71676 Med Genet 1992; 29: 716-723 SYNDROME OF THE MONTH J Med Genet: first published as 10.1136/jmg.29.10.716 on 1 October 1992. Downloaded from Recognition of thalidomide defects R W Smithells, C GH Newman Thalidomide: a brief history Thirty years later, subjects are still coming Thalidomide (alpha-phthalimido-glutarimide) forward (albeit, in small numbers) with claims was developed by the German firm Chemie that they have birth defects which have (or Grunenthal as an anticonvulsant drug. Early may have) been caused by thalidomide taken trials showed it to be unsuitable for this pur- by their mothers during early pregnancy, and pose but indicated that it had sedative proper- that they should therefore be accepted as bene- ties. Furthermore, it had one remarkable prop- ficiaries of whatever forms of financial assist- erty: overdoses simply caused prolonged sleep, ance may be available. In the UK, this is the not death. The drug was first marketed in Thalidomide Trust. Germany in 1957 under the name Contergan, Thalidomide caused a wide variety of birth and in the UK in April 1958 as Distaval. Later, defects, not one of which was unique to that compound preparations which combined tha- drug. Nevertheless, the nature and pattern of lidomide with other drugs were marketed for a the defects are, in most cases, characteristic wide variety of indications: Asmaval for enough to be recognisable to an experienced asthma, Tensival for hypertension, Valgraine eye. Indeed, many of the present beneficiaries for migraine, and so forth. The promotion of of the Trust have been accepted on the basis of these products laid great stress on the safety of clinical judgements, without direct evidence of thalidomide, based on the remarkable property thalidomide exposure. As the number of doc- described above. tors with wide experience of this problem is German paediatricians and geneticists small (possibly only three in the UK) and will began to see children with gross limb malfor- become smaller with the passage of time, and mations of a most unusual pattern. When two as new claims continue to arise, it seems timely cases were shown at a paediatric meeting in to record, in as much detail as possible, the Kassel by Kosenow and Pfeiffer in October observations which underlie these clinical http://jmg.bmj.com/ 1960, few people present had ever seen similar judgements. limb defects. Wiedemann in 1961 described 13 As well as describing the defects and pat- affected infants who had been referred to him terns associated with thalidomide, it will be over a period of 10 months, and noted that this appropriate to discuss 'differential diagnosis', amounted to an epidemic. He drew attention that is, recognisable defects and syndromes to a number of associated malformations in which, to a greater or lesser degree, resemble these children, including congenital heart dis- thalidomide defects. Some of these are un- on September 29, 2021 by guest. Protected copyright. ease, microphthalmos and coloboma, intestinal likely to confuse an experienced eye: others atresia, renal malformations, abnormal pinnae, can present considerable difficulty. and facial naevus. In considering a new claim, attention will In November 1961, Lenz suggested that obviously be paid to the claimant's date of these deformities resulted from the mothers birth. In the UK, thalidomide was first mar- having taken thalidomide. By a remarkable keted in April 1958, initially in very small coincidence, the same suggestion was made at quantities, so it is not to be expected that it much the same time by McBride in Australia. would damage anybody born before January Confirmation of this suggestion came rapidly 1959 (unless supplies had been obtained from from all parts of the British Isles, Kenya, West Germany). Sales in the UK stopped in Japan, Sweden, Belgium, Switzerland, November 1961. Had consumption stopped at Lebanon, Israel, Peru, Canada, Brazil, the the same time, no 'thalidomide babies' should Netherlands, and the USA. The drug had have been born after August 1962. However, been released only for clinical trials in the many people still had tablets containing thali- USA because of concerns following reports domide in their homes, and either did not hear 5 North Grange Mews, from Europe of irreversible peripheral neur- promptly of its dangers, or did not realise that North Grange Road, itis as a side effect of thalidomide. Conse- their tablets contained thalidomide. In fact, Leeds LS6 2EW. con- children with defects accepted as attributable R W Smithells quently there were very few cases. By trast, it had been on sale over the counter in to thalidomide (though not necessarily with Leon Gillis Unit, Germany, and there were consequently more documentary evidence of prescription) con- Queen Mary's affected children there than else. In tinued to be born up to about May 1963, and, Hospital, anywhere Roehampton. the UK the drug was available on prescription very exceptionally, beyond this date. C G H Newman only, but it was used very widely for, among In trying to establish a yardstick or bench- of mark for bona fide thalidomide defects, it is Correspondence to other problems, common symptoms early Professor Smithells. pregnancy. necessary to start with cases in which there is Recognition of thalidomide defects 717 very good evidence of thalidomide intake in with limb defects, and these certainly account early pregnancy. Unfortunately, the investig- for the majority of cases. However, almost any J Med Genet: first published as 10.1136/jmg.29.10.716 on 1 October 1992. Downloaded from ator has never seen the pregnant mother swal- organ of the body could be affected. The low a tablet. Absolute certainty is therefore second major group of defects involves the unattainable, and we must settle for a scale of ears, the eyes, and the nerve supplies to the probability. The evidence may include the face, the eye muscles, and the lacrimal (tear) following. glands. Internal defects commonly affected the (1) A dated prescription for thalidomide, the heart, the kidneys and urinary tract, the ali- date falling within or before (but not too mentary tract, and the genital tract, and none long before) the period ofembryonic sensit- was unique to thalidomide. The early morta- ivity to the drug (34 to 50 days after the lity rate among 'thalidomide babies' was about beginning of the last menstrual period). 40%, largely as a result of serious internal (2) A doctor's statement, preferably a sworn malformations. Consequently, internal defects affidavit, that he supplied such a prescrip- are much less common among survivors than tion at such a time, but kept no record of it. they were among the whole group at birth. (3) A mother's statement (preferably sworn) Most of the serious internal defects caused that she took thalidomide at the relevant problems at or soon after birth which either time, with an indication of its source required treatment or led to death. Some de- (which is not necessarily a prescription). fects of the kidneys and female genital tract (4) A mother's ability to identify the tablet she which can only be shown by special tests did took, when shown a selection of tablets. not become apparent until many years after Fortunately, all tablets containing thalido- birth. It is possible that there are still unde- mide were readily identifiable and could be tected internal problems in people aged 30 recognised or described by reasonably ob- years or more, but as time passes it becomes servant people. increasingly unlikely that any such hidden At this point it is appropriate to mention two defects will cause significant problems. They important paradoxes. First, although a few will therefore play little part in the diagnosis of mothers may have claimed untruthfully to thalidomide damage in the future. have taken thalidomide (acting in what they A small but important group of thalidomide believed to be their child's best interests), a related problems includes conditions which vastly greater number of the mothers of accep- are not present at birth but develop later. ted Trust beneficiaries denied any knowledge Abnormalities of the spine were recognised of any drug consumption during pregnancy. early, and of the knees rather later. Other There is a negative drug history in about 50% bones/joints may also be affected. It is to be of accepted cases, and there is unlikely to be expected that the thalidomide damaged people any such evidence in the future. will be prone to the same ills as beset the rest of The second paradox is that, bearing in mind the population. A causal connection with thali- that 2 to 3% of all babies born have significant domide would be suggested if a particular http://jmg.bmj.com/ birth defects, and that thalidomide consump- disease was more common among the thalido- tion was widespread in 1960 to 1961, some mide population than among the general popu- mothers who undoubtedly took the drug when lation from which they came, or if the disease pregnant (though probably outside the sensi- presented at an unusual age or in an unusual tive period) gave birth to babies with defects way. quite unrelated to thalidomide. It is also pos- sible for a baby exposed to thalidomide during on September 29, 2021 by guest. Protected copyright. the sensitive period to be born with a variety of Some general features of thalidomide defects, of which some, but not all, are drug damage induced. Authorities differ about the possi- At birth, many thalidomide babies exhibited a bility that a fetus exposed to thalidomide dur- central facial naevus of the 'stork mark' variety ing the sensitive period might be born without in the centre of the forehead (which is common birth defects.