SIXTH WEEK

SEVENTH WEEK

omide seems to cause almost all its deformities when the mother takes the drug during the fourth, fifth or sixth week of pregnancy,

EIGHTH WEEK

as limb buds, ears, intestinal tract, heart and blood vessels are forming and going through first growth. These embryos are normal.

[From the American Journal of Diseases of Children, August 1962, vol. 104, pp. 111–113]

THALIDOMIDE-A LESSON IN REMOTE EFFECTS OF DRUGS

In late January, 1962, my attention was attracted to reports of an outbreak of congenital malformations in children being born in Germany and its possible relation to a specific drug. Because of my interest in congenital malformations of the heart I decided to examine the situation myself. My trip was supported by grants from the International Society of Cardiology Foundation, the Heart Association of Maryland, and the National Institutes of Health. I traveled throughout West Germany with the exception of West Berlin. The results of this investigation seem to me so important and so pressing that I feel it my duty to report them to the medical profession without further delay.

The malformation with which I was concerned was phocomelia; the name comes from the Greek words Phokos, meaning seal, and Melos, meaning extremities. According to definition the development of the limb buds is so affected that the hands and feet arise from the trunk in a way suggestive of the flippers of a seal. Actually the injury affects the long bones of arms and legs; the hands and feet arise beyond the affected bone. In some instances the arms are rudimentary— 4 such children are shown in Figure 1. The malformation involves both sides, but usually one side is more seriously affected than the other. The legs, too, may be affected. In 50% of the cases the arms only were affected, and in another 25% both the arms and legs are affected. At birth, a central hemangioma extending from the forehead over the nose to form a moustache on the upper lip is considered by Pfeiffer as characteristic of the syndrome. In some babies the external ear was absent. In the most severe cases malformation of the gut occurred accompanied by duodenal stenosis and anal atreasia, asplenia, and occasionally by a malformation of the heart. Mental retardation was found in only approximately 1%.

Phocomelia had long been known as a rare malformation. In 1959 a few cases were seen; these increased in 1960. By 1961 there was a veritable “epidemic” of phocomelia in Germany. Last November, Lenz suggested the possibility that the occurrence of the sudden outbreak of this malformation was connected with the use of a new sleeping tablet. The drug is known as thalidomide. It is a synthetic preparation whose chemical structure is shown in Figure 2. The drug was made by Grünenthal and marketed as Contergan in Germany, Distaval in the British Commonwealth, Softenon in Portugal, Kevadon (on trial in the U.S.A., but not released by the Food and Drug Administration), and Talimol in Canada. Thalidomide was also added to other medicines. The German drugs known as Algosediv, Peracon Expectorans, Grippex, and Polygripan all contain thalidomide, and so do the English drugs, Valgis, Tensival, Valgraine, and Asmaval.

The drug was invented by a German firm and first marketed during 1958; by 1960 it became Germany's most popular sleeping tablet and tranquilizer. The drug was sold without prescription until its long-continued use was found to cause polyneuritis; thereafter it was sold freely on prescription.

In November, 1961, W. Lenz in Hamburg (Germany) and W. G. McBride in Australia independently and almost simultaneously realized there was a close association between the new sleeping tablet and the outbreak of phocomelia. Both doctors reported their findings to their respective manufacturers in Germany and in Australia, and they also reported them to their Medical Societies. As soon as A. Spiers in Scotland heard these reports he checked his 10 recent cases of phocomelia with great care and obtained positive proof that 8 of the 10 mothers had taken Distaval. Thus, in three widely separated parts of the world, phocomelia occurred in the offspring of women who had taken thalidomide in early pregnancy. The drug was withdrawn from the market at the end of November, 1961. Since then much circumstantial evidence of the relation between thalidomide and phocomelia has been collected. Lenz told me in March, 1962, that he had collected 50 cases of women with infants who have phocomelia in whom he knows the date of the last menstrual period (in about one-half of the instances the date of conception) as well as the date at which Contergan was taken, either as recorded on a hospital chart or a photostatic copy of the prescription. He found the sensitive period was between the 30th and 60th day after the last menstrual period; in most cases the drug had been taken between the 30th and 50th day. In the cases in which the date of conception was known the sensitive period was from the 28th to 42d day inclusive.

The sensitive period may be found to vary, and some women may prove to be immune, but the circumstantial evidence is overwhelming that the drug, if

H

N

Thalidomide.

FIGURE 2.

taken during a sensitive period, can cause phocomelia. A single dose of thalidomide at the sensitive time is thought sufficient to damage the embryo.

The most conservative estimate is that by August 1962, 3,500 babies will have been born in Germany with phocomelia; two-thirds of whom will live. England will probably have several hundred. The drug was not passed by the U.S. Food and Drugs Administration; therefore, its use was not permitted to the U.S. Army of Occupation in Germany, and consequently the wives of men in our Armed Forces have been spared. There were 16,000 births in 1961 among the wives of the Army of Occupation, and no cases had been reported up to March 10. 1962. The U.S. Army Headquarters had no knowledge of cases of phocomelia which might have occurred among German wives of American soldiers who were cared for by German doctors.

Although our law requiring careful tests on animals before a drug is released by the Food and Drug Administration has been a tremendous protection to our country, nevertheless, the routine testing of the effects of drugs on the offspring of pregnant animals is not regularly required. Needless to say, this experience in Germany and the British Commonwealth illustrates the need for stricter laws and for routine testing of the effect of all drugs on pregnant animals.

Definite proof that thalidomide does cause phocomelia must await further confirmatory animal experimentation or the cessation of the outbreak in August, 1962, which will be eight months after the withdrawal of the drug. Nevertheless, the circumstantial evidence is so strong that this drug does cause congenital malformations, and the effects on the children are so terrible that I feel that the situation should be brought to the immediate attention of the medical profession in this country. It is also important to remember that in many instances the damage is done before the mother knows she is pregnant. Therefore, young women must learn to be cautions about new drugs. Until research concerning the proper tests has been completed, doctors must bear in mind that sleeping tablets, tranquillizers, and other apparently innocent drugs may do terrible harm to the rapidly growing embryo and the unborn child.

HELEN B. TAUSSIG, M.D., Professor of Pediatrics, Johns Hopkins Hospital, Baltimore.

[From Science, May 25, 1962, vol. 136, No. 3517]

DANGEROUS TRANQUILITY

In late January 1962 my attention was attracted to an outbreak of congenital malformations in children in Germany and its possible relation to a specific drug. Because of my interest in congenital malformations of the heart I decided to examine the situation myself.

The malformation was phocomelia, which is characterized by reduction in the length of the long bones of the arms or legs, or both. In extreme cases the appendages are reduced to completely functionless nubbins. Occasionally the external ear is absent, and in the most severe cases the visceral organs are badly malformed.

Phocomelia has long been known as a rare malformation. In Germany, a few cases were seen in 1959, more were seen in 1960, and cases in "epidemic” numbers were seen in 1961. By November 1961, W. Lenz of Hamburg and W. G. McBride in Australia suggested that the outbreak was connected with the use of a new sleeping pill and tranquilizer containing thalidomide [alpha-(Nphthalimido) glutarimide]. A. Spiers in Scotland confirmed the relation by show

ing that the mothers of at least eight out of ten of the affected babies had taken the drug. Thalidomide was on trial in the United States, but fortunately it had not been approved for use by the Food and Drug Administration, owing to the fact that polyneuritis developed in some users and owing also to Dr. Frances O. Kelsey's doubt about the safety of its use in pregnancy.

The drug was first marketed in Germany in 1958, and by 1960 it had become Germany's most popular sleeping tablet and tranquilizer. It was sold without prescription until the polyneuritis showed up; thereafter it was sold freely on prescription.

Thalidomide was withdrawn from the market in Germany by November 1961 and slightly later in England, Australia, and Canada. Much additional circumstantial evidence of the relation between thalidomide and phocomelia has now been collected. Lenz (personal communication) has studied 50 cases of women whose offspring have phocomelia and who had also taken the drug during pregnancy. He finds that the period of sensitivity is between days 30 and 60 after the last menstrual period, and that in most cases the drug had been taken between days 30 and 50. In those cases in which the date of conception was known, the period of sensitivity was from the 28th to the 42nd day.

The most conservative estimate is that by August 1962 some 3500 babies with phocomelia will have been born in Germany and several hundred will have been born in England and elsewhere.

Definite proof that thalidomide does cause phocomelia must await further confirmatory animal experimentation or cessation of the outbreak in August 1962, 8 months after withdrawal of the drug. Nevertheless, the circumstantial evidence that this drug does cause congenital malformations is so strong, and the effects on the children are so terrible, that I feel the situation should be brought to the immediate attention of the public in this country. It is also important to remember that in many instances the damage is done before the mother knows she is pregnant. Therefore, young women must learn to be cautious about new drugs. Until new laws have become effective, and indeed until research for the proper tests on pregnant animals has been completed, physicians must bear in mind that sleeping tablets, tranquilizers, and other apparently innocent drugs may do terrible harm to the rapidly growing embryo and the unborn child.— HELEN B. TAUSSIG, M.D., Johns Hopkins Hospital, Baltimore, Md.

(This editorial is based on a longer editorial to be published soon in the New England Medical Journal.)

[From American Journal of Obstetrics and Gynecology, St. Louis, vol. 84, No. 7, p. 979, Oct. 1, 1962]

To the Editors:

PHOCOMELIA AND THALIDOMIDE

This is a comment with reference to the article, "Phocomelia," by P. M. Dunn, A. M. Fisher, and H. G. Kohler of Birmingham, England, as well as your editorial in the same issue (August 1). As part of a government mission to Europe to inspect these babies, I think the magnitude of the tragedy can scarcely be overstated.

At the end of November, 1961, when the possible relation between thalidomide and phocomelia was reported, the drug was withdrawn from the West German and British markets. Nevertheless, the incidence in West Germany is terrific. The most conservative estimate is that a minimum of 3,500 infants will be born with phocomelia by August, 1962, 8 months after the withdrawal of the drug.

Phocomelia has appeared where the drug has been available. Thus, the British Commonwealth has several hundred cases of phocomelia. Sweden has reported 25 cases with 100 per cent history of Contergan. Belgium has a number of such cases; Softonon is sold there. Italy has recently reported 5 cases in 5 weeks. Brazil has an epidemic of phocomelia related to thalidomide. Canada had both Talimol and Kevadon and, unfortunately, these drugs were not withdrawn until April 1, 1962; therefore, it will be November before the last of these unfortunate babies have been born. The United States Army of Occupation in West Germany has been spared because the United States Food and Drug Administration refused the application of the Merrill Company to market Kevadon and no drugs are permitted in the United States military services which have not been approved by the Food and Drug Administration. A few cases, however, will undoubtedly occur in the United States as travelers from other countries have bought the drug abroad and brought it to this country.