Young: Medical Genetics
Chapter 9
The Thalidomide Tragedy
Molecular structure of the drug thalidomide
The drug thalidomide was developed by a German pharmaceutical firm in the 1950s and was used widely in many parts of the world from 1958 to 1961 as a powerful sedative and antiemetic. Unfortunately it soon emerged that thalidomide is one of the most teratogenic agents ever discovered (p.182). In November 1961, Lenz in Europe and McBride in Australia independently correctly linked thalidomide with an outbreak of congenital limb defects of epidemic proportion. The drug was rapidly withdrawn but not before approximately 12 000 babies had been affected. As discussed below, many of these infants also had severe internal anomalies resulting in an early mortality rate of close to 40%. Amongst developed nations only the United States was spared because of caution on the part of the US Food and Drug administration authority in licensing the drug due to concern about possible neurological side effects.
The structures most commonly affected in ‘thalidomide babies’ were the upper limbs, although almost all external and internal organs were vulnerable. The most characteristic defect, phocomelia, consisted of absence of a central portion of the upper limb with digits attached to the remaining proximal portion. The most sensitive period for upper limb defects was from 27 to 30 days post conception, although exposure at any time between 20 and 35 days post conception could have adverse effects. Other limb abnormalities noted included absence of individual bones or structures such as the thumb, radius, ulna or humerus. Pre-axial polydactyly (i.e. an extra thumb as opposed to post-axial polydactyly = an extra little finger) was also reported. Defects in the lower limbs followed a similar pattern, but were less common and symmetrical.
Other organs and structures affected included the face, heart, kidneys, genitalia and alimentary tract. Facial haemangiomata were common and some children had absent ears and/or eyes with occasional cleft lip/palate. Cardiac defects included atrial and ventricular septal defects as well as more complex lesions which often proved fatal. Absent or abnormal kidneys, undescended testes, vaginal atresia, uterine abnormalities, duodenal atresia and imperforate anus were amongst the more common malformations reported in other systems.
The mechanism by which thalidomide exerts its teratogenic effects is still not fully understood. Possible actions include inhibition of angiogenesis and alteration of gene expression through incorporation into DNA guanine sites. An overall effect of inhibiting the growth of new vessels may be an over-simplification, but would be consistent with the observed outcome. Although thalidomide was withdrawn from use following recognition of its teratogenicity, it is now used on a carefully regulated basis for the treatment of leprosy and certain forms of cancer, most notably multiple myeloma. Amongst its many actions it exerts an anti-inflammatory effect by suppressing production of tumour necrosis factor (TNF), so that it is sometimes used to suppress some of the unpleasant TNF induced symptoms of cancer such as night sweats, pyrexia and weight loss.
The only possible beneficial outcome of what is now referred to as the ‘thalidomide tragedy’ was that much tighter regulations were introduced for monitoring drug safety, in parallel with the establishment of malformation registers and surveillance systems. Consequently it is very unlikely that the world will ever witness another teratogenic outbreak on a similar scale.
Reference
Smithells RW, Newman CGH (1992) Recognition of thalidomide defects. Journal of Medical Genetics, 29, 716-723.