(Extract from a lecture given at the 1992 UNITH Congress)
More than thirty years ago, in November 1961, I became involved in the history of thalidomide, and up until the present day I have never lost contact with the problem. It is quite impossible to relate in one lecture the whole complicated story of the initial synthesis of the drug in 1954, of its marketing in 1957, its spread to many countries in Europe, Asia, Australia, America, Africa and of the following epidemic of malformations of the limbs and ears, often accompanied by malformations of the internal organs. So I decided to restrict my account to the most essential aspects.
Though the first child afflicted by thalidomide damage to the ears was born on December 25, 1956, it took about four and a half years before an Australian gynaecologist, Dr McBride of Sydney, suspected that thalidomide was the cause of limb and bowel malformations in three children he had seen at Crown Street Women’s Hospital. A short letter from McBride was published in the Lancet. The Liverpool Company received the news from Australia on November 21, 1961, almost exactly the same time as similar news from Germany.
I suspected thalidomide to be the cause of an outbreak of limb and ear malformation in Western Germany for the first time on November 16. I felt sufficiently certain from continuing investigations to warn Chemie Grunenthal by a phone call. It took ten more days of intensive discussions with representatives of the producer firm, of health authorities and of experts before the drug was withdrawn, largely due to reports in the press. Dispute on the question whether thalidomide did or did not cause malformations was going on for months, though independent confirmation of Dr. McBride’s and my observations rapidly accumulated. Chemie Grunenthal continued to deny teratogenic effects of thalidomide for years, but there was a growing suspicion that this was not due to honest ignorance but to the purpose of weakening the accusations against the firm.
In some countries, e.g. Belgium, Brazil, Canada, Italy and Japan, thalidomide continued to be sold for several months. From an increasing number of well documented cases in which the mother had definitely taken thalidomide in early pregnancy, it has become possible to delineate the spectrum of malformations attributable to the drug. These were:
1. Absence of the auricles with deafness
2. Defects of the muscles of the eye and of the face
3. Absence of hypoplysia of arms, preferentially affecting the radius and the thumb
4. Thumbs with three joints
5. Defects of the femur and tibia
6. Malformations of the heart, the bowel, the uterus and the gallbladder
On the other hand, it has been possible to recognise types of limb defects which are certainly not caused by thalidomide. The clear distinction of thalidomide from non-thalidomide cases is important for two reasons, first as a basis for compensation, second for genetic counselling. Affected individuals and their parents have a right to know whether there is any re-occurrence risk for children or brothers, sisters and of the patients that have the same malformations. In most cases a careful study of the type of malformations will permit a clear and reliable diagnosis, but some doubtful cases remain. In all definite thalidomide cases, children born later following a pregnancy without thalidomide, did not show similar malformations. The same is true for the children of thalidomide victims. In the compensation scheme, however, thalidomide was also acknowledged in some doubtful cases. So a few children born to mothers or fathers erroneously acknowledged as thalidomide cases, had similar malformations. I have information on six such cases born in Belgium, Bolivia, Russia, West Germany, England and Japan.
Thalidomide may cause quite different malformations in different children. In one case, the ears are missing, there is deafness and paralysis of the muscles of the eyes and the face, but the limbs are normal. In another, the ears are normal, but the arms are missing. In a third case there are severely shortened arms with only two or three fingers, accompanied by internal malformations. In a fourth case only the thumbs are abnormal with three joints, possibly accompanied by a narrowing of the anus.
Thalidomide does not produce malformations if only taken before the 34th day after the last menstruation and usually no malformation if taken only after the 50th day. Within the sensitive period from day 35 to day 49, there is the following sequence:
35th-37th day Absence of the ears and deafness
39th-41st day Absence of arms
43rd-44th day Phocomelia with three fingers
46th-48th day Thumbs with three joints
If thalidomide has been taken throughout the sensitive period, the consequence may be severe defects of ears, arms and legs and of internal malformations, which often led to early death. About 40% of thalidomide victims died before their first birthday.
The epidemic of limb and ear malformations followed the sales figures of thalidomide eight months later. Thalidomide was withdrawn in Germany at the end of November 1961. An abrupt end of the malformation epidemic was expected by the end of July 1962, and so it happened. In Japan, where thalidomide was finally withdrawn in September 1962, the peak of the epidemic occurred at a time when the epidemic in Germany had ended. In other countries like Ireland, Italy, the Netherlands, Sweden and the United Kingdom, similar parallels between time and amount of thalidomide sales and the consecutive malformations epidemic were found.
The first accusations against Chemie Grunenthal reached the Public Prosecutors Office at the County Court of Aachen by the end of 1961. On May 27, 1968, a criminal lawsuit was started by the Public Prosecutor against seven men of Chemie Grunenthal. The case was that they had put on sale a drug which caused an unacceptable degree of bodily harm without having tested it properly, and that they had failed to react on information on side effects in due time, and instead had tried to suppress information. The first two and a half months of the trial were concerned with peripheral neuropathy caused by thalidomide.
The court had its final session on December 18, 1970, two years and nearly seven months after it had started. There was neither a sentence nor an acquittal. The Attorneys of the plaintiffs had reached an out of court agreement on compensation of the victims on April 10, 1970. Chemie Grunenthal had agreed to pay DM100 million to the children with malformations attributable to thalidomide. The court confirmed that thalidomide was a teratogenic and stressed that it was more important to change the whole system (i.e. promotions and sales of drugs, of legal control and of the attitude of the doctors and patients) than to find and punish a few individual scapegoats for errors or commissions which might have occurred in any pharmaceutical company.
On December 17, 1971, the Federal Ministry of Health established the foundation ‘Hilfswerk fur behinderte Kinder’ (institution to help handicapped children), which put the agreement on a legal basis, thereby taking over the responsibility for the compensation scheme.
The Committee of Trustees was set up to distribute the money given by Chemie Grunenthal and an additional sum contributed by the Federal Government. In 1971 and 1972 I gave my opinion on the causation of malformations in about 1,600 cases, and in 1973 on about 800 additional cases. Compensation however started not before 1972. The number of thalidomide victims covered by the German compensation scheme was 2,866. Countries like Canada, Italy, Japan, Sweden and the United Kingdom were not included in the German scheme as in these countries other firms than Chemie Grunenthal had sold thalidomide. The British, Canadian, Japanese and Swedish thalidomide victims got similar compensation following litigation. The only country in which there appears to be no regulation of compensation is Italy.
The Grunenthal compensation scheme included other countries in which thalidomide had been sold by the German Company or produced by licence such as Austria, Belgium, Brazil, Finland, the Netherlands, Portugal, Syria and Mexico. The malformations attributable to thalidomide in these countries did not differ from those seen in West Germany and in cases in which the time of intake was definitely known it coincided with the sensitive period as derived from information on German cases. Race, food styles, or climate did not appear to play any role.
In 1971, I was asked by Mr. Nishida and his colleagues, attorneys of the plaintiffs in the Japanese thalidomide trial against Dai Nippon Company, and the Japanese Ministry of Health, to come to Japan to serve as an expert witness at the Tokyo District Court. Three years later, on October 26, 1974 a formal settlement was made at the Tokyo District Court with respect to 39 families involved in the Tokyo litigation. Similar formal settlements for the litigation in Kyoto, Osaka, Nagoya, Gifu, Okayama, Hiroshima and Fukuoka shortly followed. About 300 thalidomide victims were acknowledged by the medical committees set up by the Japanese Ministry of Health.
Professor Dr. W. Lenz died in February 1995.
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