From paracetamol to penicillin, the discovery of new drugs and medications has helped to cure countless diseases and alleviate symptoms for almost every condition imaginable. The early twentieth century in particular saw a huge wave of new medicines created and introduced. However, flawed experiments, incorrect assumptions, and sometimes plain negligence meant that some drugs ended up doing more harm than good, with the repercussions still being felt decades later.
Diethylstilbestrol (better known as DES) was a synthetic estrogen created in 1938, and entered the market for medical use in 1941. It was first marketed as a treatment for menopausal symptoms, and as a way to stop unwanted lactation in women who had given birth. However, as DES grew in popularity, it began to be prescribed for a much wider variety of conditions, including some very questionable and controversial treatments.
What was DES used for?
During the 1940s DES began to be used to prevent miscarriages after a study conducted by Olive Watkins Smith in 1948. She suggested that, based on animal experiments, DES could enhance the production of estrogen and progesterone, thereby reducing the risk of complications during pregnancy. Smith ran a trial where 632 women who had suffered previous miscarriages were given DES whilst pregnant to see if it made them less likely to miscarry again. Smith reported a significant improvement compared to other women who had not taken DES. Due to this study, and the fact that DES was very cheap to produce and buy, it became a common prescription throughout the 1950s and 1960s.
Doctors and researchers were soon finding other uses for synthetic estrogen. From the 1950s up until 1975, DES was prescribed to prepubescent girls to stop them growing “too tall”. Parents were concerned that their daughters would find it difficult to find husbands, or enter certain professions, such as flight attendants or ballet dancers. DES also became a popular morning-after pill, particularly among college students. Famously, Alan Turing was forced to take DES to induce chemical castration as a “treatment” for homosexual behaviour.
Raising doubts
Although Smith was a well respected researcher, there were some serious flaws in her 1948 trial. Firstly, there had been no control group; all participants were given DES, and were compared to other studies looking at abnormal bleeding during pregnancy. There was also little consideration for other possible factors that might have affected the results. In short, there was no way to prove that DES had indeed made the improvements that Smith claimed. The study was not intentionally misleading, but it erroneously concluded that DES helped to prevent miscarriages. Later studies showed that it did not.
Between 1950 and 1952, a double-blind clinical trial was conducted at the University of Chicago in order to rectify some of the problems of the initial study. The new trial showed that there was actually no benefit to taking DES during pregnancy. In 1958 new articles were appearing in medical journals showing that there was no statistical evidence to support the use of DES in pregnancy. Other studies also found that use of DES during pregnancy was in fact associated with increased spontaneous abortions, premature delivery, complications during delivery, and neonatal deaths.
Not just ineffective
By 1966 the long term effects of DES were beginning to become apparent. In 1970 seven cases of adolescent adenocarcinoma (a cancer which affects glandular cells) were reported in Boston. These initial diagnoses were concerning, as this type of cancer was extremely rare, and generally only presented in post-menopausal women. A year later, five more cases were reported in New York, all in women under 20 years old, and the connection was made between DES exposure in-utero and vaginal cancer. These new findings quickly led the FDA to suggest that it should not be used during pregnancy.
However, the use of DES was never completely banned, and it was still prescribed for other reasons. Some physicians continued to prescribe it to girls to prevent excessive height, despite the known risks. Women who underwent this treatment experienced decreased fertility alongside a plethora of other unwanted side effects.
DES was also a popular emergency contraceptive in university health services, due to an influential study published in 1971. It was still recommended as emergency contraception for use in situations such as rape until 1975, when the FDA ruled that DES must be labelled as unsuitable for use as a contraceptive. However, in 1978 an official task force reported that DES was still being prescribed and taken as a contraceptive.
Calls for justice
The revelations about the negative effects of DES caused a wave of public outrage, and the United States in particular saw a large number of lawsuits against the drug’s manufacturers. It was unclear just how many women had been affected by DES, especially as the study conducted in 1952 had failed to inform its 1,646 subjects that they were even part of an experiment, let alone whether or not they had been given DES during their pregnancy. Estimates suggest that as many as 2 million women may have been exposed in the US alone.
As the use and manufacture of DES had been so widespread, it was impossible for claimants to identify which particular manufacturer had produced the medication taken by their mothers. This resulted in a landmark decision in 1980 that established the doctrine of market share liability, meaning that all manufacturers of DES were equally found to be at fault because the drugs were identical and completely interchangeable. Many claimants settled for damages, though the amounts were often undisclosed.
Legacy
The story of DES demonstrates a number of lessons that researchers and doctors have thankfully taken on board. Firstly, the key discovery that drugs could pass through the placental barrier means that doctors are now far more cautious when prescribing medications to pregnant women.
Secondly, research into new medications is now conducted much more rigorously than in 1948, and new ethical guidelines give patients the right to give informed consent or refusal before participating in clinical trials. Of course, DES was by no means the first, nor last medication found to have devastating side effects; the thalidomide scandal in the UK shows remarkable parallels to the experience of those affected by DES.
The effects of DES exposure are still being documented today. As recently as 2011, a study conducted by the National Institutes of Health found that the daughters of women who took DES while pregnant now have an increased risk of twelve separate medical conditions. Studies have also found higher rates of breast cancer in women who took DES, and an increased risk of health problems in sons born to DES mothers. There are still ongoing studies to determine the effects of DES on the grandchildren of women given DES; unfortunately, we may continue to see the consequences of DES use for many more years to come.
Sources and further reading
https://www.nih.gov/news-events/news-releases/women-exposed-des-womb-face-increased-cancer-risk
https://diethylstilbestrol.co.uk/
https://en.wikipedia.org/wiki/Diethylstilbestrol
https://en.wikipedia.org/wiki/Birth_defects_of_diethylstilbestrol
https://www.nytimes.com/2009/07/28/health/28book.html
https://pubmed.ncbi.nlm.nih.gov/12286762/
https://journals.sagepub.com/doi/pdf/10.1177/019262337400200201