Fetal Alcohol Syndrome

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Background

Adverse fetal, neonatal, and pediatric effects occur with maternal alcohol consumption during pregnancy. The diagnosis of fetal alcohol syndrome (FAS) is based on findings in the following 3 areas: (1) characteristic facial anomalies (see image below), (2) growth retardation (intrauterine growth restriction and failure to have catch-up growth), and (3) CNS involvement (cognitive impairment, learning disabilities, or behavioral abnormalities).



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Facial characteristics of a child with fetal alcohol syndrome.

Prenatal exposure to alcohol is associated with a variable spectrum of effects referred to as fetal alcohol spectrum disorders (FASD), with fetal alcohol syndrome at the most severe end of that spectrum. Children with fetal alcohol syndrome disorder may have clinically significant CNS involvement but few or no characteristic physical features.

Lemoine et al first described the pattern of malformation associated with heavy prenatal alcohol exposure in France in 1968, and Jones and Smith first described it in the United States in 1973.[1] Prenatal alcohol exposure is of substantial public health concern for the following reasons: (1) FAS is the leading known cause of mental retardation, (2) fetal alcohol syndrome or fetal alcohol syndrome disorder is associated with persistent physical and neurodevelopmental abnormalities,[2] and (3) fetal alcohol syndrome disorder crosses all socioeconomic groups and affects all races and ethnicities. The costs for 1 child with fetal alcohol syndrome are estimated to be $2 million over a lifetime, and costs of fetal alcohol syndrome to the American taxpayer are more than $321 million each year.

Pathophysiology

Alcohol crosses the placenta and rapidly reaches the fetus. Extensive studies have demonstrated equivalent fetal and maternal alcohol concentrations, suggesting an unimpeded bidirectional movement of alcohol between the 2 compartments. The fetus appears to depend on maternal hepatic detoxification because the activity of alcohol dehydrogenase (ADH) in the fetal liver is less than 10% of that observed in the adult liver. Furthermore, the amniotic fluid acts as a reservoir for alcohol, prolonging fetal exposure.

The mechanism for the spectrum of adverse effects on virtually all organ systems of the developing fetus is unknown. Ethanol and its metabolite acetaldehyde can alter fetal development by disrupting cellular differentiation and growth, disrupting DNA and protein synthesis and inhibiting cell migration. Both ethanol and acetaldehyde modify the intermediary metabolism of carbohydrates, proteins, and fats. Both also decrease the transfer of amino acids, glucose, folic acid, zinc, and other nutrients across the placental barrier, indirectly affecting fetal growth due to intrauterine nutrient deprivation. Elevated levels of erythropoietin in the cord blood of newborns exposed to alcohol are reported and suggest a state of chronic fetal hypoxia.

Studies have shown that prenatal alcohol exposure affects the hypothalamic-pituitary-adrenal (HPA) axis as well as alters basal and poststress cortisol levels.[3] In a Canadian study involving 26 children (aged 6-14 y) and 32 control children, Keiver et al found significantly elevated cortisol levels in the afternoon and at bedtime in those with known high prenatal exposure to alcohol (alcohol exposure rank 4) relative to those with low/unknown levels of prenatal alcohol exposure (alcohol exposure rank 3) and the control group. The investigators suggest these findings provide evidence for HPA dysregulation due to chronic fetal alcohol exposure, which may lead to long-term psychologic and medical morbidity.[3]

Epidemiology

Frequency

United States

Although careful comprehensive studies have not been performed and though passive surveillance systems are inadequate to measure the incidence of fetal alcohol syndrome or fetal alcohol syndrome disorder, the incidence of fetal alcohol syndrome in the United States is estimated to be 1-2 cases per 1000 live births. The incidence is related to the population studied, with highest incidence reported in areas where heavy drinking during pregnancy is common and where attention to diagnosis is greatest.

To date, no comprehensive population-based study with careful and standardized diagnostic methods applied to a large, representative sample of children has been performed. Likewise, the incidence of the broad spectrum of fetal alcohol syndrome disorder has not been well studied. However, data in one sample demonstrated that approximately 1 in 100 children have alcohol-related effects.

Among the subset of high-risk pregnant drinkers, estimated incidences of fetal alcohol syndrome differ because of variable definitions of heavy drinking and inconsistent methods of diagnosis. Therefore, rates range from 4% to as much as 44%.

International

Estimated rates of fetal alcohol syndrome in international settings are sparse in the literature. They are based on variable definitions and methods of ascertainment and range from 1 in 1000 to less than 1 in 10,000 live births. However, in some extremely high-risk areas, such as selected communities in South Africa where binge drinking in pregnancy is relatively common, careful in-school assessments have shown that rates of fetal alcohol syndrome may be as high as 4-5% of all children in the normal first grade in school.

Mortality/Morbidity

Adverse effects on the outcome of pregnancy, in addition to fetal alcohol syndrome disorder, have been noted with chronic or heavy alcohol use. These effects include an increased risk for spontaneous abortion, placental abruption, preterm delivery, amnionitis, stillbirth, and sudden infant death syndrome.

Commonly associated factors, such as maternal tobacco or other substance abuse, low socioeconomic status, and poor nutrition, complicate the morbidity and mortality associated with prenatal alcohol exposure.

Race

Regardless of race or ethnicity, fetal alcohol syndrome and fetal alcohol syndrome disorder occur in women who drink heavily during pregnancy. Rates of fetal alcohol syndrome appear to be highest among groups of low socioeconomic status. What is unknown is how these findings are related to a high prevalence of risky drinking in some populations; compromised nutritional status or general health; and, therefore, reduced resiliency to the effects of alcohol, possible genetic susceptibility, or a combination of these and other factors.

History

In the absence of sensitive and specific biomarkers of fetal alcohol syndrome (FAS), and given the common reluctance or inability of women to accurately disclose the quantity and frequency of their alcohol consumption, validating maternal reports of alcohol use is difficult. Furthermore, this information may not be available for children who are not in the care of their biologic mothers. Therefore, the US Institute of Medicine guidelines allow for a diagnosis of fetal alcohol syndrome in cases in which a documented history of exposure to alcohol is not available. The following 3 diagnostic subcategories are based on the history obtained and give the criteria for diagnosis in each category, as described in the guidelines of the US Institute of Medicine.

Fetal alcohol syndrome with confirmed maternal alcohol exposure includes the following:

Fetal alcohol syndrome without confirmed maternal alcohol exposure includes the following:

Partial fetal alcohol syndrome with confirmed maternal alcohol exposure includes the following:

Other categories that can be used when heavy maternal alcohol use is documented and other causes are ruled out include the following:

Physical

In newborns, alcohol withdrawal is uncommon. Neonates of women who have been drinking immediately before delivery may have alcohol on their breath for several hours, and blood levels of these babies are similar to those of the mother. Hypoglycemia and acidosis may be present. Withdrawal symptoms are agitation, hyperactivity, and marked tremors lasting 72 hours followed by approximately 48 hours of lethargy. Seizures may develop.

Although a wide variety of structural, growth, and functional abnormalities are reported to occur more frequently in infants and children prenatally exposed to alcohol than in others, the principal features of children with fetal alcohol syndrome or fetal alcohol syndrome disorder (FASD) are discussed below.[4, 5, 6, 7]

Key characteristic craniofacial abnormalities include the following:

Other craniofacial abnormalities are as follows:

CNS and neurobehavioral abnormalities include the following:

Skeletal abnormalities include the following:

Other major congenital anomalies include the following:

Functional problems include the following:

Growth deficiency include the following:

Causes

Although many factors may modify the risk, the primary and only necessary cause of fetal alcohol syndrome or fetal alcohol syndrome disorder is maternal alcohol consumption.

The quantity and pattern of maternal drinking and, therefore, the dose and duration of exposure to alcohol are the critical factors in conferring risk.

Current evidence supports the conclusion that women who drink heavily during pregnancy may produce children with features of fetal alcohol syndrome. Low-to-moderate levels of maternal alcohol consumption have not been well studied in human pregnancy, but evidence has not suggested a threshold dose below which no effects on cognitive performance or behavior are seen. In the absence of adequate data, no level of alcohol consumption in pregnancy is known to be safe, and the US Surgeon General advises women who are pregnant or who may be pregnant to abstain from alcohol consumption throughout the gestation.

Numerous studies demonstrated that the risk of alcohol-related effects increases according to maternal consumption in a dose-dependent fashion. Furthermore, heavy episodic, or binge, drinking is the riskiest pattern of consumption. Therefore, women who have the potential to become pregnant and who are binge drinkers may continue this pattern of consumption in the early weeks of an unrecognized pregnancy and therefore be at risk for fetal alcohol syndrome or fetal alcohol syndrome disorder.

Evidence indicates that alcohol primarily affects brain development. Therefore, drinking in all 3 trimesters poses a risk. As a consequence, women can reduce their risk for alcohol-related birth outcomes by reducing the dose or by discontinuing the consumption of alcohol as soon as possible in the pregnancy.

Several conditions or characteristics may modify risk for fetal alcohol syndrome or fetal alcohol syndrome disorder among women who consume sufficient quantities of alcohol in pregnancy.

Women older than 30 years and/or those with a long history of alcohol consumption may be most likely to give birth to a child with fetal alcohol syndrome or fetal alcohol syndrome disorder.

Poor maternal nutritional status may also increase the likelihood of having an alcohol-affected child.

Having one child with fetal alcohol syndrome further increases the risk of producing subsequent children with fetal alcohol syndrome.

Genetic susceptibility to fetal alcohol syndrome has been suggested in some studies, with alcohol dehydrogenase (ADH) polymorphisms as a risk factor. In particular, the ADH 2*2 and 2*3 alleles, which result in rapid metabolism of alcohol to acetaldehyde, were shown to be protective against FAS. However, the mechanism by which this protective effect occurs is unknown. Some suggest that rapid metabolism of alcohol to acetaldehyde lowers peak blood alcohol levels and therefore lowers fetal exposure. As an alternative, rapid metabolism may increase levels of acetaldehyde with associated noxious effects on the mother and therefore reduce levels of alcohol consumption, which lowers fetal exposure.

Mouse models have demonstrated deficiencies in neuronal nitric oxide synthase worsens microcephaly and neuronal loss when exposed to alcohol.[8]

Laboratory Studies

In patients with suspected fetal alcohol syndrome (FAS), consider chromosomal analysis to rule out unbalanced translocations or visible deletions. Also consider fluorescent in-situ hybridization (FISH) of 22q11 region to rule out deletion.

Imaging Studies

Multiple studies have demonstrated differences in brain size and shape, especially in the parietal lobe, cerebellar vermis, corpus callosum, and caudate nucleus, as well as aberrations of growth in the frontal lobes compared to age-matched and sex-matched controls. However, each study has significant limitations, specifically study size and control ascertain.

Similarly, normative values for size, growth rates, and volumes of these regions have not been delineated; therefore, routine use of magnetic resonance imaging (MRI) is usually not warranted.[9]

The advent of optical coherence tomography (OCT) shows promise as a preliminary screening tool for rapidly phenotyping and quantifying congenital heart defects associated with prenatal alcohol exposure.[10] In 3-dimensional (3-D) avian embryo heart models of fetal alcohol syndrome, OCT was able to identify embryonic structures and cardiac anomalies (eg, ventricular septal defects, missing/misaligned vessels) in high resolution.[10]

Diffusion tensor imaging (DTI) and tractography (DTI-tractography) also shows promise in evaluating the effects of prenatal alcohol exposure on the brain structure of newborns.[11] When DTI-tractography was used to analyze white matter development in 11 newborns whose mothers drank alcohol during pregnancy compared to 9 age- and community-matched controls whose mothers either drank lightly or did not drink alcohol during pregnancy, the strongest white matter network association found with maternal drinking was axial diffusivity, with the strongest relations in the medial and inferior white matter. The investigators did not find a consistent and significant relation between fractional anisotropy and alcohol exposure, which differs from findings in older individuals who were prenatally exposed to alcohol.[11]

Medical Care

The medical care of the child with fetal alcohol syndrome (FAS) or fetal alcohol syndrome disorder (FASD) is treatment for associated birth defects and intervention for potential cognitive and behavioral abnormalities.

Consultations

If fetal alcohol syndrome or fetal alcohol syndrome disorder is suspected, consult a subspecialist (eg, geneticist, developmentalist) to confirm the diagnosis and provide guidance for formulating an ongoing care plan.

Medication Summary

Some children with fetal alcohol syndrome or fetal alcohol syndrome disorder present with clinically significant impulsivity, hyperactivity, oppositional behavior, and/or sleep disorders. Medication may assist with these symptoms. However, whether these abnormalities due to prenatal alcohol exposure respond to medications that successfully treat these behaviors when they are due to other or unknown causes is not established. Therefore, the successful use of medication may depend on the individual child's history and presentation.

Deterrence/Prevention

The US Institute of Medicine has outlined a public health model of prevention for fetal alcohol syndrome (FAS). This model includes 3 levels: universal, selective, and indicated.

Universal prevention attempts to promote the health and well-being of all individuals in a society or particular community by educating women about the risks of alcohol for the developing fetus and about the importance of avoiding alcohol consumption during pregnancy. This type of prevention can be accomplished with public education and primary care.

Selective prevention and intervention is targeted to individuals in the population who are at increased risk (ie, women of reproductive age who drink alcohol and who have the potential to become pregnant). This step can be accomplished with effective screening for alcohol use and with brief interventions.

Indicated prevention and intervention is intended for the highest-risk women who are drinking risky amounts of alcohol and who are likely to become pregnant (eg, women who have previously delivered an affected child and who continue to drink). This level of prevention and intervention might be accomplished with treating such women for alcohol dependence and with case management.

Prognosis

The prognosis for individuals with fetal alcohol syndrome or fetal alcohol syndrome disorder (FASD) is wide ranging. Some data suggest that having a confirmed diagnosis of fetal alcohol syndrome improves the prognosis, perhaps because this improves access to services. Other studies of fetal alcohol syndrome suggest that early diagnosis improves the prognosis because implementation of early intervention programs occurs at a younger age.

In one study, researchers followed up the natural history of a group of individuals with fetal alcohol syndrome or fetal alcohol syndrome disorder aged 12-51 years. Although no comparison group was included, rates of various mental, social, and legal problems were documented as follows:

In a more recent study, Swedish investigators evaluating the psychosocial outcomes of 79 adults with fetal alcohol syndrome also found higher rates of special education, unemployment, disability, prescriptions for psychotropic drugs, and hospitalizations for alcohol abuse and psychiatric disorders compared to their age-, sex-, and birth place – matched cohorts.[12] However, both groups had similar levels of criminal offences.

Patient Education

Keys to working successfully with children who have fetal alcohol syndrome or fetal alcohol syndrome disorder are structure, consistency, variety, brevity, and persistence. Because children with fetal alcohol syndrome or fetal alcohol syndrome disorder lack internal structure, caretakers need to provide external structure for them. Be consistent in response and routine so that the child believes the world is predictable.

Because of serious problems maintaining attention, be brief in explanations and directions but also use various ways to get and keep the child's attention.

Author

Keith K Vaux, MD, Professor of Medicine, Clinical Chief and Division Director, Division of Medical Genetics, Department of Medicine, University of California, San Diego, School of Medicine; Director, Rare Disease Program, Rady Children's Hospital San Diego and UC San Diego

Disclosure: Nothing to disclose.

Coauthor(s)

Christina Chambers, MPH, PhD, Associate Professor of Pediatrics and Family and Preventive Medicine, University of California at San Diego; Assistant Professor, Graduate School of Public Health, San Diego State University

Disclosure: Nothing to disclose.

Specialty Editors

Mary L Windle, PharmD, Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

Arun K Pramanik, MD, MBBS, Professor of Pediatrics, Louisiana State University Health Sciences Center

Disclosure: Nothing to disclose.

Chief Editor

Ted Rosenkrantz, MD, Professor, Departments of Pediatrics and Obstetrics/Gynecology, Division of Neonatal-Perinatal Medicine, University of Connecticut School of Medicine

Disclosure: Nothing to disclose.

Additional Contributors

Oussama Itani, MD, FAAP, FACN, Clinical Associate Professor of Pediatrics and Human Development, Michigan State University; Medical Director, Department of Neonatology, Borgess Medical Center

Disclosure: Nothing to disclose.

Acknowledgements

The authors gratefully acknowledge the contributions of Christine D Dittmer, MD, and Sarah L Lentz-Kapua, MD, to the writing and development of this article.

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Facial characteristics of a child with fetal alcohol syndrome.

Facial characteristics of a child with fetal alcohol syndrome.