Contergan is the West German trade name for thalidomide. The chemical structure is shown in Figure 7. Thalidomide is a synthetic drug which, as the story is told in West Germany, was first conceived and made by Ciba and found by them to have no effect on animals; therefore, it was discarded. In 1958 Grünenthal developed the drug and tried it on animals; they, too, found it had no effect on animals. Thereupon it occurred to the inventors that it might be useful in epilepsy and was marketed as an anticonvulsant drug. It was soon found to be worthless for epilepsy but it caused sleep. Thereafter, it was sold as a sleeping tablet, a sedative, and tranquilizer. It had a prompt action, gave a natural deep sleep and no hangover. It appeared innocent and safe. Man could not commit suicide with it. It became West Germany's most popular sleeping tablet and was widely used in hospitals and in mental institutions. Thalidomide was added as a sedative to other drugs such as algosediv (thalidomide and acetylsalicylic acid), peracon expectorans, grippex, and polygripan; thus it was used for grippe, neuralgia, asthma, and as a cough medicine. A liquid form was made for children. It was used in hospitals to quiet a child for an electroencephalogram. It became West Germany's baby-sitter. It was also found useful as an antiemetic in pregnancy. The drug was manufactured "by the ton" and sold without prescription. Inasmuch as the drug was cheap and an excellent sedative, the sale was tremendous. The rights to market the drug were sold to pharmaceutical firms in other countries. In the British Commonwealth it was marketed by Distillers (Biochemicals) as Distaval. In Portugal it was sold as Softenon and it was manufactured in the United States as Kevadon (but it was never passed by our Food and Drug Administration). It was sold both as Kevadon and Talimol in Canada. Thalidomide was also added to the English drugs known as Valgis, Tensival, Valgraine, and Asmaval. I do not know whether the drug was added to any Portugese preparations.

In April, 1961, a new form of polyneuritis appeared: tingling of the hands, sensory disturbance, and later, atrophy of the thumb and motor disturbances. It was soon recognized that the long continued use of Contergan in adults was responsible for polyneuritis; furthermore, unless the drug was promptly discontinued, the polyneuritis was irreversible. Thereafter, the drug was placed upon prescription. Nevertheless, it remained a very popular drug and continued to be widely used in hospitals and also in the home.

As previously stated, on Nov. 8 it occurred to Dr. Lenz that Contergan was probably responsible for the catastrophic outbreak of phocomelia. On Nov. 15 he warned Grüenthal that he suspected Contergan was the cause of phocomelia and that the drug should be withdrawn. On Nov. 20, 1961, at the Düsseldorf Pediatric Meeting, Lenz (5) reported he suspected a specific drug was the cause of the "Wiedemann syndrome" and that he had warned the company that the drug should be withdrawn. He did not name the drug. That night a physician came up to him and said, "Will you tell me confidentially, is the drug Contergan? I ask because we have such a child and my wife took Contergan." In the next few days he received a half dozen letters asking the same question and saying, "My wife took Contergan and we have such a child." A couple of days later it was generally known among the doctors that Contergan was the drug under suspicion. On Nov. 26 Grüenthal withdrew the drug from the market. On Nov. 28 the Ministry of Health issued a firm but cautious statement that Contergan was suspected to be a major factor in the production of phocomelia and stated that the drug had been withdrawn from the market. Women were warned not to take the drug. The announcement was carried on the front page of every newspaper, on the radio, and on television.

Phocomelia not only suddenly appeared in Germany, but the same unusual type of malformation equally suddenly made its appearance in Australia. In April, 1961, Dr. W. G. McBride (6) in a relatively short time saw 3 babies born with severe phocomelia. He saw no more such infants until the fall of 1961. In October and November, 1961, he saw 3 more such infants. Thereupon he reviewed the 6 cases and he found that all 6 mothers had received Distaval in early pregnancy. Dr. McBride communicated his findings to the Australian Branch of Distillers Limited and they in turn cabled their London office on Nov. 27, 1961. Distaval is the English trade name for Contergan. Thus, within a couple of days the English firm received similar reports from 2 widely separated countries. The drug was promptly withdrawn from the market. The latest report is that it is available to hospitals in limited sales.

McBride (7) in a brief note in the Dec. 16 Lancet, reported a 20% increase in severely malformed babies from the use of Distaval in early pregnancy. The malformation affected the mesenchymal tissue, both the long bones, and the musculature of the gut. Had anyone else seen anything like it? Lenz 8 replied to his letter in the Jan. 12 issue of the Lancet.

Spiers (9) in Stirlingshire, Scotland, had seen 10 infants with severe phocomelia during 1961. He immediately set to work to ascertain whether his cases were associated with Distaval. On questioning mothers and doctors he obtained a history of Distaval in 2 of the patients. Then he went to the office where all prescriptions are filed and with the names of the patients and the approximate date on which the medicine was given, he asked to have the prescriptions checked. It took 3 weeks. During this time he interviewed the mothers and in 2 instances the mothers finally remembered they had taken sleeping tablets and produced the bottles from which the tablets had been taken. The tablets therein were stamped DT/DL. Ultimately, he obtained positive proof that 8 out of 10 of these patients had taken Distaval in early pregnancy.

Thus, between Nov. 20, 1961, and January, 1962, the circumstantial evidence rapidly accumulated in different parts of the world which indicated that thalidomide played an important role in the production of phocomelia.

Further studies were instituted everywhere. Many clinics reported a history of the ingestion of Contergan could readly be obtained from the women in one-half of the instances but not in all cases.

A few, but remarkably few, prospective studies were instituted. One obstetrician asked each of 65 patients whether Contergan had been taken in early pregnancy and obtained a positive reply in only a single instance. He said if that woman had an abnormal baby he would believe Lenz. She did!

Professor Von Masselbach made a prospective study of 350 patients in his obstetrical clinic. Thirteen women had taken Contergan, 6 in the second half of pregnancy and 7 in the first half, i.e., in the first 42 months. Among these 7 women, 2 had babies with phocomelia, 1 had a baby with an anal atresia, and 4 were normal.

In Düsseldorf, in a group of 300 women who had not taken Contergan, all the babies were healthy, whereas one-half of the women who took Contergan had abnormal children. These investigators also had collected 40 cases over a 2-year period. Seventy-five per cent of these mothers gave a history of Contergan. Since

the records were not checked, the history of Contergan was recorded as probable but not proven. Dr. Weicker 10 in Bonn was collecting 100 cases of phocomelia with a history of Contergan. In March, 1962, when I was in Bonn, he had over 90 such cases.

Dr. Lenz (13) undertook a study to ascertain in how many patients who had given birth to infants with phocomelia he could obtain proof that the mother had taken Contergan during early pregnancy. He considered a case as proven only by a photostatic copy of a prescription or by a hospital record showing the date and amount of Contergan given. The difficulty in obtaining such information was great because prior to April, 1961, the drug was sold without prescription. By and large, women in the early months of pregnancy are not cared for in a hospital. Dr. Lenz, however, found that a number of women had been admitted to a hospital for some minor operation before they knew they were pregnant. Many of these patients had received a sleeping tablet while in the hospital and thereby Dr. Lenz could obtain proof that Contergan had been prescribed. In many West German hospitals sleeping tablets are given by the nurses as freely as laxatives are given in the United States.

Few of us can remember what medicine we took a year or more ago. Far less, exactly when and how much we took. In some instances, however, special events enabled the patient to remember the date or the approximate time during which she took a sleeping tablet. Travel was a common event. Many people do not sleep well when traveling. Such persons usually know if and approximately when they took sleeping tablets. One woman knew the date she took a sleeping tablet: it was the night the neighboring farm house had burned down.

Another woman recalled she had taken Contergan for 3 nights after her fatherin-law had been murdered. The date was clearly imprinted on her mind. Two other incidents reported by Dr. Lenz illustrate how difficult it may be to obtain accurate information. In one instance in which the mother gave birth to a baby with phocomelia, the doctor swore the mother had not received Contergan. He

Alpha (N-phthalimido)

glutarimide

Fig. 7.-Formula of thalidomide.

had prescribed an entirely different sedative. On investigation at the pharmacy where the mother had bought the medicine, Dr. Lenz found the prescription was stamped "drug not in stock, Contergan given instead."

In another instance in which Dr. Lenz talked with the parents for more than one-half hour and both denied the mother had taken Contergan, 3 weeks later Dr. Lenz received a letter (I read the letter) saying: "I have been told not to write but I can no longer sleep without telling you I did take Contergan but, as my husband was once in a hospital for drug addiction, I had promised I would never take such a drug; I could not tell him I had broken my promise."

By the middle of March, 1962, Dr. Lenz had analyzed 50 cases (13) in which he interviewed parents, reviewed hospital records, and determined the date of the last menstrual period and in many instances he obtained the date of conception and also had proof of the date on which Contergan had been taken. Forty-five of 50 women had taken the drug between the 30th and 50th day and 5 had taken it between the 50th and 60th day after the last menstrual period. Among the 21 instances in which the date of conception was known, the mothers had taken contergan between the 28th and 42nd day (inclusive) after conception. Although the exact time during which the drug has a teratogenic action may be found to vary slightly, the period in which it affects the development of the embryo appears to be relatively brief.

These observations clarify the finding of Dr. W. Hillmich (14) of Göttingen who made a prospective study of 99 patients who had taken Contergan during pregnancy. He found none had taken the drug in the first 3 weeks; one had taken it in the fourth week, none in the fifth, one in the sixth, none in the seventh, and one in the eighth week. All of the remaining patients had taken the drug after the ninth week of pregnancy. The mother who had Contergan on the 42nd day after the last menstrual period was the only one who had an abnormal baby. The woman who had taken Contergan in the 6th week had taken it on the 51st day after her last menstrual period which is probably safe provided she had a normal ovulation time. All others had taken the drug well after the sensitive period.

The incidence of phocomelia in West Germany is terrific. Studies from the Institute of Human Genetics in Münster showed that between 1949 and 1959 they saw an average of 4 children per year with severe malformation of the extremities. These malformations included peromelia (amputation of a limb), amelia (absence of a limb which may be the extreme either of peromelia or of phocomelia), micromelia (a small limb), and phocomelia. Even the phocomelia of former years differed from the present phocomelia in that it was usually unilateral. Suddenly, in 1959, 3 cases of bilateral phocomelia were seen in that institute; 26 cases occurred in 1960 and 96 cases in 1961. Furthermore, to date 13 pairs of twins have been registered; hence they estimated there should be 1,300 cases.

The Minister of Health of Westphalia has set up a name registry for all children with defective hands and arms, i.e., all children who would need orthopedic help. This registry included clubbed hands and polydactylism as well as phocomelia. They estimate that about 80% of these cases will be phocomelia. As of Jan. 1, 1962, they had 800 registered cases and at that time reports had been received from only one-half of Westphalia. I saw the pile of records for January and February, 1962. These had not yet been counted but there must have been approximately 200. This indicates that there will be probably 1,500 to 2,000 such children in Westphalia and the North Rhineland by August, 1962. This estimate agrees with the estimate from Münster. Westphalia is but one section of West Germany. Thus the estimation of 3,500 to 4,000 cases appears to be a minimal figure. Probably the number will be far larger. Two-thirds of the children are expected to live.

We visited Freiburg because it was reported that there were 100 cases there. At the University Clinic, Dr. Keller advised me that they had seen approximately 10 or 20 cases and showed me one infant in the hospital. He kindly offered to look up the exact number. Subsequently, he wrote me that they had seen 37 infants in the clinic and they had received reports of 200 such infants born in the environs of Freiburg.

In contrast to these findings, Dr. Immon at the Headquarters of the United States Army of Occupation in Heidelberg told me on March 6 that he was reasonably confident that there had been no cases of phocomelia among the 16,000 babies born in the U.S. military hospitals in Germany in 1961. He had

traveled extensively and had visited all their hospitals. He had been shown the unusual cases but had seen no infants with phocomelia up to March 12, 1962. Further, they were certain that any and all such infants would be immediately evacuated to the United States. All evacuations passed through their office and no case of phocomelia had been reported. As of April 14, no such cases had been received from overseas at the Walter Reed Hospital in Washington, D.C. In a recent letter, Dr. Immon reported one infant born with phocomelia in a U.S. Army hospital. The infant's mother, who was a German, volunteered the information that she had taken Contergan in early pregnancy.

Alas, the incidence in England is also high. Reports are steadily appearing in the Lancet of the occurrence of phocomelia in infants born of women who have taken thalidomide in early pregnancy. Dr. Clifford Parsons (15) advised me that at a recent medical meeting almost everyone in the audience had seen at least one such case. The total incidence is expected to be in the hundreds but fortunately not in the thousands.

Reports are still coming in from all over the world which show that phocomelia has occurred where Contergan has been used. As of March 22, 7 cases were reported in Sweden in which Contergan had been purchased in Germany; 2 cases in Belgium and the Contergan was known to have been bought in Germany; 4 cases in Switzerland with a history of the ingestion of Contergan; 7 cases in Lebanon where the Portuguese preparation, Softenon, is available; 1 case in Israel and the mother took Distaval; 1 case in Peru and the father had obtained Contergan in Germany. Seven cases have been reported in Canada in women who had taken Kevadon in early pregnancy. One sad instance in the United States is that of a German woman who had married an American, and brought Contergan with her to the United States. She took the drug and has given birth to twins; one has phocomelia and the other duodenal atresia and a rectovaginal fistula. As yet, I have received no information of the incidence of phocomelia in Portugal. Dr. Lenz, however, has written me that he has learned of an outbreak of phocomelia in Brazil associated with thalidomide.

There are, however, still many perplexing problems. One concerns twins. Usually both twins are affected even when they are dizygotic but not always to the same extent, as in the above mentioned case. Another case is known in which one twin died at 5 months and was delivered at term with the living twin. The living twin had a phocomelia and the bones of the dead twin were normal. I learned of a physician who had taken Contergan until she developed peripheral neuritis. Thereupon she stopped taking the drug until she was pregnant and then took it again through 2 successive pregnancies and both children were normal. The question arises as to how early in pregnancy did she take the drug, or is she one of the fortunate women?

Everyone admits that no information is available concerning how many women may have taken the drug in the sensitive period and have had a normal child.

Some doctors in Germany are still doubtful about the exact role of Contergan. Most doctors, however, believe that Contergan plays a major role. Dr. Pfeiffer remarked that most phenomena are more complicated than they seem and therefore he cannot believe that the cause of phocomelia is as simple as Contergan alone. Nevertheless, he, too, believes that Contegan plays a major role. Many English physicians believe there must be some other substance or factor which also causes phocomelia because a history of Distaval cannot be obtained in every case. No relation has been found between the amount of the drug ingested and the severity of the malformation. A single dose of 100 mg. is thought to be sufficient to cause severe phocomelia and repeated doses may give only a mild abnormality.

The only other drug with which I am familiar1 which is similar to Contergan is glutethimide (Doriden). Although in a few instances, a history of glutethimide, not Contergan, has been obtained glutethimide has been widely used in Switzerland since 1955 and phocomelia was not known until 1961 and then only a few cases were seen and in most instances, a history of Contergan was obtained.

Little is known concerning the metabolism of thalidomide or how it is excreted from the body, nor the length of time the teratogenic factor persists in the body. Virtually all that is known is that it is insoluble in water and in fat.

1 My attention has recently been called to 2 other drugs which contain radicles similar to thalidomide, namely, bemegride (Megimide) and chlorthalidone (Hygroton).