DESCRIPTION

• First described in 1973 as fetal alcohol syndrome (FAS), the condition has since been recognized as a spectrum disorder with wide-ranging features.
• Fetal alcohol spectrum disorder (FASD) is composed of five conditions that are used to describe the wide-ranging neurologic and physical effects that prenatal alcohol exposure can have on the fetus. These are as follows:
  • Classic FAS (FAS)
  • Partial FAS (pFAS)
  • Alcohol-related neurodevelopmental disorder (ARND)
  • A neurobehavioral disorder associated with prenatal alcohol exposure (ND-PAE)
  • Alcohol-related birth defects (ARBD)
• The four major features of FASD include the following:
  • A spectrum of CNS neurodevelopmental and behavioral differences
  • A spectrum of craniofacial differences
  • Intrauterine and/or postnatal growth restriction
  • Maternal alcohol use during pregnancy
• Severity of clinical features are related to both the amount of alcohol consumed during pregnancy and the timing of exposure, with earlier and heavier exposures associated with more severe phenotypes.
• Classic FAS accounts for only a small fraction of all cases of FASD.
• There are no biomarkers that confirm or rule out the presence of FASD. The diagnosis depends on a positive history of maternal alcohol use during pregnancy and the presence of at least one of the three other major features.

EPIDEMIOLOGY

• FASD is common, occurring in approximately 1% of all live births in the United States.
• Classic FAS is less common, occurring in 0.5 to 2 per 1,000 live births.
• Alcohol use during pregnancy is a significant public health problem. According to the Centers for Disease Control and Prevention (CDC), 7.6% of pregnant women reported alcohol use during the month prior to being surveyed and 1.4% reported binge drinking.

RISK FACTORS

• Although any amount of alcohol consumed anytime during pregnancy can be associated with fetal damage, the highest risk for FASD occurs in children whose mothers consume ≥4 oz of alcohol per occasion per week (peak blood alcohol level is more important than a lower sustained blood alcohol level).
• Alcohol is considered both a structural and a behavioral teratogen.
  • Alcohol consumption during the first trimester is more likely to result in congenital malformations.
  • Later alcohol consumption is more likely to be associated with growth and developmental/behavioral issues.
• Risk factors for alcohol use during pregnancy include poverty, homelessness, substance use by one’s partner, and preconception substance use.
• Additional risk factors include low educational attainment, history of multiple miscarriages and stillbirths, social isolation, history of physical or sexual abuse, and current interpersonal violence.
• Binge drinking (consumption of ≥4 oz of alcohol at one time) appears to be particularly harmful to the developing fetal brain and causes most risk for development of FASD. Risk appears to be even greater when binge drinking is combined with poor maternal nutrition.
• Genetic factors also play a role in susceptibility to the in utero effects of alcohol:
  • Maternal and fetal variants in ADH1B, a gene in the alcohol dehydrogenase enzyme family, can increase or decrease risk of FASD in the fetus.
  • Concordance of FASD is higher in monozygotic than in dizygotic twins, suggesting a genetic predisposition.

GENERAL PREVENTION

• Women who are pregnant or may become pregnant should avoid alcohol. No level of alcohol consumption is considered “safe.”
• Women with alcohol use disorder (alcohol abuse or dependence) who are or may become pregnant should seek assistance by enrolling in an appropriate cessation program.
• In the United States, the Alcoholic Beverage Labeling Act was passed in 1988, requiring health warning labels to indicate the risk of alcohol consumption during pregnancy as a result of recognition of the harmful effects of alcohol on the developing fetus.

PATHOPHYSIOLOGY

• The exact mechanisms by which alcohol causes its teratogenic effects are not known.
• Alcohol and acetaldehyde, one of its metabolites, are teratogens that cause irreversible damage to the developing CNS. The damage is widespread and causes both a decrease in brain volume and malformations in brain structures.
• High levels of alcohol consumption during the first trimester of pregnancy result in an increased likelihood of craniofacial, cardiac, and skeletal malformations, as well as an increased risk of spontaneous abortion.
• High levels of alcohol exposure after the first trimester are associated with intrauterine growth restriction (IUGR), microcephaly, and neurobehavioral deficits caused by alcohol’s disruption of normal gene expression.
• Alcohol exposure can result in epigenetic alterations that can repress the normal expression of genes.

HISTORY

• Pregnancy history: factors suggestive of prenatal alcohol exposure:
  • Maternal history of alcohol use (binge drinking, average number of drinks per day, timing of alcohol use during pregnancy); a definitive diagnosis of FASD cannot be made without evidence of maternal alcohol use during pregnancy (obtaining this evidence may be difficult in infants who have been placed in foster care or who have been adopted).
  • Maternal history of exposure to other potentially teratogenic agents during pregnancy: cocaine and other substance use, cigarettes, etc.
  • History of any risk factors listed above (poverty, homelessness, substance use by partner, low educational attainment, social isolation, history of physical or sexual abuse, etc.)
  • Other prenatal historical information:
    • Previous history of spontaneous abortion (miscarriages), stillbirths, neonatal demise
    • History of maternal health problems
• Birth history suggestive of prenatal alcohol exposure:
  • IUGR (inappropriately low birth weight)
  • Signs of alcohol withdrawal during the neonatal period (including jitteriness, irritability, poor feeding, seizures)
  • Presence of microcephaly
  • Presence of congenital malformations (cleft of lip and/or palate, congenital heart disease, etc.)
  • Admission to an intensive care nursery
  • Presence of social service issues in newborn period
• Family history (in 1st- or 2nd-degree relatives) suggestive of FASD
  • History of FASD
  • History of neurodevelopmental differences
  • History of pregnancy loss or neonatal demise
  • History of alcoholism and/or substance use
  • Cause of death
• Postnatal history suggestive of FASD
  • Delay in attainment of developmental milestones
  • Slow growth (weight, height, and head circumference)
  • Presence of neurobehavioral differences in infancy, including poor feeding, irritability, jitteriness, and irregular sleep patterns
  • Presence of neurobehavioral differences in preschool-age or school-age years; specific issues: hyperactivity, inattention, learning differences, fine motor function differences, coordination differences, differences in academic performance, differences in problem-solving ability, difference in social skills (difficulties with peer interactions), differences in executive functions such as cognitive planning and concept formation, differences in understanding consequences of actions, difficulty in controlling impulses, and difficulties with activities of daily living
  • Presence of neurobehavioral differences in adolescence and adulthood (in addition to the above):
    • Substance use
    • Criminal behavior
    • Inability to hold a job
    • Inability to live independently

PHYSICAL EXAM

• Physical features in newborn period suggestive of FASD:
  • Birth weight ≤10th percentile
  • Birth length ≤10th percentile
  • Neonatal head circumference ≤10th percentile
  • Craniofacial differences including the following:
    • Short palpebral fissures (measured from inner canthus to outer canthus)
    • Flat nasal bridge with epicanthal folds
    • Thin upper vermilion border of the lip with flattening of the philtrum
    • Hypoplastic cheeks
    • Minor anomalies of the ears
  • Presence of congenital malformations including cleft of lip and/or palate and congenital heart disease
• Postnatal physical features suggestive of FASD:
  • Growth deficiency (may persist throughout life)
  • Microcephaly with poor head growth
  • Craniofacial features as noted above
  • Congenital malformations as noted above
  • Skeletal abnormalities:
    • Clinobrachydactyly of the 5th fingers (short and in-turned)
    • Hypoplastic finger and toenails, especially of the 5th fingers and toes
    • Spinal anomalies, including scoliosis (congenital or acquired) and vertebral segmental anomalies
    • Radioulnar synostosis

DIFFERENTIAL DIAGNOSIS

• By physical features
  • “Normal variant” (physical and developmental issues consistent with family history)
  • Genetic syndromes that overlap with some features of FASD:
    • Silver-Russell syndrome
    • Other teratogenic syndromes:
      • Fetal hydantoin syndrome and other anticonvulsant syndromes
      • Maternal phenylketonuria effects
    • Chromosome microdeletion/duplication syndromes:
      • 22q11.2 deletion syndrome (aka DiGeorge syndrome, velocardiofacial syndrome)
      • 15q11.2 duplication syndrome
    • Cardiofacial syndromes
      • Noonan syndrome
      • Williams syndrome
• By neurobehavioral features
  • Fragile X syndrome
  • Multiple single-gene disorders

DIAGNOSTIC TESTS & INTERPRETATION

GENERAL MEASURES

• The role of the pediatrician and the medical home is to support early identification of FASD and the associated neurobehavioral diagnoses through appropriate medical and developmental specialist referrals and to oversee the development of a multidisciplinary treatment plan.
• Specific medical referrals should include the following:
  • Medical geneticist for establishment of diagnosis and provision of genetic counseling to the family
  • Developmental-behavior pediatrician, psychologist, and/or neuropsychologist to carry out developmental, cognitive, adaptive, social, and behavioral evaluations; to clarify diagnoses; and to provide referrals for appropriate services
  • Neurologist, especially if child has history of seizure disorder
  • Ophthalmologist (baseline exam in early childhood and then follow-up every 2 years)
  • Otolaryngologist, including audiology and hearing test (Consider brainstem auditory evoked response [BAER] at 6 to 12 months.)
  • Mental health professionals (child psychiatrist and psychologist, behavior management specialist)
  • Other specialists, when needed, including endocrinologist, plastic surgeon, etc.
• Social service referrals are also needed.
  • Because of the neurobehavioral consequences of the condition, families require a tremendous amount of support when raising children with FASD. Social workers, substance use counselors, family advocates, legal advisors, and others may be needed to assist families during their child’s life.

FOLLOW-UP RECOMMENDATIONS

PROGNOSIS

• The prognosis of children with FASD is extremely variable and depends on the severity of features and the availability and timing of therapeutic interventions. Approximately 25% of people with FASD have intellectual disability (IQ <70). Average IQ in individuals with FASD is 85.9; however, a wide range of IQ exists.
• >60% of children with FASD manifest severe behavioral problems.
• The neurocognitive/neurobehavioral effects of FASD can lead to poor academic performance, legal problems, employment difficulties, and secondary mental health problems; 35% develop an alcohol or drug problem; many are unable to live independently as adults.

ICD 10

• Q86.0 Fetal alcohol syndrome (dysmorphic)
• P04.3 Newborn affected by maternal use of alcohol