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The Thalidomide tragedy and the birth of experimental teratology

P.H. Saldanha

Unidade de Aconselhamento Genético, Instituto de Biociências, Universidade de São Paulo, Caixa Postal 11461, 05422-970 São Paulo, SP, Brasil

ABSTRACT

The history of the "Thalidomide Tragedy" is analyzed from the initial use of the drug in West Germany, followed by its commercialization in various European countries, as well as the prohibition of its fabrication in the U.S.A.
Initially indicated as a "panacea" for several ills, thalidomide was widely consumed by pregnant women, causing the greatest iatrogenic epidemic in medical history from the end of the 1950's until its teratogenic activity was suspected, on an epidemiologic basis, by Lenz and McBride, published in November 1961; about 10,000 victims resulted on a worldwide basis.
Besides its considerable teratological effects, this drug also had revolutionary effects on the methodological evolution of epidemiological surveys, anamnestic techniques, and, principally, on the evaluation of embriotoxic effects of new medicat ions and therapeutic agents used by pregnant patients, establishing the modern basis of experimental teratology. This is placed in perspective along the development of science as a response to practical problems.
The epidemiology of congenital malformations of both genetic and exogenous origin is reviewed, especially those caused by drugs and medicines responsible for numerous malformation and syndromes, such as thalidomide syndrome.
The "Thalidomine Tragedy" in Brazil is viewed, based on the legal trial made by the victims, including a historical analysis, from the introduction of medications containing thalidomide, its commercialization, and the founding of associations to aid the victims.
The differential diagnosis of thalidomide syndrome is discussed, along with the associated malformations and congenital defects present in the 252 compensation claim cases, analyzing the types and severity of the malformations, the medicine used, the epidemiological evolution, and the geographic distribution of "Thalidomide Syndrome" patients within Brazil.

Keywords: Thalidomide; birth; experimental teratology.

REFERENCES

Andrei, E. (1959-1964). Compêndio Médico (1^a, 2^a, 3^a, 4^a e 5^a eds.). Organização Andrei, São Paulo.

Bergsma, D. (1979). Birth Defects Compendium. 2nd. edn. Alan R. Liss, New York.

Birch-Jensen, A. (1949). Congenital deformities of the upper extremities. Opera Ex Domo Biol. Hered. Hum. Univ. Hafn., vol. 19. Ejnar Munksgaard, Copenhage.

Brent, R.L. (1986). Methods of evaluating the alleged teratogenicity of environmental agents. In: Teratogen Update: Environmentally Induced Birth Risks (Server, J.L. and Brent, R.L., eds.). Alan R. Liss, New York, pp. 199-201.

Brent, R.L. (1993). Congenital malformation case report: The Editor's and Reviewer's Dilemma. Amer. J. Med. Genet. 47: 872-874.

Budavari, S. (1989). The Merck Index. 11th. edn. Rahway, N.J., Merck & Co., pp. 1458.

Burley, D. (1961). Neuropathy after thalidomide ("Distival"). Brit. Med. J. 2: 1268.

Burns, J.J. (1970). Pharmacological aspects of Teratology. Congenital Malformations (Clarke-Fraser, F. and McKusick, V.A., eds.). Proceedings of the III International Conference. The Hague, The Netherlands, 7-13 september, 1969. Excepta Medica, Amsterdam, pp. 173-179.

Clarke-Fraser, F. (1964). Experimental teratogenesis in relation to congenital malformations in man. In: Congenital Malformations. (Fishbein, M., ed.). Proceedings of the II International Conference, New York, 14-19 July, 1963). International Medical Congress, New York, pp. 277-287.

Delahunt, C.S. and Lassen, L.J. (1964). Thalidomide syndrome in monkeys. Science 146: 1300-1305.

Dyban, A.P. and Akimova, I.M. (1966). Significance of vitamin B complex and genetic factors in relation to thalidomide in rat embryos. Arch. Anat. 51: 3-17 (em russo: Apud Shepard, 1983).

Ellenhorn, M.J. (1964). The FDA and the prevention of drug embryopathy. Bull. New York Acad. Med. 40: 661.

Fabro, S. (1981). Biochemical basis of thalidomide teragenicity. In: Biochemical Basis of Chemical Teratogenesis (Juchav, R.R., ed.). Elsevier-North-Holland, New York, pp. 157-178 (Apud Shepard, 1983).

Florence, A.L. (1960). Is thalidomide to blame? Brit. Med. J. 2: 1954. Freire-Maia, N., Quelce-Salgado, A. and Koehler, R.A. (1959).

Hereditary bone aplasias and hypoplasia of the upper extremities. Acta Genet. 9: 33-40.

Giroud, A.H., Tuchmann-Duplessis and Mercier-Parot, L. (1962). Observations sur les repercussions tératogenes de la thalidomide chez la souris et le lapin. Compt. Rend. Séanc. Soc. Biol. 156: 765-768.

Gordon, G.B., Spielberg, S.P., Blake, D.A. and Balasubramonian, V. (1981). Thalidomide teratogenesis: evidence for a toxic arene oxide metabolite. Proc. Natl. Acad. Sci. 78: 2545-2548. (Apud Shepard, 1983).

Grouchy, J. and Turleau, C. (1977). Clinical Atlas of Human Chromosomes. John Wiley, New York.

Henkel, L. and Willert, H.G. (1969). Dysmelia - a classification and a pattern of malformation in a group of congenital defects of the limbs. J. Bone Jt. Surg. 51b: 399-414.

Hill, L.L. (1937). Congenital abnormalit ies-phocomelus and congenital absence of radius. Surgery, Gynecology and Obstetrics 65: 475-479

Homi, C. (1920). A case of phocomelus. Lancet ii: 128.

Iffy, L., Shepard, T.H., Jacobovitz, A., Lemire, R.J. and Kerner, P. (1967). The rate of growth in young human embryos of streeters horizons XIII to XXIII. Acta Anat. 66: 178-186. (Apud Shepard, 1983).

Jonsson, N.A., Mikiver, L. and Selberg, V. (1972). Chemical structure and teratogenic properties. II. Synthesis and teratogenic activity on rabbits of some derivatives of phthalimide, isoindoline-1-one, 1,2benzisothiazoline-3-onel, 1-dioxide and 4(3H) quinazolinenone. Acta Pharmacol. Sueca 9: 431-446. (Apud Shepard, 1983).

Kelsey, F.O. (1965). Problems raised for the FDA by the occurrence of thalidomide embryopathy in Germany, 1960-1961. Amer. J. Publ. Health 55: 703-707.

Knapp, K., Lenz, W. and Nowack, E. (1962). Multiple congenital abnormalities. Lancet ii: 725.

Laredo, J., Cunha, A.J.B., Brunoni, D., Rosenfeld, G. and Bonfim, R. (1974). Apresentação de um caso recente de síndrome da talidomida em decorrência de sua utilização ein pacientes com lepra. Ciênc. Cult. 26 (supl.): 233-234.

Lenz, W. (1961a). Diskussionsbemerkung zu dem Vortrag von R.A. Pfeiffer und K. Kasenow: Zur Frage dex exogenen Enstehung Schwerer Extremitätemnissbildungen. Tagung der Rheinischwestfälischen Kinderärztevereinigung in Düsseldorf 19: 11.

Lenz, W. (1961b). Lindliche Missbildung nach Medicamenten- Einnahme Während der gravidität? Deutsch Med. Wochens. 86: 2555.

Lenz, W. (1962). Thalidomide and congenital abnormalities. Lancet i: 45.

Lenz, W. (1964). Chemicals and malformations in man. In: Congenital Malformations (Fishbein, M., ed.). Proceedings of the II International Conference, 14-19 July, 1963, International Medical Congress, New York, pp. 263-276.

Lenz, W. (1965). Epidemiology of congenital malformations. Ann. New York Acad. Sci. 123: 228-236.

Lenz, W. (1966). Malformations caused by drugs in pregnancy. Amer. J. Dis. Child. 112: 99-106.

Lenz, W. and Knapp, K. (1962a). Foetal malformations due to thalidomide. German Med. Mont. 7: 253-256.

Lenz, W. and Knapp, K. (1962b). Thalidomide embriopathy. Arch. Environ. Health 5: 100-105.

McBride, W.G. (1961). Thalidomide and congenital abnormalities. Lancet ii: 1358.

McBride, W.G. (1974). Fetal nerve cell degeneration produced by thalidomide in rabbits. Teratology 10: 283-292.

McKusick, V.A. (1992). Mendelian Inheritance in Man (Catalog of Autosomal Dominant, Autosomal Recessive, and X-Linked Phenotypes). 10th edn. The Johns Hopkins University Press, Baltimore.

Mellin, G.W. and Katzenstein, M. (1962a). The saga of Thalidomide. Engl. J. Med. 267: 1184-1193.

Mellin, G.W. and Katzenstein, M. (1962b). the saga of Thalidomide (Concluded). New Engl. J. Med. 267: 1238-1244.

Miller, O.J. (1979). Genetic problems related dto reproduction. In: Counseling in Genetics (Hsia, Y.E., Hirschhorn, K., Silverberg, R.L. and Godmilow, L., eds.). Alan R. Liss, New York, pp. 81-109.

Nesbit, R.E.L. (1962). Abnormalities and diseases of the placenta and appendages (other than hydatiform mole and chlorionepithelioma). In: Gynecologic and Obstetric Pathology (Novak, E.R. and Woodruff, J.D., eds.). W.B. Saunders, Philadelphia, pp. 505-506.

Neubert, D. and Köhler, F. (1970). Hypothetical explanation of the embryotoxic action of thalidomide. Exp. Pharm. 266: 408-409.

Persaud, T.V.N. (1977). Problems of Birth Defects (from Hippocrates to Thalidomide and After). MTP Press, Lancaster, England. Pfeiffer, R.A. and Kasenow, W. (1962). Thalidomide and congenital abnormalities. Lancet i: 45-46.

Pliess, G. (1962). Thalidomide and congenital malformations. Lancet ii: 1128.

Saldanha, P.H. (1962a). Aspectos genéticos da teratologia humana. Rev. Paul. Med. 61: 368-382.

Saldanha, P.H. (1962b). Freqüência de deformidades dos membros na população de São Paulo. Ciênc. Cult. 14: 161.

Saldanha, P.H. (1964a). Frequency of congenital malformations in mixed populations of Southern Brazil. In: Congenital Malformations (Fishbein, M., ed.). Proceedings of the II International Conference, New York, 14-19 July, 1963. Internacional Medical Congress, New York, pp. 323-333.

Saldanha, P.H. (1964b). Genética das malformações congênitas. Rev. Paul. Med. 65: 270-289.

Saldanha, P.H. (1965). Epidemiologia e genética populacional dos defeitos hereditários. Ciénc. Cult. 17: 461-512.

Saldanha, P.H. (1966). Genética e Epidemiologia. In: Plástica do Nariz (Farina, R., ed.). Calvário, São Paulo, pp, 53-103.

Saldanha, P.H. (1978). Perspectivas em Genética Médica. Rev. Hosp. Clin. Fac. Med. São Paulo 33: 114-120.

Saldanha, P.H. (1985). Clinical medicine and genetics. Rev. Brasil. Genet. 8: 205-208.

Saldanha, P.H. (1986). Recent Trends in Medical Genetics (Marimoto, K.M. and Gopinath, P.M., eds.). Adv. Biosci. 56: 151-153. Pergamon Press, Oxford.

Saldanha, P.H., Cavalcanti, M.A. and Lemos, M.L. (1963). Incidência de defeitos congênitos na população de São Paulo. Rev. Paul. Med. 63: 211-229.

Schmidt, M. (1980). Síndrome da talidomida e condições afins. Dissertação de Mestrado, Universidade Federal do Rio Grande do Sul, Porto Alegre.

Schmidt, M. and Salzano, F.M. (1980). Dissimilar effects in dizygotic twins. Acta Genet. Med. Gemellol. 29: 295-297.

Schinzel, A.A. (1984). Catalogue of Unbalanced Chromosome Aberrations in Man. Walter de Gruyter, Berlin.

Schumacher, H.J. (1975). Chemical structure and teratogenic properties. In: Methods for Detection of Environment Agents that Produce Congenital Defects (Shepard, T.H., Miller, J.R. and Marois, M., eds.). North Holand-American Elsivier, pp. 65-77. (Apud Shepard, 1983).

Shannon, E.J., Miranda, R.O., Morales, M.J. and Hastings, R.C. (1981). Inhibition of de novo Ig M antibody synthesis by thalidomide as a relevant mechanism of action in leprosy. Scand. J. Immunol. 13: 553-562.

Shepard, T.H. (1983). Catalog of Teratogenic Agents. 4th edn. Baltimore, Md. The Johns, Hopkins University Press, pp. 414-418.

Sheskin, J. (1980). The treatment of lepra reaction in lepromatous Leprosy. Int. J. Dermatol. 19: 318-322.

Siggers, D.C. (1979). Heart-Hand syndrome. In: Birth Defects Compendium. 2nd. edn. (Bergsma, D., ed.). Alan R. Liss, New York, pp. 455-456.

Smith, D.W. (1982). Recognizable Patterns of Human Malformations. 3rd. edn. W.B. Saunders, Philadelphia.

Smithells, R.W. (1973). Defects and disabilities of thalidomide children. Brit. Med. J. 1: 269-272.

Smithells, R.W. and Leck, I. (1963). The incidence of limb and ear defects since the withdrawal of thalidomide. Lancet i: 1095-1097.

Somers, G.F. (1962). Thalidomide and congenital abnormalities. Lancet i: 912.

Speirs, A.L. (1962). Thalidomide and congenital abnormalities. Lancet i: 303-305.

Spencer, K.E.V. (1962). Thalidomide and congenital abnormalities. Lancet ii: 100.

Staples, R.E. and Holtkamp, D.E. (1963). Effects of parental thalidomide treatment on gestation and facial development. Exper. Molec. Pathol. (Suppl.) 2: pp. 81-106. (Apud Shepard, 1983).

Stockinger, L. and Koch, H. (1969). Teratologische Untersuchung einer Neuen, dem Thalidomid Strukturell Nahestehenden Sedativ-hypnotisch Wirksamen Verbindung (k-2004). Arzneim. Forschung 19: 167-169. (Apud Shepard, 1983).

Swinyeard, C.A. (1979). Fetal Thalidomide Syndrome. In: Birth Defects Compendium. 2nd. edn. (Bergsma, D., ed.). Alan R. Liss, New York, pp. 438-439.

Taussig, H.B. (1962). A study of the German outbreak of phocomelia. Amer. Med. Assoc. 180: 1106-1114.

Tuchmann-Duplessis, H. (1972). Teratogenic drug screening: present procedures and requirements. Teratology 5: 221-223.

Tuchmann-Duplessis, H. (1974). Was the thalidomide accident predictable? Expert opinion a Académie de Paris. University René Decartes UER Biomedicale. Laboratoire de Embriologie (cópia mimeografada), pp. 1-36.

Tuchmann-Duplessis, H. (1975). Drug Effects on the Fetus. ADIS Press, New York, pp. 143-147.

Warkany, J. (1971). Congenital Malformations (Notes and Comments). Year Book Medical Publishers, Chicago, pp. 49-129.

Weicker, H. (1963). Klinik und Epidemiologie der Thalidomid Embryopathie. Bull. Soc. Roy. Beige Gynecol. Obstét. 33: 21. (Apud Warkany, 1971).

Wepler, W. (1937). Die sogenaunte Phokomelie. Deutsch Med. Wschr. 63: 1302-1308. (Apud Lenz, 1966).

Wuest, H.M., Fox, R.R. and Crary, D.D. (1968). Relationship between teratogenicity and structure in the thalidomide field. Experientia 24: 993-994.

WHO (World Health Organization) (1967). Principles for the testing of drugs for teratogenicity (Report of a WHO Scientific Group World Health Organization). Tech. Report Ser. no. 364: 1-18.

Wilson, J.G. (1959). Experimental studies on congenital malformations. J. Chronic Dis. 10: 111-130.

Wilson, J.G. (1960). Factors involved in causing congenital malformations. Bull. New York Acad. Sci. 36: 145-157.

Wilson, J.G. (1971). Use of primates in teratological research and testing. In: Malformations Congénitales des Mammifères (Tuchmann-Duplessis, H., ed.). Masson, Paris, pp. 273-290.

Wilson, J.G. (1974). Teratologic causation in man and dits evaluation in non-human primates. In: Birth Defects (Motulsky, A.G. and Lenz, W., eds.). roceedings of the IV International Conference. Viena, Austria, 2-8 september, 1973. Amsterdam, Excerpta Medica, pp. 191-203.

Wilson, J.G. and Clarke-Fraser, F. (1976). Handbook of Teratology. Plenum Press, New York.

Wilson, J.G. and Gavan, J.A. (1967). Congenital malformations in non-human primates: spontaneous and experimentaly induced. Anat. Record 158: 99-110.