Fetal Alcohol Spectrum Disorder

Fetal alcohol spectrum disorder (FASD) is a group of neonatal pediatric disorders caused by maternal alcohol consumption during pregnancy Pregnancy Pregnancy is the time period between fertilization of an oocyte and delivery of a fetus approximately 9 months later. The 1st sign of pregnancy is typically a missed menstrual period, after which, pregnancy should be confirmed clinically based on a positive β-hCG test (typically a qualitative urine test) and pelvic ultrasound. Pregnancy: Diagnosis, Maternal Physiology, and Routine Care. The term entails a range of physical and neurodevelopmental effects. Classification is based on severity and clinical presentation. Diagnosis is based on a history of prenatal alcohol exposure and the presence of characteristic physical and developmental abnormalities. Management involves surgical correction of structural anomalies and early initiation of support services to promote best outcomes.

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Overview

Definition

Fetal alcohol spectrum disorder (FASD) Consists of the postnatal physical, developmental, cognitive, and psychiatric deficits noted in a patient who has been exposed to alcohol while in utero.

Epidemiology

  • Prevalence:
    • 1.5% of live births in the United States
    • 0.77% of live births globally:
      • Highest prevalence in WHO European region
      • Lowest prevalence in WHO Eastern Mediterranean region
  • Most common cause of teratogenic intellectual disability
  • Leading preventable cause of intellectual disability in the United States
  • Seen commonly in children who:
    • Are in the foster care system
    • Are in psychiatric care facilities
    • Have been placed in child protective services or the juvenile justice system
  • Maternal risk factors include:
    • Older maternal age
    • Having a previous child with FASD
    • History of poor prenatal care Prenatal care Prenatal care is a systematic and periodic assessment of pregnant women during gestation to assure the best health outcome for the mother and her fetus. Prenatal care prevents and identifies maternal and fetal problems that adversely affect the pregnancy outcome. Prenatal Care
    • History of social isolation
    • History of substance abuse

Etiology

  • Only known cause is intrauterine alcohol exposure.
  • Increased risk of developing FASD with:
    • High-dose exposure (blood alcohol content (BAC) > 150 mg/dL)
    • Chronic alcohol ingestion
    • Binge drinking
  • Prevalence increases in parallel with the increase in amount of alcohol consumed during pregnancy Pregnancy Pregnancy is the time period between fertilization of an oocyte and delivery of a fetus approximately 9 months later. The 1st sign of pregnancy is typically a missed menstrual period, after which, pregnancy should be confirmed clinically based on a positive β-hCG test (typically a qualitative urine test) and pelvic ultrasound. Pregnancy: Diagnosis, Maternal Physiology, and Routine Care.

Classification

Being an umbrella term, FASD has multiple conditions nested within it:

  • Fetal alcohol syndrome (FAS)
  • Partial fetal alcohol syndrome (pFAS)
  • Alcohol-related neurodevelopmental disorder (ARND)
  • Neurobehavioral disorder associated with prenatal alcohol exposure (ND-PAE)
  • Alcohol-related birth defects (ARBD)

Pathophysiology

Alcohol is a teratogen that has irreversible effects:

  • Exact mechanism unknown
  • Teratogenic effects can occur during any stage of pregnancy Pregnancy Pregnancy is the time period between fertilization of an oocyte and delivery of a fetus approximately 9 months later. The 1st sign of pregnancy is typically a missed menstrual period, after which, pregnancy should be confirmed clinically based on a positive β-hCG test (typically a qualitative urine test) and pelvic ultrasound. Pregnancy: Diagnosis, Maternal Physiology, and Routine Care.
  • No safe level of alcohol consumption during pregnancy Pregnancy Pregnancy is the time period between fertilization of an oocyte and delivery of a fetus approximately 9 months later. The 1st sign of pregnancy is typically a missed menstrual period, after which, pregnancy should be confirmed clinically based on a positive β-hCG test (typically a qualitative urine test) and pelvic ultrasound. Pregnancy: Diagnosis, Maternal Physiology, and Routine Care

Factors that contribute to pathogenesis:

  • Ethanol and its metabolites transfer across placenta Placenta The placenta consists of a fetal side and a maternal side, and it provides a vascular communication between the mother and the fetus. This communication allows the mother to provide nutrients to the fetus and allows for removal of waste products from fetal blood. Placenta, Umbilical Cord, and Amniotic Cavity.
  • Fetus cannot metabolize alcohol: depends on maternal alcohol dehydrogenase for hepatic detoxification
  • Amniotic fluid acts as reservoir for alcohol (prolongs fetal exposure).
  • Ethanol directly affects fetus’s developing CNS by interfering with:
    • Cell proliferation and differentiation
    • Neuronal and glial cell migration

Variation in susceptibility of fetus affected by:

  • Pattern of alcohol ingestion:
    • Increased risk with high-dose exposure of BAC > 150 mg/dL
    • Increased risk with binge drinking
  • Maternal and fetal genetics Genetics Genetics is the study of genes and their functions and behaviors. Basic Terms of Genetics
  • Maternal nutritional status
  • Maternal age
  • Other concurrent teratogenic exposures

Clinical Presentation

Various combinations of features can be present.

  • Characteristic craniofacial features:
    • Short palpebral fissures
    • Midface hypoplasia with long, smooth philtrum
    • Thin upper lip
    • Epicanthal folds
    • Decreased interpupillary distance
  • Growth retardation:
    • < 10th percentile for weight and/or height
    • Prenatal
    • Postnatal
  • CNS: structural
    • Microcephaly
    • Absent corpus callosum
  • Neurologic:
    • Abnormal reflexes
    • Abnormal tone
    • Seizures Seizures A seizure is abnormal electrical activity of the neurons in the cerebral cortex that can manifest in numerous ways depending on the region of the brain affected. Seizures consist of a sudden imbalance that occurs between the excitatory and inhibitory signals in cortical neurons, creating a net excitation. The 2 major classes of seizures are focal and generalized. Seizures
  • Functional:
    • Intellectual disability
    • Speech delays
    • Difficulty with executive function
    • Memory problems
    • Abnormal motor function
    • Poor impulse control
    • Hyperactivity and concentration deficits
    • Poor social skills and adaptive functions
  • Cardiovascular:
    • Ventricular septal defect (VSD)
    • Patent ductus arteriosus Patent ductus arteriosus The ductus arteriosus (DA) allows blood to bypass pulmonary circulation. After birth, the DA remains open for up to 72 hours and then constricts and involutes, becoming the ligamentum arteriosum. Failure of this process to occur results in patent ductus arteriosus (PDA), a condition that causes up to 10% of congenital heart defects. Patent Ductus Arteriosus (PDA) ( PDA PDA The ductus arteriosus (DA) allows blood to bypass pulmonary circulation. After birth, the DA remains open for up to 72 hours and then constricts and involutes, becoming the ligamentum arteriosum. Failure of this process to occur results in patent ductus arteriosus (PDA), a condition that causes up to 10% of congenital heart defects. Patent Ductus Arteriosus (PDA))
    • Atrial septal defect Atrial Septal Defect Atrial septal defects (ASDs) are benign acyanotic congenital heart defects characterized by an opening in the interatrial septum that causes blood to flow from the left atrium (LA) to the right atrium (RA) (left-to-right shunt). Atrial Septal Defect (ASD)
    • Tetralogy of Fallot Tetralogy of Fallot Tetralogy of Fallot is the most common cyanotic congenital heart disease. The disease is the confluence of 4 pathologic cardiac features: overriding aorta, ventricular septal defect, right ventricular outflow obstruction, and right ventricular hypertrophy. Tetralogy of Fallot
    • Heart-lung fistulas
  • Musculoskeletal:
    • Hockey stick palmar creases
    • Limb dislocation
    • Pectus excavatum and carinatum
    • Hemivertebrae
    • 5th finger clinodactyly
  • Ophthalmologic:
    • Strabismus Strabismus Strabismus is the misalignment of the eyes while fixating the gaze on an object. Strabismus can be idiopathic, but it may also be caused by cerebral palsy, uncorrected refractive errors, and extraocular muscle or cranial nerve dysfunction. Strabismus
    • Ptosis
    • Optic nerve hypoplasia
  • Genitourinary:
    • Aplastic, dysplastic, or hypoplastic kidney
    • Horseshoe kidney
  • Auditory:
    • Conductive hearing loss Hearing loss Hearing loss, also known as hearing impairment, is any degree of impairment in the ability to apprehend sound as determined by audiometry to be below normal hearing thresholds. Clinical presentation may occur at birth or as a gradual loss of hearing with age, including a short-term or sudden loss at any point. Hearing Loss
    • Sensorineural hearing loss Hearing loss Hearing loss, also known as hearing impairment, is any degree of impairment in the ability to apprehend sound as determined by audiometry to be below normal hearing thresholds. Clinical presentation may occur at birth or as a gradual loss of hearing with age, including a short-term or sudden loss at any point. Hearing Loss
Male baby with fas syndrome

Fetal alcohol spectrum disorder: infant with characteristic facial features

Image: “Male baby with FAS syndrome” by Teresa Kellerman. License: CC BY-SA 3.0

Diagnosis

Accurate and early diagnosis of FASD at < 6 years of age is important to enable interventions and improve outcomes.

  • Diagnostic evaluation by interdisciplinary team is needed, including:
    • Developmental pediatrics
    • Neurology
    • Neuropsychology
    • Genetics
    • Occupational therapy
  • Various sets of diagnostic criteria, including:
    • Growth retardation
    • Facial dysmorphism
    • CNS abnormalities
    • Structural birth defects
    • Prenatal alcohol exposure:
      • Quantity
      • Frequency
      • Timing during pregnancy Pregnancy Pregnancy is the time period between fertilization of an oocyte and delivery of a fetus approximately 9 months later. The 1st sign of pregnancy is typically a missed menstrual period, after which, pregnancy should be confirmed clinically based on a positive β-hCG test (typically a qualitative urine test) and pelvic ultrasound. Pregnancy: Diagnosis, Maternal Physiology, and Routine Care

Management

There is currently no treatment for FASD; management focuses on early intervention and prevention.

  • Correction of surgically amenable congenital defects
  • Parent training to meet increased medical and developmental needs of child
  • Early interventional therapies (birth to age 3):
    • Occupational therapy
    • Physical therapy
    • Speech therapy
  • Behavioral interventions to develop:
    • Executive function
    • Social skills
    • Adaptive skills
  • Educational support services:
    • Academic skills
    • Vocational training
  • Psychotropic medications for:
    • ADHD
    • Anxiety
    • Mood dysregulation

Prognosis and prevention

  • Lack of diagnosis and management increases risk for:
    • Adverse childhood events
    • Poor school performance
    • Trouble with law enforcement/incarceration
    • Inappropriate sexual behavior
    • Unemployment
    • Substance abuse
    • Mental health disorders
    • Premature death
  • Prevention:
    • Education about effects of alcohol on fetus
    • Promotion of alcohol abstinence
    • Screening to identify high-risk pregnant women

Differential Diagnosis

  • ADHD: neurodevelopmental disorder characterized by a pattern of inattention and/or hyperactivity/impulsivity that occurs in ≥ 2 different settings for more than 6 months. The clinical presentation of ADHD varies in severity. Diagnosis is made on the basis of neuropsychological assessment. Management includes education, behavioral modification, educational support services, and pharmacologic therapy.
  • Fragile X syndrome Fragile X syndrome Fragile X syndrome (FXS), also known as Martin-Bell syndrome, is a genetic condition with X-linked inheritance. Both boys and girls may be affected, but the severity is much worse in boys. Characteristic features include a long face, prominent forehead and chin, large ears, flat feet, and large testes post-puberty for boys. Fragile X Syndrome: most common genetic cause of intellectual disability. Fragile X syndrome Fragile X syndrome Fragile X syndrome (FXS), also known as Martin-Bell syndrome, is a genetic condition with X-linked inheritance. Both boys and girls may be affected, but the severity is much worse in boys. Characteristic features include a long face, prominent forehead and chin, large ears, flat feet, and large testes post-puberty for boys. Fragile X Syndrome is caused by an X-linked mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations in the FMR1 gene and is diagnosed by DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure analysis. Clinical presentation includes characteristic physical features of long, narrow facies, large ears, and macroorchidism. Cognitive impairment, abnormal behavior, and seizures are also features. Management includes developmental, behavioral, and educational interventions. Medication may be used for cognitive and behavioral aspects.
  • Williams syndrome Williams syndrome Williams syndrome (WS), also known as Williams-Beuren syndrome (WBS), is a genetic disease caused by a microdeletion on chromosome 7. Affected individuals have a characteristic elfin facies and short stature. Cognitive, developmental, and behavioral issues are common. Additionally, cardiovascular, connective tissue, endocrine, and renal anomalies may be present. Williams Syndrome: autosomal dominant Autosomal dominant Autosomal inheritance, both dominant and recessive, refers to the transmission of genes from the 22 autosomal chromosomes. Autosomal dominant diseases are expressed when only 1 copy of the dominant allele is inherited. Autosomal Recessive and Autosomal Dominant Inheritance genetic disorder caused by microdeletions on chromosome 7. The clinical presentation of Williams syndrome Williams syndrome Williams syndrome (WS), also known as Williams-Beuren syndrome (WBS), is a genetic disease caused by a microdeletion on chromosome 7. Affected individuals have a characteristic elfin facies and short stature. Cognitive, developmental, and behavioral issues are common. Additionally, cardiovascular, connective tissue, endocrine, and renal anomalies may be present. Williams Syndrome includes characteristic facial features such as short palpebral fissures, long philtrum, and epicanthal folds. Cardiovascular, neurodevelopmental, renal, endocrine, and growth abnormalities are also present. Diagnosis is made by genetic testing. Management involves addressing cardiovascular anomalies and providing interventions for neurodevelopmental issues.

References

  1. National Organization on Fetal Alcohol Syndrome. Retrieved April 10, 2021, from www.nofas.org/about-fasd/
  2. American Academy of Pediatrics Fetal Alcohol Spectrum Disorders Toolkit. Common definition. Retrieved April 10, 2021, from http://www.aap.org/en-us/advocacy-and-policy/aap-health-initiatives/fetal-alcohol-spectrum-disorders-toolkit/Pages/Common-Definitions.aspx 
  3. Riley EP, Infante MA, Warren KR. (2011). Fetal alcohol spectrum disorders: an overview. Neuropsychol Rev. https://pubmed.ncbi.nlm.nih.gov/21499711/ 
  4. Sokol RJ, Delaney-Black V, Nordstrom B. (2003). Fetal alcohol spectrum disorder. JAMA. https://pubmed.ncbi.nlm.nih.gov/14665662/ 
  5. Weitzman C, Rojmahamangkol P. (2020). Fetal alcohol spectrum disorder: management and prognosis. UpToDate. Retrieved April 9, 2021, from https://www.uptodate.com/contents/fetal-alcohol-spectrum-disorder-management-and-prognosis
  6. Centers for Disease Control. (2020). Fetal alcohol spectrum disorders. https://www.cdc.gov/ncbddd/fasd/facts.html
  7. Waz W, Lee T. (2020). Williams syndrome Williams syndrome Williams syndrome (WS), also known as Williams-Beuren syndrome (WBS), is a genetic disease caused by a microdeletion on chromosome 7. Affected individuals have a characteristic elfin facies and short stature. Cognitive, developmental, and behavioral issues are common. Additionally, cardiovascular, connective tissue, endocrine, and renal anomalies may be present. Williams Syndrome. UpToDate. Retrieved April 10, 2021, from https://www.uptodate.com/contents/williams-syndrome
  8. Centers for Disease Control. (2020). Fragile X syndrome Fragile X syndrome Fragile X syndrome (FXS), also known as Martin-Bell syndrome, is a genetic condition with X-linked inheritance. Both boys and girls may be affected, but the severity is much worse in boys. Characteristic features include a long face, prominent forehead and chin, large ears, flat feet, and large testes post-puberty for boys. Fragile X Syndrome. https://www.cdc.gov/ncbddd/fxs/facts.html

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