Thalidomide and other teratogens

SIGNIFICANCE: Teratogenesis is the development of defects in the embryo or fetus caused by exposure to chemicals, radiation, or other environmental conditions. Thalidomide, a sedative whose ingestion by pregnant women led to the birth of abnormal babies in the late 1950s and early 1960s, is one of the more publicized examples of a chemical teratogen.

Teratogenesis and Its Causes

Teratogenesis is the development of structural or functional abnormalities in an embryo or fetus due to the presence of a toxic chemical or other environmental factor. The term is derived from the Greek words teras (monster) and genesis (birth). The phenomenon is usually attributed to exposure of the mother to some causative agent during the early stages of pregnancy. These may include chemicals, excessive radiation exposure, viral infections, or drugs. Drugs that are taken by the father may be teratogenic only if they damage the chromosomes of a spermatozoan that then joins with the egg to form a zygote.

For many centuries, the impression that malformed babies were conceived as a result of the intercourse between humans and devils or animals dominated society. Seventeenth century English physiologist William Harvey attributed teratogenesis to embryonic development. In the nineteenth century, the French brothers Étienne and Isidore Geoffroy Saint-Hilaire outlined a systematic study on the science of teratology. In the United States, the importance of teratogens was first widely covered during the 1940s, when scientists discovered that pregnant women who were affected by German measles (rubella) often gave birth to babies that had one or more birth defects. In the 1940s and 1950s, the consumption of diethylstilbestrol (DES) before the ninth week of gestation to prevent miscarriage was found to produce cancer in the developing fetus. Animal studies have also shown that defective offspring result from the use of hallucinogens such as lysergic acid diethylamide (LSD).

A broader definition of teratogenesis may include other minor birth defects that are more likely to be genetically linked, such as clubfoot, cleft lip, and cleft palate. These defects can often be treated in a much more effective way than those caused by toxic substances. Clubfoot, for example, which can be detected by the unusual twisted position of one or both feet, may be treated with surgery and physical therapy within the first month after birth. Brachydactyly (short digits) in rabbits has been linked to a recessive gene that causes a local breakdown of the circulation in the developing bud of the embryo, which is followed by necrosis (tissue death) and healing. In more extreme cases of agenesis, such as limb absence, a fold of amnion (embryonic membrane) was found to cause strangulation of the limb. Agenesis has been observed with organs such as kidneys, bladders, testicles, ovaries, thyroids, and lungs. Other genetic teratogenic malformations include anencephaly (absence of brain at birth), microcephaly (small-size head), hydrocephaly (large-size head caused by accumulation of large amounts of fluids), spina bifida (failure of the spine to close over the spinal cord), cleft palate (lack of fusion in the ventral laminae), and hermaphrodism (presence of both male and female sexual organs).

Thalidomide and Its Impact

Thalidomide resembles glutethimide in its sedative action. Laboratory studies of the late 1950s and early 1960s had shown thalidomide to be a safe sedative for pregnant women. As early as 1958, the West German government made the medicine available without prescription. Other Western European countries followed, with the medicine available only upon physician’s prescription. It took several years for the human population to provide the evidence that laboratory animals could not. German physician Widukind Lenz established the role of thalidomide in a series of congenital defects. He proved that administration of the drug during the first twelve weeks of the mother’s pregnancy led to the development of phocomelia, a condition characterized by peromelia (the congenital absence or malformation of the extremities caused by the abnormal formation and development of the limb bud from about the fourth to the eighth week after conception), absence or malformation of the external ear, fusion defects of the eye, and absence of the normal openings of the gastrointestinal system of the body.

The United States escaped the thalidomide tragedy to a great extent because of the efforts of Frances O. Kelsey, MD, of the US Food and Drug Administration (FDA). She had serious doubts about the drug’s safety and was instrumental in banning the approval of thalidomide for marketing in the United States. Other scientists such as Helen Brooke Taussig, a pioneer of pediatric cardiology and one of the physicians who outlined the surgery on babies with the Fallot (blue baby) syndrome, played a key role in preventing the approval of thalidomide by the FDA. It is estimated that about seven thousand births were affected by the ingestion of thalidomide.

The thalidomide incident made all scientists more skeptical about the final approval of any type of medicine, especially those likely to be used during pregnancy. The trend intensified the fight against any chemicals that might affect the fetus during the first trimester, when it is particularly vulnerable to teratogens. Alcohol and tobacco drew many headlines in the media in the 1990s. Both have been shown to create congenital problems in mental development and learning abilities. At the same time, regulation of new FDA-approved medicine became much stricter, and efforts to study the long-term effects of various pharmaceuticals increased. Surprisingly, thalidomide itself has been used successfully in leprosy cases and, in conjunction with cyclosporine, to treat cases of the immune reaction that appears in many bone-marrow transplant patients. Since the 1990s, thalidomide has been used to treat some of the complications of the human immunodeficiency virus (HIV) and acquired immunodeficiency syndrome (AIDS).

In addition to drugs, many other agents can affect fetal development. Essentially, any factor with the potential to cause DNA mutations has a high probability of being teratogenic. Consequently, early in pregnancy, women are advised to limit their exposure to a variety of potential teratogens, such as excess radiation, toxic chemicals, tobacco, alcohol, and other drugs. Prevention might even include work reassignment to limit or eliminate the woman’s normal exposure to teratogens. Unfortunately, teratogenesis can occur early in the pregnancy, before the woman is even aware that she is pregnant. Prevention by avoidance is therefore essential. According to a 2024 study published in the journal JAMA Network Open, about one in sixteen women were exposed to some form of teratogen medication during pregnancy, particularly in the first trimester.

Key terms

• congenital defecta defect or disorder that occurs during prenatal development
• peromeliathe congenital absence or malformation of the extremities caused by abnormal development of the limb bud from about the fourth to the eighth week after conception; the ingestion of thalidomide by pregnant women can cause this disorder in fetuses

Bibliography

Ferretti, Patrizia, et al., eds. Embryos, Genes, and Birth Defects. 2d ed. Hoboken: Wiley, 2006. Print.

Giavini, Erminio, and Elena Menegola. "Biomarkers of Teratogensis: Suggestions from Animal Studies." Reproductive Toxicology 34.2 (2012): 180–85. Print.

Holmes, L. B. “Teratogen-Induced Limb Defects.” American Journal of Medical Genetics 112.3 (2002): 297–303. Print.

McCredie, Janet. Beyond Thalidomide: Birth Defects Explained. London: Royal Society of Medicine, 2007. Print.

Moore, Keith L., T. V. N. Persaud, and Mark H. Torchia. Before We Are Born: Essentials of Embryology and Birth Defects. 8th ed. Philadelphia: Elsevier, 2013. Print.

Schardein, James L. Chemically Induced Birth Defects. 3d ed. New York: Dekker, 2000. Print.

Stephens, Trent D., and Rock Brynner. Dark Remedy: The Impact of Thalidomide and Its Revival as a Vital Medicine. Cambridge, Mass.: Perseus, 2001. Print.

Vajda, Frank J. E., et al. "Teratogenesis in Repeated Pregnancies in Antiepileptic Drug-Treated Women." Epilepsia 54.1 (2013): 181–86. Print.

Winterstein, Almut G., et al. "Prenatal Care Initiation and Exposure to Teratogenic Medications." JAMA Network Open, vol. 7, no. 2, 1 Feb. 2024, doi:10.1001/jamanetworkopen.2023.54298. Accessed 6 Sept. 2024.