animal models of prenatal alcohol exposure demonstrate abnormal brain structure and function following prenatal alcohol exposure, although a consistent pattern has not been identified [19]. The range of abnormalities includes reduced brain volume with specific reductions in the frontal lobe, striatum and caudate nucleus, thalamus, hippocampus, and cerebellum; thinning of the corpus callosum; and abnormal functioning of the amygdala [20-28]. These areas influence cognition, impulse control and judgment, emotional processing, transfer of information between the hemispheres, memory and learning, motor coordination, ability to work toward goals, spatial perception, and perception of time. In addition, increasing numbers of epigenetic studies correlate alcohol exposure in utero with alteration of DNA methylation and gene expression in animal models and humans [29-31].
A "safe" threshold or pattern of alcohol consumption has not been identified [5,32-35]. The fetus is particularly vulnerable to maternal alcohol consumption because of inefficient elimination and prolonged exposure [36]. Alcohol is eliminated from the fetal compartment at a rate of only 3 to 4 percent of the maternal rate. In addition, much of the alcohol excreted by the fetus into the amniotic fluid is "recycled" through fetal swallowing of amniotic fluid and intramembranous absorption.
Alcohol has the potential to cause deleterious effects at all stages of gestation [34,37-39]. Significant alcohol exposure during the first trimester is associated with facial anomalies and major structural anomalies, including brain anomalies [37]; exposure in the second trimester increases the risk of spontaneous abortion; exposure in the third trimester predominantly affects weight, length, and brain growth [37,40-42]. However, neurobehavioral effects may occur with a range of exposures throughout gestation, even in the absence of facial or structural brain anomalies.
The teratogenic effects may vary depending upon the quantity and pattern (eg, binge drinking, daily drinking) of alcohol consumption, maternal and fetal genetics, maternal age, maternal nutrition, and smoking, among other factors [35,43-50]. (See "Alcohol intake and pregnancy", section on 'Safe level of alcohol intake'.)
EPIDEMIOLOGY
Prevalence — Estimates of the prevalence of FASD vary with the study population, method of ascertainment, and the definition [51-54]. In a meta-analysis of 24 studies with active case ascertainment, the estimated global prevalence of FASD in the general population of children age 0 to 16.4 years was 0.77 percent (95% CI 0.5-1.2 percent) [51]. The prevalence was highest (2 percent) in the WHO European region and lowest (0.01 percent) in the WHO Eastern Mediterranean region but may have been underestimated in some countries because of inadequate methods of identification or stigma related to alcohol consumption. The prevalence of FASD in the United States was 1.5 percent. In a subsequent cross-sectional study with active case surveillance among 13,146 first-grade children from four diverse regions of the United States, conservative estimates of prevalence ranged from 1.1 to 5 percent [53].
In meta-analyses, the prevalence of FASD is increased in Aboriginal children, children in foster care or orphanages, adopted children, children in the juvenile justice system, children receiving special education, children in psychiatric care, and in populations with low socioeconomic status [51,54].
Fetal alcohol syndrome (FAS) is less common than other types of FASD. In the cross-sectional study, among the 222 children with an FASD, 12 percent met criteria for FAS, 47 percent met criteria for partial FAS, and 41 percent met criteria for alcohol-related neurodevelopmental disorder [53].
The prevalence of FAS increases with increasing alcohol consumption during pregnancy, as illustrated by observational studies demonstrating a prevalence of FAS of 0.2 percent in the general United States population at a time when the prevalence of maternal alcohol consumption was 12.2 percent [55-57]; a prevalence of FAS of 1 percent in a single county foster care population with a prevalence of maternal alcohol consumption ranging from 15 to 48 percent [58]; and a prevalence of FAS of 4.7 percent in the Washington State Fetal Alcohol Syndrome Diagnostic and Prevention Network cohort, with a prevalence of alcohol consumption of 100 percent [59].
The prevalence of alcohol consumption during pregnancy is discussed separately. (See "Alcohol intake and pregnancy", section on 'Epidemiology of alcohol use'.)
Risk in subsequent pregnancies — The risk of FASD in subsequent pregnancies is high if mothers continue to drink alcohol (estimated to be as high as 70 percent based on data from observational studies) [60]. This highlights the need to evaluate other children born to the same mother, even if they no longer live with the biologic family [61].
Risk factors — Children are at greater risk for FASD if they have a sibling with an FASD, have ever lived in an orphanage or been placed in foster care, are in psychiatric care, or have current or past involvement with child protective services or the juvenile justice system [51,58,60,62,63].
Maternal and psychosocial risk factors for FASD include [11,64-68]:
●Higher maternal age
●Higher gravidity and parity
●History of miscarriages and stillbirths
●Inadequate prenatal care
●Poor maternal nutrition during pregnancy
●History of FASD in previous children
●Substance use, including tobacco
●Mental health problems, including depression
●History of physical or sexual abuse
●Social isolation, including living in a rural area during pregnancy
●Intimate partner violence
●Alcohol and drug use by the mother's intimate partner at the time of pregnancy
●Other maternal family members with substance use at the time of pregnancy
●Poverty
Despite these risk factors, all women are at risk of giving birth to a child with an FASD if they consume alcohol during pregnancy.
CLINICAL FEATURES — The clinical features of FASD include three characteristic facial features (short palpebral fissures, thin vermillion border, and smooth philtrum) (picture 1), central nervous system (CNS) abnormalities, and growth retardation [3,9,10,69].
Spectrum of findings — Various combinations of these features form the criteria for the diagnosis of fetal alcohol syndrome (FAS), partial fetal alcohol syndrome (pFAS), alcohol-related neurodevelopmental disorder (ARND) [70], alcohol-related birth defects (ARBD), and neurobehavioral disorder associated with prenatal alcohol exposure (ND-PAE) (table 1). FAS and pFAS tend to be more recognizable than ARND and ND-PAE because of the characteristic facial dysmorphology and growth retardation. A longitudinal cohort study suggested that a combination of dysmorphology, growth, and neurobehavioral features may identify children with an FASD by 9 to 18 months of age [68]. Other birth defects may be observed in individuals with prenatal alcohol exposure, which helps to make a diagnosis of ARBD. However, physical features of prenatal alcohol exposure are absent in as many of 75 percent of affected children [71].The predominant clinical features may vary with age [68]. Facial dysmorphism may be apparent at birth (though may not be recognized). Growth retardation may occur prenatally or postnatally. CNS impairment may not be apparent until the child is in school [72]. Most individuals with an FASD are diagnosed during childhood. In a large case series of individuals with an FASD, 90 percent were diagnosed before age 16 years; the average age at diagnosis was 9.9 years (range seven days to 50.8 years) [59]. In the Centers for Disease Control and Prevention Fetal Alcohol Syndrome Surveillance project, the average age at ascertainment of FAS was 48.3 months [73].
Facial dysmorphism and minor anomalies — Short palpebral fissures, thin vermillion border, and smooth philtrum are the characteristic facial dysmorphisms of FASD (picture 1). These characteristic dysmorphisms are required for a diagnosis of FAS, and pFAS but are not necessary to diagnose ND-PAE (which may be more difficult to recognize in their absence) (table 1) [3,9,10]. Facial features may be less distinctive (but still present) after puberty [74,75].
Other facial features and minor congenital anomalies that may occur [9,76-78] but are not included in the diagnostic criteria are listed below with their frequency in a series of 370 children with FAS [9].
●Hypoplastic midface – 58 percent
●Epicanthal folds – 55 percent
●Decreased interpupillary distance (≤25th percentile) – 55 percent
●Flat nasal bridge – 48 percent
●Altered palmar crease (eg, "hockey stick" configuration of the upper palmar crease) (figure 1) – 47 percent
●5th finger clinodactyly – 40 percent
●Long philtrum (≥90th percentile) – 33 percent
●Anteverted nares – 32 percent
●Camptodactyly – 31 percent
●Decreased intercanthal distance (≤25th percentile) – 28 percent
●Ptosis – 17 percent
●"Railroad track" ears (ie, a prominent horizontal crus and prominent and parallel inferior crus of the anthelix) (figure 2) – 15 percent
●Heart murmur – 14 percent
●Strabismus – 9 percent
●Limited elbow supination – 8 percent
●Hypoplastic nails – 6 percent
●Prognathism – 6 percent
●Hypertrichosis – 5 percent
Structural birth defects and other abnormalities — Prenatal alcohol exposure may result in structural birth defects and other abnormalities that usually occur in conjunction with other findings that are more characteristic of FASD and helpful in diagnosing ARBD. Abnormalities may occur in the following systems [9,59,78-82]:
●Cardiac – The reported prevalence of congenital heart disease (CHD) in children with FAS is approximately 2 percent [9], which is somewhat higher than the prevalence in the general population (approximately 1 percent). (See "Newborn screening for critical congenital heart disease using pulse oximetry", section on 'Prevalence of critical congenital heart disease'.)
Associated CHD defects may include atrial septal defect, ventricular septal defect, and conotruncal heart defects (eg, aberrant great vessels, Tetralogy of Fallot). (See "Isolated atrial septal defects (ASDs) in children: Classification, clinical features, and diagnosis", section on 'Clinical features' and "Isolated ventricular septal defects in infants and children: Anatomy, clinical features, and diagnosis", section on 'Clinical features' and "Pathophysiology, clinical features, and diagnosis of tetralogy of Fallot" and "Pathophysiology, clinical features, and diagnosis of tetralogy of Fallot", section on 'Clinical features'.)
●Skeletal – Large joint flexion contractures, pectus excavatum, pectus carinatum, Klippel-Feil syndrome, vertebral segmentation defect, hemivertebrae, scoliosis, radioulnar synostosis, hypoplastic nails, shortened fifth digits, clinodactyly of the fifth finger, camptodactyly.
●Renal – Aplastic, dysplastic, hypoplastic kidney, or horseshoe kidney; ureteral duplications, hydronephrosis. (See "Overview of congenital anomalies of the kidney and urinary tract (CAKUT)" and "Renal ectopic and fusion anomalies".)
●Ocular – Strabismus, ptosis, retinal vascular anomalies, optic nerve hypoplasia, refractive problems secondary to microphthalmia; vision problems were reported in 28 percent of patients from one large series [59] (see "Evaluation and management of strabismus in children" and "Congenital anomalies and acquired abnormalities of the optic nerve", section on 'Hypoplasia' and "Vision screening and assessment in infants and children")
●Auditory – Conductive or sensorineural hearing loss; in one large series, chronic hearing loss occurred in 18 percent of patients with an FASD [59]. (See "Hearing loss in children: Screening and evaluation".)
Central nervous system involvement — CNS involvement (clear evidence of brain involvement or neurobehavioral impairment) is a characteristic feature of FASD and required for a diagnosis of FAS, pFAS, ARND, and ND-PAE (table 1) [3,9,10].
Types of central nervous system involvement — Approximately 70 percent of children with heavy prenatal alcohol exposure (>4 drinks at least once per week or >14 drinks per week throughout the pregnancy) have neurobehavioral effects, even if they do not meet criteria for FAS [83,84]. In a series of 1400 individuals (newborn to adult) with confirmed alcohol exposure (any level), 90 percent presented with moderate to severe neurobehavioral effects [59]. However, approximately 85 percent had other prenatal and postnatal risk factors that contribute to neurobehavioral problems (eg, poor prenatal care, exposure to illicit drugs, family history of learning disabilities, neglect, abuse, etc).
CNS involvement in FASD may result in a complex range of neurodevelopmental and behavioral disabilities that may not be apparent until the child is in school [40,72,85]. The clinical manifestations may vary from patient to patient, and in individual patients, performance may vary from day to day [61,86].
The manifestations of CNS involvement may vary with age [9,61,74,87-89]:
●Infancy – Irritability, jitteriness, autonomic instability, problems regulating state (eg, sleep, attention, arousal), and delayed development
●Childhood – Hyperactivity, inattention, cognitive impairment, emotional reactivity, learning disabilities, hypotonia, auditory and visual impairment, seizures, deficits in memory and reasoning
●Adolescence and young adulthood – Adverse effects related to primary deficits in social skills, adaptive function, and executive function (eg, school disruption, inability to maintain employment, inappropriate sexual behavior) (see 'Associated problems' below)
CNS involvement usually is classified as structural, neurologic, or functional.
●Structural abnormalities include decreased head circumference (usually defined as ≤10th percentile for age and sex or if height and weight are <10th percentile, head circumference ≤3rd percentile) or structural abnormalities on neuroimaging (eg, reduction in size or change in shape of the corpus callosum, cerebellum, or basal ganglia) [3,4,9,10].
In one series of 1400 patients with an FASD, 12 percent had microcephaly (defined by head circumference <3rd percentile) [59]. Microcephaly was more frequent among patients with FAS or pFAS than other FASDs (45 versus 25 percent). Among those who underwent imaging, 18 percent had magnetic resonance imaging abnormalities.
●Neurologic abnormalities include "hard" neurologic signs (eg, abnormal reflexes, abnormal tone, cranial nerve deficits) and recurrent seizures that are not due to postnatal insult or infection [4,9].
A 2014 meta-analysis of 10 observational studies found an association between diagnosis of FASD or moderate to heavy prenatal alcohol exposure and gross motor impairment (odds ratio 2.9, 95% CI 2.1-4.0) [90]. Impaired gross motor skills included balance, coordination, and ball skills (eg, throwing, catching, kicking).
●Functional abnormalities may occur in multiple domains [3,59,70,91]. The following manifestations have been observed in longitudinal and case-control studies:
•Cognitive – The overall intelligence quotient (IQ) of individuals with an FASD is usually above the threshold for intellectual disability (ie, 70) but may range from 20 to 120; children with FAS tend to have lower IQs than children with pFAS, ARND, or ND-PAE [74,92]; in a population of 1400 individuals with prenatal alcohol exposure, 8 percent had IQ <70; among the 154 with FAS, 20 percent had IQ <70 [59].
Difficulties in arithmetic are the most common, but difficulties in reading and spelling also may occur; other cognitive problems may include impaired memory and slow processing speed [3,71,74,93,94].
Relative areas of cognitive strength include verbal abilities, particularly vocabulary and grammatical skills [3].
•Executive function (eg, difficulty planning and relating cause and effect; failure to consider consequences of actions; poor organization; impaired judgment; inability to generalize knowledge from one situation to another) [3,74].
•Memory problems, including getting lost in new or familiar locations and forgetting recent events, how to perform specific tasks, content of conversations, placement of items around the house, and everyday routines [95].
•Motor function (eg, poor gross motor coordination, poor fine motor and visual-spatial coordination [eg, poor handwriting legibility and speed], hypotonia) [92,96-98].
•Problems with hyperactivity, attention, or concentration (eg, difficulty encoding information and difficulty shifting aspects of attention [eg, from visual to auditory targets]), which appear to differ from "classic" attention deficit hyperactivity disorder (ADHD) (eg, problems with focus and sustaining attention) [74,99,100].
•Social skills and adaptive function (eg, poor understanding of social cues, seeming lack of remorse after misbehaving, lack of appropriate initiative, lack of reciprocal friendships, social withdrawal, poor personal hygiene; gullibility) [71,74,101-105].
Relative social strengths include high levels of social motivation [102] and friendliness [106].
Associated problems — Problems associated with the neurobehavioral effects of prenatal alcohol exposure may include:
●Abnormal eating behaviors and eating difficulties (eg, oral aversion and sensitivity to texture, difficulty chewing and handling silverware, pica, poor appetite), which may contribute to postnatal growth retardation [107].
●Difficulty getting along with peers related to poor social skills and vulnerability to bullying and abuse [3,71,74]. In a large case series of patients with an FASD, nearly 70 percent had social problems [59].
●Unrealistic expectations or being labeled as "lazy" or "oppositional" if parents and/or educators believe that they are functioning at higher levels than they actually are (based on their relative strength in language) or if the expectations are based on a particularly good day (given the wide variability in day-to-day performance) [3,61].
●Difficulty with activities of daily living may lead to lack of independence in adolescence and adulthood and difficulty maintaining employment [74,88].
●Disrupted school experience (eg, suspended, expelled, dropped out); in a large case series of patients with an FASD, 14 percent of children and 53 percent of adolescents and adults had disrupted school experience [59].
●Problems with impulse control and judgment may lead to inappropriate sexual behaviors (eg, exposure, inappropriate sexual advances or touching, promiscuity). In a series of 415 patients with an FASD, repeated inappropriate sexual behaviors were reported in 39 percent of children, 48 percent of adolescents, and 52 percent of adults [71]; inappropriate sexual behavior among female individuals with an FASD was associated with a personal history of physical or sexual violence.
●The combination of strong verbal skills, naïve social skills, and difficulty with impulse control and judgment may lead to participation in criminal activity and encounters with law enforcement (eg, charged, arrested, convicted), or confinement (in juvenile detention, jail, or prison) [3,4,71,88]. In a series of 415 patients, 14 percent of children and 60 percent of adolescents and adults reported encounters with law enforcement [71].
●Problems with alcohol or drugs and/or inpatient alcohol or drug treatment. In a series of 415 patients, 35 percent of adolescents and adults reported problems with alcohol or drugs [71].
Comorbid mental health conditions — Individuals with an FASD may have comorbid mental health disorders, including conduct disorders, oppositional defiant disorder, anxiety, adjustment disorder, sleep disorder, depression, or substance use disorder [4,82,88]. In a series of 1064 patients ≥5 years at the time of FASD diagnosis, 74 percent had documentation of one or more mental health disorders, including ADHD (54 percent), oppositional defiant disorder (9 percent), posttraumatic stress disorder (7 percent), and depression (5 percent) [59]. FASD may increase the severity or complexity of these conditions [61].
Growth retardation — Prenatal or postnatal growth retardation is a characteristic feature of FASD in most diagnostic schema and required for a diagnosis of FAS [3,9,10,108]. It may be part of the clinical constellation of pFAS without documented prenatal alcohol exposure and ND-PAE but is not required for diagnosis (table 1). Poor growth that begins in utero tends to continue through infancy and childhood. Short stature may persist into adolescence and adulthood [59].
In a series of 1400 patients (newborn to adult) with confirmed alcohol exposure evaluated for FASD from a single state (4 percent with FAS, 7 percent with pFAS, 28 percent with static encephalopathy/alcohol-exposed [severe dysfunction without the FAS facial phenotype], and 52 percent with neurodevelopmental disorder/alcohol-exposed [moderate dysfunction without the facial phenotype]), 34 percent had height and/or weight below the 10th percentile [59].
APPROACH TO EVALUATION AND DIAGNOSIS — FASDs usually are diagnosed by clinicians with expertise in FASD and other birth defects/developmental disabilities (eg, developmental-behavioral pediatrician, child neurologist, clinical geneticist/dysmorphologist), generally in the context of a multidisciplinary evaluation [3,9,10,69,109,110].
Accurate diagnosis of FASD is important because [9,69,71,111-114]:
●Early diagnosis is associated with improved outcomes
●It enables interventions and support for the patient and family (eg, job skills training) (see "Fetal alcohol spectrum disorder: Management and prognosis")
●In combination with maternal support and services, it can prevent the birth of subsequent children with an FASD (see "Fetal alcohol spectrum disorder: Management and prognosis", section on 'Prevention')
●Children diagnosed with an FASD may avoid unnecessary interventions for other conditions in the differential diagnosis (eg, medication for attention deficit hyperactivity disorder), and children in whom FASD is excluded can continue to be evaluated for other neurodevelopmental conditions (see 'Differential diagnosis' below)
The American Academy of Pediatrics (AAP) has developed an "Flow Diagram for Medical Home Evaluation of Fetal Alcohol Spectrum Disorders (FASD)" [109] and a "Fetal Alcohol Spectrum Disorders Patient Checklist for Pediatric Medical Home Providers" [115] to assist the primary care provider in the identification, diagnosis, and referral of a child with a possible FASD.
Clinical suspicion — FASD should be considered in children with clinical features associated with FASDs, including [8,9,68,116] (see 'Clinical features' above):
●Facial dysmorphism, particularly short palpebral fissures, thin vermillion border, and smooth philtrum (picture 1) (see 'Facial dysmorphism and minor anomalies' above)
●Intrauterine and/or postnatal growth retardation
●Microcephaly
●Structural brain anomaly
●Recurrent nonfebrile seizures
●Developmental, learning, and cognitive problems, including school failure
●Behavioral problems (eg, hyperactivity, impaired executive functioning skills)
●Social-emotional problems
It is particularly important to consider FASD in children with developmental, learning, cognitive, or behavioral problems. In observational studies, behavioral problems associated with FASDs (eg, negative mood, being difficult to handle) were noted by caregivers in infants as young as six months, and parents' and teachers' complaints about attention, adaptive, and learning problems were strong predictors of an FASD diagnosis [117,118]. However, in a cross-sectional study with active case ascertainment, although many caregivers were aware of their children's learning and behavioral challenges, only 2 of 222 children who met criteria for FASD had a previous diagnosis [53].
FASD also should be suspected in children with risk factors for FASD, including those with a history of having lived in an orphanage or foster care, those with current or past involvement with child protective services or the juvenile justice system, and those with siblings with an FASD [51,58,60,62,63,109]. Among 547 foster care or adopted children (4 to 18 years of age) who underwent comprehensive evaluation at a mental health clinic specializing in the treatment of high-risk children and adolescents, 28.5 percent were diagnosed with an FASD [63]. Among children ultimately diagnosed with an FASD, 80 percent were previously undiagnosed. (See 'Risk factors' above.)
Given the importance of making an accurate diagnosis and the difficulties in differentiating central nervous system (CNS) effects of prenatal alcohol exposure from other neurodevelopmental disorders and adverse environmental factors, referral to an FAS/FASD clinic is recommended by the AAP and the Centers for Disease Control and Prevention [3,4,109]. (See 'Indications for referral' below.)
Pending specialist evaluation, the primary care provider can provide guidance about behavior management and promotion of healthy development, as well as referral for early intervention services. (See "Fetal alcohol spectrum disorder: Management and prognosis", section on 'General recommendations'.)
Comprehensive evaluation — The comprehensive evaluation for FASD is ideally performed in an FAS/FASD clinic by an interdisciplinary team of specialists with expertise in FAS and other birth defects/developmental disabilities [2,8]. The interdisciplinary team may include a developmental-behavioral pediatrician, neurologist, neuropsychologist, speech-language pathologist, occupational therapist, geneticist, and family advocate. The geneticist is particularly helpful in excluding alternative or coexisting diagnoses and determining the need for genetic testing (eg, chromosomal microarray analysis) [76,119].
The goals of the comprehensive evaluation include confirmation of prenatal alcohol exposure, exclusion of other diagnoses, identification of comorbidities, and determination of the child's individual neurobehavioral profile of strengths and areas of need, which is helpful in formulating a management plan. (See "Fetal alcohol spectrum disorder: Management and prognosis", section on 'Approach to management'.)
If multidisciplinary evaluation is not available, primary care providers may be able to share facial images with experts electronically, and the school system may be able to provide neurocognitive assessments. For interested clinicians, the AAP provides guidance for developing an FASD team [120].
Prenatal alcohol exposure — In most diagnostic schema, documented prenatal alcohol exposure is necessary for a diagnosis of partial fetal alcohol syndrome (pFAS), alcohol-related neurodevelopmental disorder (ARND), alcohol-related birth defects (ARBD), and neurobehavioral disorder associated with prenatal alcohol exposure (ND-PAE) [3,10]. FAS, and in some schemas pFAS, can be diagnosed without confirming prenatal alcohol exposure if other criteria are met (table 1) [3,4,9].
●Asking about alcohol exposure – Questions related to alcohol consumption must be asked in a nonjudgmental manner. One approach is to ask the questions in the following sequence, first introducing them with a statement such as, "I ask the parents of all of my patients standard health questions so that I can understand factors that may affect their health and the health of their child" [9,13,121-124]:
•General health history (eg, general health, dietary intake, pregnancy history)
•Current drinking patterns
•Drinking patterns before pregnancy
•Drinking patterns during pregnancy
•Gestational age when the mother recognized she was pregnant
Although often not available, critical information about maternal prenatal alcohol consumption includes [2,9,13]:
•The quantity of alcohol consumed per occasion (ie, number of standard drinks per drinking day; a standard drink is defined as 12 ounces [360 mL] of beer or wine cooler, 5 ounces [150 mL] of wine, or 1.5 ounces [45 mL] of liquor)
•The frequency of drinking
•When during the pregnancy the mother drank alcohol
●Definition of prenatal alcohol exposure – A "safe" threshold or pattern of alcohol consumption has not been identified [32,33,125]. Any amount of alcohol may be significant and alcohol has the potential to cause deleterious effects at all stages of gestation. Binge drinking (ie, ≥4 standard drinks on a single occasion) and drinking throughout pregnancy are considered particularly harmful [125-128].
We agree with the 2016 National Institute on Alcohol Abuse and Alcoholism (NIAAA) consensus guidelines, which define documented prenatal alcohol exposure as one or more of the following (beginning three months before recognition of pregnancy or a positive pregnancy test documented in the medical record and continuing until delivery) [9]:
•≥6 drinks per week for ≥2 weeks
•≥3 drinks per occasion on ≥2 occasions
•Documentation of alcohol-related social or legal problems (eg, history of citations for driving while intoxicated or history of treatment for an alcohol-related condition)
•Documentation of intoxication by blood, breath, or urine alcohol content testing
•Increased prenatal risk associated with drinking during pregnancy as assessed by a validated screening tool (see "Screening for unhealthy use of alcohol and other drugs in primary care", section on 'Pregnancy')
•If verified in additional studies (an active area of research), positive testing with established alcohol-exposure biomarker(s) (eg, analysis of fatty acid ethyl esters, phosphatidylethanol, and/or ethyl glucuronide in maternal hair, fingernails, urine, or blood; placenta; or meconium); a 2016 systematic review concluded that existing biomarkers were not sufficiently sensitive and specific to support clinical use, but that biomarkers in meconium and placenta tissue appear to be the most promising [129]
●Sources for documentation of prenatal alcohol exposure – The history of prenatal alcohol exposure can be obtained from the birth mother; family members of the birth mother; foster or adoptive parents; employees of social services agencies who directly observed maternal drinking behavior during pregnancy; or medical records documenting positive blood alcohol levels, alcohol treatment, or social, legal, or medical problems related to drinking during pregnancy [3,8,9]. (See "Screening for unhealthy use of alcohol and other drugs in primary care", section on 'Pregnancy' and "Alcohol intake and pregnancy", section on 'Screening for alcohol misuse'.)
●Reliable exclusion of prenatal alcohol exposure – Reliable exclusion of prenatal alcohol exposure precludes a diagnosis of FASD [4,8]. Reliable exclusion of prenatal alcohol exposure may occur if the mother knew the date of conception (ie, planned pregnancy) and did not drink alcohol from that day forward or if the mother was prevented from drinking for any reason (eg, incarceration).
●Challenges to confirmation – Confirmation of prenatal alcohol exposure can be challenging for a number of reasons:
•The mother may be uncertain about how much alcohol was consumed after conception but before pregnancy recognition, particularly if the pregnancy was unplanned.
•The mother may under-report alcohol consumption during pregnancy because of fear, shame, guilt, and worry that the child may be removed from her custody.
•The child and mother may have been separated (eg, through foster care, adoption, maternal death, or incarceration); in several case series, as many as 80 percent of children with FAS experience early separation from their parents [59,61,71,74,130].
Physical examination — Physical examination findings included in the criteria for one or more FASD include (table 1) [3,9,10]:
●Facial dysmorphism (short palpebral fissures, thin vermillion border, and smooth philtrum):
•Instructions for measuring palpebral fissure length are available from the FAS Diagnostic and Prevention Network and the AAP toolkit (picture 2); palpebral fissure length can be assessed according to the Thomas chart [131] or, for school-age children, using photographs and computer software [132]. However, palpebral fissure length measured in photographs may be consistently lower than palpebral fissure length measured in person [133,134].
•Thinness of the vermillion border and smoothness of the philtrum are usually assessed with the University of Washington Lip Philtrum Guide (picture 3) [135].
●Growth retardation – Growth retardation is usually defined by height and/or weight ≤10th percentile for age, sex, race/ethnicity (if available), and gestation. Documentation of growth retardation may require obtaining previous growth records and plotting of growth parameters from birth through current age.
●Decreased head circumference – Decreased head circumference is defined by head circumference ≤10th percentile for age and sex or, if weight and height are <10th percentile, by head circumference ≤3rd percentile.
●Neurologic abnormalities, including "hard" neurologic signs (eg, abnormal reflexes, abnormal tone, cranial nerve deficits). (See "Detailed neurologic assessment of infants and children".)
●Structural birth defects that may occur in conjunction with an FASD and are clues to the diagnosis of ARBD. (See 'Structural birth defects and other abnormalities' above.)
In addition, it is important to observe parent-child interactions. Many children with an FASD are raised in postnatal environments characterized by high psychosocial stress that can interfere with effective parenting. Observations of parent-child interactions may help to identify targets for psychosocial services or intervention. (See "Fetal alcohol spectrum disorder: Management and prognosis", section on 'Approach to management'.)
Neurocognitive assessment — Developmental and cognitive assessment may be necessary to confirm CNS involvement (table 1), exclude other developmental disabilities, and determine the child's profile of strengths and areas of need [9]. Cognitive testing provides standardized procedures for measuring knowledge and abilities in various areas (eg, reading, writing, math, executive functions, language, comprehension etc). It also may identify areas of difficulty that were not suspected.
Neurocognitive assessment usually is performed by the FAS/FASD clinic or the multidisciplinary team and may include:
●Standardized tests of intellectual and adaptive functioning (table 3)
●Assessment of memory, including working memory
●Assessment of executive function
●Assessment of language
●Assessment of visual motor integration and sensory processing
●Assessment of processing speed
Normal intelligence quotient (IQ) does not exclude FASD if other criteria are met.
Behavioral assessment — Behavior problems in children with an FASD may include [3,40]:
●Difficulty regulating mood
●Problems with executive function
●Inattention, short attention span, hyperactivity, impulsivity, poor impulse control [136,137]
●Irritability or negative affect [138]
●Sleep difficulty [139]
●Impaired social skills
●Indiscriminate social approach [101,102]
●Impaired adaptive functioning
These behavior problems are not pathognomonic for FASD but may help to meet criteria for functional CNS involvement (table 1). (See 'Central nervous system involvement' above.)
Primary care providers can screen for behavior problems using validated behavior screening tests. If the child has a positive behavior screen and the child has a history of prenatal alcohol exposure, referral to an FAS/FASD clinic or multidisciplinary team is warranted. (See 'Indications for referral' below and "Developmental-behavioral surveillance and screening in primary care", section on 'Choice of screening test'.)
Diagnostic criteria — The diagnosis of FASD centers on prenatal alcohol exposure and two or three clinical features (table 1):
●Characteristic facial dysmorphisms (picture 1):
•Short palpebral fissures; instructions for measuring palpebral fissure length are available from the FAS Diagnostic and Prevention Network and the AAP toolkit (picture 2); palpebral fissure length can be assessed according to the Thomas chart [131] or, for school-age children, using photographs and computer software [132]
•Thin vermillion border (University of Washington Lip-Philtrum Guide rank 4 or 5 (picture 3))
•Smooth philtrum (University of Washington Lip-Philtrum Guide rank 4 or 5 (picture 3))
●CNS involvement (structural, neurologic, or functional)
●Growth retardation – Growth retardation is an important clinical feature in most diagnostic schema [3,9,10]; however, it is not included in the 2015 Canadian guidelines for diagnosis of FASD [8]
However, there is no universally accepted set of diagnostic criteria for FASD [14]. Four diagnostic schemas are widely used:
●The NIAAA consensus guidelines (2005) [12], which were updated in 2016 [9]
●The University of Washington Four-Digit Diagnostic Code [10]
●The National Task Force on Fetal Alcohol Syndrome/Fetal Alcohol Effect (FAS/FAE) "Guidelines for referral and diagnosis" [3]
●Fetal Alcohol Spectrum Disorders: Canadian Guidelines for Diagnosis [11], which were updated in 2015 (table 2) [8]
Each of the schemas was developed by expert consensus. They all focus on facial dysmorphism and CNS involvement but may differ with respect to inclusion of growth retardation and/or the requirements to fulfill diagnostic criteria (eg, number of facial dysmorphisms, percentile threshold for palpebral fissure, requirements for CNS involvement). The discordance among these criteria [140,141] highlight the importance of the history of prenatal alcohol exposure [140].
In the absence of universal diagnostic criteria for FASD, the diagnostic criteria for FASD continue to be refined [13,14]. It is important for clinicians to be familiar with the existing diagnostic schemas that describe children with and without facial dysmorphology. Preferences for diagnostic criteria vary locally (eg, the 2015 Canadian guidelines use different nomenclature and diagnostic criteria (table 2) [8]). Less stringent criteria are more inclusive but may lead to over-diagnosis; more stringent criteria may lead to under-diagnosis. This highlights the need for clinicians with expertise in assessing FASD to be involved in the evaluation and ongoing care of children with suspected FASD. (See 'Indications for referral' below.)
In addition to fulfilling the diagnostic criteria, other causes of facial dysmorphism, CNS abnormalities, growth retardation, and structural birth defects (eg, genetic syndromes, adverse environmental factors) must be considered, as well as the possibility of FASD co-occurring with such conditions [3,40,119]. (See 'Differential diagnosis' below.)
The major diagnostic criteria for FASD are as follows:
●Fetal alcohol syndrome – Diagnosis of FAS requires at least two features of facial dysmorphology (ie, short palpebral fissures, thin vermillion border, and smooth philtrum (picture 1)), growth retardation, and CNS involvement (structural, neurologic, or functional abnormalities). If all of these criteria are met, prenatal alcohol exposure need not be documented (table 1). (See 'Clinical features' above.)
●Partial fetal alcohol syndrome – Children with pFAS have documented prenatal alcohol exposure but do not meet all of the criteria for FAS. Diagnosis of pFAS requires at least two of the facial characteristics of FAS (picture 1), growth retardation or CNS involvement, and documented prenatal alcohol exposure. However, the 2016 NIAAA consensus guidelines also permit pFAS to be diagnosed without confirmed prenatal alcohol exposure if there are at least two cardinal facial features, growth retardation or structural brain involvement, and neurobehavioral impairment (table 1) [9]. (See 'Prenatal alcohol exposure' above and 'Clinical features' above.)
●Alcohol-related neurodevelopmental disorder – Children with ARND have documented prenatal alcohol exposure and CNS involvement, which requires only neurobehavioral impairment. (See 'Prenatal alcohol exposure' above and 'Central nervous system involvement' above.)
●Neurobehavioral disorder associated with prenatal alcohol exposure – Children with ND-PAE have confirmed prenatal alcohol exposure and impaired neurocognitive function (eg, intellectual disability, executive function, memory, visual-spatial reasoning), self-regulation (eg, mood, attention, impulse control), and adaptive function (eg, communication, daily living skills, motor skills) (table 4A-C) [13]. In addition, the impairments must affect function and must not be due to other teratogens or genetic or medical conditions [15]. (See 'Differential diagnosis' below.)
Children can be diagnosed with both FAS and ND-PAE; the diagnosis of ND-PAE was created primarily to capture the mental health effects of prenatal alcohol exposure [15].
●Alcohol-related birth defects – Children with ARBD have documented prenatal alcohol exposure and one specific major malformation from intrauterine alcohol exposure. (See 'Prenatal alcohol exposure' above and 'Structural birth defects and other abnormalities' above.)
DIFFERENTIAL DIAGNOSIS
Facial features — The facial dysmorphology seen in fetal alcohol syndrome (FAS) and partial fetal alcohol syndrome (pFAS) can resemble other genetic conditions (table 5) [4,142].
Growth retardation and microcephaly — Other causes of prenatal and postnatal growth retardation and microcephaly in children are discussed separately:
●Prenatal growth retardation (table 6) (see "Infants with fetal (intrauterine) growth restriction" and "Fetal growth restriction: Evaluation and management")
●Postnatal growth retardation (table 7A-B) (see "Causes of short stature" and "Diagnostic approach to children and adolescents with short stature" and "Poor weight gain in children older than two years in resource-abundant countries", section on 'Diagnostic approach' and "Poor weight gain in children younger than two years in resource-abundant countries: Etiology and evaluation", section on 'Causes')
●Microcephaly (table 8) (see "Microcephaly in infants and children: Etiology and evaluation" and "Microcephaly: A clinical genetics approach")
Neurobehavioral phenotype — Neurobehavioral problems in FASD may be related to prenatal alcohol exposure, a coexisting condition, environmental factors, a different neurodevelopmental disorder, or a combination of these factors [40]. The characteristic facial features help to distinguish FAS and pFAS from other causes of neurobehavioral problems. However, in children who lack characteristic facial features, it may not be possible to differentiate neurobehavioral disorders associated with prenatal alcohol exposure from other neurobehavioral disorders and/or neurobehavioral disorders associated with environmental factors. The history of prenatal alcohol exposure is crucial to the differential diagnosis in this situation.
Referral to a clinician with expertise in FASD and a broad array of birth defects/developmental disabilities is warranted to ensure appropriate evaluation and diagnosis. (See 'Indications for referral' below.)
In children who lack characteristic facial features, it may not be possible to differentiate neurobehavioral disorders associated with prenatal alcohol exposure from neurobehavioral disorders with other or unknown etiologies, including [13]:
●Attention deficit hyperactivity disorder (see "Attention deficit hyperactivity disorder in children and adolescents: Clinical features and diagnosis", section on 'Clinical features')
●Autism spectrum disorder (see "Autism spectrum disorder: Clinical features")
●Global developmental delay or intellectual disability (see "Intellectual disability (ID) in children: Clinical features, evaluation, and diagnosis")
●Oppositional defiant disorder
●Conduct disorder
●Mood disorders (eg, depression, bipolar disorder) (see "Pediatric unipolar depression: Epidemiology, clinical features, assessment, and diagnosis", section on 'Clinical features' and "Pediatric bipolar disorder: Clinical manifestations and course of illness", section on 'Clinical presentation')
●Disinhibited social engagement disorder
●Reactive attachment disorder
●Posttraumatic stress disorder (see "Posttraumatic stress disorder in children and adolescents: Epidemiology, pathogenesis, clinical manifestations, course, assessment, and diagnosis")
●Sleep disorder (see "Assessment of sleep disorders in children")
●Substance use disorder (see "Substance use disorder in adolescents: Epidemiology, pathogenesis, clinical manifestations and consequences, course, assessment, and diagnosis")
●Schizophrenia
Environmental factors that may contribute to a neurobehavioral profile similar to that in FASD include [3,4]:
●Early adversity, trauma, and loss
●Exposure to multiple substances in utero (see "Infants with prenatal substance use exposure")
●Poor prenatal environment
●Disrupted home environment (eg, placement in foster care) (see "Comprehensive health care for children in foster care", section on 'Complex childhood trauma and toxic stress')
●Poverty
●Child abuse or neglect
●Ongoing parental substance use
These environmental factors may contribute to complex childhood trauma and "toxic stress," which affects areas of the brain involved in executive function, memory, emotional regulation, attention, and stress reactivity [143,144]. It is not always possible to tease out the specific contribution of prenatal alcohol exposure from other environmental factors. However, a detailed psychosocial history may be helpful, particularly if central nervous system abnormalities were present before the exposure to adverse environmental factors [4]. (See "Comprehensive health care for children in foster care", section on 'Complex childhood trauma and toxic stress'.)
INDICATIONS FOR REFERRAL — Children who are suspected to have an FASD should be referred to a qualified team of specialists for thorough assessment that includes examination for facial dysmorphic features and a complete neurobehavioral evaluation [3,8]. These specialists may consist of developmental behavioral pediatricians, psychiatrists, psychologists, neurologists, clinical geneticists, speech and language pathologists, occupational therapists, social workers, and educational therapists [3]. If a specialized FASD team is not available, we suggest referral to a local specialist with expertise in FASD (eg, a developmental/behavioral pediatrician, clinical geneticist) for initial evaluation.
Simultaneous with the referral for multidisciplinary FASD evaluation, the child should be referred for intervention services. In the United States, intervention services may be provided by Early Intervention (for children younger than three years), preschool special education services, or through the public school system. (See "Developmental-behavioral surveillance and screening in primary care", section on 'Early intervention or special education services'.)
Indications for referral to an FASD multidisciplinary team include [3,4,145]:
●Prenatal alcohol exposure (as defined in the 2016 National Institute on Alcohol Abuse and Alcoholism consensus guidelines) [9] (see 'Prenatal alcohol exposure' above)
For children with less than minimal exposure and no characteristic features (characteristic facial dysmorphism, growth retardation, central nervous system [CNS] abnormalities), the child's growth and development should be closely monitored. (See "Developmental-behavioral surveillance and screening in primary care", section on 'Follow-up'.)
●Parental or caregiver concerns for FASD (even when prenatal alcohol exposure is unknown or denied)
●Unknown prenatal alcohol exposure and:
•Characteristic facial dysmorphology (picture 1) (see 'Facial dysmorphism and minor anomalies' above)
•One or more facial features in addition to growth deficits (see 'Growth retardation' above)
•One or more facial features in addition to CNS abnormalities (see 'Central nervous system involvement' above)
If multidisciplinary evaluation is not available, primary care providers may be able to share facial images with experts electronically, and the school system may be able to provide neurocognitive assessments. For interested clinicians, the American Academy of Pediatrics provides guidance for developing an FASD team [120].
RESOURCES — Additional information about FASD is available from the following websites:
●In the United States:
•American Academy of Pediatrics Fetal Alcohol Spectrum Disorders Program
•The 2015 Canadian Guidelines for diagnosis of FASD across the lifespan
•The Centers for Disease Control and Prevention
•National Organization on Fetal Alcohol Syndrome
•University of Washington FAS Diagnostic and Prevention Network
●In the United Kingdom:
•National Organisation for Foetal Alcohol Syndrome-UK
•Locate alcohol addiction services (United Kingdom)
●In Australia:
•Australian guide to the diagnosis of FASD, including E-learning modules
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Fetal alcohol spectrum disorder" and "Society guideline links: Alcohol consumption".)
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or email these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient education" and the keyword[s] of interest.)
●Basics topic (see "Patient education: Fetal alcohol syndrome (The Basics)")
SUMMARY
●Fetal alcohol spectrum disorder (FASD) is an umbrella term that encompasses the range of physical, mental health, behavioral, and cognitive effects that can occur in individuals with prenatal alcohol exposure. FASDs include fetal alcohol syndrome (FAS), partial fetal alcohol syndrome (pFAS), alcohol-related neurodevelopmental disorder (ARND), alcohol-related birth defects (ARBD), and neurobehavioral disorder associated with prenatal alcohol exposure (ND-PAE). (See 'Terminology' above.)
●Alcohol is a teratogen with irreversible central nervous system (CNS) effects. It has the potential to cause deleterious effects at all stages of gestation. The effects may vary depending upon the quantity and pattern of alcohol consumption, maternal and fetal genetics, maternal age, maternal nutrition, and smoking, among other factors. (See 'Pathogenesis' above.)
●Risk factors for FASD include having a sibling with an FASD, having lived in an orphanage or been in foster care, or current or past involvement with child protective services. (See 'Risk factors' above.)
●FASD should be suspected in children with clinical features of FASD, including (see 'Clinical features' above and 'Clinical suspicion' above):
•Facial dysmorphism, particularly short palpebral fissures, thin vermillion border, and smooth philtrum (picture 1)
•Intrauterine and/or postnatal growth retardation
•Microcephaly
•Structural brain anomaly
•Recurrent nonfebrile seizures
•Developmental, learning, and cognitive problems, including school failure
•Behavioral problems (eg, hyperactivity, impaired executive functioning skills)
•Social-emotional problems
●Diagnostic criteria focus on facial dysmorphology (picture 3), growth retardation, CNS abnormalities, and prenatal alcohol exposure (table 1). (See 'Diagnostic criteria' above and 'Comprehensive evaluation' above.)
In addition, it is important to consider other causes of facial dysmorphism (table 5), growth retardation, and CNS effects. (See 'Differential diagnosis' above.)
●Children who are suspected to have an FASD should be referred to a qualified team of specialists for thorough assessment that includes examination for facial dysmorphic features, growth, and a complete neurobehavioral evaluation, which includes intelligence quotient (IQ) testing, an assessment of memory (including working memory), executive function, language, visual motor integration, functional and adaptive skills, and processing speed. (See 'Indications for referral' above and 'Neurocognitive assessment' above.)
1 : The Economic Burden of Fetal Alcohol Spectrum Disorder in Canada in 2013.
2 : The Economic Burden of Fetal Alcohol Spectrum Disorder in Canada in 2013.
3 : The Economic Burden of Fetal Alcohol Spectrum Disorder in Canada in 2013.
4 : Guidelines for identifying and referring persons with fetal alcohol syndrome.
5 : Guidelines for identifying and referring persons with fetal alcohol syndrome.
6 : Guidelines for identifying and referring persons with fetal alcohol syndrome.
7 : Guidelines for identifying and referring persons with fetal alcohol syndrome.
8 : Fetal alcohol spectrum disorder: a guideline for diagnosis across the lifespan.
9 : Updated Clinical Guidelines for Diagnosing Fetal Alcohol Spectrum Disorders.
10 : Diagnosing the full spectrum of fetal alcohol-exposed individuals: introducing the 4-digit diagnostic code.
11 : Fetal alcohol spectrum disorder: Canadian guidelines for diagnosis.
12 : A practical clinical approach to diagnosis of fetal alcohol spectrum disorders: clarification of the 1996 institute of medicine criteria.
13 : Neurobehavioral Disorder Associated With Prenatal Alcohol Exposure.
14 : Alcohol-Related Neurobehavioral Disabilities: Need for Further Definition and Common Terminology.
15 : Alcohol-Related Neurobehavioral Disabilities: Need for Further Definition and Common Terminology.
16 : Comparison of Alcohol-Related Neurodevelopmental Disorders and Neurodevelopmental Disorders Associated with Prenatal Alcohol Exposure Diagnostic Criteria.
17 : Comparison of Alcohol-Related Neurodevelopmental Disorders and Neurodevelopmental Disorders Associated with Prenatal Alcohol Exposure Diagnostic Criteria.
18 : Fetal alcohol spectrum disorders: an overview.
19 : Radiological Findings on Structural Magnetic Resonance Imaging in Fetal Alcohol Spectrum Disorders and Healthy Controls.
20 : Imaging the impact of prenatal alcohol exposure on the structure of the developing human brain.
21 : What does diffusion tensor imaging reveal about the brain and cognition in fetal alcohol spectrum disorders?
22 : Magnetic resonance imaging outcomes from a comprehensive magnetic resonance study of children with fetal alcohol spectrum disorders.
23 : Brain imaging and fetal alcohol spectrum disorders.
24 : White matter microstructure in fetal alcohol spectrum disorders: A systematic review of diffusion tensor imaging studies.
25 : Lifelong Impacts of Moderate Prenatal Alcohol Exposure on Neuroimmune Function.
26 : Graded Cerebellar Lobular Volume Deficits in Adolescents and Young Adults with Fetal Alcohol Spectrum Disorders (FASD).
27 : Reduced Hippocampal Volumes Partially Mediate Effects of Prenatal Alcohol Exposure on Spatial Navigation on a Virtual Water Maze Task in Children.
28 : Neurodevelopment in adolescents and adults with fetal alcohol spectrum disorders (FASD): A magnetic resonance region of interest analysis.
29 : Hippocampal DNA Methylation in a Mouse Model of Fetal Alcohol Spectrum Disorder That Includes Maternal Separation Stress Only Partially Explains Changes in Gene Expression.
30 : DNA methylation abundantly associates with fetal alcohol spectrum disorder and its subphenotypes.
31 : Embryonic ethanol exposure alters expression of sox2 and other early transcripts in zebrafish, producing gastrulation defects.
32 : Fetal alcohol spectrum disorder.
33 : Fetal alcohol spectrum disorders-- implications for child neurology, part 1: prenatal exposure and dosimetry.
34 : Association Between Prenatal Alcohol Exposure and Craniofacial Shape of Children at 12 Months of Age.
35 : Patterns of Prenatal Alcohol Use That Predict Infant Growth and Development.
36 : Review of ethanol dispersion, distribution, and elimination from the fetal compartment.
37 : Prenatal alcohol exposure patterns and alcohol-related birth defects and growth deficiencies: a prospective study.
38 : Critical Periods for Prenatal Alcohol Exposure: Evidence From Animal and Human Studies.
39 : Prenatal alcohol exposure and academic achievement at age six: a nonlinear fit.
40 : Prenatal alcohol exposure and academic achievement at age six: a nonlinear fit.
41 : Prenatal alcohol exposure and risk of birth defects.
42 : Prenatal alcohol exposure and risk of birth defects.
43 : Maternal risk factors in fetal alcohol syndrome: provocative and permissive influences.
44 : The impact of maternal age on the effects of prenatal alcohol exposure on attention.
45 : Genetic polymorphisms: impact on the risk of fetal alcohol spectrum disorders.
46 : The plausibility of maternal nutritional status being a contributing factor to the risk for fetal alcohol spectrum disorders: the potential influence of zinc status as an example.
47 : Protective effects of the alcohol dehydrogenase-ADH1B allele in children exposed to alcohol during pregnancy.
48 : Maternal age, alcohol abuse history, and quality of parenting as moderators of the effects of prenatal alcohol exposure on 7.5-year intellectual function.
49 : Fetal alcohol exposure and IQ at age 8: evidence from a population-based birth-cohort study.
50 : Genetic predisposition to fetal alcohol syndrome: association with congenital disorders of N-glycosylation.
51 : Global Prevalence of Fetal Alcohol Spectrum Disorder Among Children and Youth: A Systematic Review and Meta-analysis.
52 : Worldwide Prevalence of Fetal Alcohol Spectrum Disorders: A Systematic Literature Review Including Meta-Analysis.
53 : Prevalence of Fetal Alcohol Spectrum Disorders in 4 US Communities.
54 : Prevalence of fetal alcohol spectrum disorder among special subpopulations: a systematic review and meta-analysis.
55 : Estimating the prevalence of fetal alcohol syndrome. A summary.
56 : Fetal alcohol syndrome--Alaska, Arizona, Colorado, and New York, 1995-1997.
57 : Alcohol use among pregnant and nonpregnant women of childbearing age - United States, 1991-2005.
58 : Application of the fetal alcohol syndrome facial photographic screening tool in a foster care population.
59 : Profile of the first 1,400 patients receiving diagnostic evaluations for fetal alcohol spectrum disorder at the Washington State Fetal Alcohol Syndrome Diagnostic&Prevention Network.
60 : Fetal alcohol syndrome in families.
61 : Fetal alcohol spectrum disorders--implications for child neurology, part 2: diagnosis and management.
62 : Prevalence of fetal alcohol spectrum disorders in child care settings: a meta-analysis.
63 : Misdiagnosis and missed diagnoses in foster and adopted children with prenatal alcohol exposure.
64 : Characteristics of mothers who have children with fetal alcohol syndrome or some characteristics of fetal alcohol syndrome.
65 : Maternal risk factors for fetal alcohol syndrome in the Western cape province of South Africa: a population-based study.
66 : Maternal risk factors for fetal alcohol syndrome and partial fetal alcohol syndrome in South Africa: a third study.
67 : Prenatal care of women who give birth to children with fetal alcohol spectrum disorder in a universal health care system: a case-control study using linked administrative data.
68 : Early-Life Predictors of Fetal Alcohol Spectrum Disorders.
69 : Recommendations from a consensus development workshop on the diagnosis of fetal alcohol spectrum disorders in Australia.
70 : Characterizing Alcohol-Related Neurodevelopmental Disorder: Prenatal Alcohol Exposure and the Spectrum of Outcomes.
71 : Risk factors for adverse life outcomes in fetal alcohol syndrome and fetal alcohol effects.
72 : Another perspective on 'the effect of different alcohol drinking patterns in early to mid pregnancy on the child's intelligence, attention, and executive function'.
73 : Fetal alcohol syndrome surveillance: age of syndrome manifestation in case ascertainment.
74 : Fetal alcohol syndrome in adolescents and adults.
75 : Prenatal alcohol exposure and long-term developmental consequences.
76 : Diagnosing fetal alcohol syndrome: new insights from newer genetic technologies.
77 : Population differences in dysmorphic features among children with fetal alcohol spectrum disorders.
78 : Fetal alcohol spectrum disorders: Extending the range of structural defects.
79 : Congenital heart defects and fetal alcohol spectrum disorders.
80 : Fetal alcohol spectrum disorders in Finland: clinical delineation of 77 older children and adolescents.
81 : Fetal alcohol spectrum disorders in Finland: clinical delineation of 77 older children and adolescents.
82 : Comorbidity of fetal alcohol spectrum disorder: a systematic review and meta-analysis.
83 : Further development of a neurobehavioral profile of fetal alcohol spectrum disorders.
84 : Toward a neurobehavioral profile of fetal alcohol spectrum disorders.
85 : Prenatal Alcohol Exposure, FASD, and Child Behavior: A Meta-analysis.
86 : Maternal drinking during pregnancy: attention and short-term memory in 14-year-old offspring--a longitudinal prospective study.
87 : The fetal alcohol syndrome.
88 : Fetal alcohol spectrum disorders in young adulthood.
89 : Psychiatric conditions associated with prenatal alcohol exposure.
90 : Gross motor deficits in children prenatally exposed to alcohol: a meta-analysis.
91 : Comorbid Mental Disorders in Fetal Alcohol Spectrum Disorders: A Systematic Review.
92 : A review of the neurobehavioral deficits in children with fetal alcohol syndrome or prenatal exposure to alcohol.
93 : Drinking during pregnancy decreases word attack and arithmetic scores on standardized tests: adolescent data from a population-based prospective study.
94 : Prenatal alcohol exposure and ability, academic achievement, and school functioning in adolescence: a longitudinal follow-up.
95 : Everyday memory difficulties in children and adolescents with Fetal Alcohol Spectrum Disorder.
96 : Patterns of cognitive-motor development in children with fetal alcohol syndrome from a community in South Africa.
97 : Functional handwriting performance in school-age children with fetal alcohol spectrum disorders.
98 : Fine motor skills in children with prenatal alcohol exposure or fetal alcohol spectrum disorder.
99 : Neurobehavioral characteristics of children with fetal alcohol spectrum disorders in communities from Italy: Preliminary results.
100 : Focused and shifting attention in children with heavy prenatal alcohol exposure.
101 : Natural history of the fetal alcohol syndrome: a 10-year follow-up of eleven patients.
102 : Re-examining the core features of autism: a comparison of autism spectrum disorder and fetal alcohol spectrum disorder.
103 : Children with fetal alcohol spectrum disorders: problem behaviors and sensory processing.
104 : Children with fetal alcohol spectrum disorders: a descriptive profile of adaptive function.
105 : Sensory processing and adaptive behavior deficits of children across the fetal alcohol spectrum disorder continuum.
106 : Risk factors for behavioural problems in foetal alcohol spectrum disorders.
107 : Abnormal Eating Behaviors Are Common in Children with Fetal Alcohol Spectrum Disorder.
108 : Fetal Alcohol Growth Restriction and Cognitive Impairment.
109 : Fetal Alcohol Growth Restriction and Cognitive Impairment.
110 : Fetal Alcohol Growth Restriction and Cognitive Impairment.
111 : Distinguishing between attention-deficit hyperactivity and fetal alcohol spectrum disorders in children: clinical guidelines.
112 : Interventions for children with fetal alcohol spectrum disorders (FASDs): overview of findings for five innovative research projects.
113 : Investigating the efficacy of an attention training programme in children with foetal alcohol spectrum disorder.
114 : Comparison of the 4-digit diagnostic code and the Hoyme diagnostic guidelines for fetal alcohol spectrum disorders.
115 : Comparison of the 4-digit diagnostic code and the Hoyme diagnostic guidelines for fetal alcohol spectrum disorders.
116 : Pediatricians' knowledge, training, and experience in the care of children with fetal alcohol syndrome.
117 : Role of caregiver-reported outcomes in identification of children with prenatal alcohol exposure during the first year of life.
118 : Factors predictive of a fetal alcohol spectrum disorder diagnosis: Parent and teacher ratings.
119 : Utility of Genetic Testing in Fetal Alcohol Spectrum Disorder.
120 : Utility of Genetic Testing in Fetal Alcohol Spectrum Disorder.
121 : Cross-cultural evaluation of two drinking assessment instruments: alcohol timeline followback and inventory of drinking situations.
122 : Primary care validation of a single-question alcohol screening test.
123 : Screening for problem drinking: does a single question work?
124 : The Role of Integrated Care in a Medical Home for Patients With a Fetal Alcohol Spectrum Disorder.
125 : Are Low-to-Moderate Average Alcohol Consumption and Isolated Episodes of Binge Drinking in Early Pregnancy Associated with Facial Features Related to Fetal Alcohol Syndrome in 5-Year-Old Children?
126 : Binge pattern of alcohol consumption during pregnancy and childhood mental health outcomes: longitudinal population-based study.
127 : Prenatal exposure to binge drinking and cognitive and behavioral outcomes at age 7 years.
128 : Maternal alcohol consumption producing fetal alcohol spectrum disorders (FASD): quantity, frequency, and timing of drinking.
129 : Objective Measures of Prenatal Alcohol Exposure: A Systematic Review.
130 : Characteristics of children who have full or incomplete fetal alcohol syndrome.
131 : Palpebral fissure length from 29 weeks gestation to 14 years.
132 : Normal distribution of palpebral fissure lengths in Canadian school age children.
133 : Validation of the facial photographic in fetal alcohol spectrum disorder screening and diagnosis.
134 : Canadian palpebral fissure length growth charts reflect a good fit for two school and FASD clinic-based U.S. populations.
135 : Canadian palpebral fissure length growth charts reflect a good fit for two school and FASD clinic-based U.S. populations.
136 : Defining the behavioral phenotype in children with fetal alcohol spectrum disorders: a review.
137 : Attention deficits in children exposed to alcohol prenatally.
138 : Infant stress reactivity and prenatal alcohol exposure.
139 : Sleep and sensory characteristics in young children with fetal alcohol spectrum disorder.
140 : A Comparison Among 5 Methods for the Clinical Diagnosis of Fetal Alcohol Spectrum Disorders.
141 : Comparing diagnostic classification of neurobehavioral disorder associated with prenatal alcohol exposure with the Canadian fetal alcohol spectrum disorder guidelines: a cohort study.
142 : Fetal alcohol spectrum disorders: a practical clinical approach to diagnosis.
143 : The lifelong effects of early childhood adversity and toxic stress.
144 : The science of early life toxic stress for pediatric practice and advocacy.
145 : Fetal alcohol spectrum disorder: development of consensus referral criteria for specialist diagnostic assessment in Australia.