children born in West Germany will be between 3500 and 6000. Two out of three are expected to live. Most are apparently of normal mentality.

The drug was withdrawn from the British market five days after the withdrawal in West Germany. The Guardian, Manchester, has predicted that August will see the birth of 800 deformed English children. The Ministry of Health has begun to fit 50 victims with artificial limbs.

EIGHT IN CANADA

An article prepared for the May 19 issue of Maclean's Magazine said that at the time of writing eight victims of phocomelia had been born in Canada, two of them to physicians' wives who had used "samples of thalidomide donated to their husbands."

Because the Department of Health did not order thalidomide withdrawn from sale until March 2, Maclean's said the last Canadian casualties are not expected until November.

The cause of the West German outbreak was hard to trace. Hereditary factors, blood incompatibility between parents, abnormal chromosomes, radioactive faliout, X-rays, detergents, food preservatives-all of these things, and more, were suspected, checked and discarded as possibilities.

A Hamburg pediatrician, Dr. Widukind Lenz, made preliminary studies showing that about 20 per cent of the mothers who brought deformed infants to his clinic had taken Contergan. Dr. Taussig wrote:

"On Nov. 8, 1961, it occurred to him that Contergan was the cause. He requestioned his patients and the incidence promptly rose to about 50 per cent. Many of the patients said they had considered the drug too innocent to mention it on the questionnaire

MAKER WARNED

"On Nov. 15 he warned Grunethal (the manufacturer) that he suspected Contergan was the cause and that the drug should be withdrawn."

Five days later, at a pediatric meeting in Dusseldorf he reported his suspicions and his actions but did not name the drug. That night Dr. Taussig related, “a physician came up to him and said, 'Will you tell me confidentially, is it the drug Contergan? I ask because we have such a child and my wife took Contergan.'

"A couple of days later it was generally known that Contergan was the drug under suspicion. On Nov. 26 Grunenthal withdrew the drug from the market. On Nov. 28 the Ministry of Health issued a firm but cautious and widely publicized statement that Contergan was suspected to be a major factor in the production of phocomelia."

Dr. Taussig reported that an Australian physician, Dr. W. G. McBride, saw three severe cases in April, 1961, and three more in October and November. "He found that all six mothers had taken Distaval in early pregnancy," the Journal article said.

In Stirlingshire, Scotland, Dr. A. L. Spiers saw 10 severe phocomelia victims during 1961 and ultimately “obtained positive proof that 8 out of 10 of these patients had taken Dista val."

DIFFICULT CONNECTION

Making the connection-which some physicians say is not conclusively established-was extraordinarily difficult.

Dr. Lenz, for example, had to contend with the lack of records during the time when Contergan was sold without prescription, and with his patients' natural difficulty in recalling if and precisely when they had taken a sleeping pill months earlier.

"In one instance," Dr. Taussig wrote, a doctor "swore the mother had not received Contergan. He had prescribed an entirely different sedative. On investigation at the pharmacy. . . Dr. Lenz found the prescription was stamped 'drug not in stock, Contergan given instead'."

Dr. Taussig said the investigations of Dr. Lenz in particular indicate that the embryo is endangered if a mother takes thalidomide within about 20 to 40 days after conception, a time when she may not even know that she is pregnant. He believes that during that sensitive period the chances that a mother who has taken the drug will deliver a deformed baby are at least two in five.

COMPANY VIEW

The Merrell firm says that conclusive proof is lacking for such assumptions and cites a clinic in Kiel at which, Merrell reported, half of the deformed children were delivered to mothers who probably had not taken thalidomide.

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

Dr. Kelsey said the molecular complex of thalidomide is being broken down and studied in an effort to determine the causative agent in thalidomide.

In all of this Dr. Taussig sees compelling reason for caution in the use of new drugs by women of child-bearing age. A Canadian physician interviewed by Maclean's said, "There is too much demand on the part of the public for relief of mild or even moderately severe symptoms. People won't put up with even the slightest discomfort or headache; they demand medication from their doctor. If they can't get it from one, they'll go to another."

Dr. Taussig also wants the 1938 Food and Drug Act strengthened to provide greater assurance that new drugs will not harm unborn children. But to Assistant FDA Commissioner Winton B. Rankin, the significant thing about the law is that it gave Dr. Kelsey the weapon she needed to block the marketing of thalidomide in the United States.

"The American public," he said, "owes her a vote of thanks.”

The 47-year-old Dr. Kelsey lives at 5811 Brookside dr., Chevy Chase, with her husband and daughters, Susan, 15, and Christine, 12.

She is grateful for the praise-but recognizes that, had thalidomide proved to be as safe as the applicant believed, "I would have been considered unreasonable."

She intends to go on "playing for that 10th chance in 10" to assure safety in new drugs "to the best of my ability." For 20 years she taught pharmacology. She knows the dangers, and she has not the slightest intention of forgetting them.

[From the Journal of the American Medical Association, June 30, 1962, vol. 180, pp. 1106-1114]

A STUDY OF THE GERMAN OUTBREAK OF PHOCOMELIA

THE THALIDOMIDE SYNDROME

(By Helen B. Taussig, M.D.)1

In late January of this year I heard that a large number of infants had been born in West Germany with severe malformations of the extremities and that a sleeping tablet was suspected as the cause. I immediately went to West Germany to investigate the situation and traveled throughout West Germany with exception of West Berlin.

It was indeed true that a new clinical syndrome had appeared. The outstanding feature was phocomelia. Phocomelia means "seal extremities"; the word comes from 2 Greek words phokos meaning "seal" and melos meaning "extremities." In phocomelia the bones between the hand and the shoulder are defective or absent and the hands or rudimentary fingers arise directly from the end of the affected bone as the flippers of a seal. The first 2 such cases were presented by Kosenow and Pfeiffer (1) as an exhibit at the German Pediatric Meeting in Kassel in 1960. At this exhibit Kosenow and Pfeiffer reported that no hereditary factor was found, nor was any blood incompatibility demonstrable and no chromosomal abnormality was detected. Little attention was paid to the exhibit. Dr. Guido Fanconi, however, studied the cases and stated he had never seen the clinical syndrome. In retrospect, it is surprising that so little attention was paid to this exhibit because during 1960 infants with this syndrome had been brought to almost every pediatric clinic in West Germany.

Phocomelia has long been known as a rare malformation but usually affects only one limb. Dr. Grüber of Göttingen, who is now 86 years old and has devoted

1 From the Department of Pediatrics, the Johns Hopkins University, School of Medicine, and the Harriet Lane Home of the Johns Hopkins Hospital. Dr. Taussig's trip was supported by the International Society for Cardiology Foundation, the Heart Association of Maryland, and the National Institutes of Health.

81-280-68-pt. 4- -25

his life to malformations in man and animal, told me he had seen as many individuals with 2 heads as he had with phocomelia.

Suddenly in 1961 the incidence of phocomelia increased rapidly. Almost every clinic in West Germany admitted 3 times as many such infants in 1961 as in 1960. The data in Table 1 shows the incidence which was reported to me in March, 1962, by various university pediatric clinics in West Germany and also in 3 centers in the British Commonwealth. By the time of the 1961 pediatric meeting in Düsseldorf almost all pediatricians were aware of the outbreak of phocomelia. TABLE 1.-INCIDENCE OF PHOCOMELIA IN THE VARIOUS UNIVERSITY PEDIATRIC CLINICS

1 These include peromelia, amelia, and micromelia as well as phocomelia-per year.

In September, 1961, Wiedemann (2) reported the first series of 33 such children and delineated the clinical syndrome. As in most malformations, the severity varies but the pattern is remarkably specific. The essential feature of the abnormality concerns the long bones of the extremities (Figs 1 and 2). The prehensile is lost (Fig. 3). The hand arises directly from the distal end of the affected bone. The radius is absent or both radius and ulna are defective; in some instances only one short bone remains; in extreme cases the radius, ulna, and humerus are lacking and the hand buds arise from the shoulders (Fig. 1). Both sides are affected but not usually with equal severity. The legs may be affected in the same manner; in most instances the deformity of legs is less severe (Fig. 2). The tibia fails to form. The fibula also may not form and the femur may be short. The hip girdle is not fully developed and there is a dislocation of the hip with external rotation of the stub of the femur. The feet are externally rotated. Polydactylism and syndactylia of the toes are common (Fig. 3). In the extremely severe cases the arms and the legs are missing (Fig. 4). In some instances the external ear is missing and the internal auditory canal is abnormally low (Fig. 5). Usually hearing is not grossly impaired. Unilateral facial paralysis is relatively common. The vast majority of children are of normal mentality.

Pfeiffer and Kosenow (4) noted that a mid-line facial hemangioma on the forehead which extended over the nose to form a "moustache" on the upper lip was almost pathognomic of the syndrome (Fig. 1). A saddle nose was also common. These features diminish and tend to disappear as the infant grows. In some

Pylorospasm...

TABLE 3.-OTHER MALFORMATIONS OCCURRING IN 203 CASES OF PHOCOMELIA

Duodenal stenosis..
Duodenal atresia..

Esophageal atresia.

Anal atresia..

Cardiac abnormalities.

Anencephaly

Microcephaly..

Eye malformations..

Nasal obstruction_

1 Courtesy of Dr. W. Lenz, Hamburg, Germany. 2 Doubtful.

instances, usually in severe cases the internal organs are affected. Malrotation of the gut occurs with duodenal stenosis and anal atresia (Fig. 6). Asplenia may occur and the musculature of the uterus may be so affected as to make a bihorned uterus. A variety of cardiac malformations have also been reported but these did not fall into any specific pattern. Thus hypoplasia of the aorta, defects of the auricular and ventricular septa, all forms of transposition of the great vessels, tetralogy of Fallot, and pulmonary stenosis have all been reported. The frequency with which the various abnormalities occur in Dr. Lenz's series are shown in Table 2. The variety of other malformations is shown in Table 3. Pfeiffer and Kosenow (4) reported extensive family studies on 34 children. They found no similar traits among the relatives and no consanguinity among the parents. Chromosomal analysis of 12 patients showed no chromosomal aberration either in the number or form of the chromosomes. Four of 6 pairs of dizygotic twins had the same type of malformation but the twins were not equally affected. These investigators thought that the causative factor was exogenous and acted during

the critical phase of development, i.e. between the third and sixth week of pregnancy.

Although the critical time was similar to that of German measles viral infection was excluded by the steady increase in the number of patients over a 2-year period and also by the distribution of the cases. Viruses know no territorial borders. This epidemic remained strikingly centered in West Germany. German pediatricians became aware of the problem. Extensive studies had been instituted in a number of centers. Lenz in Hamburg. Weicker in Bonn, Wiedemann (2) in Kiel, and Pfeiffer and Kosenow (4) in Münster each undertook special studies. Many doctors suspected radioactive fallout. Lengthy questionnaires were sent out inquiring about X-ray exposure, hormones, detergents, foods (and food preservatives), contraceptive measures, and tests for pregnancy. Most of these were retrospective studies. Dr. Lenz's initial studies showed that approximately 20% of his patients had taken Contergan. On Nov. 8 it occurred to him that Contergan was the cause. He requestioned his patients and the incidence promptly rose to about 50%. Many of the patients stated that they had considered that drug too innocent to mention it on the questionnaire.