Fetal Alcohol Spectrum Disorder

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 Prevalence The total number of cases of a given disease in a specified population at a designated time. It is differentiated from incidence, which refers to the number of new cases in the population at a given time. Measures of Disease Frequency:
  • 1.5% of live births in the United States
  • 0.77% of live births globally:
    • Highest prevalence Prevalence The total number of cases of a given disease in a specified population at a designated time. It is differentiated from incidence, which refers to the number of new cases in the population at a given time. Measures of Disease Frequency in WHO European region
    • Lowest prevalence Prevalence The total number of cases of a given disease in a specified population at a designated time. It is differentiated from incidence, which refers to the number of new cases in the population at a given time. Measures of Disease Frequency in WHO Eastern Mediterranean region
• Most common cause of teratogenic intellectual disability Disability Determination of the degree of a physical, mental, or emotional handicap. The diagnosis is applied to legal qualification for benefits and income under disability insurance and to eligibility for social security and workman’s compensation benefits. ABCDE Assessment
• Leading preventable cause of intellectual disability Disability Determination of the degree of a physical, mental, or emotional handicap. The diagnosis is applied to legal qualification for benefits and income under disability insurance and to eligibility for social security and workman’s compensation benefits. ABCDE Assessment 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 Child protective services Local governmental offices which investigate reports of abuse and neglect of children, and act to assure a safe environment for minors. Child Abuse or the juvenile justice Justice An interactive process whereby members of a community are concerned for the equality and rights of all. Research Ethics 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 use disorder

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 Prevalence The total number of cases of a given disease in a specified population at a designated time. It is differentiated from incidence, which refers to the number of new cases in the population at a given time. Measures of Disease Frequency increases in parallel with the increase in amount of alcohol consumed during pregnancy Pregnancy The status during which female mammals carry their developing young (embryos or fetuses) in utero before birth, beginning from fertilization to birth. Pregnancy: Diagnosis, Physiology, and Care.

Classification

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

• Fetal alcohol syndrome Fetal alcohol syndrome An umbrella term used to describe a pattern of disabilities and abnormalities that result from fetal exposure to ethanol during pregnancy. It encompasses a phenotypic range that can vary greatly between individuals, but reliably includes one or more of the following: characteristic facial dysmorphism, fetal growth retardation, central nervous system abnormalities, cognitive and/or behavioral dysfunction, birth defects. The level of maternal alcohol consumption does not necessarily correlate directly with disease severity. Alcohol Use Disorder (FAS)
• Partial fetal alcohol syndrome Fetal alcohol syndrome An umbrella term used to describe a pattern of disabilities and abnormalities that result from fetal exposure to ethanol during pregnancy. It encompasses a phenotypic range that can vary greatly between individuals, but reliably includes one or more of the following: characteristic facial dysmorphism, fetal growth retardation, central nervous system abnormalities, cognitive and/or behavioral dysfunction, birth defects. The level of maternal alcohol consumption does not necessarily correlate directly with disease severity. Alcohol Use Disorder (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 The status during which female mammals carry their developing young (embryos or fetuses) in utero before birth, beginning from fertilization to birth. Pregnancy: Diagnosis, Physiology, and Care.
• No safe level of alcohol consumption during pregnancy Pregnancy The status during which female mammals carry their developing young (embryos or fetuses) in utero before birth, beginning from fertilization to birth. Pregnancy: Diagnosis, Physiology, and Care

Factors that contribute to pathogenesis:

• Ethanol Ethanol A clear, colorless liquid rapidly absorbed from the gastrointestinal tract and distributed throughout the body. It has bactericidal activity and is used often as a topical disinfectant. It is widely used as a solvent and preservative in pharmaceutical preparations as well as serving as the primary ingredient in alcoholic beverages. Ethanol Metabolism and its metabolites transfer across placenta Placenta A highly vascularized mammalian fetal-maternal organ and major site of transport of oxygen, nutrients, and fetal waste products. It includes a fetal portion (chorionic villi) derived from trophoblasts and a maternal portion (decidua) derived from the uterine endometrium. The placenta produces an array of steroid, protein and peptide hormones (placental hormones). Placenta, Umbilical Cord, and Amniotic Cavity.
• Fetus cannot metabolize alcohol: depends on maternal alcohol dehydrogenase Alcohol dehydrogenase A zinc-containing enzyme which oxidizes primary and secondary alcohols or hemiacetals in the presence of nad. In alcoholic fermentation, it catalyzes the final step of reducing an aldehyde to an alcohol in the presence of nadh and hydrogen. Ethanol Metabolism for hepatic detoxification
• Amniotic fluid Amniotic fluid A clear, yellowish liquid that envelopes the fetus inside the sac of amnion. In the first trimester, it is likely a transudate of maternal or fetal plasma. In the second trimester, amniotic fluid derives primarily from fetal lung and kidney. Cells or substances in this fluid can be removed for prenatal diagnostic tests (amniocentesis). Placenta, Umbilical Cord, and Amniotic Cavity acts as reservoir Reservoir Animate or inanimate sources which normally harbor disease-causing organisms and thus serve as potential sources of disease outbreaks. Reservoirs are distinguished from vectors (disease vectors) and carriers, which are agents of disease transmission rather than continuing sources of potential disease outbreaks. Humans may serve both as disease reservoirs and carriers. Escherichia coli for alcohol (prolongs fetal exposure).
• Ethanol Ethanol A clear, colorless liquid rapidly absorbed from the gastrointestinal tract and distributed throughout the body. It has bactericidal activity and is used often as a topical disinfectant. It is widely used as a solvent and preservative in pharmaceutical preparations as well as serving as the primary ingredient in alcoholic beverages. Ethanol Metabolism 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 Hypoplasia Hypoplastic Left Heart Syndrome (HLHS) with long, smooth philtrum
  • Thin upper lip Upper Lip Melasma
  • 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 Disability Determination of the degree of a physical, mental, or emotional handicap. The diagnosis is applied to legal qualification for benefits and income under disability insurance and to eligibility for social security and workman’s compensation benefits. ABCDE Assessment
  • Speech delays
  • Difficulty with executive function
  • Memory Memory Complex mental function having four distinct phases: (1) memorizing or learning, (2) retention, (3) recall, and (4) recognition. Clinically, it is usually subdivided into immediate, recent, and remote memory. Psychiatric Assessment problems
  • Abnormal motor Motor Neurons which send impulses peripherally to activate muscles or secretory cells. Nervous System: Histology function
  • Poor impulse control
  • Hyperactivity Hyperactivity Attention Deficit Hyperactivity Disorder and concentration deficits
  • Poor social skills and adaptive functions
• Cardiovascular:
  • Ventricular septal defect Ventricular Septal Defect Tetralogy of Fallot (VSD)
  • Patent ductus arteriosus Ductus arteriosus A fetal blood vessel connecting the pulmonary artery with the descending aorta. 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) ( ASD ASD Autism spectrum disorder (ASD) is a neurodevelopmental disorder marked by poor social skills, restricted interests/social interactions, and repetitive/stereotyped behaviors. The condition is termed a “spectrum” because of the wide variability in the severity of symptoms exhibited. Autism Spectrum Disorder)
  • 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 Pectus Excavatum Cardiovascular Examination 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 Ptosis Cranial Nerve Palsies
  • Optic nerve Optic nerve The 2nd cranial nerve which conveys visual information from the retina to the brain. The nerve carries the axons of the retinal ganglion cells which sort at the optic chiasm and continue via the optic tracts to the brain. The largest projection is to the lateral geniculate nuclei; other targets include the superior colliculi and the suprachiasmatic nuclei. Though known as the second cranial nerve, it is considered part of the central nervous system. The 12 Cranial Nerves: Overview and Functions hypoplasia Hypoplasia Hypoplastic Left Heart Syndrome (HLHS)
• Genitourinary:
  • Aplastic, dysplastic, or hypoplastic kidney
  • Horseshoe kidney Horseshoe Kidney Congenital Renal Abnormalities
• Auditory:
  • Conductive hearing loss Conductive hearing loss Hearing loss due to interference with the mechanical reception or amplification of sound to the cochlea. The interference is in the outer or middle ear involving the ear canal; tympanic membrane; or ear ossicles. Hearing Loss
  • Sensorineural hearing loss Sensorineural hearing loss Hearing loss resulting from damage to the cochlea and the sensorineural elements which lie internally beyond the oval and round windows. These elements include the auditory nerve and its connections in the brainstem. Hearing Loss

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 Genetics Genetics is the study of genes and their functions and behaviors. Basic Terms of 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 The status during which female mammals carry their developing young (embryos or fetuses) in utero before birth, beginning from fertilization to birth. Pregnancy: Diagnosis, Physiology, and Care

Management

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

• Correction of surgically amenable congenital Congenital Chorioretinitis defects
• Parent training to meet increased medical and developmental needs of child
• Early interventional therapies (birth to age 3):
  • Occupational therapy
  • Physical therapy Physical Therapy Becker Muscular Dystrophy
  • Speech therapy Speech Therapy Treatment for individuals with speech defects and disorders that involves counseling and use of various exercises and AIDS to help the development of new speech habits. Myotonic Dystrophies
• Behavioral interventions to develop:
  • Executive function
  • Social skills
  • Adaptive skills
• Educational support services:
  • Academic skills
  • Vocational training
• Psychotropic medications for:
  • ADHD ADHD Attention deficit hyperactivity disorder is a neurodevelopmental disorder characterized by a pattern of inattention and/or hyperactivity-impulsivity that occurs in at least 2 different settings for more than 6 months. Although the patient has normal intelligence, the disease causes functional decline. Attention Deficit Hyperactivity Disorder
  • Anxiety Anxiety Feelings or emotions of dread, apprehension, and impending disaster but not disabling as with anxiety disorders. Generalized Anxiety Disorder
  • Mood dysregulation

Prognosis Prognosis A prediction of the probable outcome of a disease based on a individual’s condition and the usual course of the disease as seen in similar situations. Non-Hodgkin Lymphomas and prevention

• Lack of diagnosis and management increases risk for:
  • Adverse childhood events
  • Poor school performance
  • Trouble with law enforcement/ incarceration Incarceration Inguinal Canal: Anatomy and Hernias
  • Inappropriate sexual behavior
  • Unemployment
  • Substance use disorder
  • Mental health disorders
  • Premature Premature Childbirth before 37 weeks of pregnancy (259 days from the first day of the mother’s last menstrual period, or 245 days after fertilization). Necrotizing Enterocolitis death
• Prevention:
  • Education about effects of alcohol on fetus
  • Promotion of alcohol abstinence
  • Screening Screening Preoperative Care to identify high-risk pregnant women

Differential Diagnosis

• ADHD ADHD Attention deficit hyperactivity disorder is a neurodevelopmental disorder characterized by a pattern of inattention and/or hyperactivity-impulsivity that occurs in at least 2 different settings for more than 6 months. Although the patient has normal intelligence, the disease causes functional decline. Attention Deficit Hyperactivity Disorder: neurodevelopmental disorder characterized by a pattern of inattention Inattention Attention Deficit Hyperactivity Disorder and/or hyperactivity Hyperactivity Attention Deficit Hyperactivity Disorder/ impulsivity Impulsivity Attention Deficit Hyperactivity Disorder that occurs in ≥ 2 different settings for more than 6 months. The clinical presentation of ADHD ADHD Attention deficit hyperactivity disorder is a neurodevelopmental disorder characterized by a pattern of inattention and/or hyperactivity-impulsivity that occurs in at least 2 different settings for more than 6 months. Although the patient has normal intelligence, the disease causes functional decline. Attention Deficit Hyperactivity Disorder 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 Disability Determination of the degree of a physical, mental, or emotional handicap. The diagnosis is applied to legal qualification for benefits and income under disability insurance and to eligibility for social security and workman’s compensation benefits. ABCDE Assessment. 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 X-linked Genetic diseases that are linked to gene mutations on the X chromosome in humans or the X chromosome in other species. Included here are animal models of human X-linked diseases. Common Variable Immunodeficiency (CVID) 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 Gene A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. Basic Terms of Genetics and is diagnosed by DNA analysis DNA analysis Biochemical identification of mutational changes in a nucleotide sequence. Hyper-IgM Syndrome. Clinical presentation includes characteristic physical features of long, narrow facies, large ears, and macroorchidism. Cognitive impairment, abnormal behavior, and 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 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 Chromosome In a prokaryotic cell or in the nucleus of a eukaryotic cell, a structure consisting of or containing DNA which carries the genetic information essential to the cell. Basic Terms of Genetics 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 Genetic Testing Detection of a mutation; genotype; karyotype; or specific alleles associated with genetic traits, heritable diseases, or predisposition to a disease, or that may lead to the disease in descendants. It includes prenatal genetic testing. Myotonic Dystrophies. Management involves addressing cardiovascular anomalies and providing interventions for neurodevelopmental issues.