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Cyclopia and other anomalies following maternal ingestion of salicylates
Volume 96 Number 6
Brief clinical and laboratory observations
and child, a l t h o u g h the familial cases usually occur in siblings. 1~This would be analogous to the congenital form of m y o t o n i c dystrophy, w h i c h is attributed to the comb i n e d effect of a m a t e r n a l i n t r a u t e r i n e factor which affects the fetus w h o has also inherited from the m o t h e r the d o m i n a n t gene for myotonic dystrophy; such infants have m a r k e d muscle weakness a n d flexion contractures. 1~ Our thanks to Ann Stark, M.D., for referring this patient, to Roger Williams, M.D., for helpful suggestions, and to James Peter, M.D., Ph.D., for the assay of the antibodies to acetylcholine receptors.
REFERENCES 1. Namba T, Brown SB, and Grob D: Neonatal myasthenia gravis: report on two cases and review of the literature, Pediatrics 45:488, 1970. 2. Shepard MK: Arthrogryposis multiplex congenita in sibs, Birth Defects 7:127, 1971. 3. Holmes LB: The malformed newborn: Practical perspectives, distributed by the Massachusetts Developmental Disabilities Council, t976.
4.
5.
6.
7.
8. 9.
10.
11.
10 6 9
Mease AD, Yeatman GW, and Pettett G: A syndrome of ankylosis, facial anomalies and pulmonary hypoplasia secondary to fetal neuromuscular dysfunction, Birth Defects 12:193, 1976. Dimmick JE, Berry K, Macleod PM, and Hardwick DF: Syndrome of ankylosis, facial anomalies, and pulmonary hypoplasia: a pathologic analysis of one infant, Birth Defects 13:133, 1977. Smith DW, Clarren SK, and Se,dgwick Harvey MA: Hyperthermia as a possible teratogenic agent, J PEDIAI-R 92:878, 1978. Toyka KV, Drachman DB, Griffin DE, et al: Myasthenia gravis. Study of humorat immune mechanisms by passive transfer of mice, N Engl J Med 296:125, 1977. Drachman DB, and Sokotoff L: The role of movement in embryonic joint development, Dev Biol 14-401, 1966. Jago RH: Arthrogryposis following treatment of maternal tetanus with muscle relaxants, Arch Dis Child 45:277, 1970. Namba T, Brunner NG, Brown SB, Muguruma M, and Grob D: Familial myasthenia gravis, Report of 27 patients in 12 families and review of 164 patients in 73 families, Arch Neurol 25:49, 1970. Dyken PR, and Harper PS: Congenital dystrophia myotonica, Neurology 23:465, 1973.
Cyclopia and other anomalies following maternal ingestion of salicylates Raghbir Benawra, M.D., Henry H. Mangurten, M.D.,* and David R. Duffell, M.D., Park Ridge and Arlington Heights, Ill.
THE TERATOGENIC POTENTIAL o f salicylate has b e e n described in a n i m a l studies, 1-~ a n d several retrospective h u m a n studies also have implicated the teratogenic effects of sMicylate? 5 A recent study by Slone et al 6 has questioned this relationship, a l t h o u g h the authors did not eliminate the possibility o f grossly excessive ingestion as b e i n g teratogenic. Corb S indicated that the answer to the question o f salicylate teratogenicity in the h u m a n m a y n e v e r be answered because o f the inability to study this prospectively in m a n . W e recently saw a n i n f a n t with cyclopia a n d other significant a n o m a l i e s whose m o t h e r h a d taken aspirin daily t h r o u g h o u t the first trimester o f pregnancy. Because of the c o n t i n u e d uncertainty regarding the role o f aspirin in i n d u c i n g a n o m a l i e s in man, we are p r o m p t e d to add this report.
From the Section of Neonatology, Lutheran General Hospital, and the Department of Pathology, Northwest Community Hospital. *Reprint address: High-Risk Nursery, Lutheran General Hospital, 1775 West Dempster, Park Ridge, IL 60068.
0022-3476/80/061069+03500.30/0 9 1980 The C. V. Mosby Co.
CASE R E P O R T This 1,500 gm boy was born at term to a 20-year-old gravida 2, para 0, abortus 1, mother. Because of intrauterine growth retardation, rubella and other congenital infection titers were performed during the pregnancy and found to be negative. The mother had a history of self-diagnosed "migraine" for the preceding six years, for which she had taken self-prescribed aspirin 10 to 15 tablets (3 to 4.5 gin) daily. She continued the above regimen during the first trimester of this pregnancy, following which she switched to acetaminophen 6 to 10 tablets daily. No other drugs were ingested during the pregnancy. She also smoked two packs of cigarettes per day. Labor was uneventful. Acesarean section was performed because of breech presentation. The infant was cyanotic and flaccid, with absent cry and reflexes. Examination of the head revealed cyclopia. There was a 2 x 0.5 cm rudimentary cleft in the central area of the face, through which neural tissue could be seen. Above this cavity was a polypoid proboscis (Fig. 1). There was a duplication of the phallus and an imperforate anus (Fig. 2). Bilateral talipes equinovarus was noted. The infant had poor respiratory effort, and died at 1% hours of age. Cardiac blood obtained immediately postmorte/n subsequently revealed normal chromosomes.
10 7 0
Brief clinical and laboratory observations
Fig. 1. View of the head, indicating cyclopia, bulging and soft frontal area, rudimentary cleft in central area of face, and polypoid proboscis, AUTOPSY
FINDINGS
The head circumference was 30.5 cm, with crown-heel length 39.3 cm. The frontal bones were absent, and the brain was in the form of a mass that appeared to represent fused cerebral hemispheres. There was a single ventricle with absent corpus callosum. The midbrain and cerebellum appeared intact. The pituitary gland was not identified. The lungs were atelectatic, and the heart revealed the right atrium to be markedly dilated with a thickened wall; the tricuspid valve was absent, and there was a small rudimentary r i g h t ventricle. The gastrointestinal tract appeared normal except for a 1 cm area of constriction in the distal rectum, with a blind ending at this point. Both kidneys and ureters were absent; a small bladder was identified. The testes appeared normal. The umbilical cord was located paracentrally; only two umbilical vessels were identified. DISCUSSION Various authors have implicated transplacental exposure to salicylates as a cause of congenital anomalies in both humans and animals. Warkany and Takacs 1 induced congenital malformations in rats by administering high doses of salicylate to pregnant rats during early stages of gestation; the most striking anomaly was craniorachischisis, an important finding since the origin of this lesion is closely related to anencephaly, exencephaly, spina bifida,
The Journal of Pediatrics June 1980
Fig. 2. View of genitalia and anal area, revealing duplication of phallus and imperforate anus.
and possibly cyclopia. Anomalies less frequently found in this study included exencephaly, facial clefts, eye defects, gastroschisis, and irregularities of the vertebrae, and ribs. Other animal studies that have demonstrated similar results following salicylate injection of the pregnant mother have been performed by Trasler ~ and by Larsson and Eriksson. 3 Although a number of authors have strongly incriminated salicylate as a cause of congenital anomalies in human offspring, several others have presented conflicting data. The strongest evidence against the role of aspirin in teratogenicity was recently presented by Slone et al. GIn a large collaborative study, they concluded that aspirin ingestion during pregnancy is not associated with congenital anomalies. However, women who were considered to have had "heavy exposure" to aspirin were defined as those who took aspirin for at least eight days during at least one of the first four months of pregnancy. These authors in fact allowed the possibility that more excessive ingestion might be teratogenic. McNieP reported eight infants whose mothers had ingested aspirin or other salicylate-containing medications during the first trimester; all had significant congenital anomalies, including one with anencephaly. Nelson and Forfar 4 found an increased incidence of significant malformations in infants of mothers who ingested aspirin during the first month of pregnancy. The infant described in the current report was born to a
Volume 96 Number 6
mother who ingested aspirin throughout the first trimester. Although she also took acetaminophen, this was not ingested until the second trimester, following discontinuation of aspirin therapy. She also smoked heavily throughout the pregnancy, but there are no reports relating smoking during pregnancy to congenital anomalies. Cyclopia has received considerable attention because of the relatively high incidence in other mammals and the ease of experimental production of this lesion in lower animal forms. Agents which have induced this malformation in animals include magnesium salts, alcohol, lithium chloride, vitamin A, triparanol (an agent that inhibits cholesterol synthesis), and radiation? In human beings, cyclopia may occur sporadically or in association with a variety of chromosomal abnormalities, especially D trisomy. 9 No reports have been cited relating cyclopia to salicylate or other drugs ingested by the mother. Because of the normal cytogenetic studies in our infant, in association with daily maternal ingestion of aspirin early in pregnancy, we believe that cyclopia and possibly the other malformations were secondary to the effects of salicylate, though a coincidental occurrence cannot be ruled out. Although not specifically reported to produce cyclopia in experimental animals, salicylates have been found to cause other central nervous system malformations, e.g., craniorachischisis, anencephaly, exencephaly, and hydrocephaly? The presence of imperforate anus is of interest in view of Potter and Craig's TM observation that malformations of the visceraare common in cyclopia. The finding of absent kidneys and ureters is compatible with a recent study by Woo and Hoar, 1~in which rats exposed to
Brief clinical and laboratory observations
10 7 1
salicylate early in gestation were found to have increased incidence of retarded renal development and permanent renal abnormalities. The authors gratefully acknowledge the secretarial assistance of Mrs. Mary Lou Mumford. REFERENCES
1. Warkany J, and Takacs E: Experimental production of congenital malformations in rats by salicylate poisoning, Am J Pathol 35:315, 1959. 2. Trasler DG: Aspirin-induced cleft lip and other malformations in mice, Lancet 1:606, 1965. 3. LarssonKS, and Eriksson M: Salicylate-induced fetal death and malformations in two mouse strains, Acta Paediatr Scand 55:569, 1966. 4. Nelson MM, and Forfar JO: Associations between drugs administered during pregnancy and congenital abnormalities of the fetus, Br Med J 1:523, 1971. 5. McNielJR: The possible teratogenic effect of salicylates on the developing fetus, Clin Pediatr 12:347, 1973. 6. SloneD, Heinonen OP, Kaufman DW, et al: Aspirin and congenital malformations, Lancet 1:1373, 1976. 7. Corby DG: Aspirin in pregnancy: Maternal and fetal effects, Pediatrics 62:(Suppl):930, 1978. 8. Warkany J: Cyclopia, in Warkany J: Congenital malformations. Notes and comments, Chicago, 1971, Year Book Medical Publishers, Inc., pp 202-205. 9. BergsmaDR: Cyclopia, in Birth defects atlas and compendium, Washington, D.C., 1973, The National Foundation, p 317. 10. Potter EL, and Craig JM: Pathology of the fetus and the infant, ed 3, Chicago, 1975, Year Book Medical Publishers Inc., p 530. II. Woo DC, and Hoar RM: Apparent hydronephrosis as a normal aspect of renal development in late gestation of rats: The effects of methyl salicylate, Teratology 66:191, 1972.
Neurologic complicationsfollowing temporal artery catheterization Marilyn J. Bull, M.D., Richard L. Schreiner, M.D.,* Bhuwan P. Garg, M,D., Nancy M. Hutton, James A. Lemons, M.D., and Edwin L. Gresham, M.D., Indianapolis, Ind
SEVERE RESPIRATORY DISTRESS in the newborn infant requires frequent monitoring of arterial Po~, Pco~, and pH. Although transcutaneous Po~ monitoring is From the Departments of Pediatrics and Neurology, Indiana University School of Medicine. Presented in part at the Midwest Society Jbr Pediatric Research, October 30-31, 1979, Cincinnati, Ohio. *Reprint address: Department of Pediatrics, Indiana University School of Medicine, 1100 West Michigan St., Indianapolis, IN 46223.
0022-3476/80/061071 +03500.30/0 9 1980 The C. V. Mosby Co.
useful in the management of these neonates, it has not replaced the need for frequent arterial blood sampling. Arterial cannulation is, therefore, often required for monitoring arterial oxygen concentration in the most severely ill infants. Suggested sites for the arterial lines
I
Abbreviations used TAC: temporal artery cutdown CAT: computerized axial tomography
I
Brief clinical and laboratory observations
and child, a l t h o u g h the familial cases usually occur in siblings. 1~This would be analogous to the congenital form of m y o t o n i c dystrophy, w h i c h is attributed to the comb i n e d effect of a m a t e r n a l i n t r a u t e r i n e factor which affects the fetus w h o has also inherited from the m o t h e r the d o m i n a n t gene for myotonic dystrophy; such infants have m a r k e d muscle weakness a n d flexion contractures. 1~ Our thanks to Ann Stark, M.D., for referring this patient, to Roger Williams, M.D., for helpful suggestions, and to James Peter, M.D., Ph.D., for the assay of the antibodies to acetylcholine receptors.
REFERENCES 1. Namba T, Brown SB, and Grob D: Neonatal myasthenia gravis: report on two cases and review of the literature, Pediatrics 45:488, 1970. 2. Shepard MK: Arthrogryposis multiplex congenita in sibs, Birth Defects 7:127, 1971. 3. Holmes LB: The malformed newborn: Practical perspectives, distributed by the Massachusetts Developmental Disabilities Council, t976.
4.
5.
6.
7.
8. 9.
10.
11.
10 6 9
Mease AD, Yeatman GW, and Pettett G: A syndrome of ankylosis, facial anomalies and pulmonary hypoplasia secondary to fetal neuromuscular dysfunction, Birth Defects 12:193, 1976. Dimmick JE, Berry K, Macleod PM, and Hardwick DF: Syndrome of ankylosis, facial anomalies, and pulmonary hypoplasia: a pathologic analysis of one infant, Birth Defects 13:133, 1977. Smith DW, Clarren SK, and Se,dgwick Harvey MA: Hyperthermia as a possible teratogenic agent, J PEDIAI-R 92:878, 1978. Toyka KV, Drachman DB, Griffin DE, et al: Myasthenia gravis. Study of humorat immune mechanisms by passive transfer of mice, N Engl J Med 296:125, 1977. Drachman DB, and Sokotoff L: The role of movement in embryonic joint development, Dev Biol 14-401, 1966. Jago RH: Arthrogryposis following treatment of maternal tetanus with muscle relaxants, Arch Dis Child 45:277, 1970. Namba T, Brunner NG, Brown SB, Muguruma M, and Grob D: Familial myasthenia gravis, Report of 27 patients in 12 families and review of 164 patients in 73 families, Arch Neurol 25:49, 1970. Dyken PR, and Harper PS: Congenital dystrophia myotonica, Neurology 23:465, 1973.
Cyclopia and other anomalies following maternal ingestion of salicylates Raghbir Benawra, M.D., Henry H. Mangurten, M.D.,* and David R. Duffell, M.D., Park Ridge and Arlington Heights, Ill.
THE TERATOGENIC POTENTIAL o f salicylate has b e e n described in a n i m a l studies, 1-~ a n d several retrospective h u m a n studies also have implicated the teratogenic effects of sMicylate? 5 A recent study by Slone et al 6 has questioned this relationship, a l t h o u g h the authors did not eliminate the possibility o f grossly excessive ingestion as b e i n g teratogenic. Corb S indicated that the answer to the question o f salicylate teratogenicity in the h u m a n m a y n e v e r be answered because o f the inability to study this prospectively in m a n . W e recently saw a n i n f a n t with cyclopia a n d other significant a n o m a l i e s whose m o t h e r h a d taken aspirin daily t h r o u g h o u t the first trimester o f pregnancy. Because of the c o n t i n u e d uncertainty regarding the role o f aspirin in i n d u c i n g a n o m a l i e s in man, we are p r o m p t e d to add this report.
From the Section of Neonatology, Lutheran General Hospital, and the Department of Pathology, Northwest Community Hospital. *Reprint address: High-Risk Nursery, Lutheran General Hospital, 1775 West Dempster, Park Ridge, IL 60068.
0022-3476/80/061069+03500.30/0 9 1980 The C. V. Mosby Co.
CASE R E P O R T This 1,500 gm boy was born at term to a 20-year-old gravida 2, para 0, abortus 1, mother. Because of intrauterine growth retardation, rubella and other congenital infection titers were performed during the pregnancy and found to be negative. The mother had a history of self-diagnosed "migraine" for the preceding six years, for which she had taken self-prescribed aspirin 10 to 15 tablets (3 to 4.5 gin) daily. She continued the above regimen during the first trimester of this pregnancy, following which she switched to acetaminophen 6 to 10 tablets daily. No other drugs were ingested during the pregnancy. She also smoked two packs of cigarettes per day. Labor was uneventful. Acesarean section was performed because of breech presentation. The infant was cyanotic and flaccid, with absent cry and reflexes. Examination of the head revealed cyclopia. There was a 2 x 0.5 cm rudimentary cleft in the central area of the face, through which neural tissue could be seen. Above this cavity was a polypoid proboscis (Fig. 1). There was a duplication of the phallus and an imperforate anus (Fig. 2). Bilateral talipes equinovarus was noted. The infant had poor respiratory effort, and died at 1% hours of age. Cardiac blood obtained immediately postmorte/n subsequently revealed normal chromosomes.
10 7 0
Brief clinical and laboratory observations
Fig. 1. View of the head, indicating cyclopia, bulging and soft frontal area, rudimentary cleft in central area of face, and polypoid proboscis, AUTOPSY
FINDINGS
The head circumference was 30.5 cm, with crown-heel length 39.3 cm. The frontal bones were absent, and the brain was in the form of a mass that appeared to represent fused cerebral hemispheres. There was a single ventricle with absent corpus callosum. The midbrain and cerebellum appeared intact. The pituitary gland was not identified. The lungs were atelectatic, and the heart revealed the right atrium to be markedly dilated with a thickened wall; the tricuspid valve was absent, and there was a small rudimentary r i g h t ventricle. The gastrointestinal tract appeared normal except for a 1 cm area of constriction in the distal rectum, with a blind ending at this point. Both kidneys and ureters were absent; a small bladder was identified. The testes appeared normal. The umbilical cord was located paracentrally; only two umbilical vessels were identified. DISCUSSION Various authors have implicated transplacental exposure to salicylates as a cause of congenital anomalies in both humans and animals. Warkany and Takacs 1 induced congenital malformations in rats by administering high doses of salicylate to pregnant rats during early stages of gestation; the most striking anomaly was craniorachischisis, an important finding since the origin of this lesion is closely related to anencephaly, exencephaly, spina bifida,
The Journal of Pediatrics June 1980
Fig. 2. View of genitalia and anal area, revealing duplication of phallus and imperforate anus.
and possibly cyclopia. Anomalies less frequently found in this study included exencephaly, facial clefts, eye defects, gastroschisis, and irregularities of the vertebrae, and ribs. Other animal studies that have demonstrated similar results following salicylate injection of the pregnant mother have been performed by Trasler ~ and by Larsson and Eriksson. 3 Although a number of authors have strongly incriminated salicylate as a cause of congenital anomalies in human offspring, several others have presented conflicting data. The strongest evidence against the role of aspirin in teratogenicity was recently presented by Slone et al. GIn a large collaborative study, they concluded that aspirin ingestion during pregnancy is not associated with congenital anomalies. However, women who were considered to have had "heavy exposure" to aspirin were defined as those who took aspirin for at least eight days during at least one of the first four months of pregnancy. These authors in fact allowed the possibility that more excessive ingestion might be teratogenic. McNieP reported eight infants whose mothers had ingested aspirin or other salicylate-containing medications during the first trimester; all had significant congenital anomalies, including one with anencephaly. Nelson and Forfar 4 found an increased incidence of significant malformations in infants of mothers who ingested aspirin during the first month of pregnancy. The infant described in the current report was born to a
Volume 96 Number 6
mother who ingested aspirin throughout the first trimester. Although she also took acetaminophen, this was not ingested until the second trimester, following discontinuation of aspirin therapy. She also smoked heavily throughout the pregnancy, but there are no reports relating smoking during pregnancy to congenital anomalies. Cyclopia has received considerable attention because of the relatively high incidence in other mammals and the ease of experimental production of this lesion in lower animal forms. Agents which have induced this malformation in animals include magnesium salts, alcohol, lithium chloride, vitamin A, triparanol (an agent that inhibits cholesterol synthesis), and radiation? In human beings, cyclopia may occur sporadically or in association with a variety of chromosomal abnormalities, especially D trisomy. 9 No reports have been cited relating cyclopia to salicylate or other drugs ingested by the mother. Because of the normal cytogenetic studies in our infant, in association with daily maternal ingestion of aspirin early in pregnancy, we believe that cyclopia and possibly the other malformations were secondary to the effects of salicylate, though a coincidental occurrence cannot be ruled out. Although not specifically reported to produce cyclopia in experimental animals, salicylates have been found to cause other central nervous system malformations, e.g., craniorachischisis, anencephaly, exencephaly, and hydrocephaly? The presence of imperforate anus is of interest in view of Potter and Craig's TM observation that malformations of the visceraare common in cyclopia. The finding of absent kidneys and ureters is compatible with a recent study by Woo and Hoar, 1~in which rats exposed to
Brief clinical and laboratory observations
10 7 1
salicylate early in gestation were found to have increased incidence of retarded renal development and permanent renal abnormalities. The authors gratefully acknowledge the secretarial assistance of Mrs. Mary Lou Mumford. REFERENCES
1. Warkany J, and Takacs E: Experimental production of congenital malformations in rats by salicylate poisoning, Am J Pathol 35:315, 1959. 2. Trasler DG: Aspirin-induced cleft lip and other malformations in mice, Lancet 1:606, 1965. 3. LarssonKS, and Eriksson M: Salicylate-induced fetal death and malformations in two mouse strains, Acta Paediatr Scand 55:569, 1966. 4. Nelson MM, and Forfar JO: Associations between drugs administered during pregnancy and congenital abnormalities of the fetus, Br Med J 1:523, 1971. 5. McNielJR: The possible teratogenic effect of salicylates on the developing fetus, Clin Pediatr 12:347, 1973. 6. SloneD, Heinonen OP, Kaufman DW, et al: Aspirin and congenital malformations, Lancet 1:1373, 1976. 7. Corby DG: Aspirin in pregnancy: Maternal and fetal effects, Pediatrics 62:(Suppl):930, 1978. 8. Warkany J: Cyclopia, in Warkany J: Congenital malformations. Notes and comments, Chicago, 1971, Year Book Medical Publishers, Inc., pp 202-205. 9. BergsmaDR: Cyclopia, in Birth defects atlas and compendium, Washington, D.C., 1973, The National Foundation, p 317. 10. Potter EL, and Craig JM: Pathology of the fetus and the infant, ed 3, Chicago, 1975, Year Book Medical Publishers Inc., p 530. II. Woo DC, and Hoar RM: Apparent hydronephrosis as a normal aspect of renal development in late gestation of rats: The effects of methyl salicylate, Teratology 66:191, 1972.
Neurologic complicationsfollowing temporal artery catheterization Marilyn J. Bull, M.D., Richard L. Schreiner, M.D.,* Bhuwan P. Garg, M,D., Nancy M. Hutton, James A. Lemons, M.D., and Edwin L. Gresham, M.D., Indianapolis, Ind
SEVERE RESPIRATORY DISTRESS in the newborn infant requires frequent monitoring of arterial Po~, Pco~, and pH. Although transcutaneous Po~ monitoring is From the Departments of Pediatrics and Neurology, Indiana University School of Medicine. Presented in part at the Midwest Society Jbr Pediatric Research, October 30-31, 1979, Cincinnati, Ohio. *Reprint address: Department of Pediatrics, Indiana University School of Medicine, 1100 West Michigan St., Indianapolis, IN 46223.
0022-3476/80/061071 +03500.30/0 9 1980 The C. V. Mosby Co.
useful in the management of these neonates, it has not replaced the need for frequent arterial blood sampling. Arterial cannulation is, therefore, often required for monitoring arterial oxygen concentration in the most severely ill infants. Suggested sites for the arterial lines
I
Abbreviations used TAC: temporal artery cutdown CAT: computerized axial tomography
I