The Diethylstilbestrol Legacy

A Powerful Case Against Intervention in Uncomplicated Pregnancy

2016 Report Abstract

Although the basic tenet of medicine is “First, do no harm,” history is filled with good intentions that were at best unhelpful and at worst harmful. Because medicine seeks to cure afflictions, there is an overwhelming desire on the part of health providers and patients to administer treatment. In certain settings, treatment can be reasonable despite a risk of adverse consequences: for example, if the disease is cured or its morbidity abated and the treatment consequences are less disabling than the disease itself.

In the absence of overt disease, the question of whether to apply an intervention is far more challenging. The safety of interventions must be weighed against the population’s level of risk, the morbidity and/or mortality associated with the disease, and the intervention’s efficacy (eg, BRCA1 mutation, mastectomy, reduced breast cancer risk). Interventions must meet an especially high standard of safety and efficacy when administered in low-risk populations or in settings in which the morbidity associated with the disease is minor. In the worst-case scenario, an intervention may be both ineffective for its primary purpose and cause iatrogenic illness.

The Diethylstilbestrol Legacy: A Powerful Case Against Intervention in Uncomplicated Pregnancy,
Pediatrics, November 2016, VOLUME 138 / ISSUE Supplement 1, Supplement_1/S42.abstract, November 2016.

Interventions in pregnancy are especially problematic because of the complex physiology of the condition and the possibility of causing short- and long-term adverse consequences in both the mother and her offspring. The continuing story of diethylstilbestrol (DES), a synthetic estrogen, shows the importance of caution when evaluating the merits of interventions involving pregnant women. With regard to DES, investigators believed that pregnancy loss was caused in part by a decrease in estrogen and that administering DES to pregnant women would help maintain a healthy pregnancy. Moreover, because endogenous estrogen concentrations increase dramatically during a healthy pregnancy, supplementation with DES was deemed harmless. During its early years of use, DES was administered to women with threatened pregnancy loss or a history of pregnancy loss. Eventually, DES was advertised to the medical community for “routine prophylaxis in ALL pregnancies” and administered to women with otherwise healthy pregnancies.

By the time DES was formally evaluated, it was standard of care in high-risk obstetrics practices. The first clinical trial to determine the efficacy of DES, reported in 1953, showed that DES did not improve pregnancy outcome. (Indeed, a subsequent reanalysis of the data revealed that DES increased the risk of spontaneous abortion, preterm birth, and neonatal death) Despite lack of evidence supporting a benefit, DES continued to be prescribed during pregnancy until 1971, when a small study showed a stunning 40-fold increase in the risk of clear cell adenocarcinoma (CCA) of the vagina and cervix in girls and young women who were prenatally exposed to DES. Several months later, the Food and Drug Administration issued a bulletin indicating that the use of DES was contraindicated in pregnancy. By then, however, millions of women, along with their sons and daughters, had been needlessly exposed.

In addition to the increased risk of CCA of the vagina and cervix, daughters exposed in utero to DES also suffered from an increased occurrence of reproductive tract abnormalities, infertility, and pregnancy complications; earlier menopause; twice the incidence of cervical dysplasia; and a possible elevated risk of breast cancer and continued increased risk of CCA in middle age. Recent preliminary data indicate the possibility of an increased risk of cardiovascular disease and diabetes in the prenatally exposed women. Mothers administered DES during pregnancy have an increased risk of breast cancer incidence and mortality. Sons who were exposed in utero have an increased risk of genitourinary defects and a possible increase in testicular cancer. The possibility of epigenetic transmission with consequent adverse outcomes in the offspring of prenatally exposed women is under investigation. Preliminary findings showed increased menstrual irregularity and a possible excess of ovarian cancer in very young women.

The link between prenatal DES exposure and subsequent adverse health outcomes, most of which are fairly common, may easily have escaped detection. The investigation of DES outcomes was initiated solely because a rare tumor occurred in a cluster of cases at an unusually young age, decades before the usual age of presentation. This historical example underscores the necessity of carefully weighing the risks and benefits of interventions in pregnancy and long-term monitoring of the health outcomes in mothers and offspring.

Whether and/or when to use pharmaceutical intervention in pregnancy continues to pose special challenges. At the present time, progesterone used to prevent pregnancy loss appears to be effective, although more data are needed. Thus far, there is little evidence of short-term adverse consequences for the offspring, but continued monitoring of mothers and offspring is warranted to identify any short- or long-term adverse effects. The use of progestins for luteal phase and early pregnancy support after in vitro fertilization is routine, and there are even fewer data on potential short- and long-term risks of this therapy. The tragic legacy of DES supports a cautious approach to the use of pregnancy interventions and assiduous appraisal of their effects.

Rebecca Troisi, Elizabeth E. Hatch, Linda Titus,
Reviewed by Dr Robert Hoover,

Click to download the full paper.

More DES DiEthylStilbestrol Resources

Bioaccumulation of Antibiotic Pollution in Marine Food Webs

Antibiotic Pollution in Marine Food Webs in Laizhou Bay, North China: Trophodynamics and Human Exposure Implication

2017 Study Abstract

Little information is available about the bioaccumulation and biomagnification of antibiotics in marine food webs.

Here, we investigate the levels and trophic transfer of 9 sulfonamide (SA), 5 fluoroquinolone (FQ), and 4 macrolide (ML) antibiotics, as well as trimethoprim in nine invertebrate and ten fish species collected from a marine food web in Laizhou Bay, North China in 2014 and 2015.

All the antibiotics were detected in the marine organisms, with SAs and FQs being the most abundant antibiotics. Benthic fish accumulated more SAs than invertebrates and pelagic fish, while invertebrates exhibited higher FQ levels than fish.

Antibiotic Pollution in Marine Food Webs in Laizhou Bay, North China: Trophodynamics and Human Exposure Implication, Environmental Science & Technology, DOI: 10.1021/acs.est.6b04556, January 20, 2017.

Generally, SAs and trimethoprim biomagnified in the food web, while the FQs and MLs were biodiluted. Trophic magnification factors (TMF) were 1.2–3.9 for SAs and trimethoprim, 0.3–1.0 for FQs and MLs. Limited biotransformation and relatively high assimilation efficiencies are the likely reasons for the biomagnification of SAs. The pH dependent distribution coefficients (log D) but not the lipophilicity (log KOW) of SAs and FQs had a significant correlation (r = 0.73; p < 0.05) with their TMFs.

Although the calculated estimated daily intakes (EDI) for antibiotics suggest that consumption of seafood from Laizhou Bay is not associated with significant human health risks, this study provides important insights into the guidance of risk management of antibiotics.

Do we have the proper guard rails for first-in-man clinical trials?

Consider drug efficacy before first-in-human trials

“On 17 January 2016, a healthy man was declared brain-dead after receiving an experimental drug in a first-in-human trial in France. Four of five other subjects receiving the same dose have serious, ongoing neurological complications. Investigations into the trial described many troubling safety practices, such as steep increases in dose levels delivered to sequential subjects without sufficient delays to check for safety.

Ethical review boards must focus on clinical promise as well as safety to hold the first tests of drugs in humans to a higher standard.

Image credit Richard Wilkinson.

The year since has brought intense scrutiny about how the debacle could have been anticipated and prevented. However, another issue is still largely overlooked: the duty to evaluate whether an experimental treatment is promising enough to warrant testing on people.”…

… continue reading Consider drug efficacy before first-in-human trials, by Jonathan Kimmelman and Carole Federico, Nature, 30 January 2017.

Adult ADHD

Illness inflation – How everyday conditions become medical disorders

Drugs for treatment of adult ADHD carry risk of dependence, abuse.

. A persistent condition?
. Questionable diagnosis
. A surprising death
. Little research on benefits vs. harm
. A move to the mainstream

– Read Drugs for treatment of adult ADHD carry risk of dependence, by Journal Sentinel‘s special report: Illness inflation, How everyday conditions become medical disorders.
– Enjoy our health infographics album on Flickr.

Low Testosterone

Illness inflation – How everyday conditions become medical disorders

Millions may have ‘low testosterone. But critics say it is just about getting older and fatter.

Independent experts say the new definition is an example of ‘medicalization’ – turning common evolution into medical conditions that call for treatment.

Female sexual interest/arousal disorder

Illness inflation – How everyday conditions become medical disorders

Sexual desire: risky drugs with minimal benefit being used to treat dubious conditions.

. New conditions, new treatments
. The search for a female drug
. ‘I would never have done it’
. More drugs in the pipeline

– Read Sexual desire: Risky drugs with minimal benefit being used to treat dubious conditions, by Journal Sentinel‘s special report: Illness inflation, How everyday conditions become medical disorders.
– Enjoy our health infographics album on Flickr.

Intermittent explosive disorder

Illness inflation – How everyday conditions become medical disorders

Millions may have ‘intermittent explosive disorder’. But critics say it is just bad behavior.

Independent experts say the new definition is an example of ‘medicalization’ – turning common behaviors into medical conditions that call for treatment.

– Read Millions may have ‘intermittent explosive disorder.’ But critics say it is just bad behavior, by Journal Sentinel‘s special report: Illness inflation, How everyday conditions become medical disorders.
– Enjoy our health infographics album on Flickr.

2016 Changes to how NICE appraises drugs and other health technologies

The National Institute for Health and Care Excellence is an executive non-departmental public body of the Department of Health in the UK

The recent proposals by NICE and NHS England to change arrangements for evaluating and funding drugs and other health technologies not only tidy up the processes, but introduce some important new elements.

The four proposed elements are to:

  1. Introduce a “fast track” NICE technology appraisal process for the most promising new technologies, which fall below an incremental cost-effectiveness ratio of £10,000 per QALY (quality adjusted life year).
  2. Operate a “budget impact threshold” of £20 million, set by NHS England, to signal the need for a dialogue with companies to agree special arrangements to better manage the introduction of new technologies recommended by NICE.
  3. Vary the timescale for the funding requirement when the budget impact threshold is reached or exceeded, risking disruption to the funding of other services.
  4. Automatically fund, from routine commissioning budgets, treatments for very rare conditions (highly specialised technologies) up to £100,000 per QALY (5 times greater than the lower end of NICE’s standard threshold range), and provide the opportunity for treatments above this range to be considered through NHS England’s process for prioritising other highly specialised technologies.

James Raftery: Changes to how NICE appraises drugs and other health technologies, BMJ Blog, 2 Dec, 16.

The first of these is non-contentious and probably should have been introduced long ago. It is estimated to reduce appraisal time by 25%. Some interventions are likely to be cost effective if they are even mildly effective and incur low cost. From 2007 to 2014, around 15% of NICE’s technology appraisals fell at or below £10k per QALY.

Specialised services, of which 146 exist, cover a diverse range of disparate and complex services, from services for long-term conditions, such as renal and mental health problems, to services for uncommon conditions such as rare cancers. Funded by a variety of means and lacking standard data, responsibility for commissioning specialised services was shunted from agency to agency until 2013 when NHS England took on responsibility.

Proposals two and three, which are to do with specialised services, reflect the recent rows over funding drugs for hepatitis C when NICE’s approval of sofosbufir led to delays by NHS England due their total cost impact. Besides a BMJ investigation, this led to a considered review by the House of Commons Public Accounts Committee (PAC).

The PAC showed that between 2013–14 and 2015–16, the budget for specialised services increased from £13 billion to £14.6 billion, or 6.3% a year, well above that for the NHS. By 2020–21, the budget for these services is expected to rise to £18.8 billion, 16% of the total NHS budget.

In 2013–14, NHS England overspent on specialised services by £377 million (2.9%) and in 2014–15, it overspent by £214 million (1.5%). In 2014–15, the Cancer Drugs Fund accounted for £136 million of the overspend.

NHS England told the PAC that about three-quarters of NICE recommended drugs apply to specialised services and that most of the budget increase for 2016–17 was related to NICE approved drugs.

The PAC showed that the arrangements for pricing (Department of Health), appraising (NICE) and funding (NHS England) of specialized services were misaligned. It recommended that the Department of Health and NHS England should, in collaboration with NICE, ensure affordability is considered when making decisions that have an impact on specialised services. Proposals 2 and 3 formalise arrangements between NICE and NHS England for appraising and funding these services.

The fourth proposal marks the most radical change by setting the cost per QALY threshold for highly specialised (as opposed to specialised) technologies at £100k, which is five times greater than the lower end of NICE’s standard threshold range. Although this reflects the higher thresholds that have been allowed for some extreme “orphan drugs,” it lacks any coherent rationale besides political necessity. This leaves NICE with at least three cost per QALY thresholds, one of £20k-30k for standard technologies, one of around £50k for end of life technologies and one of £100k for highly specialised technologies.

Our health care, health system and the pharmaceutical industry

Cartoon by Simon Kneebone, 1985

Cartoon by Simon Kneebone for a 1985 article “DES – the wonder drug you should wonder about“.
As pertinent today as 31 years ago!

Stilbetin 1 mg

DES Manufacturer: ER Squibb & Sons, New-York

image of squibb-stilbetin-1mg
DES was sold under many different names.

DES was sold under many names including Distilbène®, Stilbetin®, Stilboestrol-Borne®, Benzestrol®, Chlorotrianisene®, Estrobene® and Estrosyn® to name just a few.

Many different companies manufactured and marketed this drug under more than 200 different brand names.

These Stilbetin Squibb Diethylstilbestrol Tablets U.S.P. 1 mg were manufactured by ER Squibb & Sons, New-York.

DES Drugs Pictures
Some Squibb & Sons DES Cases
More DES DiEthylStilbestrol Resources