American Journal of Medical G e n e t i c s 44:782-785 (1992)
Congenital Defects of the Limbs and Alcohol Exposure in Pregnancy: Data From a Population Based Study Ursula G. Roster and Patricia A. Baird Klinik fur Frauenheilkunde und Geburtshilfe, Medizinische Universitat zu Lubeck, Liibeck, Germany (U.G.F.) and Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada (P.A.B.) Limb deficiency may occur in offspring prenatally exposed to alcohol. In a study on limb deficiency occurring in 1,213,913 consecutive liveborn infants in British Columbia, born in the years 1952-1984, a total of 659 cases with limb deficiency was identified. Cases with documented maternal alcohol abuse in pregnancy in this group were analyzed separately. W e found eight cases with severe prenatal alcohol exposure (6 F, 2 MI. I n six of the eight cases a terminal transverse defect of the forea r m or hand was present. In the remaining two cases ulnar defects were identified. These observations give further support to the hypothesis that intrauterine alcohol exposure may cause limb defects. This h a s also been demonstrated in experimental animals. Terminal transverse defects made u p a larger proportion of cases with known alcohol exposure (6/8) than of cases where alcohol exposure was not noted (217/651) (x2 = 6.13; P < 0.025) in this study. The defects primarily involved the right hand a n d forearm. This suggests a vascular origin of the limb defects after intrauterine alcohol exposure. 0
1992 Wiley-Liss,Inc.
KEY WORDS: limb defects, fetal alcohol effects, vascular origin INTRODUCTION Recent studies in North America show that approximately 19% of men and 4% of women are addicted to alcohol [Omenn, 19881. Alcohol abuse in pregnancy leads to severe teratogenic effects in the offspring of
Received for publication December 27, 1991; revision received April 7, 1992. Address reprint requests to Dr. U.G. Roster, Klinik fur Frauenheilkunde und Geburtshilfe, Medizinische Universitat zu Liibeck, Ratzeburger Allee 160, 2400 Liibeck, Germany.
0 1992 Wiley-Liss, Inc.
approximately 40% of females who are chronically addicted [Majewski, 19871. The clinical manifestations of fetal alcohol syndrome (FAS) are well recognized [Jones and Smith, 19731. Characteristics include a distinct facial appearance, mental impairment, behaviour difficulties, cardiac defects, and in some cases severe defects of other organs. Limb deficiency as a consequenceof intrauterine alcohol exposure of the fetus was found in animal studies Wronick, 19761.In humans the spectrum of skeletal anomalies in cases of FAS or in those with documented severe prenatal alcohol exposure includes hypoplastic terminal phalanges of the fingers or toes, radio-ulnar synostosis, and Klippel-Feil anomalies [Spiegelet al., 19791. Severe defects of the limbs and tetraamelia has been described in single cases [Herrmann et al., 1980; van Rensburg, 1981; Aro, 1983; Pauli and Feldman, 19861. MATERIAL AND METHODS As part of a larger study on limb defects occurring among 1,213,913 consecutive livebirths in British Columbia [Froster-Iskenius and Baird, 19891, cases with documented maternal alcohol consumptionduring pregnancy were analyzed separately. This population-based study was made possible through the existence of an ongoing Health Surveillance Registry (Registry), which documents all cases with congenital, genetic, or handicapping conditions born in the province of British Columbia since 1952, under strict rules of confidentiality. The Registry receives information from over 60 sources, including the Physicians Notice of Birth and Hospital Separation notices, which enable consistent and reliable ascertainment, as detailed previously [Baird, 19871.The Registry codes diagnoses according to the ICD9 of the World Health Organization [WHO, 19781. For each patient, up to 15 diagnoses can be registered [FrosterIskenius and Baird, 19891. In addition, cross-reference to other relatives is possible so that if a mother is on the Registry because of chronic maternal disease this will be noted. For this study all cases with limb deficiency were identified in which maternal alcohol consumption during pregnancy was documented. They were analyzed with respect to type of limb defect present and according
Limb Defects
783
to associated malformations present in other organ systems.
Anomalies in other organ systems The most frequently associated anomaly among liveborns with limb defects and intrauterine exposure to RESULTS alcohol were cardiac defects (cases 2, 4). In two cases During the period 1952 to 1984 a total of 1,213,913 additional potentially teratogenic agents, thalidomide livebirths occurred in British Columbia. Out of this and cocaine, were taken during the first trimester of cohort 659 cases were registered with limb defects, giv- pregnancy (cases 2,9). The pattern of limb defects in the ing an incidence of 5.67 per 10,000 liveborns [Froster- case exposed to thalidomide resembles the anomalies Iskenius and Baird, 19891. Among those cases there observed in cases with thalidomide as the only terwere eight individuals in which severe maternal alcohol atogenic agent LLenz and Knapp, 19621 (Table I), but problems during pregnancy were documented. In six of mental retardation was also present, which is more ofthese cases an almost identical defect, i.e., a terminal ten present in FAS. Because of the limb defects in this transverse defect of the right arm or hand was found case being characteristic for thalidomide exposure, this (Table I).This is a significant over-representation of this case was excluded from the numerical analysis. In case 9 particular form of defect in cases with known alcohol (Table I) the abuse of cocaine occurred in the 4th week of exposure compared to the occurrence of this particular gestation, and this infant had an abnormality of the left limb defect in the study population without known expo- ear in addition to a limb defect. sure (217/651) (x2 = 6.13; P < 0.025). Three of these eight cases were born in 1980, but an Since 1964 the Registry also has collected information evaluation for regional clustering was not revealing, regarding stillbirths with birth defects. The definition and no other common event could be related to these 3 of stillbirth is death > 20 weeks and weight > 500 g, as cases. previously detailed [Froster-Iskenius and Baird, 19891. Among a total of 30 stillbirths with limb defects born DISCUSSION during the study period, one case with documented The pattern of limb deficiency in the infants identified heavy maternal drinking during pregnancy was found (case 10) (Table I). This case had terminal longitudinal as exposed to alcohol during prenatal life is remarkably defects of the upper limbs. Detailed information on other consistent. There is an overrepresentation of terminal anomalies, especially those compatible with FAS or in- transverse defects, which is significantly higher than formation on birthweight, was not available in all cases. the occurrence of this kind of defect in other infants with Because of Registry policy, cases could not be personally limb defects not known to have been exposed. This sugreexamined t o answer these questions. Minor anomalies gests a causal association between this particular type will be underascertained in Registry data, because of limb defect and alcohol abuse in pregnancy. The inciregistration of cases frequently is done by persons un- dence of transverse terminal defects in the livebirths in skilled in recognizing minor anomalies. Therefore the B.C. for the period 1966 to 1984 was 1.6 per 10,000. In patients with FAS various associated skeletal analysis is limited to the reliable information on major limb defects, and unless, specifically noted, no comment anomalies have been reported, including radio-ulnar can be made on minor anomalies compatible with FAS. synostosis and fusion of the metacarpals [Jaffer et al.,
TABLE I. Limb Defects and Associated Anomalies in Liveborns Exposed to Maternal Alcohol Abuse Case 1
Sex f
Yob 60
Limbs defect T1, phalanx V, left
2"
f
62
It, humeri, radii femora, tibiae, fibulae
3
m
75
4
f f f f
80 80 80
T1, phalanx V, right T1, phalanx 11-V, left Tt, metacarpals, right Tt, metacarpals, left Tt, metacarpals, right Tt, metacarpals, right Tt, metacarpals, right Tt,metacarpals, right
5 6
7 8 9
m f
83 83 84
f
79
Other anomaly Cleft palate epicanthus, deafness, accessory nipples, short stature, radio-ulnar synostosis, fusion C2iC3 clinocamptodactyly m.r. (I.&. 30) deafness, VSD nevus flammeus flexion contracture of knees, constriction ring around right lower leg Strabismus hydrocephalus
Remarks 46, XX
Thalidomide
Tetralogy of Fallot
Birthweight 2,280 g
Premature
Birthweight 1,740 g
Ear dysplasia left < right
Cocaine abuse at 4 weeks gestation
Stillbirth 10
a
T1, phalanx, 111-V, right T1, phalanx, 1-111, left
Excluded from numerical analysis.
Birthweight 400 g (17 week gestation)
784
Froster and Baird
1981; Cremin and Jaffer, 19811. In the Native NorthAmerican Indian population fusion of the cervical spine and Klippel-Feil anomaly have been frequently found among patients with fetal alcohol syndrome [Neidengard et al., 1978; Wood and Newman, 1981; Tredwell, 19811and have been considered to be a specific ethnic expressionoffetal alcohol syndrome. Of our cases, three (cases 1,5,and 6; Table I) had been registered as a Native North American Indian, while all other cases were of Caucasian origin. A very high level of alcohol consumption has been reported in cases with amelia [van Rensburg, 1981; Pauli and Feldman, 19861 with 6-12 beers plus 4 g of liquor consumed in 3-6 days per week. In our study the exact amount of alcohol could not be evaluated, so that a relationship between the amount of alcohol consumed and the severity of the defect cannot be assessed. Among the cases presenting with amelia in our survey of limb defects in British Columbia [Froster-Iskenius and Baird, 19901 we did not find maternal alcohol abuse documented. In mice exposed to large amounts of alcohol during embryonic development different skeletal anomalies have been observed, including ectrodactyly [Kronick, 1976; Zimmerman et al., 19901and ossification anomalies [Chernoff, 19771. However, the pattern of skeletal anomalies in animal studies differs from that observed in humans, including the findings of the present study. This is not contradictory since teratogenic effects in animals do not necessarily resemble anomalies in humans caused by any specific agent and vice versa. The observations from our study suggest that skeletal anomalies and limb defects are part of the spectrum of teratogenic effects of alcohol in humans as well. In comparison to animal studies it appears likely that in humans two factors mainly contribute t o the severity and expression of the teratogenic potency of alcohol: the genetic background and the amount of alcohol consumed. Thus among the Native North-American Indian population fairly specific skeletal anomalies have been observed, such as radio-ulnar synostosis and Klippel-Feil anomalies. In our study three cases were of Native North-American origin (patients 1, 5 , 6). In patient 1 radio-ulnar synostosis and fusion of the cervical spine were documented, while in patients 5 and 6 only a terminal transverse deficiency at the level of the metacarpals was noted. We recognize that due to the nature of data collection by the Registry only those cases with severe alcohol abuse would be likely to have the prenatal exposure documented. It is likely that many additional cases were exposed to alcohol, but this was not noted. However, if the relationship of prenatal alcohol exposure to terminal transverse defects of the limbs is a causative one, this does not negate our findings. The underascertainment of exposure would give a falsely increased frequency of cases with transverse terminal defects in the “unexposed” group and thus minimize the difference. In spite of this, terminal transverse defects were found to be much more common in our alcohol exposed group. The pathogenesis of limb defects occurring after alcohol exposure prenatally is not known. A vascular patho-
genesis is a possibility, because the observed limb defects, have been suggested to have a vascular origin [Hoyme et al., 19821, which has also been discussed for some of the associated anomalies such as the KlippelFeil anomaly [Brill et al., 19871. The fact that almost all cases in our study with defects after maternal alcohol exposure were female raises the possibility that fetuses of this sex are more susceptible to the effect of alcohol on the developing limb. The sex ratio among children with FAS in a B.C. Registry-based study [Wong, 19831was 89 males to 67 females. This is significantly different from our group of patients with limb defects after alcohol exposure, where more females were affected.
ACKNOWLEDGEMENTS Dr. UG Froster was supported by a grant from the Deutsche Forschungsgemeinschaft (F’r 653/1-2). Dr. PA Baird was supported by the Medical Research Council of Canada (MA-9279).Strict conditions of confidentiality are maintained with respect to the B.C. Health Surveillance Registry data. REFERENCES Aro T (1983): Maternal disease, alcohol consumption and smoking during pregnancy associated with reduction limb defects. Early Hum Dev 9:49-57. Baird PA (1987): Measuring birth defects and handicapping disorders in the population: The British Columbia Health Surveillance Registry. Can Med Assoc J 136:109-111. Brill CB, Peyster RG, Keller MS, Galtman L (1987): Isolation of the right subclavian artery with subclavian steal in a child with Klippel-Feil anomaly: An example of the subclavian artery supply disruption sequence. Am J Med Genet 26:933-940. Chernoff GF (1977): The fetal alcohol syndrome in mice: An animal model. Teratology 15223-230. Cremin BJ, Jaffer Z (1981): Radiological aspects of the fetal alcohol syndrome. Pediatr Radio1 11:151-153. Roster-Iskenius UG, Baird PA (1989): Limb reduction defects in over one million consecutive livebirths. Teratology 39:127-135. Froster-Iskenius UG, Baird PA (1990): Amelia: Incidence and associated defects in a large population. Teratology 41:23-31. Herrmann J, Pallister PD, Opitz JM (1980): Tetraectrodactyly and other skeletal manifestations in the fetal alcohol syndrome. Eur J Pediatr 133:221-226. Hoyme HE, Jones KL, van Allen MI, Saunders BS, Benirschke K (1982):Vascular pathogenesis of transverse limb reduction defects. J Pediatr 1012339-843. Jaffer Z, Nelson M, Beighton P (1981):Bone fusion in the fetal alcohol syndrome. J Bone Joint Surg 63B:569-571. Jones KL, Smith DW (1973): Recognition ofthe fetal alcohol syndrome in early infancy. Lancet 11999-1001. Kronick J B (1976): Teratogenic effects of ethyl alcohol administered to pregnant mice. Am J Obstet Gynecol 124:676-680. Lenz W, Knapp K (1962): Die Thalidomid-Embryopathie. Dtsch Med Wochenschr 24:1232-1242. Majewski F (1987): Die Alkoholembryopathie-eine haufige und vermeidbare Schadigung. In Majewski F (ed): Die Alkohol embryopathie. Frankfurt/Main: Umwelt und Medizin Verlagsgesellschaft, pp 189-196. Neidengard L, Carter TE, Smith DW (1978):Klippel-Feilmalformation complex in fetal alcohol syndrome. Dis Child 132:929-930. Omenn GS (1988):Genetic investigations on alcohol metabolism and of alcoholism. Am J Hum Genet 43:579-581. Pauli RM, Feldman P F (1986): Major limb malformations following intrauterine exposure to ethanol: Two additional cases and literature review. Teratology 33:273-280.
Limb Defects SPiegel PG,Pekman WM, Rich BH, VerSteeg CN, Nelson v, Dudnikov M (1979):The orthopedic aspects of the fetal alcohol syndrome. Clin Orthopaed tlel Res 139:58-63. "redwell ST (1981):Fetal alcohol syndrome: Orthopedic considerations. BC Med J 23:328. van Rensburg LJ (1981): Major skeletal defects in the fetal alcohol syndrome. SA Med J 2:687-688. WHO (1978): International Classification of Diseases, 9th Revision. Geneva, Switzerland: WHO.
785
Wong N (1983): Fetal alcohol syndrome in British Columbia. Unpublished data. Wood W ,Newman D (1981): Fetal alcohol syndrome: Radiological findings, BC Med J 23:31-32. Zimmerman EF, Scott WJ, Collins MD (1990): Ethanol-induced limb defects in mice: Effects of strain and ~015-45-13, Teratolou 41~453-462.
Congenital Defects of the Limbs and Alcohol Exposure in Pregnancy: Data From a Population Based Study Ursula G. Roster and Patricia A. Baird Klinik fur Frauenheilkunde und Geburtshilfe, Medizinische Universitat zu Lubeck, Liibeck, Germany (U.G.F.) and Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada (P.A.B.) Limb deficiency may occur in offspring prenatally exposed to alcohol. In a study on limb deficiency occurring in 1,213,913 consecutive liveborn infants in British Columbia, born in the years 1952-1984, a total of 659 cases with limb deficiency was identified. Cases with documented maternal alcohol abuse in pregnancy in this group were analyzed separately. W e found eight cases with severe prenatal alcohol exposure (6 F, 2 MI. I n six of the eight cases a terminal transverse defect of the forea r m or hand was present. In the remaining two cases ulnar defects were identified. These observations give further support to the hypothesis that intrauterine alcohol exposure may cause limb defects. This h a s also been demonstrated in experimental animals. Terminal transverse defects made u p a larger proportion of cases with known alcohol exposure (6/8) than of cases where alcohol exposure was not noted (217/651) (x2 = 6.13; P < 0.025) in this study. The defects primarily involved the right hand a n d forearm. This suggests a vascular origin of the limb defects after intrauterine alcohol exposure. 0
1992 Wiley-Liss,Inc.
KEY WORDS: limb defects, fetal alcohol effects, vascular origin INTRODUCTION Recent studies in North America show that approximately 19% of men and 4% of women are addicted to alcohol [Omenn, 19881. Alcohol abuse in pregnancy leads to severe teratogenic effects in the offspring of
Received for publication December 27, 1991; revision received April 7, 1992. Address reprint requests to Dr. U.G. Roster, Klinik fur Frauenheilkunde und Geburtshilfe, Medizinische Universitat zu Liibeck, Ratzeburger Allee 160, 2400 Liibeck, Germany.
0 1992 Wiley-Liss, Inc.
approximately 40% of females who are chronically addicted [Majewski, 19871. The clinical manifestations of fetal alcohol syndrome (FAS) are well recognized [Jones and Smith, 19731. Characteristics include a distinct facial appearance, mental impairment, behaviour difficulties, cardiac defects, and in some cases severe defects of other organs. Limb deficiency as a consequenceof intrauterine alcohol exposure of the fetus was found in animal studies Wronick, 19761.In humans the spectrum of skeletal anomalies in cases of FAS or in those with documented severe prenatal alcohol exposure includes hypoplastic terminal phalanges of the fingers or toes, radio-ulnar synostosis, and Klippel-Feil anomalies [Spiegelet al., 19791. Severe defects of the limbs and tetraamelia has been described in single cases [Herrmann et al., 1980; van Rensburg, 1981; Aro, 1983; Pauli and Feldman, 19861. MATERIAL AND METHODS As part of a larger study on limb defects occurring among 1,213,913 consecutive livebirths in British Columbia [Froster-Iskenius and Baird, 19891, cases with documented maternal alcohol consumptionduring pregnancy were analyzed separately. This population-based study was made possible through the existence of an ongoing Health Surveillance Registry (Registry), which documents all cases with congenital, genetic, or handicapping conditions born in the province of British Columbia since 1952, under strict rules of confidentiality. The Registry receives information from over 60 sources, including the Physicians Notice of Birth and Hospital Separation notices, which enable consistent and reliable ascertainment, as detailed previously [Baird, 19871.The Registry codes diagnoses according to the ICD9 of the World Health Organization [WHO, 19781. For each patient, up to 15 diagnoses can be registered [FrosterIskenius and Baird, 19891. In addition, cross-reference to other relatives is possible so that if a mother is on the Registry because of chronic maternal disease this will be noted. For this study all cases with limb deficiency were identified in which maternal alcohol consumption during pregnancy was documented. They were analyzed with respect to type of limb defect present and according
Limb Defects
783
to associated malformations present in other organ systems.
Anomalies in other organ systems The most frequently associated anomaly among liveborns with limb defects and intrauterine exposure to RESULTS alcohol were cardiac defects (cases 2, 4). In two cases During the period 1952 to 1984 a total of 1,213,913 additional potentially teratogenic agents, thalidomide livebirths occurred in British Columbia. Out of this and cocaine, were taken during the first trimester of cohort 659 cases were registered with limb defects, giv- pregnancy (cases 2,9). The pattern of limb defects in the ing an incidence of 5.67 per 10,000 liveborns [Froster- case exposed to thalidomide resembles the anomalies Iskenius and Baird, 19891. Among those cases there observed in cases with thalidomide as the only terwere eight individuals in which severe maternal alcohol atogenic agent LLenz and Knapp, 19621 (Table I), but problems during pregnancy were documented. In six of mental retardation was also present, which is more ofthese cases an almost identical defect, i.e., a terminal ten present in FAS. Because of the limb defects in this transverse defect of the right arm or hand was found case being characteristic for thalidomide exposure, this (Table I).This is a significant over-representation of this case was excluded from the numerical analysis. In case 9 particular form of defect in cases with known alcohol (Table I) the abuse of cocaine occurred in the 4th week of exposure compared to the occurrence of this particular gestation, and this infant had an abnormality of the left limb defect in the study population without known expo- ear in addition to a limb defect. sure (217/651) (x2 = 6.13; P < 0.025). Three of these eight cases were born in 1980, but an Since 1964 the Registry also has collected information evaluation for regional clustering was not revealing, regarding stillbirths with birth defects. The definition and no other common event could be related to these 3 of stillbirth is death > 20 weeks and weight > 500 g, as cases. previously detailed [Froster-Iskenius and Baird, 19891. Among a total of 30 stillbirths with limb defects born DISCUSSION during the study period, one case with documented The pattern of limb deficiency in the infants identified heavy maternal drinking during pregnancy was found (case 10) (Table I). This case had terminal longitudinal as exposed to alcohol during prenatal life is remarkably defects of the upper limbs. Detailed information on other consistent. There is an overrepresentation of terminal anomalies, especially those compatible with FAS or in- transverse defects, which is significantly higher than formation on birthweight, was not available in all cases. the occurrence of this kind of defect in other infants with Because of Registry policy, cases could not be personally limb defects not known to have been exposed. This sugreexamined t o answer these questions. Minor anomalies gests a causal association between this particular type will be underascertained in Registry data, because of limb defect and alcohol abuse in pregnancy. The inciregistration of cases frequently is done by persons un- dence of transverse terminal defects in the livebirths in skilled in recognizing minor anomalies. Therefore the B.C. for the period 1966 to 1984 was 1.6 per 10,000. In patients with FAS various associated skeletal analysis is limited to the reliable information on major limb defects, and unless, specifically noted, no comment anomalies have been reported, including radio-ulnar can be made on minor anomalies compatible with FAS. synostosis and fusion of the metacarpals [Jaffer et al.,
TABLE I. Limb Defects and Associated Anomalies in Liveborns Exposed to Maternal Alcohol Abuse Case 1
Sex f
Yob 60
Limbs defect T1, phalanx V, left
2"
f
62
It, humeri, radii femora, tibiae, fibulae
3
m
75
4
f f f f
80 80 80
T1, phalanx V, right T1, phalanx 11-V, left Tt, metacarpals, right Tt, metacarpals, left Tt, metacarpals, right Tt, metacarpals, right Tt, metacarpals, right Tt,metacarpals, right
5 6
7 8 9
m f
83 83 84
f
79
Other anomaly Cleft palate epicanthus, deafness, accessory nipples, short stature, radio-ulnar synostosis, fusion C2iC3 clinocamptodactyly m.r. (I.&. 30) deafness, VSD nevus flammeus flexion contracture of knees, constriction ring around right lower leg Strabismus hydrocephalus
Remarks 46, XX
Thalidomide
Tetralogy of Fallot
Birthweight 2,280 g
Premature
Birthweight 1,740 g
Ear dysplasia left < right
Cocaine abuse at 4 weeks gestation
Stillbirth 10
a
T1, phalanx, 111-V, right T1, phalanx, 1-111, left
Excluded from numerical analysis.
Birthweight 400 g (17 week gestation)
784
Froster and Baird
1981; Cremin and Jaffer, 19811. In the Native NorthAmerican Indian population fusion of the cervical spine and Klippel-Feil anomaly have been frequently found among patients with fetal alcohol syndrome [Neidengard et al., 1978; Wood and Newman, 1981; Tredwell, 19811and have been considered to be a specific ethnic expressionoffetal alcohol syndrome. Of our cases, three (cases 1,5,and 6; Table I) had been registered as a Native North American Indian, while all other cases were of Caucasian origin. A very high level of alcohol consumption has been reported in cases with amelia [van Rensburg, 1981; Pauli and Feldman, 19861 with 6-12 beers plus 4 g of liquor consumed in 3-6 days per week. In our study the exact amount of alcohol could not be evaluated, so that a relationship between the amount of alcohol consumed and the severity of the defect cannot be assessed. Among the cases presenting with amelia in our survey of limb defects in British Columbia [Froster-Iskenius and Baird, 19901 we did not find maternal alcohol abuse documented. In mice exposed to large amounts of alcohol during embryonic development different skeletal anomalies have been observed, including ectrodactyly [Kronick, 1976; Zimmerman et al., 19901and ossification anomalies [Chernoff, 19771. However, the pattern of skeletal anomalies in animal studies differs from that observed in humans, including the findings of the present study. This is not contradictory since teratogenic effects in animals do not necessarily resemble anomalies in humans caused by any specific agent and vice versa. The observations from our study suggest that skeletal anomalies and limb defects are part of the spectrum of teratogenic effects of alcohol in humans as well. In comparison to animal studies it appears likely that in humans two factors mainly contribute t o the severity and expression of the teratogenic potency of alcohol: the genetic background and the amount of alcohol consumed. Thus among the Native North-American Indian population fairly specific skeletal anomalies have been observed, such as radio-ulnar synostosis and Klippel-Feil anomalies. In our study three cases were of Native North-American origin (patients 1, 5 , 6). In patient 1 radio-ulnar synostosis and fusion of the cervical spine were documented, while in patients 5 and 6 only a terminal transverse deficiency at the level of the metacarpals was noted. We recognize that due to the nature of data collection by the Registry only those cases with severe alcohol abuse would be likely to have the prenatal exposure documented. It is likely that many additional cases were exposed to alcohol, but this was not noted. However, if the relationship of prenatal alcohol exposure to terminal transverse defects of the limbs is a causative one, this does not negate our findings. The underascertainment of exposure would give a falsely increased frequency of cases with transverse terminal defects in the “unexposed” group and thus minimize the difference. In spite of this, terminal transverse defects were found to be much more common in our alcohol exposed group. The pathogenesis of limb defects occurring after alcohol exposure prenatally is not known. A vascular patho-
genesis is a possibility, because the observed limb defects, have been suggested to have a vascular origin [Hoyme et al., 19821, which has also been discussed for some of the associated anomalies such as the KlippelFeil anomaly [Brill et al., 19871. The fact that almost all cases in our study with defects after maternal alcohol exposure were female raises the possibility that fetuses of this sex are more susceptible to the effect of alcohol on the developing limb. The sex ratio among children with FAS in a B.C. Registry-based study [Wong, 19831was 89 males to 67 females. This is significantly different from our group of patients with limb defects after alcohol exposure, where more females were affected.
ACKNOWLEDGEMENTS Dr. UG Froster was supported by a grant from the Deutsche Forschungsgemeinschaft (F’r 653/1-2). Dr. PA Baird was supported by the Medical Research Council of Canada (MA-9279).Strict conditions of confidentiality are maintained with respect to the B.C. Health Surveillance Registry data. REFERENCES Aro T (1983): Maternal disease, alcohol consumption and smoking during pregnancy associated with reduction limb defects. Early Hum Dev 9:49-57. Baird PA (1987): Measuring birth defects and handicapping disorders in the population: The British Columbia Health Surveillance Registry. Can Med Assoc J 136:109-111. Brill CB, Peyster RG, Keller MS, Galtman L (1987): Isolation of the right subclavian artery with subclavian steal in a child with Klippel-Feil anomaly: An example of the subclavian artery supply disruption sequence. Am J Med Genet 26:933-940. Chernoff GF (1977): The fetal alcohol syndrome in mice: An animal model. Teratology 15223-230. Cremin BJ, Jaffer Z (1981): Radiological aspects of the fetal alcohol syndrome. Pediatr Radio1 11:151-153. Roster-Iskenius UG, Baird PA (1989): Limb reduction defects in over one million consecutive livebirths. Teratology 39:127-135. Froster-Iskenius UG, Baird PA (1990): Amelia: Incidence and associated defects in a large population. Teratology 41:23-31. Herrmann J, Pallister PD, Opitz JM (1980): Tetraectrodactyly and other skeletal manifestations in the fetal alcohol syndrome. Eur J Pediatr 133:221-226. Hoyme HE, Jones KL, van Allen MI, Saunders BS, Benirschke K (1982):Vascular pathogenesis of transverse limb reduction defects. J Pediatr 1012339-843. Jaffer Z, Nelson M, Beighton P (1981):Bone fusion in the fetal alcohol syndrome. J Bone Joint Surg 63B:569-571. Jones KL, Smith DW (1973): Recognition ofthe fetal alcohol syndrome in early infancy. Lancet 11999-1001. Kronick J B (1976): Teratogenic effects of ethyl alcohol administered to pregnant mice. Am J Obstet Gynecol 124:676-680. Lenz W, Knapp K (1962): Die Thalidomid-Embryopathie. Dtsch Med Wochenschr 24:1232-1242. Majewski F (1987): Die Alkoholembryopathie-eine haufige und vermeidbare Schadigung. In Majewski F (ed): Die Alkohol embryopathie. Frankfurt/Main: Umwelt und Medizin Verlagsgesellschaft, pp 189-196. Neidengard L, Carter TE, Smith DW (1978):Klippel-Feilmalformation complex in fetal alcohol syndrome. Dis Child 132:929-930. Omenn GS (1988):Genetic investigations on alcohol metabolism and of alcoholism. Am J Hum Genet 43:579-581. Pauli RM, Feldman P F (1986): Major limb malformations following intrauterine exposure to ethanol: Two additional cases and literature review. Teratology 33:273-280.
Limb Defects SPiegel PG,Pekman WM, Rich BH, VerSteeg CN, Nelson v, Dudnikov M (1979):The orthopedic aspects of the fetal alcohol syndrome. Clin Orthopaed tlel Res 139:58-63. "redwell ST (1981):Fetal alcohol syndrome: Orthopedic considerations. BC Med J 23:328. van Rensburg LJ (1981): Major skeletal defects in the fetal alcohol syndrome. SA Med J 2:687-688. WHO (1978): International Classification of Diseases, 9th Revision. Geneva, Switzerland: WHO.
785
Wong N (1983): Fetal alcohol syndrome in British Columbia. Unpublished data. Wood W ,Newman D (1981): Fetal alcohol syndrome: Radiological findings, BC Med J 23:31-32. Zimmerman EF, Scott WJ, Collins MD (1990): Ethanol-induced limb defects in mice: Effects of strain and ~015-45-13, Teratolou 41~453-462.
