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Neuroscience and Biobehavioral Reviews 31 (2007) 168171 www.elsevier.com/locate/neubiorev

Review

Fetal alcohol syndrome: Historical perspectives

Faye Calhoun, Kenneth Warren
National Institute on Alcohol Abuse and Alcoholism, National Institute of Health, Bethesda, MD, USA

Abstract Fetal alcohol syndrome (FAS), the most severe manifestation of the adverse effects of alcohol on foetal development, was rst described in the French medical literature by Lemoine et al. in 1968 [Les Gfants des parents alcholiques: anomalies observes a propos de 127 cas (The children of alchoholic parents: anomalies observed in 127 cases). Quert in Medicine 8, 476482]. Five years later, Jones et al., 1973. Pattern of malformation in offspring of chronic alcholic mothers. Lancet 1, 11291267] were the rst to delineate systematically the association between maternal alcohol abuse and a specic pattern of birth defects and to provide diagnostic criteria for this condition. Several diagnostic systems have since been developed with a view to capturing the wide spectrum of physical and behavioral anomalies resulting from prenatal alcohol exposure. The purpose of the current paper is to outline the evolution of FAS as a medical diagnosis. r 2006 Elsevier Ltd. All rights reserved.
Keywords: Fetal alcohol syndrome; Diagnosis

Contents 1. 2. 3. Historical background . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . The discovery of fetal alcohol syndrome (FAS) . . . . . . . . . . . . Diagnosis of a spectrum of alcohol exposure-related conditions . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 168 169 169 170

1. Historical background Although the association between maternal alcoholism and birth defects was initially treated as a new observation (This seems to be the rst reported association between maternal alcoholism and aberrant morphogenesis in the offspringJones et al., 1973), several reports later pointed out that the deleterious effects of alcohol on the developing fetus had been known for centuries (Erb and Andresen, 1978; Clarren and Smith, 1978; Tenbrinck and Buchin, 1975). One of the earliest reference to this association is found in an ancient Greek and Roman belief
Corresponding author.

E-mail address: fcalhoun@willco.niaaa.nih.gov (F. Calhoun). 0149-7634/$ - see front matter r 2006 Elsevier Ltd. All rights reserved. doi:10.1016/j.neubiorev.2006.06.023

that the alcohol intoxication at the time of procreation results in the birth of a damaged child (Jones and Smith, 1973; Green, 1974). Several articles have also quoted the Aristotles admonishment: Foolish, drunken and harebrained women most often bring forth children like unto themselves, morose and languid (Krous, 1981). There was also an ancient Carthaginian custom prohibiting drinking on the wedding night. It is believed that this custom was meant to prevent conception under the inuence of alcohol. The JudaeoChristian tradition also recognized ill-effects of drinking during pregnancy, as evidenced by a verse in the Old Testament, Judges 13:7 (Holy Bible: New International Version, 1978). Some reviewers have been quick to point out that the foregoing historical references to the adverse effects of

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drinking during pregnancy have been misconstrued. In fact, in ancient Greece, Rome and Carthage, the belief was not that drinking during pregnancy harmed the child, but that intoxication at the moment of conception led to deformity. Besides, the ancient belief was that the fathers drunkenness could affect the conception, as much as or more than the womans. Thus, it appears hasty to conclude that the teratogenicity of alcohol has been known since antiquity. There exist, however, more recent reports documenting the adverse effects of maternal drinking on the developing foetus. In the 1700s, the physicians group in England described children of alcoholic woman as weak, feeble, and distempered children, who must be instead of an advantage and strength, a charge to their Country (Royal College of Physicians of London, 1726) and born weak and sillyy shrivelled and old, as though they had numbered many years(Committee of the Middlesex Sessions, 1736 Goodacre (1965). William Sullivan, deputy medical ofcer of the Convict Prison, in Parkhurst, England, described the offspring of imprisoned alcoholic women (Sullivan, 1899). Of 600 children born to these woman, 55.8% were born dead or died before age 2. The rate of infant mortality doubled in alcoholic women. Eighty women had three or more infant deaths. Later-born children had an increased risk compared to earlier births. The rate of familial alcoholism in this population was high, with one or both parents of 61% of these women being alcoholics. Finally, the 299 surviving children born to mothers with a previous child death were not productive members of the society as they aged. In this report, Sullivan (1899) concluded that alcohol had a direct toxic effect on the embryo (Golden, 2005). Surprisingly, similar epidemiologic reports linking to maternal drinking to birth defects did not appear in the literature until the 1980s. 2. The discovery of fetal alcohol syndrome (FAS) Clinically, FAS was not documented in the medical literature until 1968, when Lemoine and colleagues in France published a paper titled, Outcome of children of alcoholic mothers. In this paper Lemoine et al. documented some commonly occuring problems in over 100 offspring of woman who drank heavily during pregnancy. While the authors documented many of the physical and behavioral patterns in these children, their conclusions had relatively little impact. This article neither presented denitive diagnostic criteria, nor did their observation lead to recognition of FAS in France or elsewhere in Europe. Three papers published in the British medical journal The Lancet (Jones et al., 1973; Jones and Smith, 1973; Jones et al., 1974) laid the foundation for the novel diagnosis of FAS. These three articles were written by members of the Dysmorphology Unit at the University of Washington School of Medicine in Seattle, headed by Dr. David Smith. The rst article titled, Pattern of malformation in offspring in chronic alcoholic mothers (Jones et al.,

1973) presented detailed case report of three Native American, three black and two white children. The article noted the shared anomalies among these children, including developmental delay, microcephaly, prenatal and postnatal growth deciency, short palpebral ssures, epicanthal folds, small jaws and attened midface, joint anomalies, and altered palmer crease patterns. The authors concluded their observations claiming, the data are sufcient to establish that maternal alcoholism can cause serious aberrant fetal development. The term fetal alcohol syndrome was rst introduced in the second article (Jones and Smith, 1973), which described three additional cases of alcohol-related birth defects (ARBD). In the third article, the authors provided further evidence for the teratogenicity of alcohol using data from the Collaborative Perinatal Project of the National Institute of Neurological Disease and Stroke. The data were retrospective and based on chart reviews. They were able to identify 23 woman with a history of chronic alcoholism and six cases of suspected FAS among these 23 women drawn from a total sample of 55,000 cases. 3. Diagnosis of a spectrum of alcohol exposure-related conditions The above three publications by Jones and colleagues were quickly followed by a large number of articles, letters to editor, and case reports describing newly recognized patients with FAS (Ferrier et al., 1973; Christoffel and Salafsky, 1975, Mulvihill et al., 1976; Hanson et al., 1976; Turner, 1979). Like the initial Lancet articles, these reports were based on case studies, typically small in number. These reports addressed a range of issues, including correlation between the extent of defects in offspring and the severity of mother drinking, and contributions from factors such as malnutrition, smoking, inadequate prenatal care to the development of morphological differences (Majewski, 1981; Bingol et al., 1987). Clinicians also soon recognized that physical and neurobehavioral outcomes of prenatal alcohol exposure was variable, ranging from the classic form to a few minor anomalies. Clarren and Smith (1978) introduced the term, suspected fetal alcohol effects (FAE) to denote the partial expression of the syndrome. In 1980, the Fetal Alcohol Study Group of the Research Society on Alcoholism reformulated the diagnostic criteria, incorporating the nomenclature, fetal alcohol effects. Unfortunately, health care professionals subsequently misapplied the term FAE, using it to label any child with behavioral problems coming from families with suspected alcohol abuse. Because of this imprecision, Aase et al. (1995) suggested that the term FAE be abandoned. In 1996, a committee appointed by the Institute of Medicine (IOM) recommended adopting a new classication of fetal alcohol spectrum disorders. This included: FAS with and without a conrmed history of alcohol exposure, partial FAS, ARBD, and alcohol-related neurodevelopmental disorders (ARND). In the late 1990s,

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another diagnostic system was developed by Astley and Clarren, which came to be known as the 4-Digit Diagnostic Code. To increase the reliability of diagnosis, Astley and Clarren (2000) developed scales to assess clinically signicant characteristics of the face such as philtrum and the vermillion border. Although the IOM criteria and the 4-Digit Code have recognized the wide spectrum of outcomes produced by prenatal alcohol exposure, these two diagnostic systems have limitations. For example, two diagnostic categories introduced by the IOM report to replace the label FAE were found to be ambiguous. The question of the utility of multiple categories created by the 4-Digit Code has been questioned (Kodituwakku, 2003; Hoyme et al., 2005). Accordingly, a few new diagnostic systems have been introduced recently. The Canadian diagnostic guidelines are one new classication system, developed by harmonizing the IOM criteria and the 4-Digit Code. The Canadian guidelines employ the objective measures from the 4-Digit Code and use the IOM diagnostic categories. The authors have described the diagnostic process in detail (which consists of screening and referral, physical examination and differential diagnosis, and neurobehavioral assessment), and underscore the necessity of a multidisciplinary team for accurate and comprehensive diagnosis. The sensitivity and specicity of the Canadian guidelines have not been established yet. The Revised IOM Diagnostic Classication System (Hoyme et al., 2005) is very similar in its approach to that proposed by the Canadian Working Group. Like the Canadian guidelines, it recommends a multidisciplinary approach (including input from experienced physicians, psychologists, educational diagnosticians and skilled maternal interviewers), sets forth an objective method of morphological assessment and stresses differential diagnosis prior to assigning a diagnosis in the FASD continuum. However, as opposed to the Canadian system, the Revised IOM Diagnostic Criteria have been eld tested in a large multi-racial international cohort of children prenatally exposed to alcohol and have been found to accurately dene the range of FASD. Recently, the National Task Force on FAS and FAE have also issued guidelines for Referral and Diagnosis (Centers for Disease Control and Prevention, 2004). The focus of this task force was to provide diagnostic criteria for FAS. The task force underscored, however, the necessity of developing science-based guidelines for identifying other alcohol-related conditions such as ARND. Thus, the last three decades have witnessed notable advances in the development and validation of diagnostic criteria for FAS and related disorders. There remain, however, a number of unanswered questions regarding diagnosis of FAS and related conditions. One question concerns the validity of diagnostic criteria. Although signicant advances have been made in improving the reliability of diagnosis through development of quantiable

scales, relatively little effort has been devoted to the validation of diagnostic categories. Second, ethnic variations in the expression of ABRD need to be carefully examined. Third, little is known about minor physical anomalies in children with prenatal alcohol exposure, who do not exhibit the full syndrome. A current International Collaborative Initiative on fetal alcohol spectrum disorders (CIFASD), funded by the National Institute of Alcoholism and Alcohol Abuse (NIAAA), National Institute of Health, is seeking to answer some of these questions. A number of countries, including Ukraine, Finland, Italy, South Africa, and the United States are participating in this international collaborative study. This study will allow investigating ethnic variations in the expression of key features of fetal alcohol spectrum disorders. The dysmorphology core of the consortium is examining the compatibility of measures obtained clinically and through a state-of-art 3-D camera. Objective measures obtained through camera will also afford an opportunity to detect minor physical variations of the head and face, which are not accessible to clinical examination. Therefore, the data from the international consortium are expected to help solve a number of unresolved questions regarding diagnosis of FAS over the next few years. References
Aase, J.M., Jones, K.L., Clarren, S.K., 1995. Do we need the term FAE? Pediatrics 95, 428430. Astley, S.J., Clarren, S.K., 2000. Diagnosing the full spectrum of fetal alcohol-exposed individuals: introducing the 4-digit diagnostic code. Alcohol and Alcoholism 35, 400410. Bingol, N., Schuster, C., Fuchs, M., Iosub, S., Turner, G., Stone, R.K., Gromisch, D.S., 1987. The inuence of socioeconomic factors on the occurrence of fetal alcohol syndrome. Advances in Alcohol and Substance Abuse 6, 105118. Christoffel, K.K., Salafsky, I., 1975. Fetal alcohol syndrome in dizygotic twins. Journal of Pediatrics 87 (6 Pt 1), 963967. Clarren, S.K., Smith, D., 1978. The fetal alcohol syndrome. New England Journal of Medicine 298, 10631067. Erb, L., Andresen, B.D., 1978. The fetal alcohol syndrome (FAS): a review of the impact of chronic maternal alcoholism on the developing fetus. Clinical Pediatrics (Phila) 17, 644649. Ferrier, P.E., Nicod, I., Ferrier, S., 1973. Letter: fetal alcohol syndrome. Lancet 2, 1496. Golden, J., 2005. Message in a Bottle: The Making of Fetal Alcohol Syndrome. Harvard University Press, Cambridge, MA. Goodacre, K., 1965. Guide to the Middlesex Sessions Records 15491889: Prepared for the Standin. Greater London Records Ofce, London, UK, p. 785. Green, H.G., 1974. Infants of alcoholic mothers. American Journal of Obstetrics and Gynecology 118, 713716. Hanson, J.W., Jones, K.L., Smith, D.W., 1976. Fetal alcohol syndrome. Experience with 41 patients. Journal of the American Medical Association 5, 14581460. Holy Bible: New International Version, 1978. Zondervan, Grand Rapids, MI. /http://net.bible.org/passage.php?passage=Judg+13:5,+7S. Hoyme, H.E., May, P.A., Kalberg, W.O., Kodituwakku, P., Gossage, J.P., Trujillo, P.M., Buckley, D.G., Miller, J.H., Aragon, A.S., Khaole, N., Viljoen, D.L., Jones, K.L., Robinson, L.K., 2005. A practical clinical approach to diagnosis of fetal alcohol spectrum disorders:

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F. Calhoun, K. Warren / Neuroscience and Biobehavioral Reviews 31 (2007) 168171 clarication of the 1996 Institute of Medicine criteria. Pediatrics 115, 3947. Jones, K.L., Smith, D.W., 1973. Recognition of the fetal alcohol syndrome in early infancy. Lancet 2, 9991001. Jones, K.L., Smith, D.W., Ulleland, C.N., Streissguth, A.P., 1973. Pattern of malformation in offspring of chronic alcoholic mothers. Lancet 1, 12671271. Jones, K.L., Smith, D.W., Streissguth, A.P., Myrianthopoulos, N.C., 1974. Outcome in offspring of chronic alcoholic women. Lancet 1, 10761078. Kodituwakku, P., 2003. Comments on Sandra and Joseph Jacobson and Susan Astley on FAS/FAE. In: Tremblay, R.E., Barr, R.G., Peters, R.DeV. (Eds.), Encyclopedia on Early Childhood Development. Centre of Excellence for Early Childhood Development, Montreal, Canada, pp. 16. Krous, H.F., 1981. Fetal alcohol syndrome: a dilemma of maternal alcoholism. Pathology Annual 16 (pt 1), 295311. 171 Lemoine, P., Harousseau, H., Borteyru, J.P., Menuet, J.C., 1968. Les enfants des parents alcoholiques: anomolies observees a propos de 127 cas (The children of alcoholic parents: anomalies observed in 127 cases). Quest Medical 25, 476482. Majewski, F., 1981. Alcohol embryopathy: some facts and speculations about pathogenesis. Neurobehavioral Toxicology Teratology 3, 129144. Mulvihill, J.J., Klimas, J.T., Stokes, D.C., Risemberg, H.M., 1976. Fetal alcohol syndrome: seven new cases. American Journal of Obstetrics and Gynecology 125, 937941. Royal College of Physicians of London, 1726. Annals. Royal College of Physicians, London, England, p. 253. Sullivan, W.C., 1899. A note on the inuence of maternal inebriety on the offspring. Journal of Mental Science 45, 489503. Tenbrinck, M.S., Buchin, S.Y., 1975. Fetal alcohol syndrome: report of a case. Journal of the American Medical Association 232, 11441147. Turner, E.K., 1979. Fedal alcohol syndrome. Medical Journal of Australia 10, 178.