Gene-Environment Influences on Fetal Alcohol Syndrome: State of the Science

Gloria Giarratano, PhD, APRN, CNS and Angelique White Williams, DNS, APRN, CNS, CCHC

Abstract

Alcohol ingestion during pregnancy continues to be a major medical, social, and public health problem. This article will review the state of the science and current research concerning the adverse effects of alcohol on fetal and child development. Genetic-based research will be presented as a relatively new area of knowledge that may lend insight into determining how risk of injury and susceptibility to more severe consequences of fetal alcohol syndrome can be influenced by genetic determinants, such as maternal alcohol metabolism. The health care professional's role in prevention, providing early diagnosis, physical and mental health assessments, and promoting family advocacy will be overviewed.

Keywords: genome , Fetal alcohol syndrome

INTRODUCTION

In 2005, the U.S. Surgeon General's Advisory on Alcohol Use in Pregnancy urged women who were pregnant or who may become pregnant to abstain from using all alcohol^{1, 2} . No amount of alcohol is considered safe for consumption during pregnancy. This policy was founded on a body of science that confirmed a wide range of adverse effects of prenatal alcohol exposure on the developing fetus. The array of fetal complications, including structural and facial anomalies, cognitive deficits, birth defects, and neuro-developmental disabilities, were termed fetal alcohol spectrum disorders (FASD). Although the characteristics and severity of the conditions may vary, each disorder adversely impacts the infant, child, and adolescent and has a lifelong effect on the health and well being of the affected individual. Fetal alcohol syndrome (FAS) is the diagnostic term used to identify children at the most severe end of the spectrum who have characteristic facial anomalies, growth deficits, and central nervous system problems

Prenatal alcohol exposure is the most preventable cause of birth defects, developmental disabilities, and mental retardation in the U.S.³. Yet the number of pregnancies potentially affected by alcohol exposure continues to be alarmingly high. A national survey conducted by the Centers for Disease Control and Prevention (CDC) in 2002, found that 10.1% of women surveyed reported alcohol consumption at some time during their past pregnancy⁴. Of these, 1.9% reported binge drinking during a past pregnancy (defined as 5 or more drinks on 1 occasion), and another 1.9% reported frequent use (defined as 7 or more drinks in a week) while pregnant. In the U.S. and western countries, the incidence of FAS is 1 to 2 times per 1000 live births. Yet, when the incidence of FAS is combined with all other alcohol-related conditions, the overall effects of prenatal alcohol exposure is estimated to affect 10 out of 1000 live births⁵.

STATE OF THE SCIENCE

Since the characterization of FAS more than 30 years ago, there has been a plethora of research studies aimed toward increasing our understanding of the toxic effects of alcohol on the developing fetus. Ethanol-induced toxic effects have proven complex to study due to the intricate system of cellular changes normally occurring in early development; therefore, the mechanisms of how alcohol alters development are not fully understood. It has been well established, however, that there is no one cellular mechanism that causes all the deficits associated with FAS. Progress with understanding some of these potential mechanisms and the genetic links will be highlighted below. Recent discoveries of the genetic influences on predisposition to FASD, and the severity of complications leading to FAS, will impact how we screen at-risk women and newborns and how we target prevention efforts.

TERATOGENIC EFFECTS OF ALCOHOL

Laboratory research using either model animals, such as the mouse or rat, or using in vitro approaches in which cell lines or tissue are grown in tissue culture, has contributed to current understanding of the mechanism for in utero alcohol damage⁶. The findings from animal studies cannot be transferred to humans with absolute certainty, since there are species-specific factors that influence alcohol's effects. Yet both approaches allow researchers to manipulate and mimic the conditions of alcohol consumption during pregnancy by exposing the animal, its offspring, or specific cells to alcohol.

This body of research has indicated there are multiple mechanisms responsible for the broad variations of anatomical and cognitive characteristics seen in FASD and the FAS phenotype^{7, 9}. Alcohol may act directly on fetal tissue as a teratogen, arresting or altering cell development, or it may act indirectly as a result of alcohol metabolism. Acetaldehyde is one such toxic by-product of alcohol metabolism that can accumulate in the fetal brain. Alcohol also has been shown to interfere with nutritional and hormonal factors that are necessary for normal embryonic development.

The most serious injury to the developing brain and central nervous system is most likely attributed to cell death. Cell death results either through necrosis of neurons damaged by metabolic injury or by a process of cell suicide or apoptosis^{7, 9}. One mechanism by which alcohol is thought to accelerate apoptosis (and necrosis) is by the oxidative stress of alcohol metabolism in which a large number of free radicals are expressed. Free radicals are unstable molecules formed during metabolism of alcohol that cause damage to cells and can initiate the release of apoptosis-inducing factors. Normally, free radicals are eliminated by antioxidants in the cells, but alcohol itself reduces antioxidants. This contributes further to alcohol-induced cell damage and death. This oxidative stress is also thought to damage mitochondria—the cellular organelles that generate the cell's energy.

Studies have also found that alcohol damages the fetal brain by interfering with the growth factors and neurotransmitters that regulate cell proliferation and brain development⁷. Normal neuron development requires neurons to develop and migrate to the outer layers of the cerebral cortex. Alcohol exposure at critical times can alter normal migration, and neural cells end up in abnormal positions, thus altering the connections among neurons. The growth and differentiation of serotonin-releasing neurons (i.e., serotonergic system – 5HT) has been studied with interest, since this system plays an important role in human mood disorders. Research seems to indicate that environmental influences in early development may alter neuron determination in the serotonergic system. Alteration in the function of the serotonergic system is associated with increased individual susceptibility to mental health disorders and can affect how well the individual respond to pharmaceutical agents¹⁰. Fetal alcohol exposure has reduced 5HT neurons by 30% in the mouse¹¹. If similar effects occur in humans, it is believed the result would be the delayed development of serotonergic neurons needed for normal interaction between serotonin and target sites during normal brain development. The mechanisms and long-term consequences of this delay need further study.

As a result of these teratogenic insults, children exposed to alcohol prenatally often suffer from structural changes in the brain, as well as cognitive deficits and behavioral problems. Magnetic resonance imaging (MRI) studies have shown distinct changes in the brains of individuals exposed to alcohol prenatally¹². The structures potentially affected by fetal alcohol exposure are shown in Figure 1. Overall head size is decreased in children with FAS, with structural changes observed in several key brain areas, such as the cerebellum, hippocampus, basal ganglia, and corpus callosum¹³ . Through MRI studies, prominent disproportionate reductions have been found in areas such as the parietal lobe and corpus callosum, suggesting that certain areas of the brain may be especially vulnerable to prenatal alcohol exposure. These specific brain areas are normally associated with intellectual functioning, motor abilities, memory, and executive functioning. "Executive functioning" refers to higher-level cognitive functions involved in planning and guiding behavior to achieve goals, problem solve, think abstractly and be flexible¹⁴.

In addition to affecting brain development, there are mechanisms that can also alter tissue growth and the developing nerve-muscle system¹⁵. Prenatal alcohol exposure in rats reduced muscle fiber in number and size by delaying the maturation process of the neuromuscular system. Delays in maturation may account for the reduction in birth weight, and the continued growth restriction and muscle weakness seen in children with FAS. Likewise, alcohol exposure during critical development of the cardiac neural crest predisposes the developing fetus to a host of heart defects, such as atrial and ventricular septal defects, tetralogy of Fallot, and pulmonary artery stenos is¹⁶.

VARIATIONS THAT AFFECT FAS PHENOTYPE: ENVIRONMENT AND GENES

Maternal drinking patterns

FASD and FAS are not genetically inherited conditions. A child must be exposed to prenatal alcohol in order to be affected. However, there are believed to be variations in the susceptibility and severity of the conditions based on environment-gene interactions. The environmental impact of alcohol on the fetus may vary due to the timing and dosage of alcohol; the genetic make-up of the mother who consumes and metabolizes the alcohol; and the fetus, which responds to the toxic effects of alcohol and eventually metabolizes it in later development. Maternal drinking patterns and maternal metabolism are the two most important variables that affect the levels of blood alcohol concentration (BAC) and thus influence the severity of fetal brain injury^{17, 18}.

Research has demonstrated that dosage and timing of exposure may impact the severity of the disorders¹⁹ . For example, the classic head and face anomalies have been correlated to exposure during the embryonic stage (first eight weeks). In animal research studies, the BAC is used as a precise measure of alcohol present in the bloodstream after alcohol intake. Animal studies have correlated BAC and effects on brain injury in developing rats and mice^{7, 20}. In studies such as these, the factors known to affect BAS (including time between eating and drinking, and the concentration of the alcohol consumed) were kept constant. Numerous studies conclude that brain growth is impaired more by binge-like patterns of intake than by continuous daily exposure^{21, 22}. One early study found that a lower daily dose given in a binge pattern (4.5g/kg/day over 4 hours) was more harmful to the animal than a higher daily dose consumed over eight hours (6.6 g/kg/day)²³. Based on these animal studies, it is assumed that binge drinking during this sensitive period of pregnancy (first 4-6 weeks) results in the most severe physical anomalies. However, the internal structural brain changes and the resulting cognitive injury can occur with alcohol exposure throughout the gestational period¹².

Genetic influences on alcohol intake and metabolism

Despite these findings, not all incidences of prenatal exposure to alcohol will result in FAS. The possibility that genetic risk factors play a role in the susceptibility to adverse effects was first considered when animal researchers noted that different strains of mice and chick research models were affected differently by alcohol exposure during gestation. Certain strains consistently experienced more severe alcohol-related disorders than others, even when the amount of alcohol ingested was kept constant^{20, 24}. This suggests that genetic differences in metabolism and molecular mechanisms of alcohol toxicity control teratogenic effects. At the same time, genetic risks that predispose the woman to alcohol addiction and conditioning may indirectly affect her drinking pattern. While intake is generally considered an environmental issue alone, there is now evidence that genetic variations may affect the amount of alcohol desired and the risk of dependency and addiction²⁵.

The genetic mechanisms that control alcohol metabolism, and thus blood alcohol concentrations (BAC), are of utmost interest in studying the effects of prenatal exposure, because BAC levels of the mother during critical periods of gestational development have the most direct effect on the degree and severity of fetal injury. Obviously, the more rapid and efficient metabolism of alcohol and the metabolite by-products, such as acetaldehyde and oxidative radicals, the less chance there is for adverse effects on fetal development. Genetic-based research provides an opportunity to further study how alcohol metabolism may differ among individuals because of genetic variations in the enzymes necessary to eliminate alcohol from the body.

A major pathway for alcohol elimination is oxidation of acetaldehyde to acetate. The primary enzyme involved in catalyzing alcohol to acetaldehyde and acetate is alcohol dehydrogenase (ADH). Genetic research has revealed differing genetic codes for ADH enzymes involved in the hepatic metabolism of alcohol^{26, 27}. Single nucleotide differences, known as polymorphisms, alter the enzyme catalytic activity and are hypothesized to alter the metabolism of alcohol in the liver among individuals. Although other enzymes, such as cytochrome P450 2E1 (CYP2E1), are involved in the process, ninety percent of alcohol elimination occurs through ADH oxidation. There are several classes of human alcohol dehydrogenase, but the one of most interest is from the Class 1 family, ADH1B, where three known polymorphisms are considered functionally relevant. These three variations of ADH1B are listed in Table 1, and the possible differences in prenatal alcohol exposure outcomes are outlined based on current research findings^{26, 30}.

There are obvious challenges when comparing one human study on genetic influences to another, since many are retrospective with differing levels of alcohol consumption based on self-report. In addition, case-control studies are limited to making only statistical associations and cannot prove the gene of study was, in fact, the definitive reason for differences found. However, a number of studies have concluded that in cases where the woman who consumed alcohol during a pregnancy had either the allele variant ADH1B*2 or ADH1B*3, the developing fetus was afforded some degree of protection from adverse clinical injury; those with ADH1B*1 had more deficits^{28, 29, 31}. The mechanisms responsible are not totally clear and more study is warranted. How the environmental issues, such as pattern of alcohol consumption, impacts the protective benefits is also unknown and more difficult to study. Other genetic factors, such as the role of placental enzymes and maternal-fetal interactions, also need consideration. Such factors may be the key to predicting which newborns will be at risk for the most adverse outcomes. Although promising, more population-based research is needed before polymorphisms can be used as a biomarker to identify women or newborns at higher risk of FAS. Genetic makeup alone does not account for enough of the variance in outcome. Currently, screening and intervention to prevent alcohol use in women of childbearing age remains the best strategy to prevent children born with FAS. Prenatal screening for alcohol use and timely clinical newborn and child assessments continue to be indicated to reduce exposure and target alcohol-related problems in children after birth so that early intervention can begin.

ASSESSMENT FINDINGS IN FAS

Assessment criteria for fetal alcohol effects include prenatal and postnatal growth retardation, craniofacial abnormalities, central nervous system abnormalities, and major organ malformation, such as congenital heart defects. However, the CDC recently recognized specific assessment criteria for the identification of FAS. Assessment data that has been documented and reviewed during the development of the child is critical. These include documentation of three facial abnormalities (smooth philtrum, thin vermillion border, small palpbral fissures), documentation of growth deficits, and documentation of central nervous system abnormalities (structural, neurological or functional, or combination)^{3, 32}. The presence of all the above-mentioned findings concludes a diagnosis of FAS. Figure 2 demonstrates classic cranial-facial features of FAS.

At birth, newborns will exhibit basic head and facial deformities that include long thin upper lips, small eyes, flattened maxilla, and small heads. If these deformities are not obvious at birth, the syndrome may be identified later when the infant displays poor sucking, irritability, excess growth of body hair (hirsutism), and failure to thrive³³. Growth retardation with weight, length, or head circumference below the 10^th percentile are other common assessment findings in FAS³².

With the understanding that fetal alcohol effects create changes in presentation of criteria during development, nursing assessment and documentation are significant. A crucial finding in the history of an infant with FAS is noted in CNS abnormalities. More specifically, functional abnormalities displayed in delayed motor abilities, hyperactivity behavior, and developmental deficits are obvious over time. As the child reaches preschool years, language development is delayed; motor skills are uncoordinated; and delayed growth and development milestones are displayed³⁴. School-age findings are identified in decreased cognitive functioning, school failure, and social problems. Behavioral teratogenesis continues to be demonstrated in adolescence and adulthood in the form of secondary disabilities, including mental health problems, delinquency, problems with the law, difficulty in independent living, and alcohol and drug abuse³⁵. The quality of life for adults suffering from FAS becomes a community issue and can effect the quality of life experienced by a community³⁶.

While structural findings are apparent in most cases of FAS, cognitive and functional deficits are various and individualized on a case-by-case basis. Since infants with fetal alcohol effects are easily over-stimulated, resulting in inconsolable crying, parents may have difficulty bonding and providing appropriate care³⁷. These infants grow to be children who may have difficulty relating with others and handling stressful situation. Despairing temper tantrums are seen in children with FAS, contributing to parental frustration and insecurities³². There is further evidence that fetal alcohol effects contribute to memory deficits, resulting difficulties to retain or recall information³². This causes a significant concern during school-age years of children suffering from FAS. As children suffering from the effects of FAS enter adolescence, they are faced with decreased coping strategies, making them unable to complete studies in school and establish identity among peers. As adults, children with FAS may have difficulty in skill acquisition and maintaining steady employment. These things foster antisocial behavior, a decrease in self-esteem, and powerlessness³⁸.

Thorough nursing assessment becomes essential in the health and safety of infants born with FAS. Nursing intervention in clinics, childcare facilities, and schools contribute to early identification and appropriate referrals. Nurses with specialized skills in caring for children with special health care needs and knowledge in pathogeneses are warranted. Children with FAS and their families need nurses who can navigate various health care systems and use related evidenced-based nursing interventions to enhance the quality of life for everyone involved.

Health teaching, counseling, and consultation are interventions nurses commonly use to promote health within these families^{39, 40}. Teaching and counseling foci include: how to maintain a safe environment; behavior management strategies; growth and development education; promoting parent-infant interactions; and building on the child's strengths. Child control recommendations shown to be effective include: developing routines; preparing the child for anticipated changes in his or her routine; calming techniques; communication strategies; and anger management. Linking the family with FAS advocacy groups is also important, since such groups offer ongoing support, education, and national referrals.

CONCLUSION

There is a need to understand how the effects of alcohol differ due to timing of exposure in the gestation period, dosage (BAC), and individual genetic make-up. The knowledge gained from animal model studies helps clinicians understand the clinical manifestation of the disorders and has led to more refined assessment and intervention protocols. This body of science has become a part of current public health models that emphasize prevention education and intervention for women at childbearing age. In the past ten years, genetic research has emerged to explain individual risks and offers the potential to further inform practices. In the future, genetic screening may be available to identify women most susceptible to the adverse risks of prenatal alcohol exposure – with the goal of targeting this high-risk population for prevention strategies before conception.

Table 1. Alcohol Dehydrogenase (ALDH) Enzyme Polymorphisms

Polymorphisms For ADH using Human Genome Org. nomenclature	Speculated role in alcohol metabolism and risk for Fetal alcohol spectrum disorders
ADH1B*1	Associated with a slower rate of ethanol oxidation as compared with the two alternate alleles (see below). Predominately seen in European and American populations. Associated with an increased rate of ethanol oxidation.
ADH1B*2	Significantly more common in unaffected individuals exposed to prenatal alcohol, suggesting a protective role within either the mother or the fetus against FAS. Associated with an increased rate of ethanol oxidation.
ADH1B*3	More frequently found in African Americans and believed to enable more efficient metabolism of alcohol and thus demonstrates a protective role. Maternal allele indicated protective benefits in alcohol-exposed infants: improved birth weight and length; improved scores on the Bayley Mental Development Index (MDI).

Table 2. Fetal Alcohol Syndrome Web Site Resources

Centers for Disease Control (CDC): Fetal Alcohol Syndrome FAS Community Resource Center National Organization of Fetal Alcohol Syndrome FAS Family Resource Institute Fetal Alcohol Syndrome Diagnostic and Prevention Network National Institutes of Health, National Institute on Alcohol Abuse and Alcoholism