Introduction on Working Group on Prevention of Risk Drinking in Pregnancy

April 23-24, 1998 • Ramada Inn • Bethesda, Maryland

Introduction

The National Institute on Alcohol Abuse and Alcoholism (NIAAA) and its co-sponsors, the Office of Research on Women’s Health and the Interagency Coordinating Committee on Fetal Alcohol Syndrome, convened a Working Group on Prevention of Risk Drinking in Pregnancy on April 23 through 24, 1998, in Bethesda, Maryland, to discuss lessons learned from past and current programs to prevent and intervene with women engaged in risk drinking during pregnancy. The purpose of the meeting was to generate innovative and testable ideas for a future round of NIAAA grant applications. The Institute of Medicine (IOM) recommendations for preventing fetal alcohol syndrome (FAS) provided the framework for the Working Group’s discussions. Exhibit 1 summarizes the IOM recommendations.

Exhibit 1 - Summary of Institute of Medicine Recommendations for Preventing Fetal Alcohol Syndrome

The Institute of Medicine Committee to Study Fetal AlcoholSyndrome recommends that until such time as clear dose-response relationships are established, pregnant women and those about to become pregnant be counseled to avoid alcohol consumption throughout pregnancy.

The Committee recommends greatly increased attention among sponsors of prevention initiatives, independent of the target population, to evaluating the effectiveness of programs implemented. This recommendation applies to all levels of prevention interventions.

The Committee recommends that research efforts include comparisons of prevention methods at all levels in order to provide information to policy makers about relative costs and benefits.

Indicated Prevention Interventions

The Committee recommends that a high priority be placed on research efforts to design, implement, and evaluate prevention interventions that can effectively guide pregnant women who drink heavily to alcohol treatment. Research or programs should also include:

• Implementation of appropriate screening tools, including biomarkers of alcohol exposure, to identify women who are drinking moderate to heavy amounts of alcohol during pregnancy;
• Assessment of methods to involve women’s partners and family members in interventions to decrease or stop drinking;
• Incorporation of comprehensive reproductive counseling and contraceptive services in prevention and treatment programs for substance-abusing women;
• Assessment of the effectiveness and economic benefits of protocols for case management and follow-up of women, and of their families, who have given birth to a child affected by fetal alcohol exposure;
• Development of training programs for professionals in the identification of heavy drinking, and referral to appropriate regional centers or prevention services;
• Use of multiple outcome measures to assess the effectiveness of prevention initiatives; and
• Basic research in animal models to elucidate further the mechanisms of alcohol teratogenesis, which might lead to pharmacologic or other strategies for amelioration of the effects of alcohol exposure in utero.

Selective Prevention Interventions

The Committee recommends increased research efforts to design, implement, and evaluate selective prevention interventions to decrease risks of FAS, alcohol-related birth defects (ARBD), and alcohol-related neurodevelopmental disorder (ARND) through programs aimed toward women who are pregnant or may become pregnant, and who drink alcohol. Designing such interventions will be aided by further research assessing the contributions of personal and socio-environmental risk and protective factors that affect levels of drinking by women during pregnancy.

Where the utility of specific intervention programs has been established, the Committee recommends broad implementation of successful prevention interventions. Programs developed or studied should include the following:

• Specific demographic groups that have been demonstrated to be at high risk for FAS, ARBD, and ARND, as well as those who exhibit risk factors associated with moderate to heavy alcohol consumption during pregnancy; and
• Implementation of prevention efforts in a wide range of communities and media.

Universal Prevention Interventions

The Committee recommends that although data are insufficient regarding the effectiveness of universal prevention interventions, such interventions should be continued to raise awareness about the risks of FAS, ARBD, and ARND. However, the most important approach to universal prevention is probably the development of a medical environment in which concepts of the risk of FAS, ARBD, and ARND are incorporated into routine health care. Further education efforts to reach children and adults about FAS, ARBD, and ARND through health educational curricula and other means are recommended (Institute of Medicine 1996, pp. 41-42).

Background

While middle-class women are hearing messages about the physiological, biomedical, and genetic mechanisms of alcohol’s damage during pregnancy, results of efforts to convey this same information to less educated, low-income women have been less impressive (Dufour et al., 1994; Serdula et al., 1991). Because the health of mothers before, during, and after pregnancy is important in ensuring the best possible outcome of pregnancy and the sound health and normal development of children, prevention of risk drinking is a key concern for the Institute. The Office of Research on Women’s Health (ORWH) of the National Institutes of Health (NIH) shares this concern and collaborates with NIAAA (and other NIH institutes and centers) to stimulate and support multidisciplinary, integrated approaches to women’s health issues that include the role of the family and the environment as factors in women’s abuse of alcohol and other substances. At its national meeting in November 1997, ORWH’s Working Group on Alcohol and Other Drug Use, Disorders, and Consequences recommended increased attention to the effects of maternal alcoholism on pregnancy and the impact of pharmacologic agents and alcohol on developmental neurochemistry. Results from that and other meetings have helped to inform ORWH’s ongoing review of the NIH women’s health research agenda and to promote participation in initiatives such as the Working Group on the Prevention of Risk Drinking in Pregnancy.

This report highlights the discussions and deliberations that occurred during the Prevention of Risk Drinking in Pregnancy meeting. It opens with a brief summary of:

• The history and current status of fetal alcohol syndrome FAS;
   
• Opportunities for preventing the syndrome and intervening with women at risk for bearing children with FAS; and
   
• Issues important when designing and implementing prevention/intervention programs targeted toward risk-drinking pregnant women.

The meeting was divided into a series of four panels that shared lessons learned from (1) early studies on prevention of alcohol use in pregnancy, (2) smoking prevention studies, (3) substance abuse prevention and other pregnancy risk studies, and (4) current studies on prevention of alcohol use in pregnancy. The thrust of each panel’s discussion is conveyed through abstracts of each presentation and a summary of the ensuing discussion by workgroup members.

NIAAA also asked workgroup members to define the elements of three model programs based on the Institute of Medicine’s universal, indicated, and selected approaches to intervening with FAS, as well as a fourth cross-cutting model. Workgroup members split into four breakout groups to complete that task. Although the meeting timetable did not permit the development of fully realized models, workgroup members outlined the rudiments of each approach, which appear in Appendix A.

Overview of FAS

Brief History and Current Status of FAS

Fetal alcohol syndrome is the "most common known nongenetic cause of mental retardation" (Institute of Medicine, 1996, p. 6). Yet the discovery that alcohol is a teratogen (i.e., an agent capable of causing birth defects) was not recognized by the medical community until the 1970s. Although Lemoine and colleagues first described birth defects among children born of French alcoholic mothers in the late 1960s, those reports were ignored until a group of U.S. scientists that included Drs. David Smith, Kenneth Jones, and Ann Streissguth reported similar observations in 1973. The impact of the American group ’s findings led eventually to the Surgeon General's advisory on FAS, to congressionally mandated warning labels on alcoholic beverages, and to changes in the accepted medical perspective involving the risks of alcohol consumption during pregnancy.

According to the IOM, the FAS diagnosis involves growth retardation, a unique cluster of characteristic facial features, and central nervous system (CNS) and neurobehavioral deficits. An assortment of other skeletal and organ abnormalities may also be present. As standardized by the Fetal Alcohol Group of the Research Society on Alcoholism (Rosett, 1980) and, later, modified by Sokol and Clarren (1989), the classic face of FAS consists of small head circumference or microcephaly; small, widely spaced eye slits (called palpebral fissures); a thin upper or vermilion lip border; and flattening and elongation of the area between the base of the nose and the upper lip, with underdevelopment of the two ridges or philtrum found in this area. Hypoplasia of the midfacial area is also seen. Although the facial features associated with FAS are the "most clinically unique," its CNS and neurobehavioral deficits are more troubling (Institute of Medicine, 1996, p. 71).

Manifestations of CNS and neurobehavioral deficits differ by age (Aase, 1994). In the neonate, jitteriness and hypersensitivity are most frequently observed. Slowed reaction time and intellectual functioning and deficits in abstraction, problem solving, behavioral regulation, and executive functioning are apparent by school age. Maladaptive social skills, poor social cuing, and the inability to consider or comprehend the consequences of one’s behavior are other serious aspects of FAS (Aase, 1994).

Research on FAS reveals that the risk for teratogenic injury and the severity of the injury appear to increase with greater levels of alcohol consumption (Jacobson et al., 1993). Noninvasive imaging and neurocognitive studies also show that many children who would not be classified as having FAS because the characteristic facial features are absent manifest similar structural brain abnormalities. Ultimately, these approaches may simplify diagnosis among those who do not have the classic face of FAS but suffer from alcohol-related birth defects (ARBD) (Aase, 1994; Mattson, 1994).

Research with mice demonstrated that the FAS face could be reproduced in the mouse fetus by exposure to alcohol at a time that likely corresponds to the third week of human pregnancy (Kotch and Sulik, 1992). Since alcohol-dependent women do not maintain a consistently high blood alcohol level, an embryo may escape the injury necessary to develop the characteristic FAS face but receive sufficient injury later in development to exhibit all the FAS-associated CNS and neurobehavioral deficits. The IOM recently introduced five diagnostic categories to account for these kinds of differences, although three categories –FAS, ARBD, or alcohol-related neurobehavioral disorder (ARND)– are most frequently cited (Institute of Medicine, 1996).

Over the past 25 years, well-controlled human prospective investigations and animal studies have clearly shown that alcohol is the primary teratogen responsible for FAS. Studies have also linked the type of injury to the timing of the alcohol exposure, with organ abnormalities more characteristic of early exposure and growth deficits more likely to occur later in pregnancy. No period is totally risk-free, however, and neurobehavioral problems appear to arise from exposure anywhere along the time continuum. Research also indicates that certain patterns of drinking pose more of a risk for FAS (West and Goodlett, 1990). Higher peak dose or binge drinking exerts a greater negative impact than "total dose" or steady but lower per occasion drinking patterns (Day, 1992; West and Goodlet, 1990). Other factors that increase risk are age, parity, and African-American or Native American heritage, although the reasons why are unknown (Abel–1988; Majewski, 1993; Abel and Dintcheff, 1984; Chavez et al., 1988). Genetic, environmental, and other factors may contribute to risk, but they remain obscure (Streissguth and Dehaene, 1993; Gilliam and Irtenkauf, 1990; Abel and Hannigan, 1995).

Better understanding of the mechanisms of teratogenic injury may point to one or several pharmacological approaches for intervening with or preventing alcohol-related fetal injury. Currently scientists are investigating alcohol-induced impairment in placental function that results in nutrient transport deficiencies as well as hypoxia (Schenker et al., 1992; Michaelis and Michaelis, 1994). Extensive work is also ongoing in the area of trophic factors including retinoic acid as well as nerve growth factor and the glucocorticoids (Grummer et al., 1993; Yang et al., 1994). Free radical or reactive oxygen species, which are mutative intermediaries in the development of other alcohol-related organ injuries, may also be critical components in the development of FAS (Sanchez-Amate et al., 1992; Arienti et al., 1993). In particular, the cells in the cranial nerve crest, which are important components of the brain and face, appear to be highly sensitive to reactive oxygen species (Davis et al., 1990). Finally, alcohol also has a potent effect on the cell adhesion molecule of L1 (Ramanathan et al., 1996). People with mutations in L1 have birth defects similar to those found in FAS (Wong et al., 1995).

Opportunities for Intervention

Although it is true that if women did not drink, there would be no problem with FAS, reliance on that approach alone ignores the fact that many women who are pregnant may not be aware of their condition until three or four or more weeks have passed. The likelihood of bearing a child with FAS also increases with greater exposure to alcohol; this means that treatment figures prominently in any efforts aimed at preventing the problem. These two facts, coupled with the relative rarity of FAS, complicate prevention efforts. Nevertheless, experience with past and current FAS programs, drinking and driving initiatives, and programs preventing other problems in similar populations suggests that opportunities for intervention exist.

FAS is a costly, nonreversible disorder, whose most obvious victims are children. Society’s sympathy for its youngest members suggests that communities could be mobilized to address the problem.

Policy interventions provide another alternative. The only policy interventions in force that directly relate to FAS are warning labels and messages at point of purchase. Focusing on drinking behavior as an end point offers another possible avenue for preventing problem development. The use of driver "re-education" for first-time violators of Driving Under the Influence (DUI) laws, linked to the threat of license revocation for failure to comply with training, is another possible model. Minimum drinking age and zero tolerance laws also may have application. They have had a significant impact on both consumption of alcohol and alcohol-related problems, although they have not been optimally enforced (NIAAA is currently funding research exploring the effect of full enforcement). Sales of alcoholic beverages to pregnant women also could be constrained, although enforcement may pose a problem since pregnancy is not always visible.

Some of these approaches also lend themselves to natural experiments. In remote areas of Alaska, for example, several villages have voted to establish prohibitions against the sale and importation of alcohol. Compared to "wet villages," death rates from alcohol-related motor vehicle accidents, homicides, and hypothermia are substantially lower in the "dry villages" (Landen et al., 1997). NIAAA has capitalized on the situation in Alaska to study the impact of local laws on reducing alcohol-related problems in the community.

Combining environmental and individually focused approaches may enhance the effectiveness or rethinking of interventions according to the universal, selective, and indicated categories developed by Robert Gordon and broadly disseminated by the IOM, and may lead to new applications of approaches already included in the standard prevention arsenal. The Gordon approach is interesting because it defines the target group and assigns a cost accordingly. Thus, prevention strategies aimed at higher risk groups are calculated to cost more.

Evidence also suggests that properly tailored messages can exert a major impact (e.g., Betty Ford’s revelation about her fight against breast cancer and her plea for women to seek mammograms prompted an enormous number of women to undergo screening). Perhaps pregnancy provides a similar teachable moment. Work on the expectancies associated with alcohol is also changing beliefs about what alcohol does and does not do and may influence drinking behavior. The question is, does this approach have any impact on heavy drinking or does it only help moderate drinkers? Or, by manipulating expectancies, would it be possible to change larger community perceptions about and social norms related to drinking and its consequences? Motivational interviewing is another technique that may be effective in intervening with risk drinkers on an individual level, while work conducted with families by both the National Institute of Mental Health and the National Institute on Drug Abuse suggests that the preventive potential of families, extended families, and other primary groups deserves careful study.

Issues

Based on their own experience in conducting research and designing and implementing programs to prevent risk drinking during pregnancy, workgroup members identified the following as crucial issues for consideration when developing new prevention/intervention models.

Moving Beyond Universal Prevention Approaches. Echoing the Institute of Medicine’s recommendations in its report on fetal alcohol syndrome (Institute of Medicine, 1996), the workgroup emphasized the need to move beyond universal prevention approaches (e.g., warning labels) to indicated and selective prevention approaches that account for differing levels of risk, age, and cultural identity. For example, heavy drinkers tend to enter prenatal care late in their pregnancies. While it is important for health care providers to screen for alcohol use during pregnancy and inform patients of the potential problems associated with use, the reality is that providers often do not have an opportunity to intervene with those women at highest risk until the third trimester. Carefully evaluated results from smoking cessation programs aimed at the same population at highest risk for FAS indicate that both brief intervention and tailored self-help programs reinforced by health care providers work better with lighter rather than heavier smokers–an outcome that anecdotally appears to carry over to women who engage in risk drinking during pregnancy.

Age and parity further compound the problem. Philip May suggested that prevention interventions targeting FAS specifically should be directed to women over the age of 25 because older problem drinkers are more likely to give birth to infants with FAS. Claire Coles observed that the strong relationship between birth order and FAS not only means that the children who are further along in birth order are more likely to suffer from FAS, but also that a heavy drinker could have several "normal" children before experiencing an FAS birth. This makes it difficult to persuade some women that alcohol consumption during pregnancy is risky until an FAS child is born. Lee Kaskutas’ work in California supports this view. She found that women at risk did not always find universal messages credible because they conflicted with their experience (e.g., they drank or their friends drank and still bore healthy children).

Lois Jovanovic also noted that the use of incentives to promote behavioral change–an approach effective with adolescents–has far less impact on adult women. Program planners must not assume that prevention approaches successful with one subpopulation will be universally effective. Cultural differences likewise influence applicability. While interventions promoting birth control or deferral of conception offer great promise for preventing FAS, Dr. May cautioned that this approach is anathema among some Native American tribes. Birth control is also frequently deemed unacceptable among older Hispanic women. In Dr. Jovanovic’s experience, a fatalistic outlook on life and conviction that motherhood is predestined obviate attempts to control conception among this group of women.

Targeting the Extended Family/Community as Well as the Individual. Larger environmental efforts (e.g., server training, Early Start obstetrical practice risk drinking identification programs) endorsed and operated at the community level, as well as family/social network initiatives to involve significant others in prevention/intervention efforts directed at pregnant women, are potentially important areas for increased work and scrutiny. Although programs have had mixed success in convincing partners to change their risky behaviors, workgroup members agreed that partners, family members, and significant others should be involved in prevention/intervention efforts. Findings from smoking cessation programs indicate that even when smoking partners engaged in interventions designed for the extended family fail to quit, the pregnant women involved do quit. Why this occurs is unknown, but is worth exploring.

Balancing the Health Message. For many women, appeals to protect the viability of the fetus are powerful motivators for behavioral change. However, as several workgroup members pointed out, a backlash can occur. Some women resent the primacy accorded the baby and refuse to change their behavior; many change their drinking habits during pregnancy but resume risky consumption practices once the baby is born. Results from smoking cessation programs indicate that messages balancing concern for the mother with that for the fetus help pregnant women in their efforts to quit. Having said this, workgroup members were insistent that science’s inability to specify a safe level of use should not color the resulting public health message. Michael Fleming advocated for zero tolerance of drinking during pregnancy as the only safe course.

Responding to Relapse. Like women who smoke heavily, most women with risky drinking patterns prior to pregnancy resume heavy drinking postpregnancy. New strategies are needed to address this persistent problem.

Integrating Prevention into Ongoing Systems of Care. The health and social services systems, including welfare, represent one of the few points of contact with low-income pregnant women who drink at risk levels. Numerous pilot programs have demonstrated that screening programs offered in conjunction with these services are effective in identifying women at risk. However, as Richard Schottenfeld noted, systems of care need incentives to institutionalize these interventions. At Kaiser Permanente, Northern California, the Early Start model for substance abuse prevention was careful to chart the differences in positive birth outcomes and shorter hospital stays between women who stopped using alcohol and women who did not. As Marc Usatin observed, shorter hospital stays translated into substantial cost savings, providing hospital administration with compelling evidence to continue the program and replicate the model in multiple sites across northern California. Likewise, Dr. Streissguth said that Seattle’s Birth to 3 Program used cost data to justify program operations and obtain funding from the State legislature, which included support for the University of Washington’s continued contribution to the program’s administration, training, and data collection efforts.

Weighing what systems can reasonably be expected to accomplish is another key concern. Experience from both smoking cessation and risk-drinking pilot programs suggests that health care providers are frequently uninformed about cessation methods and uncomfortable asking questions about drinking. In this context, workgroup members found that staff training was crucial; however, they cautioned that without regular bolstering, awareness declined over time. To offer incentives for health care providers to remain current, workgroup member Susan Rich suggested posting on the web a curriculum tied to continuing medical education (CME) units for ready access by physicians in practice, residents, and certified nurse practitioners. Dr. Fleming also observed that good screening tools already exist for primary care clinicians to use. The problem is making time to administer them to patients and modifying the health care financing system to ensure that practitioners are reimbursed for their time once they do screen patients. Staff retraining, institutionalization of screening programs into routine intake procedures, and reimbursement appear to be essential for continued identification of pregnant risk drinkers in primary care settings.

Reaching the Highest-Risk Drinkers. Low-income women who engage in the highest-risk drinking during pregnancy are hard to reach. Yet, as Janet Hankin pointed out, failure to intervene can be costly since women who drink heavily during one pregnancy continue to drink heavily during the next. Reflecting on experience with smoking cessation programs for essentially the same population, Thomas Glynn said that the more intensive the intervention, the more likely those women who smoked heavily were to quit. Louise Floyd added that findings from CDC-supported programs reinforced that view and showed further that intensive, interactive interventions that included face-to-face contact with service providers worked better with this subpopulation of heavy smokers than did impersonal approaches. With respect to pregnant women who continued to drink heavily during pregnancy, Carole Kenner observed that case management made a substantial difference in influencing them to abstain.

Coordinating and Sequencing Interventions to Address Multiple Risks. Workgroup members agreed that women who drink heavily during pregnancy also tend to smoke and use illicit drugs. Reporting on his experience with pregnant cocaine abusers, Dr. Schottenfeld expressed concern about the timing and sequencing of the interventions needed to address polydrug abuse. After years of work with pregnant smokers, a substantial proportion of whom drank, Patricia Mullen noted that it was still unclear whether women should stop smoking and drinking at the same time. Given the strong association among substances, research on simultaneous versus sequential interventions is imperative. Aligned with that is the need for guidance in operationalizing and coordinating proven approaches in community-based public health settings.

Promoting Self-Disclosure. Unlike tobacco and illicit drugs, there is no gold standard for assessing alcohol use beyond a few hours after ingestion. As a result, researchers and providers must rely on women's self-reports, which may be unreliable. A number of approaches have been tested to increase disclosure. For example, questions about alcohol and drugs have been embedded in routine physical health histories; taped and electronic questionnaires have been used to avoid judgmental interviewer reactions and promote a sense of anonymity; and the "bogus pipeline method" (a technique that suggests that information provided will be confirmed by another test) has been employed to encourage honest responses. In the smoking cessation programs for pregnant women conducted by the University of Alabama at Birmingham, a "dipstick" technology that measures cotinine is used to confirm "quit" status. Although technology is not currently available to test for alcohol, Lesa Woodby thought that development of a similar tool should be encouraged. In their smoking prevention work, researchers at the Center for Health Promotion Research and Development in Houston, Texas, include multiple-choice questions that give women a chance to indicate progress made in reducing smoking/drinking while still revealing smoking/drinking patterns. According to Dr. Mullen, this method has doubled the rate of disclosure. In her work with diabetic pregnant women, Dr. Jovanovic provides them with opportunities to prove that they are complying with their care plan and also involves them as partners in the health care team by making them responsible for measuring their own blood sugar and adjusting their treatment accordingly.

Employing Harm Reduction Strategies and Pharmacological Adjuncts. Results from smoking cessation research reveal that programs achieved more success in reducing smoking than in moving women to quit. Although not ideal, reducing intake has been shown to have positive health benefits for both mother and child. Pharmacological adjuncts (e.g., nicotine patch/nasal spray/gum) are not yet approved for pregnant women. Given the likely improvements in outcome possible with the addition of these proven therapies, efforts demonstrating their safety and efficacy when used by pregnant women are urgently needed.

Focusing on Epidemiology, Advocacy, and Program Continuation. Both Dr. May and Dr. Streissguth reinforced the importance of epidemiological data to better define needed services and provide a baseline against which to measure progress. Such data also play a key role in ensuring program continuation because they provide the evidence advocates need to argue on behalf of programs and that policymakers require to justify funding decisions. Provisions for ongoing program evaluation and the development of continuation strategies should be built into initial program designs and given high priority. Without concentrated attention to these issues, even the most effective programs are unlikely to survive.

Emphasizing Preconceptional Drinking Behavior. An estimated 50% of pregnancies in the United States are unplanned, and it is during the third week of gestation that the facial features associated with FAS develop. To prevent FAS, efforts to prevent risk drinking also must be directed toward women of child-bearing age before they become pregnant. In this context, health messages must be carefully individualized for each target group (e.g., adolescents and young women with no previous experience of pregnancy, women with children, women with children with FAS or ARBD).

Sanctioning FAS Mothers. Although the idea of sanctioning women who have FAS babies generated controversy among workgroup members, it is clear that innovative approaches to linking behavior to consequences deserve study. Mary Dufour described one FAS mother who did not understand the relationship between cause (heavy drinking during pregnancy) and effect (bearing a child with FAS) as evidence for the need for increased educational, as opposed to punitive, efforts. Barbara Morse said that women receiving treatment at Boston City Hospital talk about their reluctance to ask for treatment because of the possible penalties that might be levied against them (e.g., losing custody of their children). With a more positive approach, she believes a large subgroup of risk-drinking women would be more responsive to treatment opportunities. Bud Perrine suggested using drunk driving programs as a model. With apprehension for a first violation, drivers attend education and counseling classes; with a second violation, their licenses are revoked. A similar, graduated approach or functional equivalent might have application for pregnant risk drinkers. Regarding prevailing attitudes toward mothers with FAS children, he also observed that communities attack drunk driving so aggressively because the victims are random and could be anyone. With FAS, that is not the case, and since the victims are alcohol abusers’ children, the merits of sanctioning are less clear.

References

Aase, J.M. Clinical Recognition of FAS: Difficulties of Detection and Diagnosis. Alcohol Health Res World 18(1): 5-9, 1994.

Abel, E.L. Fetal Alcohol Syndrome in Families. Neurotoxicol Teratol 10(1): 1-2, 1988.

Abel, E.L., and Dintcheff, B.A. Factors Affecting the Outcome of Maternal Alcohol Exposure: I. Parity. Neurobehav Toxicol Teratol 6(5): 373-377, 1984.

Abel, E.L., and Hannigan, J.H. Maternal Risk Factors in Fetal Alcohol Syndrome: Provocative and Permissive Influences. Neurotoxicol Teratol 17(4): 445-462, 1995.

Arienti, G., DiRenzo, G.C., Cosmi, E.V., Carlini, E., and Corazzi, L. Rat Brain Microsome Fluidity as Modified by Prenatal Ethanol Administration. Neurochem Res 18(3): 335-338, 1993.

Chavez, G.F., Cordero, J.F., and Becerra, J.E. Leading Major Congenital Malformations Among Minority Groups in the United States, 1981-1986. MMWR: CDC Surveillance Summaries 37:17-24, 1988.

Davis, W.L., Crawford, L.A., Cooper, O.J., Farmer, G.R.,Thomas, D.L., and Freeman, B.L. Ethanol Induces the Generation of Reactive Free Radicals by Neural Crest Cells in Vitro. J Craniofac Genet Dev Bio 10(3): 277-293, 1990.

Day, N.L. The Effects of Prenatal Exposure to Alcohol. Alcohol Health Res World 16(3): 238-244, 1992.

Dufour, M.C., Williams, G.D., Campbell, K.E., and Aitken, S.S. Knowledge of FAS and the Risks of Heavy Drinking During Pregnancy, 1985-1990. Alcohol Health Res World 18(1): 86-92, 1994.

Gilliam, D.M., and Irtenkauf, K.T. Maternal Genetic Effects on Ethanol Teratogenesis and Dominance of Relative Embryonic Resistance to Malformation. Alcohol Clin Exp Res 14(4): 539-545, 1990.

Grummer, M.A., Langhough, R.E., and Zachman, R.D. Maternal Ethanol Ingestion Effects on Fetal Rat Brain Vitamin A as a Model for Fetal Alcohol Syndrome. Alcohol Clin Exp Res 17(3): 592-597, 1993.

Institute of Medicine, Executive Summary, Fetal Alcohol Syndrome: Diagnosis, Epidemiology, Prevention, and Treatment. Stratton, K.; Howe, C.; and Battaglia, F. (eds.). Washington, DC: National Academy Press, 1996.

Jacobson, J.L., Jacobson, S.W., Sokol, R.J., Martier, S.S., Ager, J.W., and Kaplan-Estrin, M.G. Teratogenic Effects of Alcohol on Infant Development. Alcohol Clin Exp Res 17(1): 174-183, 1993.

Kotch, L.E., and Sulik, K.K. Experimental Fetal Alcohol Syndrome: Proposed Pathogenic Basis for a Variety of Associated Facial and Brain Anomalies. Am J Med Genet 44(2): 168-176, 1992.

Landen, M.G., Beller, M., Propst, M., Middaugh, J., and Moolenaar, R.L. Alcohol-Related Injury Death and Alcohol Availability in Remote Alaska. JAMA 278(21): 1755-1758, 1997.

Majewski, F. Alcohol Embryopathy: Experience with 200 Patients. Dev Brain Dysfunction 6: 248-265, 1993.

Mattson, S.N., Jernigan, T.L., and Riley, E.P. MRI and Prenatal Alcohol Exposure: Images Provide Insight into FAS. Alcohol Health Res World 18(1): 29-52, 1994.

Michaelis, E.K., and Michaelis, M.L. Cellular and Molecular Bases of Alcohol’s Teratogenic Effects. Alcohol Health Res World 18(1): 17-21, 1994.

Ramanathan, R., Wilkemeyer, M.E., Mittal, B., Perides, G., and Charness, M.E. Alcohol Inhibits Cell-Cell Adhesion Mediated by Human L1. J Cell Biol 133(2): 381-390, 1996.

Rosett, H.L. A Clinical Perspective of the Fetal Alcohol Syndrome. Alcohol Clin Exp Res 4: 119-122, 1980.

Sanchez-Amate, M.C., Marco, C., and Segovia, J.L. Physical Properties, Lipid Composition, and Enzyme Activities of Hepatic Subcellular Membranes from Chick Embryo After Ethanol Treatment. Life Sci 51(21): 1639-1646, 1992.

Schenker, S., Johnson, R.F., Mahuren, J.D., Henderson, G.I., and Coburn, S. Human Placental Vitamin B ₆ (Pyridoxal) Transport: Normal Characteristics and Effects of Ethanol. Am J Physiol 262(6): R966-R974, 1992.

Serdula, M., Williamson, D.F., Kendrick, J.S., Anda, R.F., and Byers, T. Trends in alcohol consumption by Pregnant Women, 1985 through 1988. JAMA 265(7): 876-879, Feb. 20, 1991.

Sokol, R.J., and Clarren, S.K. Guidelines for Use of Terminology Describing the Impact of Prenatal Alcohol on the Offspring. Alcohol Clin Exp Res 13(4): 597-598, 1989.

Streissguth, A.P., and Dehaene, P. Fetal Alcohol Syndrome in Twins of Alcoholic Mothers: Concordance of Diagnosis and IQ. Am J Med Gen 47(6): 857-861, 1993.

West, J.R., and Goodlett, C.R. Teratogenic Effects of Alcohol on Brain Development. Annals of Medicine 22: 319-325, 1990.

Wong, E.V., Kenwick, S., Willems, P., and Lemmon, V. Mutations in the Cell Adhesion Molecule L1 Cause Mental Retardation. Trends Neurosci 18(4): 168-172, 1995.

Yang, Z.N., Davis, G.J., Hurley, T.D., Stone, C.L., Li, T.K., and Bosron, W.F. Catalytic Efficiency of Human Alcohol Dehydrogenases for Retinol Oxidation and Retinol Reduction. Alcohol Clin Exp Res 18(3): 587-591, 1994.