Birth Defects and Fetal Alcohol Spectrum Disorder

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Albert E. Chudley, M.D., FRCPC, FCCMG

Medical Director, Program in Genetics & Metabolism
Winnipeg Regional Health Authority
Professor, Departments of Pediatrics and Child Health
Biochemistry and Medical Genetics, University of Manitoba

Health Sciences Centre
FE 229 820 Sherbrook Street
Winnipeg , Manitoba R3A 1R9
Phone: 204-787-4743
Fax: 204-787-1419
achudley@hsc.mb.ca

Table of Contents

• Introduction
• Diagnosis
• Birth Defects
• Dose and Timing of Alcohol Exposure
• Brain Effects
• Mechanisms of Teratogenesis
• Genetic Differences
• Prevention and Costs to Society
• Identifying High Risk Women and Children
• Congenital Anomalies Surveillance and FAS
• Conclusion
• References

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Introduction

Fetal alcohol syndrome (FAS) is caused by excessive maternal alcohol use during pregnancy. It is one of the leading causes of preventable congenital anomalies and developmental disabilities (Stratton et al., 1996). It presents with growth impairment, characteristic facial dysmorphic features and brain dysfunction. The full spectrum of prenatal alcohol effects is referred to as Fetal Alcohol Spectrum Disorder (FASD). The largest affected group in the spectrum is invisible as they do not present with dysmorphic features or growth impairment, but often manifest with cognitive and behavioural difficulties. It thus is difficult to estimate the full spectrum of the disorder since there are no reliable biological markers that readily define those affected. The prevalence is related to the frequency of excessive or at risk alcohol use in pregnancy and thus will vary from population to population. For the subset of individuals affected with fetal alcohol syndrome, the worldwide incidence is 1-3 in 10,000 (Abel, 1995). State-based estimates of the prevalence of fetal alcohol syndrome in the United States vary from 0.3 to 1.5 per 1,000 live born infants (CDC, 2002). The only data that estimates the prevalence of the broader spectrum including those with FAS and alcohol related neurodevelopmental disorder comes from Seattle, USA for the period 1975-1981 where the prevalence is estimated to be 9.1/1,000 (Sampson et al., 1997). In South Africa, investigators for the National Institutes of Alcoholism and Alcohol Abuse reported a fetal alcohol syndrome prevalence of 40.5 to 46.4 per 1,000 children aged 5-9 years in one Western Cape community (CDC, 2003).

In Canada no national statistics are available. In Manitoba, the minimum estimated incidence of fetal alcohol syndrome from one hospital in the northeastern region of the province by review of chart records of all 745 live births and selected examination of those qualifying or suspected to be affected children in one hospital over a one-year period was 7.2/1,000 (Williams et al., 1999). In another study in Manitoba involving a cross-sectional survey of 178 school age children from a First Nation community, the combined prevalence of FAS and partial FAS was estimated to be between 55 and 101 per 1000 (Square, 1997; Chudley et al, 1999).

Diagnosis

The diagnosis of FAS depends on the presence of the cardinal findings of dysmorphic facial features, evidence of brain dysfunction, and prenatal and postnatal growth deficiency in the presence of prenatal alcohol exposure (Clarren and Smith, 1978). The sentinel facial features consist of short palpebral fissures, midfacial hypoplasia, poorly formed philtrum, and thin vermilion border of the upper lip. A variety of other congenital anomalies have been described, including malformations of the brain, heart, kidneys, palate, and musculoskeletal system. Soon after the original description of fetal alcohol syndrome (Jones et al, 1973; Jones and Smith, 1973), substantial behavioural and cognitive effects of prenatal alcohol exposure were seen in individuals who have no sentinel features and no growth impairment. The term Fetal Alcohol Effects (FAE) (Rosette and Weiner, 1982) described this subset. The term FAE was poorly defined and its use was discouraged by prominent American dysmorphologists (Aase et al., 1995). It was replaced by the 5 diagnostic categories recommended by the Institute of Medicine, an expert panel of fetal alcohol syndrome researchers and clinicians in the United States (Stratton et al., 1996). These include fetal alcohol syndrome with prenatal alcohol exposure confirmed; fetal alcohol syndrome without prenatal alcohol exposure confirmed; partial fetal alcohol syndrome; alcohol related birth defects; alcohol related neurodevelopmental disorder. Since 2000, Fetal Alcohol Spectrum Disorder (FASD) has emerged as an umbrella term that refers to the whole spectrum of alcohol effects. However its use as a diagnostic term is problematic because of its lack of precision, which may result in confusion and criticism as witnessed with the term fetal alcohol effects. Because of these issues and others it has become clear that diagnosis requires in depth assessments of the child best done by a comprehensive multidisciplinary team approach that assesses both physical features, neurological, brain and behavioural functions. This has led to the development of Canadian standards for diagnosis (Chudley et al, 2005), which harmonized both the Institute of Medicine and 4-Digit Code systems of diagnosis (Stratton et al. 1996; Astley and Clarren, 2000; Astley, 2005).

Birth Defects

Almost all major and minor anomalies have been described in children affected by FAS (Chudley and Longstaffe, 2005). The most consistent findings in these children involve midline craniofacial defects, CNS defects, cognitive and behavioural deficits . The facial defects that correlate most closely with alcohol exposure in the first trimester are short palpebral fissures, a smooth and poorly formed philtrum and a thin vermillion border of the upper lip. Other major birth defects found in varying frequencies include:

• Brain malformations
• Craniofacial defects including facial clefting
• Ocular defects
• Deafness
• Cardiac defects (conotruncal)
• GI: bowel atresias, malrotation
• Skeletal anomalies: limb, rib and vertebral anomalies
• Integument: hemangiomas, hirsuitism

Dose and Timing of Alcohol Exposure

Animal studies and clinical experience with humans have clearly identified ethanol as a teratogen, and frequent, heavy alcohol consumption leads to fetal alcohol syndrome in some exposed children (Streissguth et al., 1980). After the widespread recognition of fetal alcohol syndrome in the 1970's and subsequently, several animal research groups confirmed that ethanol can lead to a constellation of birth defects identical to those seen in humans with fetal alcohol syndrome (Sulik et al., 1981; Astley et al., 1999). There appears to be a dose-response relationship with a high blood alcohol level, and earlier exposure during critical periods of development resulting in greatest harm (Jacobson and Jacobson, 1994). Exposure levels in humans that result in fetal alcohol syndrome usually are associated with a blood alcohol level that exceeds 150 mg/dl. However, light to moderate exposures (15 ml per day to one drink per week) are associated with some effect, in that some show growth deficits and intellectual and behavioral problems similar to, although less severe than, those found in children with fetal alcohol syndrome. A higher risk of abnormal behaviors with poor attention, learning difficulties and externalized behaviors was observed in children born to mothers who had any alcohol intake and as little as one drink per week (Sood et al., 2001). Jacobson and Jacobson (1999) indicate that "moderate" drinking has much more impact on child development when the mother consumes several drinks in a single day than when she drinks the same quantity in doses of one to two drinks per day over several days.

First trimester exposure is more likely to be associated with facial dysmorphology (Astley et al., 1999). Growth deficiency appears to be associated with second and third trimester exposure, as women who stop drinking after the fifth month of gestation tend to have children with normal growth parameters (Rosett and Weiner, 1982).

Brain Effects

The brain is vulnerable to the adverse effects of prenatal alcohol exposure through all three trimesters of the pregnancy. No specific anatomical region of the brain appears to be targeted, although malformations seen include migration abnormalities, abnormalities in the size and shape of the corpus callosum, cerebellar vermis hypoplasia, hypoplasia of the basal ganglia and hippocampus, as well as microcephaly (Mattson et al., 2001). Most individuals with fetal alcohol syndrome will show no anatomical abnormalities on brain imaging. On neuropsychological assessments, exposed individuals show functional deficits in the prefrontal cortex and hippocampus characterized by deficiencies in executive functions, working memory, and impaired information processing, attention, and place learning (Mattson and Riley, 1998: Mattson et al., 2001; Hamilton et al., 2003). Studies of children with fetal alcohol syndrome compared to children without the physical features of fetal alcohol syndrome who were born to alcoholic mothers and to normal unexposed controls indicate that, relative to controls, both the fetal alcohol syndrome and the non-fetal alcohol syndrome alcohol exposed groups were impaired on tests of language, verbal learning and memory, academic skills, fine-motor speed, and visual-motor integration. The authors suggest that heavy prenatal alcohol exposure is related to a consistent pattern of neuropsychological deficits and the degree of these deficits may be independent of the presence of physical features associated with fetal alcohol syndrome (Mattson et al., 1998).

Mechanisms of Teratogenesis

The mechanism of the teratogenic effects of alcohol is still unknown. However, candidate molecular and cellular mechanisms have been postulated (Goodlet et al., 2005) (Table 1).

Poor nutrition, emotional stress and exposure to other drugs of abuse and cigarettes may influence fetal development and potentiate the effects of prenatal alcohol exposure. Ethanol is a neurotoxin and leads to reduction in neural precursor cells and a generalized reduction in brain size. The impairments are not localized but diffuse, and they vary in severity from individual to individual. A lcohol most likely produces many of its damaging effects by exerting specific actions on molecules that regulate key developmental processes. Ethanol-induced cell death (apoptosis) in mice has been demonstrated in stage-specific cell populations of the developing brain, and may be in part related to oxidative stress. These effects are seen in the craniofacial region including the neuroectoderm, neural plate and primitive streak, neural crest of the mesencephalon/rhombencephalon junction of the rostral hindbrain, branchial arches, rhombomeres and diencephalon, basal ganglia, pons, and developing cerebellum (Dunty et al., 2001).

Other hypotheses include the potential influence of suppression of the glutamate-N-methyl-D-aspartate receptor-nitric oxide synthase system (Kimura et al., 2000), and the role of genetic variants in the one cell adhesion molecule, L1. Similarities between individuals with fetal alcohol syndrome and with L1 mutations suggest that the mechanism of developmental neurotoxicity of ethanol is partly due to effects on L1 cell adhesion molecule (Bearer, 2001). This is supported by studies that showed 1-octanol, a long-chain alcohol, significantly antagonizes the teratogenic effects of ethanol, a short-chain alcohol, in mouse whole embryo culture (Chen et al., 2001). 1-octanol decreases ethanol teratogenesis by blocking its interaction with L1. The paradoxical inhibition of ethanol teratogenicity by a longer chain 1-alcohol may lead to a strategy for developing compounds that might reduce or prevent alcohol-related birth defects.

An active peptide fragment of a neuroprotective protein of the glial-derived activity-dependent neuroprotective protein, NAPVSIPQ, prevents ethanol-induced fetal wastage and growth retardation in mice (Wilkemeyer et al., 2003). NAPVSIPQ antagonism of ethanol inhibition of L1 adhesion may play a central role in NAPVSIPQ prevention of ethanol embryotoxicity. Other pathways that may influence the embryonic and fetal brain after ethanol exposure include altered prostaglandin synthesis, disturbed free fatty acid synthesis, and inhibition of insulin signaling resulting in impaired central nervous system development and function in children with fetal alcohol syndrome.

Genetic Differences

Maternal genetic differences in acetaldehyde metabolism may have a role in fetal alcohol syndrome (Eriksson, 2001). Some individuals may be at greater risk of having affected children with fetal alcohol syndrome by virtue of their genotype. There are three different alleles of the alcohol dehydrogenase (ADH2) gene (ADH2-1, ADH2-2 and ADH2-3) with differing levels of enzymatic activity which can alter the risk of fetal alcohol effects. The ADH2-2 allele was noted to be significantly more common in control individuals than mothers of children with fetal alcohol syndrome among individuals of mixed ancestry in the Western Cape Province of South Africa. Thus ADH2-2 allele may either directly confer protection or be a marker for a protective effect against fetal alcohol syndrome (Viljoen et al., 2001). In another study, maternal genotype correlated with her chance of having an infant with alcohol-related physical features (Stoler et al., 2002). The investigators concluded that women with the ADH2-1/3 genotype may be at greater risk for having an affected infant, which may be the result of greater ingestion of alcohol. Acetaldehyde is a metabolic product of ethanol metabolism. Acetaldehyde may create both unpleasant aversive reactions that protect against excessive alcohol drinking and euphoric sensations that may reinforce alcohol drinking by increased tolerance, depending on the genotype. These effects involve catecholamine, opiate peptide, prostaglandin, histamine, and/or kinin mechanisms, as well as other risk factors such as poor nutrition and stress.

Prevention and Costs to Society

Streissguth et al., (1996) introduced the concept of secondary disabilities that characterize children and adults affected by FAS and well as those with FAE (the whole spectrum of FASD). They defined secondary disabilities as those disabilities that an individual is not born with, and that could be ameliorated through better understanding and appropriate interventions. The secondary disabilities include mental health issues (depression and suicide, psychosis), disrupted school experience, trouble with the law, confinement, inappropriate sexual behavior, alcohol and drug problems, dependent living, and problems with employment. Individuals with fetal alcohol spectrum disorder can “pass the tests, but they fail life” (personal communication, Dr. Gail Andrews).

The cost to society is enormous. Some estimate that lifetime cost is over two million US dollars per affected individual using a recalculation of information from data derived in 1980 in the United States (Harwood and Napolitano,1985)

(see http://www.fascenter.samhsa.gov/publications/cost.cfm).

A recent study in Ontario showed the annual costs associated with FASD per child were $14,342, and the cost of FASD annually to Canada of those 1 to 21 years old, was $344,208,000. The largest single components of costs were education costs and medical costs accounting for 32.6 per cent and 30.3 per cent respectively. (Stade et al., 2006). This study did not include the cost for adolescents in the justice system, so the costs are a minimum estimate.

The cost to the affected individual, the family and society is staggering. Mortality rates in children with fetal alcohol syndrome are high (Habbick et al., 1997). Effective prevention strategies must include a variety of approaches involving the general population and targeting high-risk populations. Many mothers of individuals with fetal alcohol spectrum disorder are also themselves affected by prenatal alcohol exposure, and this may have been present through several generations in some families. There appears to be a high rate of involvement of adolescents and adults affected with fetal alcohol syndrome in the criminal justice system (Fast et al., 1999; Conry and Fast, 2000; Boland et al., 2003). Many end up in jail, having become perpetrators of crime, which is often violent. Public education, warning labels, family support groups, advocacy groups, early childhood intervention programs, specialized educational and career training, addiction counseling and treatment for women, and paraprofessional mentoring programs have been helpful in reducing the birth prevalence of affected individuals, and reducing the morbidity from this disorder (Astley, 2004). An early diagnosis is associated with a lower occurrence of secondary disabilities, so that more effort has to be made to diagnose the children as soon as possible.

Identifying High Risk Women and Children

There are several reliable and validated screening questionnaires that identify pregnant women with high risk drinking patterns (Loock et al., 2005). The questionnaires are simple and are best administered by physicians, midwives or nurse practitioners to all women prior to or early in their pregnancy. These include the TWEAK, T-ACE, CAGE, BMAST, SMAST, and AUDIT screening questionnaires (Russell et al., 1994; Bradley et al, 1998). Women who score high in the questionnaire can be offered counseling to help reduce drinking in pregnancy. Identifying and intervening on behalf of mothers at risk before they become pregnant and preventing future affected children would be ideal. Primary prevention to reduce the recurrence of FAS in subsequent siblings is achievable using a mentoring program that identifies and supports mothers at risk who have an affected child (Astley et al., 2000; Clarren and Astley, 1998).

Direct measurement of ethanol concentration in the blood or in exhaled breath is only useful for very recent drinking. There are currently no reliable means to confirm maternal drinking using biochemical markers in pregnancy. High levels of whole blood-associated acetaldehyde, carbohydrate-deficient transferrin, gamma-glutamyl transpeptidase, and mean red blood cell volume may be useful markers in pregnant women. Stoler et al (1998) showed that women who reported drinking an average of one or more ounces of absolute alcohol per day had at least one positive blood marker. The infants of mothers with two or more positive markers had significantly smaller birth weights, lengths, and head circumferences than the infants with negative maternal screens. The presence of two or more positive markers was more predictive of infant outcome than any self-reporting measure. They concluded that these markers are more reliable than self-reporting methods, and that the use of these markers could lead to better efforts at detection and prevention of alcohol-induced fetal damage.

Ethanol is transesterified with fatty acids into fatty acid ethyl esters which are accumulated in meconium of babies exposed to high amounts of ethanol after the first trimester (Moore et al., 2002; Bearer 2003). Studies are currently underway to determine the use of fatty acid ethyl ester measurements in meconium from babies whose mothers are suspected to have drank in pregnancy, and to correlate fatty acid ethyl ester concentrations and specificity with developmental outcome. With appropriate informed consent, meconium could be measured in babies in the first two days of life to confirm at risk ethanol exposure in the second and third trimesters (Chan et al., 2003; Koren et al., 2003). This would alert caregivers to infants who might be at risk for alcohol effects and lead to appropriate monitoring, intervention and prevention.

Congenital Anomalies Surveillance and FAS

Currently there are no reliable statistics nor has there been a consistent approach in Canada to diagnose FASD children until recently (Chudley et al., 2005). Therefore the incidence and prevalence of FAS and FASD is unknown. Although more expertise is being developed amongst a variety of professionals to diagnose the disorder in a team approach, the challenge of diagnosing children who do not present with the physical features is substantial. O nly those with craniofacial characteristics and growth impairment (i.e. FAS) will be identified in the first several months of life. Surveillance should include multiple sources of ascertainment throughout childhood and adolescence.

Clearly there are benefits to knowing the frequency of this common disorder. Accurate reporting of cases will provide a baseline to monitor effectiveness of prevention programs. Accurate reporting of cases will allow recognition of need for improved funding of diagnostic teams, intervention treatment and prevention programs.

Canada needs to develop a comprehensive system or registry to identify children affected by prenatal alcohol exposure. This would involve multiple sources of ascertainment, and include an expanded age range beyond the first year of life, since many cases may not present or be diagnosed until later childhood. It would require an agreement on a classification system, and the availability of expert reviewers of potentially affected cases to verify diagnosis in each provincial jurisdiction. Further more, the registry could be linked to other databases in the health care, educational and social care systems that would facilitate tracking of health needs and complications, progress and measurement of success of interventions, and identifying other needs for theses children.

Conclusion

Although the diagnosis of fetal alcohol syndrome and its spectrum is a medical diagnosis, its effects on society are far reaching. Fetal alcohol spectrum disorder is potentially entirely preventable, and the diagnosis points towards two affected individuals; the drinking mother and the alcohol exposed child. Diagnosis, intervention and prevention offer some of the greatest challenges to health care providers, families and their communities. Multidisciplinary diagnostic teams are developing throughout North America and other parts of the world that provide accurate and comprehensive assessments and treatment options for affected individuals with this common disorder. We need to improve our ability to monitor the occurrence of FASD if we are to effectively identify and improve on successful prevention and intervention programs for these children.

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