Appendix A tale to remember the thalidomide disaster

Thalidomide has provided a terrible lesson to the world in regard to drug development, testing, naming, prescribing and consumption. It deserves to be remembered.

In 1960-61 in [West] Germany an outbreak of phocomelia occurred. Phocomelia means 'seal extremities'; it is a congenital deformity in which the long bones of the limbs are defective and substantially normal or rudimentary hands and feet arise on, or nearly on, the trunk, like the flippers of a seal; other abnormalities may occur. Phocomelia is ordinarily exceedingly rare.

Most [West] German clinics had no cases during the 10 years up to 1959. In 1959, in 10 clinics, 17 were seen in 1959, 126 in 1960, 477 in 1961. The European outbreak seemed confined to [West] Germany (though a similar but smaller occurrence was simultaneously noted in Australia), and this, with the steady increase, made a virus infection, such as rubella, seem an unlikely cause. Radioactive fall-out was considered and so were x-ray exposure of the mother, hormones, foods, food preservatives and contraceptives. One doctor, investigating his patients retrospectively with a questionnaire, found that 20% reported taking a proprietary medicine, Contergan, in early pregnancy. He questioned the patients again and 50% then admitted taking it; many said they had thought the drug too obviously innocent to be worth mentioning initially.14

In November 1961, the suggestion that a drug, unnamed, was the cause of the outbreak was publicly made by the same doctor at a paediatric meeting, following a report on 34 cases of phocomelia. 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'. Several letters followed, asking the same question, and it soon became widely known that the sedative drug thalidomide (Contergan, Distaval, Kevadon, Talimol, Softenon) was probably the cause.

14 Illustrating the problem of retrospective research, e.g. case-control studies; enquiries of patients are unreliable.

It was withdrawn from the [West] German market in November and from the British market in December 1961. By that time reports had also come from other countries. A case-control study showed that of 46 cases of phocomelia 41 mothers had taken thalidomide and of 300 mothers with normal babies none had taken thalidomide between the fourth and ninth week of pregnancy.

Prospective observational cohort studies were quickly made in antenatal clinics where women had yet to give birth; though few, they provided evidence incriminating thalidomide. The worst had happened, a trivial new drug was the cause of the most grisly disaster in the short history of modern scientific drug therapy. Many thalidomide babies died, but many live on with deformed limbs, eyes, ears, heart and alimentary and urinary tracts.15

The [West] German Health Ministry estimated that thalidomide caused about 10 000 birth deformities in babies, 5000 of whom survived and 1600 of whom would eventually need artificial limbs. In Britain there were probably at least 600 live births of malformed children of whom about 400 survived. The world total of survivors was probably about 10 000.

Thalidomide had been marketed in [West] Germany in 1956, in Britain in 1958, and in other countries as a sedative and hypnotic and was recommended for use in pregnant women. It had not been tested on pregnant animals. When it was eventually tested it was at first difficult to induce fetal deformity (until it was used on New Zealand White Rabbits).

Thalidomide, skilfully promoted and credulously prescribed and taken by the public — it was also sold without prescription — achieved huge popularity; it 'became [West] Germany's baby-sitter'. It was a routine hypnotic in hospitals, was even recommended to help children adapt themselves to a convalescent home atmosphere and was sold mixed with other drugs for symptomatic relief of pain,

15 For pictures of thalidomide deformities, see British Medical Journal 1962; 2: 646-647 and Journal of the American Medical Association 1962; 180:1106-1114.

cough and fever. In 1960-61 it had become evident that prolonged use of thalidomide could cause hypothyroidism and peripheral neuritis. The latter effect was the principal reason why approval for marketing in the USA, as Kevadon, had been delayed by the US Food and Drug Administration. Approval had still not been given when the fetal effects were discovered and so general distribution was avoided. Nonetheless some 'thalidomide babies'

were born in the USA following indiscriminate premarketing clinical trials.

Thalidomide has anti-inflammatory and immunosuppressant actions and retains a limited specialist use in, for example, lepromatous leprosy,16 and oral ulceration in AIDS (some cases).

The thalidomide disaster provided the impetus for the introduction of national drug regulatory authorities worldwide.

16 Further cases of congenital malformations were reported in 1994 due to lax control of thalidomide use (Lancet 343: 433 and 344:196). Thalidomide is available in the UK on a 'named-patient' basis only, with a detailed patient information leaflet and with signed patient consent.

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