Thalidomide was originally licensed in West Germany in 1957 under the name Contergan as a ‘wonder drug’ for use against anxiety, insomnia, gastritis and tension. Soon, Dr McBride, an obstetrician in Australia, started prescribing thalidomide for an ‘off label’ use to alleviate morning sickness. This rapidly became a worldwide practise as it was such an effective treatment, and off label prescriptions are not infrequent.
At the time thalidomide was developed it was thought that drugs couldn’t pass through the placenta from mother to baby, so tests to obtain licencing were not required to be run in pregnant women. The lack of data around this meant Frances Kelsey (FDA inspector) prevented thalidomide’s use in the USA despite pressure from pharmaceutical companies and FDA supervisors. She was later awarded the President’s Award for Distinguished Federal Civilian Service in 1962 by John.F.Kennedy for her efforts.
McBride soon noticed an increased prevalence in deformed limbs etc. in the babies he delivered to women he had prescribed thalidomide. On top of this, German newspapers started to report an increase in birth abnormalities, with 50% of mothers with new-borns with birth defects, having taken thalidomide in the first trimester of pregnancy. Quickly, Germany stopped licencing thalidomide and many other countries followed suit; by 1962 thalidomide was banned in almost all countries where it was previously sold.
Why does thalidomide cause birth defects?
Thalidomide has a sterogenic carbon atom meaning it exists as two enantiomers. This simply means it can exist as two molecules which are mirror images of each other, but not identical to each other. Although this seems like a minor difference that shouldn’t impact the effectiveness or safety of the drug, it means the molecules interact with biologically active molecules such as amino acids, sugars and steroids in different ways.
Tests were carried out in 1961 on mice, and showed that one of the enantiomers (S enantiomer) had teratogenic properties (ability to create malformations in embryos), but the other (R) had therapeutic properties. However, Thalidomide is racemic, meaning it contains both R and S enantiomers in equal proportions. This is because the enantiomers can interconvert in vivo (humans), essentially meaning that even if a human is injected with just one of the enantiomers, both will be present in them, as the molecule has the ability to convert between the two enantiomers.
As a result, this means that the teratogenic effects of thalidomide cannot be avoided. These effects are caused by thalidomide preventing the development of new blood vessels in the embryo. This meant that long limbs didn’t develop or were stumps, as well as eyes, hearts and urinary tracts being deformed, it can cause blindness and deafness.
As a result of the thalidomide tragedy, changes were made in the way drugs were tested, what types of drugs could be used during pregnancy and there was an increased awareness of potential side effects of drugs.