The Fetal Alcohol Syndrome ~
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KENNETH L. JONES AND DAVID W. SMITH Dysmorphology Unit, Department of Pediatrics, University of W a s h i n g t o n School of Medicine, Seattle, W a s h i n g t o n 98195, and Department of Pediatrics, University of California, S a n Diego School of Medicine, Sun Diego, California 921 03
ABSTRACT A specific pattern of malformation involving prenatal-onset growth deficiency, developmental delay, craniofacial anomalies, and limb defects is now recognized in offspring of chronic alcoholic women. Historical evidence suggests that this is not a new observation. A recent French study of 127 offspring of alcoholic mothers indicates that this specific syndrome has been recognized in other parts of the world. Many of the features of this disorder could be related to the kind of malorientation of brain structure seen at the autopsy of one patient described herein. The frequency (43%) of adverse outcome of pregnancy for chronic alcoholic women suggests that serious consideration be given to early termination of pregnancy in severely chronic alcoholic women.
A pattern of altered growth and morphogenesis, referred to as the fetal alcohol syndrome, has now been reported in 16 children, all of whom were born to severely and chronically alcoholic women who continued heavy alcohol consumption throughout pregnancy (Jones et al., ’73; Jones and Smith, ’73; Ferrier et al., ’73; Hall and Orenstein, ’74; Palmer et al., ’74).
and imperfect look.” In 1900 Sullivan investigated female alcoholics at the Liverpool Prison. He documented an increased frequency of early fetal death and early infant mortality in their offspring. Other investigators have found increased frequency of prematurity and decreased weight of surviving children born to chronic alcoholic mothers (Ladraque, ’01; Roe, ’44; Lecomte, ’50; Christiaens et al., ’60). HISTORICAL PERSPECTIVE A study reported in 1967 of 127 chilSince the initial discrimination of the dren born to alcoholic parents was recentfetal alcohol syndrome historical evidence ly called to our attention by Dr. W. Lenz has been brought to our attention indi- of Germany (Lemoine et al., ’67). Abnorcating that an association between mater- malities frequently noted in the children nal alcoholism and serious problems in were growth deficiency of prenatal onset, the offspring is not a new observation. an unusual facies, and a 25% incidence Evidence is even available from classical of malformations (in particular cleft palGreek and Roman mythology suggesting ate and cardiac malformations). Psychothat maternal alcoholism at the time of motor retardation (I& 70) associated with conception can lead to serious problems “agitation” and “character disturbances” in fetal development. This led to an an- occurred often. Animal experiments on the effects of cient Carthaginian ritual forbidding the drinking of wine by the bridal couple on ethanol on early morphogenesis have led their wedding night so that defective chilReceived Feb. 18, ’75. Accepted April 14, ’75. dren might not be conceived (Haggaro 1 Supported by the Maternal and Child Health Serand Jellinek, ’42). In 1834 a select com- vices, Health Services and Mental Administration, Department of Health, Education and Welfare Project 913, mittee of the British House of Commons NIH grants HD05961 and GM15253, and the National was established to investigate “drunken- Foundation - March of Dimes. Reprint address: Dr. David W. Smith, Department ness’’ prior to the establishment in that of2Pediatrics. RR234 Health Sciences, RD-20, Universame year of an Alcoholic Licensure Act. sity of Washington School of Medicine, Seattle, WashEvidence presented to that committee in- ington 98195. 3 Presented a s a Special Lecture at the 14th Annual dicated that infants born to alcoholic moth- Meeting of the Teratology Society, July 7-10, 1974, Uniers sometimes had a “starved, shriveled versity of British Columbia, Vancouver, B. C., Canada. TERAMLOGY, 12: 1-10.
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KENNETH L. JONES AND DAVID W. SMITH
to variable results (Sandor, '68). However, recent experiments demonstrated ethanolinduced dysmorphogenesis in chick as well as rat embryos (Sandor, '68a,b; Sandor and Amels, '71). This consisted in chicks of deformed brain vesicles and spinal cord, abnormal development of somites, and retardation of general growth.
rate averaged 65% of normal whereas the average rate of weight gain was only 30% of normal despite the fact that 6 of the children were hospitalized on numerous occasions for failure to thrive, during which time adequate caloric intake was well documented, and despite the fact that 3 of them were receiving excellent fostercare. The most striking example of postnatal growth deficiency in this syndrome occurred in an American Indian girl who, at the age of 7 months had a length and weight that were in the 50th percentile for 35 weeks' gestation. Intelligence quotients ranged from below 50 to 83 with a mean of 63. Relative to the microcephaly, head circumference was less than the 3rd percentile for chronological age at birth in 10 out of 11 patients; and in all but 1 evaluated at 1 year of age it was below the 3rd percentile for height-age as well. The short palpebral fissures were initially interpreted as being secondary to decreased growth of the eyes. Frank mi-
PATTERN OF MALFORMATION
Features shared by the 11 children who were initially evaluated with this syndrome are summarized in figure 1. One child from each of the ethnic groups in which the fetal alcohol syndrome has been recognized are depicted in figure 2. Prenatal growth deficiency has been more severe with regard to length than weight at birth. This is in direct contrast with most studies of generalized maternal undernutrition in which the newborn infants are underweight for their length. Severe postnatal growth deficiency occurred in each of the 9 patients followed for longer than 1 year. The linear growth 0
PERCENT OCCURRENCE OF ABNORMALITIES 25 50 75 100 %
t
MICROCEPHALY
I
SHORT
PERFORMANCE
1 1 9 1 1
PALPEBRAL
boo I
FISSURES
36
EPICANTHAL FOLDS I
CRANIOFACIES MAXILLARY
I
HYPOPLASIA
64
I
I
I
I
27
MICROGNATHIA
-
**c-:
JOINT
-I
18
CLEFT: PALATE ...I
73
ANOMALIES
LIMBS
73
ALTERED PALMAR CREASE PATTERN c . 3 ) . e c
1
CARDIAC ANOMALIES
OTHER
-
ANOMALOUS EXTERNAL CAPILLARY
I
36
GENITALIA
36
HEMANGIOMATA
FINE - MOTOR DYSFUNCTION Fig. 1
70
Pattern of malformation.
1
1801
THE FETAL ALCOHOL SYNDROME
Fig. 2 Three children with the fetal alcohol syndrome, (a) a 1-year-old American Indian girl, (b) a 3 9/12-year-old black girl, and ( c ) a 2 6/12-year-old white boy. Note the short palpebral fissures in all children and the strabismis and asymmetric ptosis in the black girl.
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KENNETH L . JONES AND DAVID W. SMITH
RECOGNITION OF T H E FETAL ALCOHOL crophthalmia, noted in 2 newborn infants SYNDROME I N EARLY INFANCY with the syndrome, tends to support this Two babies with the fetal alcohol syninterpretation. The joint anomalies were variable and drome, initially evaluated in the newborn consisted of congenital hip dislocation in period, are depicted in figures 3 and 4. 3 , inability to extend the elbows complete- Pertinent data relative to the maternal ly in 3 , camptodactyly of toes in 2, and history of alcoholism, early neonatal course, inability to flex the metacarpal-phalangeal and subsequent performance are presented in the following case reports. joints completely in 2 patients. The following alterations of palmarcrease patterns were present: rudimentary Case reports Patient 1. A 2-day-old American Inpalmar creases, and aberrant alignment of the palmar creases and a single upper dian male was ascertained because his mother was a severe chronic alcoholic. palmar crease, or both. Cardiac anomalies consisted of atrial Her 7 other living children, all born prior septal defect in 1 patient, patent ductus to her becoming an alcoholic, are allegedarteriosus in 1 patient, and grade III/VI ly of normal stature and intelligence. Six systolic murmurs interpreted as represent- years before the birth of patient 1 she ing ventricular septal defect in 6 patients. began drinking 2 quarts of red wine daily. Anomalies of the external genitalia con- She developed cirrhosis and nutritional sisted of hypoplastic labia majora in 3 pa- anemia and experienced delirium tremens. During that time she also had 3 lst-trimestients and a septate vagina in l. Fine-motor dysfunction was manifest by ter spontaneous abortions. Throughout her a weak grasp, poor eye-hand coordination, pregnancy with the patient she continued and tremulousness in the newborn period. to drink wine heavily. Her nutritional sta-
Fig. 3 Patient 1 at ( a ) 1 day and (b) 10 months of age. Note short palpebral fissures and hirsutism. Similarity in the newborn period to the deLange syndrome was not present at 10 months of age.
THE FETAL ALCOHOL SYNDROME
5
Fig. 4 Necropsy picture of patient 2 at 5 days of age. Note the short palpebral fissures, hirsutism, and the flat facies with maxillary hypoplasia.
tus, evaluated shortly after delivery, was normal except for iron deficiency. Serum vitamin A, vitamin C, folic acid, and total protein were normal. Maternal weight gain during pregnancy totaled 6.75 kg. Delivery was from a breech presentation after a 38-week gestation, during which time there was decreased fetal activity. One- and 5min Apgar scores were 1 and 6, respectively. The attending physician noted “alcohol on his breath.” Birth weight was 2020 g (50th percentile for 34 weeks’ gestation), birth length was 43 cm (50th percentile for 32.5 weeks’ gestation), and head circumference was 29 cm (below the 3rd percentile). There was a striking degree of hirsutism especially over the forehead. The palpebral fissures were short, measuring 1.1 cm on the right and 1.2 cm on the left. A grade II/VI systolic murmur was thought to represent a ventricular septa1 defect. There was left congenital hip dislocation and bilateral simian creases. A deep pilonidal sinus over a prominent coccyx was present. The immediate neonatal period was complicated by mild
respiratory distress lasting 5 days and requiring 40% ambient oxygen concentration, transient hypoglycemia lasting 24 h, and hyperbilirubinemia. Tremulousness, noted soon after birth, was thought to represent “alcoholic withdrawal” but did not respond to phenobarbital sedation and was still present at 10 months of age. Since being discharged from the newborn nursery he has had excellent foster care, but despite optimum stimulation and caloric intake his growth rate and development have been markedly retarded. At the time of writing he was 13 months old and was 65.5 cm long (50th percentile for 5 months), weighed 5.7 kg (50th percentile for 3 months), and had a head circumference of 41 cm (below the 3rd percentile). His developmental age was estimated at 7 months. Seizures precipitated by hyperventilation and followed by postictal lethargy were first noted at 8 months of age. Minor nonspecific electroencephalographic signs have improved, and the seizures, despite the absence of therapy, have decreased in frequency.
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KENNETH L . JONES AND DAVID W . SMITH
Patient 2 . A newborn American Indian girl was ascertained because her 40-yearold mother was a severe chronic alcoholic of unknown duration. Although no complications of alcoholism were known a blood-alcohol level determined 1 week after the child’s birth, at a time when the mother did not seem intoxicated, was 157 mg/100 ml. Maternal weight gain during pregnancy was 4.95 kg. Delivery, a t 32 weeks’ gestation, was from a vertex presentation. Apgar scores at 1 and 5 min were 5 and 8, respectively. Birth weight was 1300 g (50th percentile for 30 weeks’ gestation), birth length was 38.5 c m (50th percentile for 29 weeks’ gestation), and head circumference was 27 cm. She had marked hirsutism, especially over the forehead, microphthalmia, and a cleft of the soft palate. The following joint anomalies were present: overlapping of the 3rd over the 2nd fingers; clinodactyly of the left 5th finger; and camptodactyly of the right 3rd finger with absence of the distal interphalangeal crease. There was a systolic
murmur along the left sternal border. The vagina was septated. There were only 2 vessels in the umbilical cord. Because of the phenotypic similarity to the 18-trisomy syndrome a chromosome study was done which was interpreted as normal. Cyanosis developed at 5 h of age and multiple apneic episodes culminated in death at 5 days of age. The autopsy of that child is, to our knowledge, the first performed on a patient as having the fetal alcohol syndrome. The brain findings were of special pertinence. There were extensive developmental anomalies which resulted primarily from aberration of neuronal migration and thereby in multiple heterotopias throughout the leptomeninges and cerebral mantle as well as the subependymal regions. The strikingly abnormal external appearance of the brain (fig. 5) was due to sheets of neuronal and glial cells that had abnormally migrated out over the surface of the cerebral hemispheres. These changes, plus cellular disorganization of the cere-
Fig. 5 External appearance of brain from patient 2. Note the smooth surface of the cerebral cortex bilaterally.
THE FETAL ALCOHOL SYNDROME
7
Fig. 6 Section through cerebral cortex of brain of patient 2 . Note the apparently normal cells which have extended through small defects in the pia and have infiltrated the meninges. Disorganization of cellular elements is present throughout the cerebral mantle.
bra1 mantle, are demonstrated microscopically in figure 6. Incomplete development of the cerebral cortex was evidenced by enlarged lateral ventricles, the inner surface of which were studded with numerous nodules of heterotopic neurons (fig. 7 ) . In addition there was agenesis of the corpus callosum. Some of the structural and functional abnormalities in this syndrome, such as microcephaly, developmental delay, and motor dysfunction, may all be secondarily related to the type of malorientation of the brain observed in the patient. Even the joint anomalies could well be related to neurological impairment of the fetus, including diminished movement in utero resulting from this type of malorientation of brain structure. Recognition of the fetal alcohol syndrome can be particularly difficult in the newborn. Patient 1 was initially diagnosed as having DeLange syndrome and patient 2, 18 trisomy syndrome. Incorrect diagnosis could
lead to inappropriate counseling regarding the risk of malformations in future offspring. The risk of the fetal alcohol syndrome in future children is potentially high, as indicated by reports of multiple affected children. The 7 normal children born to the mother of patient 1 before she became a chronic alcoholic suggest that the recurrence risk might be related to control of maternal alcoholism. OUTCOME OF PREGNANCY IN CHRONIC ALCOHOLIC WOMEN
The incidence and nature of problems of morphogenesis and function in the offspring of a group of women ascertained purely by the history of chronic alcoholism have recently been set forth (Jones et al., '74). The sample of 23 was drawn from the Collaborative Perinatal Study of the National Institute of Neurological Disease and Stroke. This was a prospective study of 55,000 pregnant women and their off-
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K E N N E T H L. JONES AND DAVID W. SMITH
Fig. 7 Section through the cerebral cortex. Note the markedly enlarged ventricle, the inner surface of which is studded with numerous nodules representing heterotopic neurons.
Minimum percent
1I0
20
of cases 30
40
F
Performance Preno to I Growth Deficiency Controls Subjects
Ocular
Fig. 8 The minimum frequency of abnormalities noted in children born to chronically alcoholic mothers compared with matched controls.
THE FETAL ALCOHOL SYNDROME
spring who were followed up to 7 years postnatally in 12 medical centers. Two nonalcoholic control women were matched for each of the 23 study cases. These were matched for socioeconomic status, maternal education, race, maternal age, parity, marital status, and institution where the mother and child were followed. The results of that study suggest the overwhelming magnitude of the handicapping problems that maternal alcoholism can impose on the developing fetus. Four of the 23 offspring of women who drank before and during pregnancy died before 1 week of age, a perinatal mortality of 17% as opposed to 2% for the control group. The relative frequencies of problems in the 19 surviving offspring are set forth in figure 8. The structural anomalies listed are all common features in the fetal alcohol syndrome. It is important to realize that only the minimum frequency of individuals with each anomaly is depicted because all children were not systematically evaluated for such features as short palpebral fissures, ptosis, and strabismus as well as joint anomalies and cardiac murmurs. Regarding the incidence of the fetal alcohol syndrome 6 of the 19 ( 3 2 % ) surviving children born to chronically alcoholic women had enough abnormal features to suggest the possibility of the syndrome from the physical findings alone, whereas not one of the matched controls was so affected. The frequency of adverse outcome of pregnancy for chronically alcoholic women from this study was 43% (4 who died in the perinatal period and 6 with the fetal alcohol syndrome) as opposed to 2 % of their controls. Because of the magnitude of this risk it is recommended that serious consideration be given to early termination of pregnancy in severely chronically alcoholic women. DISCUSSION
The similarity in the overall pattern of anomalies in these children suggests a single etiology, most likely environmentally determined, by some as yet unknown effect of maternal metabolism. Regarding direct toxicity to the developing fetus the most obvious possibility is ethanol itself.
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There is good evidence in human beings and other animals that ethanol freely crosses the placenta (Waltman and Iniquez, '72). Animal studies have shown it to be distributed in the amniotic fluid and throughout multiple fetal tissues, at least during late gestation (Ho et al., '72). Other possibilities involving direct toxicity include one of the breakdown products of ethanol such as acetaldehyde or an unknown toxic agent in the alcoholic beverages the mothers were consuming. The adverse affect on growth and morphogenesis could also be the indirect consequence of generalized maternal undernutrition or deficiency of a specific nutrient or vitamin. However, neither this degree nor this pattern (birth length more severely affected than birth weight) of growth deficiency nor the pattern of malformation herein described have been reported in offspring of severely undernourished nonalcoholic women (Smith, '47). Further studies are now clearly needed to examine the amount and duration of maternal alcoholism necessary to result in offspring with the fetal alcohol syndrome. All affected children recognized to date have been the offspring of severely chronically alcoholic women who drank heavily throughout pregnancy. In addition the total spectrum of the disorder needs to be more fully delineated. Experience with other environmental teratogens would lead one to expect variable seventy of this pattern of malformation and function in offspring of chronic alcoholic women. Finally, basic studies must be performed with respect to the specific cause and possible prevention of this tragic disorder. ACKNOWLEDGMENTS
The authors wish to thank Dr. Richard Leech for interpretation of the neuropathological specimens, Mrs. Lyle Harrah and Mrs. Mary Ann Harvey for the library research studies, Mr. Bradley Gong for photography, and Mrs. Beverly Gonsowski and Mrs. Christine Hansen for secretarial assistance. LITERATURE CITED Christiaens, L., J . P. Mizon and G. Delmarle 1960 Sur l a descendance des alcoholiques. Ann. Pi. diat., 36: 37-42.
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KENNETH L. JONES AND DAVID W. SMITH
Ferrier, P. E., I . Nicod and S. Ferrier 1973 Fetal alcohol syndrome. Lancet, 2: 1496. Haggard, H. W., and E. M . Jellinek 1942 Alcohol Explored. Doubleday, Doran, New York. Hall, B. D., a n d W. A. Orenstein 1974 Noonan’s phenotype in a n offspring of a n alcoholic mother. Lancet, I : 680. Ho, B. T., G . E. Fritchie, J . E. Idanpaan-Heikkila and W. M. Moissac 1972 Q. J . Stud. Alcohol, 39: 48-94, Jones, K. L., and D. W. Smith 1973 Recognition of the fetal alcohol syndrome in early infancy. Lancet. 2: 999-1001. Jones, K. L., D. W. Smith, A. P . Streissguth a n d N . C. Myrianthopoulous 1974 Outcome i n offspring of chronic alcoholic women. Lancet, 1 . 107€&1078. Jones, K. L., D. W. Smith, C. W. Ulleland a n d A. P. Streissguth 1973 Pattern of malformation in offspring of chronic alcoholic women. Lancet, I : 1267-1271. Ladraque, P. 1901 Alcoholism et Enfants. Steinheil, Paris. Lecomte, M. 1950 Elements d’heredopathologie. Scalpel, 103: 1133-1145. Lemoine, P . , H. Harousseau, J . P. Borteyru, J . C. Menuet 1967 Les enfants de parents alcohol-
iques: anomalies observees a propos de 127 cas. Arch. Fr. Pediat., 25: 830-832. Palmer, R. H., E. M. Ouellette, L. Warner and S. R. Leichtman 1974 Congenital malformations i n offspring of a chronic alcoholic mother. Pediatrics, 53: 49G494. Roe, A. 1944 The adult adjustment of children of alcoholic parents raised in foster homes. Q. J. Stud. Alcohol., 5: 378-393. Sandor, S. 1968a T h e influence of aethyl-alcohol on the development of t h e chick embryo. Rev. Roum. Embryol. Cytol., Ser. Embryol., 5: 51-76. 1968b The influence of aethyl-alcohol o n the developing chick embryo. Rev. Roum. Embryol. Cytol., Ser. Embryol., 5: 167-171. Sandor, S . , a n d D. Amels 1971 The action of aethanol on the praenatal development of albino rats. Rev. Roum. Embryol. Cytol., Ser. Embryol., 8: 1 0 S 1 1 8 . Smith, C. J . 1947 Effects of maternal undernutrition upon the newborn infants in Holland (1944-1945). Pediatrics, 30: 2 2 S 2 4 3 . Sullivan, W. C. 1900 T h e children of the female drunkard. Med. Temp. Rev., 1 : 72-79. Waltman, R., and E. S . Iniquez 1972 Placental transfer of ethanol and its elimination a t term. Obst. Gyn., 40. 180-185.
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KENNETH L. JONES AND DAVID W. SMITH Dysmorphology Unit, Department of Pediatrics, University of W a s h i n g t o n School of Medicine, Seattle, W a s h i n g t o n 98195, and Department of Pediatrics, University of California, S a n Diego School of Medicine, Sun Diego, California 921 03
ABSTRACT A specific pattern of malformation involving prenatal-onset growth deficiency, developmental delay, craniofacial anomalies, and limb defects is now recognized in offspring of chronic alcoholic women. Historical evidence suggests that this is not a new observation. A recent French study of 127 offspring of alcoholic mothers indicates that this specific syndrome has been recognized in other parts of the world. Many of the features of this disorder could be related to the kind of malorientation of brain structure seen at the autopsy of one patient described herein. The frequency (43%) of adverse outcome of pregnancy for chronic alcoholic women suggests that serious consideration be given to early termination of pregnancy in severely chronic alcoholic women.
A pattern of altered growth and morphogenesis, referred to as the fetal alcohol syndrome, has now been reported in 16 children, all of whom were born to severely and chronically alcoholic women who continued heavy alcohol consumption throughout pregnancy (Jones et al., ’73; Jones and Smith, ’73; Ferrier et al., ’73; Hall and Orenstein, ’74; Palmer et al., ’74).
and imperfect look.” In 1900 Sullivan investigated female alcoholics at the Liverpool Prison. He documented an increased frequency of early fetal death and early infant mortality in their offspring. Other investigators have found increased frequency of prematurity and decreased weight of surviving children born to chronic alcoholic mothers (Ladraque, ’01; Roe, ’44; Lecomte, ’50; Christiaens et al., ’60). HISTORICAL PERSPECTIVE A study reported in 1967 of 127 chilSince the initial discrimination of the dren born to alcoholic parents was recentfetal alcohol syndrome historical evidence ly called to our attention by Dr. W. Lenz has been brought to our attention indi- of Germany (Lemoine et al., ’67). Abnorcating that an association between mater- malities frequently noted in the children nal alcoholism and serious problems in were growth deficiency of prenatal onset, the offspring is not a new observation. an unusual facies, and a 25% incidence Evidence is even available from classical of malformations (in particular cleft palGreek and Roman mythology suggesting ate and cardiac malformations). Psychothat maternal alcoholism at the time of motor retardation (I& 70) associated with conception can lead to serious problems “agitation” and “character disturbances” in fetal development. This led to an an- occurred often. Animal experiments on the effects of cient Carthaginian ritual forbidding the drinking of wine by the bridal couple on ethanol on early morphogenesis have led their wedding night so that defective chilReceived Feb. 18, ’75. Accepted April 14, ’75. dren might not be conceived (Haggaro 1 Supported by the Maternal and Child Health Serand Jellinek, ’42). In 1834 a select com- vices, Health Services and Mental Administration, Department of Health, Education and Welfare Project 913, mittee of the British House of Commons NIH grants HD05961 and GM15253, and the National was established to investigate “drunken- Foundation - March of Dimes. Reprint address: Dr. David W. Smith, Department ness’’ prior to the establishment in that of2Pediatrics. RR234 Health Sciences, RD-20, Universame year of an Alcoholic Licensure Act. sity of Washington School of Medicine, Seattle, WashEvidence presented to that committee in- ington 98195. 3 Presented a s a Special Lecture at the 14th Annual dicated that infants born to alcoholic moth- Meeting of the Teratology Society, July 7-10, 1974, Uniers sometimes had a “starved, shriveled versity of British Columbia, Vancouver, B. C., Canada. TERAMLOGY, 12: 1-10.
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KENNETH L. JONES AND DAVID W. SMITH
to variable results (Sandor, '68). However, recent experiments demonstrated ethanolinduced dysmorphogenesis in chick as well as rat embryos (Sandor, '68a,b; Sandor and Amels, '71). This consisted in chicks of deformed brain vesicles and spinal cord, abnormal development of somites, and retardation of general growth.
rate averaged 65% of normal whereas the average rate of weight gain was only 30% of normal despite the fact that 6 of the children were hospitalized on numerous occasions for failure to thrive, during which time adequate caloric intake was well documented, and despite the fact that 3 of them were receiving excellent fostercare. The most striking example of postnatal growth deficiency in this syndrome occurred in an American Indian girl who, at the age of 7 months had a length and weight that were in the 50th percentile for 35 weeks' gestation. Intelligence quotients ranged from below 50 to 83 with a mean of 63. Relative to the microcephaly, head circumference was less than the 3rd percentile for chronological age at birth in 10 out of 11 patients; and in all but 1 evaluated at 1 year of age it was below the 3rd percentile for height-age as well. The short palpebral fissures were initially interpreted as being secondary to decreased growth of the eyes. Frank mi-
PATTERN OF MALFORMATION
Features shared by the 11 children who were initially evaluated with this syndrome are summarized in figure 1. One child from each of the ethnic groups in which the fetal alcohol syndrome has been recognized are depicted in figure 2. Prenatal growth deficiency has been more severe with regard to length than weight at birth. This is in direct contrast with most studies of generalized maternal undernutrition in which the newborn infants are underweight for their length. Severe postnatal growth deficiency occurred in each of the 9 patients followed for longer than 1 year. The linear growth 0
PERCENT OCCURRENCE OF ABNORMALITIES 25 50 75 100 %
t
MICROCEPHALY
I
SHORT
PERFORMANCE
1 1 9 1 1
PALPEBRAL
boo I
FISSURES
36
EPICANTHAL FOLDS I
CRANIOFACIES MAXILLARY
I
HYPOPLASIA
64
I
I
I
I
27
MICROGNATHIA
-
**c-:
JOINT
-I
18
CLEFT: PALATE ...I
73
ANOMALIES
LIMBS
73
ALTERED PALMAR CREASE PATTERN c . 3 ) . e c
1
CARDIAC ANOMALIES
OTHER
-
ANOMALOUS EXTERNAL CAPILLARY
I
36
GENITALIA
36
HEMANGIOMATA
FINE - MOTOR DYSFUNCTION Fig. 1
70
Pattern of malformation.
1
1801
THE FETAL ALCOHOL SYNDROME
Fig. 2 Three children with the fetal alcohol syndrome, (a) a 1-year-old American Indian girl, (b) a 3 9/12-year-old black girl, and ( c ) a 2 6/12-year-old white boy. Note the short palpebral fissures in all children and the strabismis and asymmetric ptosis in the black girl.
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KENNETH L . JONES AND DAVID W. SMITH
RECOGNITION OF T H E FETAL ALCOHOL crophthalmia, noted in 2 newborn infants SYNDROME I N EARLY INFANCY with the syndrome, tends to support this Two babies with the fetal alcohol syninterpretation. The joint anomalies were variable and drome, initially evaluated in the newborn consisted of congenital hip dislocation in period, are depicted in figures 3 and 4. 3 , inability to extend the elbows complete- Pertinent data relative to the maternal ly in 3 , camptodactyly of toes in 2, and history of alcoholism, early neonatal course, inability to flex the metacarpal-phalangeal and subsequent performance are presented in the following case reports. joints completely in 2 patients. The following alterations of palmarcrease patterns were present: rudimentary Case reports Patient 1. A 2-day-old American Inpalmar creases, and aberrant alignment of the palmar creases and a single upper dian male was ascertained because his mother was a severe chronic alcoholic. palmar crease, or both. Cardiac anomalies consisted of atrial Her 7 other living children, all born prior septal defect in 1 patient, patent ductus to her becoming an alcoholic, are allegedarteriosus in 1 patient, and grade III/VI ly of normal stature and intelligence. Six systolic murmurs interpreted as represent- years before the birth of patient 1 she ing ventricular septal defect in 6 patients. began drinking 2 quarts of red wine daily. Anomalies of the external genitalia con- She developed cirrhosis and nutritional sisted of hypoplastic labia majora in 3 pa- anemia and experienced delirium tremens. During that time she also had 3 lst-trimestients and a septate vagina in l. Fine-motor dysfunction was manifest by ter spontaneous abortions. Throughout her a weak grasp, poor eye-hand coordination, pregnancy with the patient she continued and tremulousness in the newborn period. to drink wine heavily. Her nutritional sta-
Fig. 3 Patient 1 at ( a ) 1 day and (b) 10 months of age. Note short palpebral fissures and hirsutism. Similarity in the newborn period to the deLange syndrome was not present at 10 months of age.
THE FETAL ALCOHOL SYNDROME
5
Fig. 4 Necropsy picture of patient 2 at 5 days of age. Note the short palpebral fissures, hirsutism, and the flat facies with maxillary hypoplasia.
tus, evaluated shortly after delivery, was normal except for iron deficiency. Serum vitamin A, vitamin C, folic acid, and total protein were normal. Maternal weight gain during pregnancy totaled 6.75 kg. Delivery was from a breech presentation after a 38-week gestation, during which time there was decreased fetal activity. One- and 5min Apgar scores were 1 and 6, respectively. The attending physician noted “alcohol on his breath.” Birth weight was 2020 g (50th percentile for 34 weeks’ gestation), birth length was 43 cm (50th percentile for 32.5 weeks’ gestation), and head circumference was 29 cm (below the 3rd percentile). There was a striking degree of hirsutism especially over the forehead. The palpebral fissures were short, measuring 1.1 cm on the right and 1.2 cm on the left. A grade II/VI systolic murmur was thought to represent a ventricular septa1 defect. There was left congenital hip dislocation and bilateral simian creases. A deep pilonidal sinus over a prominent coccyx was present. The immediate neonatal period was complicated by mild
respiratory distress lasting 5 days and requiring 40% ambient oxygen concentration, transient hypoglycemia lasting 24 h, and hyperbilirubinemia. Tremulousness, noted soon after birth, was thought to represent “alcoholic withdrawal” but did not respond to phenobarbital sedation and was still present at 10 months of age. Since being discharged from the newborn nursery he has had excellent foster care, but despite optimum stimulation and caloric intake his growth rate and development have been markedly retarded. At the time of writing he was 13 months old and was 65.5 cm long (50th percentile for 5 months), weighed 5.7 kg (50th percentile for 3 months), and had a head circumference of 41 cm (below the 3rd percentile). His developmental age was estimated at 7 months. Seizures precipitated by hyperventilation and followed by postictal lethargy were first noted at 8 months of age. Minor nonspecific electroencephalographic signs have improved, and the seizures, despite the absence of therapy, have decreased in frequency.
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KENNETH L . JONES AND DAVID W . SMITH
Patient 2 . A newborn American Indian girl was ascertained because her 40-yearold mother was a severe chronic alcoholic of unknown duration. Although no complications of alcoholism were known a blood-alcohol level determined 1 week after the child’s birth, at a time when the mother did not seem intoxicated, was 157 mg/100 ml. Maternal weight gain during pregnancy was 4.95 kg. Delivery, a t 32 weeks’ gestation, was from a vertex presentation. Apgar scores at 1 and 5 min were 5 and 8, respectively. Birth weight was 1300 g (50th percentile for 30 weeks’ gestation), birth length was 38.5 c m (50th percentile for 29 weeks’ gestation), and head circumference was 27 cm. She had marked hirsutism, especially over the forehead, microphthalmia, and a cleft of the soft palate. The following joint anomalies were present: overlapping of the 3rd over the 2nd fingers; clinodactyly of the left 5th finger; and camptodactyly of the right 3rd finger with absence of the distal interphalangeal crease. There was a systolic
murmur along the left sternal border. The vagina was septated. There were only 2 vessels in the umbilical cord. Because of the phenotypic similarity to the 18-trisomy syndrome a chromosome study was done which was interpreted as normal. Cyanosis developed at 5 h of age and multiple apneic episodes culminated in death at 5 days of age. The autopsy of that child is, to our knowledge, the first performed on a patient as having the fetal alcohol syndrome. The brain findings were of special pertinence. There were extensive developmental anomalies which resulted primarily from aberration of neuronal migration and thereby in multiple heterotopias throughout the leptomeninges and cerebral mantle as well as the subependymal regions. The strikingly abnormal external appearance of the brain (fig. 5) was due to sheets of neuronal and glial cells that had abnormally migrated out over the surface of the cerebral hemispheres. These changes, plus cellular disorganization of the cere-
Fig. 5 External appearance of brain from patient 2. Note the smooth surface of the cerebral cortex bilaterally.
THE FETAL ALCOHOL SYNDROME
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Fig. 6 Section through cerebral cortex of brain of patient 2 . Note the apparently normal cells which have extended through small defects in the pia and have infiltrated the meninges. Disorganization of cellular elements is present throughout the cerebral mantle.
bra1 mantle, are demonstrated microscopically in figure 6. Incomplete development of the cerebral cortex was evidenced by enlarged lateral ventricles, the inner surface of which were studded with numerous nodules of heterotopic neurons (fig. 7 ) . In addition there was agenesis of the corpus callosum. Some of the structural and functional abnormalities in this syndrome, such as microcephaly, developmental delay, and motor dysfunction, may all be secondarily related to the type of malorientation of the brain observed in the patient. Even the joint anomalies could well be related to neurological impairment of the fetus, including diminished movement in utero resulting from this type of malorientation of brain structure. Recognition of the fetal alcohol syndrome can be particularly difficult in the newborn. Patient 1 was initially diagnosed as having DeLange syndrome and patient 2, 18 trisomy syndrome. Incorrect diagnosis could
lead to inappropriate counseling regarding the risk of malformations in future offspring. The risk of the fetal alcohol syndrome in future children is potentially high, as indicated by reports of multiple affected children. The 7 normal children born to the mother of patient 1 before she became a chronic alcoholic suggest that the recurrence risk might be related to control of maternal alcoholism. OUTCOME OF PREGNANCY IN CHRONIC ALCOHOLIC WOMEN
The incidence and nature of problems of morphogenesis and function in the offspring of a group of women ascertained purely by the history of chronic alcoholism have recently been set forth (Jones et al., '74). The sample of 23 was drawn from the Collaborative Perinatal Study of the National Institute of Neurological Disease and Stroke. This was a prospective study of 55,000 pregnant women and their off-
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K E N N E T H L. JONES AND DAVID W. SMITH
Fig. 7 Section through the cerebral cortex. Note the markedly enlarged ventricle, the inner surface of which is studded with numerous nodules representing heterotopic neurons.
Minimum percent
1I0
20
of cases 30
40
F
Performance Preno to I Growth Deficiency Controls Subjects
Ocular
Fig. 8 The minimum frequency of abnormalities noted in children born to chronically alcoholic mothers compared with matched controls.
THE FETAL ALCOHOL SYNDROME
spring who were followed up to 7 years postnatally in 12 medical centers. Two nonalcoholic control women were matched for each of the 23 study cases. These were matched for socioeconomic status, maternal education, race, maternal age, parity, marital status, and institution where the mother and child were followed. The results of that study suggest the overwhelming magnitude of the handicapping problems that maternal alcoholism can impose on the developing fetus. Four of the 23 offspring of women who drank before and during pregnancy died before 1 week of age, a perinatal mortality of 17% as opposed to 2% for the control group. The relative frequencies of problems in the 19 surviving offspring are set forth in figure 8. The structural anomalies listed are all common features in the fetal alcohol syndrome. It is important to realize that only the minimum frequency of individuals with each anomaly is depicted because all children were not systematically evaluated for such features as short palpebral fissures, ptosis, and strabismus as well as joint anomalies and cardiac murmurs. Regarding the incidence of the fetal alcohol syndrome 6 of the 19 ( 3 2 % ) surviving children born to chronically alcoholic women had enough abnormal features to suggest the possibility of the syndrome from the physical findings alone, whereas not one of the matched controls was so affected. The frequency of adverse outcome of pregnancy for chronically alcoholic women from this study was 43% (4 who died in the perinatal period and 6 with the fetal alcohol syndrome) as opposed to 2 % of their controls. Because of the magnitude of this risk it is recommended that serious consideration be given to early termination of pregnancy in severely chronically alcoholic women. DISCUSSION
The similarity in the overall pattern of anomalies in these children suggests a single etiology, most likely environmentally determined, by some as yet unknown effect of maternal metabolism. Regarding direct toxicity to the developing fetus the most obvious possibility is ethanol itself.
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There is good evidence in human beings and other animals that ethanol freely crosses the placenta (Waltman and Iniquez, '72). Animal studies have shown it to be distributed in the amniotic fluid and throughout multiple fetal tissues, at least during late gestation (Ho et al., '72). Other possibilities involving direct toxicity include one of the breakdown products of ethanol such as acetaldehyde or an unknown toxic agent in the alcoholic beverages the mothers were consuming. The adverse affect on growth and morphogenesis could also be the indirect consequence of generalized maternal undernutrition or deficiency of a specific nutrient or vitamin. However, neither this degree nor this pattern (birth length more severely affected than birth weight) of growth deficiency nor the pattern of malformation herein described have been reported in offspring of severely undernourished nonalcoholic women (Smith, '47). Further studies are now clearly needed to examine the amount and duration of maternal alcoholism necessary to result in offspring with the fetal alcohol syndrome. All affected children recognized to date have been the offspring of severely chronically alcoholic women who drank heavily throughout pregnancy. In addition the total spectrum of the disorder needs to be more fully delineated. Experience with other environmental teratogens would lead one to expect variable seventy of this pattern of malformation and function in offspring of chronic alcoholic women. Finally, basic studies must be performed with respect to the specific cause and possible prevention of this tragic disorder. ACKNOWLEDGMENTS
The authors wish to thank Dr. Richard Leech for interpretation of the neuropathological specimens, Mrs. Lyle Harrah and Mrs. Mary Ann Harvey for the library research studies, Mr. Bradley Gong for photography, and Mrs. Beverly Gonsowski and Mrs. Christine Hansen for secretarial assistance. LITERATURE CITED Christiaens, L., J . P. Mizon and G. Delmarle 1960 Sur l a descendance des alcoholiques. Ann. Pi. diat., 36: 37-42.
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KENNETH L. JONES AND DAVID W. SMITH
Ferrier, P. E., I . Nicod and S. Ferrier 1973 Fetal alcohol syndrome. Lancet, 2: 1496. Haggard, H. W., and E. M . Jellinek 1942 Alcohol Explored. Doubleday, Doran, New York. Hall, B. D., a n d W. A. Orenstein 1974 Noonan’s phenotype in a n offspring of a n alcoholic mother. Lancet, I : 680. Ho, B. T., G . E. Fritchie, J . E. Idanpaan-Heikkila and W. M. Moissac 1972 Q. J . Stud. Alcohol, 39: 48-94, Jones, K. L., and D. W. Smith 1973 Recognition of the fetal alcohol syndrome in early infancy. Lancet. 2: 999-1001. Jones, K. L., D. W. Smith, A. P . Streissguth a n d N . C. Myrianthopoulous 1974 Outcome i n offspring of chronic alcoholic women. Lancet, 1 . 107€&1078. Jones, K. L., D. W. Smith, C. W. Ulleland a n d A. P. Streissguth 1973 Pattern of malformation in offspring of chronic alcoholic women. Lancet, I : 1267-1271. Ladraque, P. 1901 Alcoholism et Enfants. Steinheil, Paris. Lecomte, M. 1950 Elements d’heredopathologie. Scalpel, 103: 1133-1145. Lemoine, P . , H. Harousseau, J . P. Borteyru, J . C. Menuet 1967 Les enfants de parents alcohol-
iques: anomalies observees a propos de 127 cas. Arch. Fr. Pediat., 25: 830-832. Palmer, R. H., E. M. Ouellette, L. Warner and S. R. Leichtman 1974 Congenital malformations i n offspring of a chronic alcoholic mother. Pediatrics, 53: 49G494. Roe, A. 1944 The adult adjustment of children of alcoholic parents raised in foster homes. Q. J. Stud. Alcohol., 5: 378-393. Sandor, S. 1968a T h e influence of aethyl-alcohol on the development of t h e chick embryo. Rev. Roum. Embryol. Cytol., Ser. Embryol., 5: 51-76. 1968b The influence of aethyl-alcohol o n the developing chick embryo. Rev. Roum. Embryol. Cytol., Ser. Embryol., 5: 167-171. Sandor, S . , a n d D. Amels 1971 The action of aethanol on the praenatal development of albino rats. Rev. Roum. Embryol. Cytol., Ser. Embryol., 8: 1 0 S 1 1 8 . Smith, C. J . 1947 Effects of maternal undernutrition upon the newborn infants in Holland (1944-1945). Pediatrics, 30: 2 2 S 2 4 3 . Sullivan, W. C. 1900 T h e children of the female drunkard. Med. Temp. Rev., 1 : 72-79. Waltman, R., and E. S . Iniquez 1972 Placental transfer of ethanol and its elimination a t term. Obst. Gyn., 40. 180-185.
