It affects the nervous system of mature people and the mesenchymal tissue of the embryo. Few animal experiments have been done. As previously mentioned, thalidomide does not induce sleep in the usual laboratory animals. Grünenthal has tried to reproduce phocomelia in rats, mice, and rabbits and has failed. In Keil the drug was fed to hens and the chicks were normal. Grünenthal has shown that the drug passes through the placenta of rabbits but in their experience the offspring were normal. Somers (16) has, however, recently reported the production of abnormalities in rabbits which are remarkably similar to those in infants. Although the offspring were not equally affected, the extremities did appear to be grossly abnormal and radiological examination of the extremities showed that the long bones were defective. Although Somers believes the ill effects of thalidomide are proven; others disagree. Murphy (17) has recently reported the production of phocomelia in the offspring of a rat by intraperitoneal injection of an enormous dose of thalidomide on the 12th day of pregnancy. Clearly these observations require confirmation. Should the observation not be confirmed, it should be remembered that thalidomide makes a horse sleep. Therefore, the horse might be found to react as man does. Simian experiments would also be of interest. Once a susceptible animal has been found, a new avenue of approach to malformations will be available. It is quite clear that the drug acts during the period in which the embryo is developing as is the case with the virus of German measles. It is equally clear that it acts at a different point or in a different way than does the virus of German measles; the resultant malformations are totally different. Furthermore, thalidomide is a synthetic chemical and it should be possible to test the action of the separate chemical radicals from which the drug is compounded. Even though this drug has not been conclusively demonstrated to have the same effect on animal and man, it does indicate that all new drugs which circulate through the blood stream should be screened for their effect on the offspring of pregnant animals. Distillers Limited is already attempting to develop tests by which to screen drugs for this serious untoward effect. It is, however, an extremely difficult problem and it demands extensive study. Our Food and Drug Act, although better than most of the other countries, should be strengthened. Women in the childbearing age must be educated not to take new drugs. Often the harm is done before they know they are pregnant and with the best of medical knowledge some other harmful preparation may be incorporated into some drug. We do not know how to completely eradicate such a danger, but let us do what we can. Thus the tragic effects of thalidomide have opened up a new avenue of approach to the etiology of malformations. What is the precise factor that causes phocomelia? Where does it act? How does it inhibit growth? Many physicians have also asked how about its effect on cancer? One sad story is, we hope, coming to an end. It should be the dawn of new and better control of drugs. Let us hope that it is also the dawn of new knowledge. SUMMARY In 1960 Kosenow and Pfeiffer reported a new clinical syndrome; the essential feature was phocomelia. The incidence of the malformations rapidly increased and by the end of 1961, thousands of children had been born with severe malformations of the extremities. The causative factor appeared to be an exogeneous agent. Many retrospective studies were instituted. Almost simultaneously Lenz in Hamburg and McBride in Australia suspected that the malformations were caused by taking thalidomide in early pregnancy. Thalidomide is a synthetic drug deveoped by Grünenthal and marketed in Germany as Contergan, in England as Distaval, in Portugal as Softenon, as Kevoadon in the United States (though not released by our Food and Drug Administration) and as Kevadon and Talimol in Canada. It was an excellent sleeping tablet and tranquilizer and was added to a number of other compounds which were used for the relief of grippe, migraine, and asthma and also for expectorants. The circumstantial evidence is overwhelming that this drug does cause severe malformations of the extremities. Grünenthal showed that the drug passed through the placenta of rabbits. Distillers, Ltd., in England, have reproduced the malformations in rabbits by feeding the drug to pregnant animals. Murphy has produced phocomelia in the rat by an enormous dose of thalidomide given intraperitonerally to a pregnant animal. Certainly new drugs, which are of use to persons of all ages and which enter the blood stream, should be screened for possible teratogenic action. Futhermore, young women must learn that nothing is foolproof and new drugs should not be taken unless absolutely necessary, as the damage often occurs before the woman knows she is pregnant. This drug shows how serious the side effects of drugs may be and it also opens up a new avenue to the study of the etiology of malformations. GENERIC AND TRADE NAMES OF DRUGS Thalidomide-Contergan (West Germany), Distaval (British Commonwealth), Bemegride-Megimide. Chlorthalidone-Hygroton. REFERENCES 1. Kosenow, W., and Pfeiffer, R. A.: Micromelia, Haemangioma und Duodenal Stenosis Exhibit, German Pediatric Society, Kassel, 1960; reported by title in Monat, Kinderheilk 109:227 (March) 1961. 2. Wiedemann, H. R.: Hinweis auf eine derzeitige Häufung hypo-und aplastscher Fehlbildungen der Gliedmasses, Med Welt 37: 1863-1866 Sept 16) 1961. 3. Wiedemann, H. R., and Aeissen, K.: Zur Frage der derzeitigen Häufung von Gliedmassen-Fehlbildungen, Med Mschr 12:816–818, 1962. 4. Pfeiffer, R. A., and Kosenow, W.: Zur Frage einer exogenen Verursachung von schweren Extremitatenmissbildungen, Muench Med Wschr 104:68–74, 1962. 5. Lenz, W.: Kindliche Missbildungen nach Medikament während the Gravidität, Deutsch Med Wschr 86:2555-2556 (Dec 29) 1961. 6. McBride, W. G.: Personal communication from Distiller, Ltd., in London, 7. McBride, W. G.: Thalidomide and Congenital Abnormalities, Lancet 2:1358 (Dec. 16) 1961. 8. Lenz, W.: Thalidomide and Congenital Anomalies, Lancet 1:45 (Jan. 6) 1962. 9. Speirs, A. L.: Thalidomide and Congenital Abnormalities, Lancet 1:303-305 (Feb. 10) 1962. 10. Weicker: Personal communication to the author. 11. Lenz, W.: Thalidomide and Congenital Abnormalities, Lancet 1:271-272 (Feb. 3) 1962. 12. Lenz, W.: Eintstehung von Missbildungen durch Medikamente, Arzt Mitt 47:494 (March 3) 1962. 13. Lenz, W.: Personal communication to the author; full report to be given at International Pediatric Congress, Lisbon, Sept., 1962. 14. Hillmich, W.: Personal communication to the author. 15. Parsons, C.: Personal communication to the author. 16. Somers, G. F.: Lancet, April 28, 1962; personal communication, Brown and Somers of Distillers, Ltd., London. 17. Murphy, M. L.: Reported at meeting of American Pediatric Society, Atlantic City, May 10, 1962. [From the Scientific American, August 1962, vol. 207, No. 2] THE THALIDOMIDE SYNDROME A MILD AND SUPPOSEDLY SAFE SEDATIVE TAKEN BY PREGNANT WOMEN HAS DEFORMED THE LIMBS AND OTHER ORGANS OF SEVERAL THOUSAND INFANTS IN WEST GERMANY ENGLAND, CANADA AND OTHER COUNTRIES (By Helen B. Taussig) Two grossly deformed infants were the subject of an exhibit at the annual meeting of the pediatricians of the Federal Republic of Germany held in October, 1960, in the city of Kassel. Photographs and X-ray pictures showed that the long bones of the infants' arms had almost completely failed to grow; their arms were so short that their hands extended almost directly from their shoulders. Their legs were less affected but showed signs of a similar distortion of growth. Both infants were also marked by a large hemangioma (strawberry mark) extending from the forehead down the nose and across the upper lip; one of them was also found to have a duodenl stenosis, that is, a constriction of the beginning of the small intestine. The physicians who presented these cases, W. Kosenow and R. A. Pfeiffer, members of the staff of the Institute of Human Genetics in Münster, had never seen quite this combination of anomalies in a single infant. They regarded it as a new clinical entity. The deformity of the limbs was characteristic of a malformation known as phocomelia, from the Greek words phoke, meaning seal, and melos, meaning limb. Phocomelia is so rare that most physicians never see it in a lifetime; moreovre, it usually affects only one limb. Kosenow and Pfeffer reported that they could find no hereditary indication for the condition in the history of either family, no incompatibility in the blood types of the parents and no abnormality in the chromosomes of the tissue cells of either child. Guido Fanconi, a Swiss pediatrician who has long been interested in congenital deformities, declared that he too had never seen infants afflicted this way. Otherwise little note was taken of the exhibit. I missed it myself, although I was at the meeting In retrospect it is surprising that the exhibit did not attract a great deal of attention. During 1960 almost every pediatric clinic in West Germany had seen infants suffering such defects. In Münster there had been 27, in Hamburg 30 and in Bonn 19. There had been perhaps a dozen cases of phocomelia in 1959, whereas in the preceding decade there had been perhaps 15 in all of West Germany. During 1961 the incidence of phocomelia increased rapidly; hundreds of afflicted infants were born. When the West German pediatricians gathered for their 1961 meeting in November at Düsseldorf, almost all of them were aware of the mysterious outbreak of phocomelia. At the meeting Widukind Lenz of Hamburg made the disclosure that he had tentatively traced the disease to a new drug that had come into wide use in sedatives and sleeping tablets. The generic name of the drug was thalidomide. Under the trade name Contergan, it had been marketed as freely as aspirin in West Germany from 1959 into the spring of 1961. Lenz had found that many mothers of "seal limb" infants admitted to the Hamburg clinic had taken this drug early in pregnancy. Contergan and other preparations containing thalidomide have now been withdrawn from sale. But infants injured by the drug are still in gestation. When the last of them has been born by the end of this summer or early in the autumn, thalidomide will have produced deformities in 4,000 or even as many as 6,000 infants in West Germany alone, and probably more than 1,000 in other countries where it has been marketed. The one-third who are so deformed that they die may be the luckier ones. It happens that thalidomide-containing drugs did not reach the market in the U.S. This was because of a lucky combination of circumstances and the alertness of a staff physician at the Food and Drug Administration-not because of the existence of any legal requirement that the drug might have failed to meet. If thalidomide had been developed in this country, I am convinced that it would easily have found wide distribution before its terrible power to cause deformity had become apparent. The marketing techniques of the pharmaceutical industry, which can saturate the country with a new drug almost as soon as it leaves the laboratory, would have enabled thalidomide to produce thousands of deformed infants in the U.S. I believe that it is essential to improve both the techniques for testing and the legal controls over the release of new drugs. The news that a large number of malformed infants had been born in West Germany and that a sleeping tablet was suspected as the cause first came to me in late January of this year. I was particularly concerned because of my lifelong interest in malformations. That a drug was implicated was of especial interest, because little is known about the cause of the various congenital anomalies that arise in the course of gestation. I immediately went to West Germany to investigate the situation, and I have also conferred and corresponded with physicians in other countries where thalidomide, under various names, has been sold. In West Germany I was told that a Swiss pharmaceutical house, interested in producing a new sedative, had first synthesized thalidomide in 1954. Because it showed no effects on laboratory animals the company discarded it. Then the West German firm Chemie Grünenthal undertook the development of the compound. Once again thalidomide showed no effect on laboratory animals. Since the structure of the molecule suggested that it should work as a sedative, Grünenthal tried it as an anticonvulsant for epileptics. It did not prevent convulsions, but it worked as a hypnotic, acting promptly to give a deep, “natural" all-night sleep without a hangover. Given the trade name Contergan, it became during 1960 the favorite sleeping table of West Germany, inexpensively available without a prescription and widely used in homes, hospitals and mental institutions. It turned out to be as safe for humans as for animals. Wouldbe suicides who tried it after it came on the market survived large doses of it without harm. Grünenthal combined thalidomide with aspirin and other medicines. Germans consumed these compounds-Algosediv, Peracon Expectorans, Grippex and Polygrippan-for such conditions as colds, coughs, grippe, nervousness, neuralgia, migraine and other headaches and asthma. A liquid form made especially for children became West Germany's baby sitter. Hospitals employed it to quiet children for electroencephalographic studies. As an antiemetic, it helped to combat the nausea of pregnancy, and of course Contergan gave many a pregnant woman a good night's sleep. Grünenthal was manufacturing it almost by the ton. Soon pharmaceutical companies in other countries began to make or market thalidomide under license from Grünenthal Distillers (Biochemicals) Ltd. sold it as Distaval in the British Isles, Australia and New Zealand. Combinations received the trade names of Valgis, Tensival (a tranquilizer), Valgraine and Asmaval. An advertisement in Great Britain emphasized the safety of the drug with a picture of a small child taking a bottle from a medicine shelf. From Portugal it went into local and international channels of distribution as Softenon. In Canada Frank W. Horner Ltd. of Montreal marketed it as Talimol and the THALIDOMIDE is a synthetic drug. In this diagram of its molecule, carbon atoms are represented by black balls, hydrogen by small gray balls, oxygen by white balls and the two nitrogen atoms by large gray balls. Canadian branch of the Wm. S. Merrell Company of Cincinnati as Kevadon. In September, 1960, the Merrell Company applied to the Food and Drug Administration for clearance to sell Kevadon in the U.S. At that time no one had reported any untoward side effects from thalidomide. During the next few months, however, German medical journals carried reports of a new polyneuritis associated with long-term use of the drug. Patients complained of tingling hands, sensory disturbances and, later, motor disturbances and atrophy of the thumb. By April, 1961, there was a sufficient number of ill effects reported in West Germany following the use of the drug to place the thalidomide compounds on the list of drugs for which prescriptions were required. (It was under prescription from the beginning in most other countries.) Nevertheless, thalidomide remained popular and continued in widespread use in the home and in hospitals. By the summer of 1961 physicians all over West Germany were realizing with alarm that an increasing number of babies were being born with disastrous deformities of their arms and legs. In Kiel, Münster, Bonn and Hamburg four different investigations were under way. From a study of 32 cases in Kiel and its environs H. R. Wiedemann found that the malformations followed a specific pattern, although they varied in severity. Abnormality of the long bones of the arms characterizes the great majority of the cases, with the legs involved in half of these. The radius or ulna (the forearm bones) or both may be absent or defective. In extreme cases the humerus (upper-arm bone) also fails to appear. Typically both arms are affected, al- | though not necessarily equally. When the legs are involved, the hip girdle is not fully developed. Dislocation of the hip and outward rotation of the stub of the femur turns the deformed feet outward. The worst cases have neither arms nor leg; since they cannot turn over in the crib or exercise they usually succumb to pneumonia. The hemangioma of the face, as Pfeiffer and Kosenow pointed out, is possibly the most characteristic feature of the syndrome. It is, however, neither harmful nor permanent. A saddle-shaped or flattened nose is common. In some cases the external ear is missing and the internal auditory canal is situated abnormally low in the head. In spite of this deformity hearing tends to be fairly good if not normal. Many of the children display paralysis of one side of the face. Many suffered from a variety of malformations of their internal organs, involving the alimentary tract and also the heart and circulatory system. Most of the children seem to be normally intelligent. Pfeiffer and Kosenow in Münster had found no evidence that the phocomelia in their first two cases was hereditary. Eventually they completed detailed studies of 34 cases, with the same result. This was surprising because many of the previous cases of phocomelia could be traced back in the family. These two investigators concluded that an unknown agent from the environment, affecting the embryo at some time between the third and sixth week of pregnancy, had caused the damage. During this period, when most women do not yet know they are pregnant, the embryo goes through the principal stages of development. Was the unknown agent a virus? An infection by rubella, or German measles, during this critical period of gestation results in severe malformations but not in phocomelia. That it might be some other virus seemed to be ruled out by the fact that the increase in the incidence of phocomelia had been steady, not abrupt, and by the fact that the cases were confined within the boundaries of West Germany. By the time of last year's pediatric meeting at Düsseldorf in late November the range of speculation included radioactive fallout. Lenz meanwhile had formed a new suspicion. Like the other investigators, he had been sending out lengthy questionnaires to the parents of deformed infants and to the physicians who attended them, asking about X-ray exposure, drugs, hormones, detergents, foods and food preservatives, contraceptive measures and tests for pregnancy. In his initial returns he noted that approximately 20 per cent of the mothers reported taking Contergan during pregnancy. On November 8, he recalls, it occurred to him that Contergan might be the cause. He now asked all the parents specifically about Contergan, and 50 per cent reported use of the drug. Many of the mothers said that they had considered the drug too innocuous to mention on the questionnaire. On November 15 Lenz warned Grünenthal that he suspected Contergan of causing the catastrophic outbreak of phocomelia and he urged the firm to withdraw it from sale. On November 20, at the pediatric meeting, he announced that he suspected a specific but unnamed drug as the cause of the "Wiedemann syn |