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Saturday, 4 January 2020

The Thalidomide Scandal (Things We Don’t Know about Pregnancy Series #10)

In 1953, a new drug was made, and by 1957 it was on the market. In the six years that followed, over 10,000 children in 46 countries were born with congenital deformities[1]. The disaster was known as the thalidomide scandal, and led to serious reforms in drug regulation and monitoring worldwide.

What happened?

Thalidomide was prescribed for insomnia, anxiety, asthma, hypertension, migraine, and morning sickness. Doctors thought that it was very safe because taking an overdose simply cast the drinker into a prolonged sleep – and did not cause death. It was also non-addictive. Nobody tested it in pregnant women or animals.

Then, in 1961, two doctors independently called out statistically high numbers of congenital abnormalities in “thalidomide babies” – 20% where the normal rate is 1.5% (or a bit higher, depending on your source)[2].

Thalidomide babies. Image via Wikipedia Commons.


No one had picked up the pattern before because this wasn’t just one kind of birth defect – it included shortened limbs, spinal deformations, facial defects like small or missing eyes or cleft lips, and internal deformations of the kidneys, heart, urinary tract, or genitals[3]. Later, high rates of dyslexia, autism, or epilepsy were also observed. 40% of deformed babies died[2]. Most of these deformities phenocopied other conditions, so no one realised they were linked.

Interestingly, the kind of birth defects caused by thalidomide seem to depend on when it is taken. If taken very early, it causes miscarriage; if taken between 20 and 36 days post ovulation (3-7 weeks), it causes deformities, and after that, brain damage[4]. Morning sickness is most common during weeks 6-12 of pregnancy. No one’s quite sure why these changing consequences arise.

The drug was recalled, but it was already out there, and babies affected by it continued to be born until 1963.

What is thalidomide?

Thalidomide is a mixture of left- and right-handed mirror image molecules made up of two rings joined together, one called phthalimide and one called glutarimide.

Thalidomide. Image via Wikipedia Commons.
In 1979, Blaschke et al. suggested that only left-handed thalidomide caused the birth defects[4].

Why?

Lots of biological molecules are handed, in particular natural sugars and amino acids, which bind to key enzymes and receptors where their right-handed mirror images cannot. What do the right-handed ones do? In nature, they don’t exist, but if they are present, they either do nothing – simply diluting the effect of the left-handed molecules, or they do something different… and that could be anything. We don’t know, and we don’t know how to predict where they might bind or react in the body!

Proving Blaschke’s theory either way proved difficult because left- and right-handed thalidomide rapidly interconvert under physiological conditions[4]. You never just get one kind.

Hands are mirror images of each other – so are molecules like thalidomide. © TWDK.

How does it work?

We don’t know. There are more than 30 proposed mechanisms for thalidomide action on the body, and in fact, it looks like it does a lot of stuff, causing mutations in DNA and cartilage, interfering with neural networks, generating reactive oxygen species (which accelerate cell ageing in the body), and inhibiting some proteins[3]. Importantly, it is antiangiogenetic, which means it stops the development of new blood cells – exactly what happens when the placenta is forming between 6 and 12 weeks of pregnancy.

Example of an electron density map. Image via Wikipedia Commons.
We do know that thalidomide binds to a target protein called cereblon, and it was this binding that eventually led scientists to prove Blaschke’s theory: because left- and right-handed thalidomide bind differently. By doping them with deuterium, this interconversion was suppressed and scientists were able to take x-ray images and electron density maps that showed right-handed thalidomide bound awkwardly, in a twisted, metastable shape. Basically, it was always ready to fall back off. Left-handed thalidomide on the “other hand”, bound comfortably and did things in the body[5]. This means that only the left-handed molecule caused the deformations.

But scientists still aren’t sure the right-handed molecule is safe. This isn’t just because it can turn into the left-handed molecule, but also because thalidomide breaks down in the body – either by metabolism or by hydrolysis – and some of the products of these reactions are also thought to be dangerous[5].

 

What now?

Today, thalidomide is still used as a drug to treat skin conditions including leprosy, Behçet’s syndrome, lupus, and graft-versus-host disease because of its anti-inflammatory properties[6], has been trialled in HIV patients as an immunomodulator[7], and suppresses solid and blood cancers because of its antiangiogenetic effects[8][9]. Now pregnant women can’t take it, nor can women who might get pregnant whilst taking it, or men who might get their partner pregnant. Other regulations have made testing on pregnant animals mandatory, restricted what can be prescribed to pregnant women, and introduced ongoing monitoring for side effects once drugs have gone on the market[10]. Whilst not being able to get any pain killers or sickness relief whilst pregnant is a pain, and animal testing is problematic, especially since some animals (like mice) have very different responses to some drugs (like thalidomide), at least we’re being cautious.

The breakthrough is that pregnant women are now recognised as an important medical category, where before it was assumed that the placenta was sterile and no drugs could cross it and, as such, pregnant women didn’t have to be treated any differently to ordinary women. Or men. Because, let’s face it, women are still massively underrepresented in clinical studies[11][12][13], along with other marginalised categories such as ethnic minorities and the elderly.

The unknowns about women’s health mean a lot of drugs are incorrectly dosed or don’t work so well, and conditions even as well known as heart attack are misdiagnosed. However, this has been recently recognised and many scientists are working to try to effect change.

There are many unknowns when it comes to pregnancy, and over the next few months, I’ll be exploring more of them with you. Look out for my next blog post, which will be about silent miscarriage.

To read our full article on the things we don't know about pregnancy, check out our site. This article will be updated as we add posts across the coming months.



References
why don't all references have links?

[1] Verheul, H.M.W., Panigrahy, D., Yuan, J. and D’amato, R.J., 1999. Combination oral antiangiogenic therapy with thalidomide and sulindac inhibits tumour growth in rabbits. British journal of cancer, 79(1), p.114.
[2] McBride, W.G., 1961. Thalidomide and congenital abnormalities. Lancet, 2(1358), pp.90927-8.
[3] Vargesson, N., 2015. Thalidomide‐induced teratogenesis: History and mechanisms. Birth Defects Research Part C: Embryo Today: Reviews, 105(2), pp.140-156.
[4] Tokunaga, E., Yamamoto, T., Ito, E. and Shibata, N., 2018. Understanding the Thalidomide Chirality in Biological Processes by the Self-disproportionation of Enantiomers. Scientific reports, 8(1), p.17131.
[5] Mori, T., Ito, T., Liu, S., Ando, H., Sakamoto, S., Yamaguchi, Y., Tokunaga, E., Shibata, N., Handa, H. and Hakoshima, T., 2018. Structural basis of thalidomide enantiomer binding to cereblon. Scientific reports, 8(1), p.1294.
[6] Melchert, M. and List, A., 2007. The thalidomide saga. The international journal of biochemistry and cell biology, 39(7-8), pp.1489-1499.
[7] Calabrese, L. and Fleischer Jr, A.B., 2000. Thalidomide: current and potential clinical applications. The American journal of medicine, 108(6), pp.487-495.
[8] Bielenberg, D.R. and D'Amore, P.A., 2008. Judah Folkman's contribution to the inhibition of angiogenesis. Lymphatic research and biology, 6(3-4), pp.203-207.
[9] Kyle, R.A. and Rajkumar, S.V., 2008. Multiple myeloma. Blood, The Journal of the American Society of Hematology, 111(6), pp.2962-2972.
[10] Heger, W., Klug, S., Schmahl, H.J., Nau, H., Merker, H.J. and Neubert, D., 1988. Embryotoxic effects of thalidomide derivatives on the non-human primateCallithrix jacchus. Archives of toxicology, 62(2-3), pp.205-208.
[11] Hall, W.D., 1999. Representation of blacks, women, and the very elderly (aged> or= 80) in 28 major randomized clinical trials. Ethnicity & disease, 9(3), pp.333-340.
[12] Rochon, P.A., Berger, P.B. and Gordon, M., 1998. The evolution of clinical trials: inclusion and representation. CMAJ: Canadian Medical Association Journal, 159(11), p.1373.
[13] Murthy, V.H., Krumholz, H.M. and Gross, C.P., 2004. Participation in cancer clinical trials: race-, sex-, and age-based disparities. Jama, 291(22), pp.2720-2726.

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