Thalidomide and Birth Defects


Thalidomide is a teratogenic drug that caused horrific birth defects when prescribed as an antiemetic to pregnant women in the 1960s. The most stereotypical defect is symmetrical limb malformations such as phocomelia, although ear, eye and internal organ defects are also observed. Thalidomide was consequently withdrawn from the market. However, Thalidomide has since been shown to have many beneficial antiinflammatory and immunomodulatory effects, and is therefore used in a regulated manner in the treatment against cancers and inflammatory disorders. Sadly, new cases of babies being born affected by thalidomide, likely due to medicine sharing, are reported in Brazil. The mechanisms of how thalidomide causes a wide range of embryonic malformations are becoming clearer; thalidomide is thought to act through molecules such as cereblon and tubulin and also affects blood vessel development and cell death, resulting in teratogenesis. Fully understanding the molecular events induced by thalidomide is essential if we are to develop a safe but clinically relevant form of the drug.

Key Concepts

  • Thalidomide was used between 1957 and 1961 as a ‘safe’ treatment for morning sickness, but was withdrawn after it was found to cause severe birth defects.
  • Thalidomide has since been shown to possess antiinflammatory, antiangiogenic and antiproliferative properties.
  • Thalidomide is now used, under strict regulations, to treat human inflammatory disorders and cancer.
  • Thalidomide causes embryonic damage in a short time‐sensitive window between day 20 and 36 postfertilisation in humans.
  • Thalidomide causes damage to the majority of the body tissues; among the most common and stereotypical damage is to the limbs.
  • Effects of thalidomide can vary depending on the species exposed, some species being more sensitive to the drug than others.
  • Evidence supports blood vessels as a primary target of thalidomide.
  • Possible other pathways involved in thalidomide‐induced embryopathy are oxidative stress induction, cell death and binding to Cereblon.
  • Cereblon acts as a target of thalidomide for treatment of multiple myeloma in adult humans.

Keywords: angiogenesis; cell death; cereblon; reactive oxygen species; time‐sensitive window; mechanisms of teratogenesis; chicken embryo; zebrafish embryo

Figure 1. Structures of thalidomide and its analogues. Thalidomide enantiomers R(+) and S(−) can interchange at physiological pH (asterisk indicates chiral centre).
Figure 2. Therapeutic mechanisms of thalidomide in adults. Illustrated are the pathways through which thalidomide is thought to act in the treatment of HHT and multiple myeloma. Figure based on data from Stewart, 2014 and Lebrin et al., 2010.
Figure 3. Thalidomide time‐sensitive window. Chart indicates the period (days and weeks postfertilisation) in which the most common defects occur. See also Table. Adapted from Vargesson, 2015 © N Vargesson(Wiley Open Access Article); Miller et al., 2005 © National Institutes of Health.
Figure 4. Thalidomide and embryonic teratogenesis. Thalidomide has been shown to induce loss of blood vessels, increased cell death and reactive oxygen species, resulting in embryonic damage. Thalidomide may cause teratogenesis through interaction with targets such as Cereblon, tubulin and/or sGC, interrupting blood vessel development and resulting in localised reactive oxygen species and cell death induction.


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Further Reading

Magazanik M (2015) Silent Shock: The Men Behind the Thalidomide Scandal and an Australian Family's Long Road to Justice. Melbourne: Text Publishing.

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Vargesson N (2011) Thalidomide. In: Gupta R (ed) Reproductive and Developmental Toxicology, pp. 395–403. Amsterdam: Academic Press Elsevier.

Zuniga A, Zeller R and Probst S (2012) The molecular basis of human congenital limb malformations. Wiley Interdisciplinary Reviews: Developmental Biology 1 (6): 803–822.

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Fraga, Lucas Rosa, Diamond, Alexandra J, and Vargesson, Neil(Jan 2016) Thalidomide and Birth Defects. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0026052]