Thalidomide: Nine things you didn’t know about the ‘poisonous pill’

Thalidomide was marketed to pregnant women as an antidote for morning sickness in the late 1950s, but the results were calamitous. An epidemic of babies born with various disabilities including limb, organ and neural damage led to its withdrawal from sale in November 1961. There were over 5000 known thalidomide survivors living worldwide in 2003, including 500 in the UK.

As a healthcare researcher, I had come to understand the thalidomide catastrophe as a systems failure: the disastrous outcome of an inadequate medications approval process. My dad, Dr Martin Johnson, was Director of the UK Thalidomide Trust between 2000 and 2014, and through him I had come to learn about its terrible impacts upon individuals and their families. I also understood that many survivors were still awaiting justice. However, in 2018, together with his co-authors Professor Ray Stokes and Tobias Arndt, dad published ‘The Thalidomide Catastrophe’, the first and only comprehensive history of thalidomide. Reading it led me to realise I had been seeing through a glass darkly. When laid bare, the thalidomide story is stunning, shocking and almost unbelievable. Here I share with you nine things I learned from the book:

Ed, aged 3

Ed, aged 3

  1. The full number of people affected by the drug reached tens of thousands. It is well known that thalidomide caused babies to be born with disabilities. However, it is highly likely that many other children died in the days and months after birth and that even more were miscarried or stillborn because of thalidomide. Johnson, Stokes and Arndt estimate that altogether, between 87,600 and 275,500 babies were affected.
  2. A single tablet had disastrous effects. Researchers have been able to link the days on which tablets were taken with specific forms of damage. For example, a tablet on days 21-22 after conception could cause damage to, or loss of the eyes. A tablet on day 24 could cause loss of the arms and a tablet on day 29 could cause loss of the legs. The key message from this is that the babies who survived thalidomide were those whose mothers took a tiny amount of the ‘poisonous pill’.
  3. Key players in the development of thalidomide are linked with the Nazi regime. The book explores this issue in meticulous depth and it is hard to summarise the evidence briefly. However, two things are clear. The first is that the Chief Scientist of Chemie Grunenthal, the Germany company who patented the drug, was Dr Heinrich Muckter. Muckter spent World War 2 (WW2) at an institution which tested drugs on Buchenwald concentration camp prisoners. The second is that Otto Ambros was a consultant for the Distillers Company, the British organisation which distributed Thalidomide in the UK. Ambros was sentenced to 8 years for his war crimes during WW2, which included using slave labour from the Auschwitz III-Monowitz concentration camp.
  4. Thalidomide seriously harmed adults too. When taken for more than 2 weeks, thalidomide could cause adults to contract ‘polyneuritis’, nerve damage involving symptoms such as tingling, numbness, excruciating muscle cramping and even partial paralysis. It could affect coordination, balance and the ability to walk. Altogether, around half a million adults were probably affected. “The Thalidomide Catatrophe” provides the response from Chemie Grunenthal to one affected surgeon who used the drug. “Thank you for your letter of 8th March 1960 in which you tell us you are increasingly suffering from paraesthesia and… probable polyneuritis… We wish to advise you that we have received no such reports to date” (p110). This letter was a lie: the company had received several reports and their false reassurance may have caused the surgeon to keep taking the harmful drug. As Johnson, Arndt and Stokes comment, these effects probably cost this surgeon his career.
    TIna Gallagher

    Tina Gallagher in 2002

  5. Warnings the drug was dangerous were ignored. To this date, Chemie Grunenthal claim that they could not have known about the harmful potential of Thalidomide. The evidence presented by Johnson, Stokes and Arndt makes this almost impossible to believe. For example, there is clear evidence Grunenthal’s Chief Scientist, Heinrich Muckter, received warnings a year before thalidomide even went to market from Dr Piacenza, an Italian doctor who undertook trials of the drug. Writing in 1956, Piacenza reported that the drug was unsuitable due to its toxicity. He described side effects in adult patients which included a whole-body rash and peripheral nerve damage. Reports from concerned physicians continued to be sent to Grunenthal, but the drug was not removed from market. Concerns were also raised about the potential harmful effects of thalidomide on unborn babies. For example, in 1959, scientist Dr Randolph Riemschneider raised concerns that thalidomide was causing birth defects in tadpoles he was experimenting with. As he later recorded, “we sent this information with photos to Chemie Grunenthal… Unfortunately, no answer was forthcoming” (p115).
  6. Even when its impact was known, Chemie Grunenthal continued to sell thalidomide. There were warnings that thalidomide was harmful before it even went to market. However, Chemie Grunenthal did not publicly acknowledge its harmful potential until 1961. In a speech on 14th July that year, Heinrich Muckter, Grunenthal’s Chief Scientist told his staff, “if I were a doctor, I would not prescribe Contergan [trade name for thalidomide] any more. Gentleman, I warn you… I see great dangers” (p41). Yet he didn’t withdraw the drug from sale until November that year. If he had pulled it immediately after his speech, more than 25% of the babies who were affected would have been saved.
  7. The impacts of thalidomide are sometimes invisible. Not all survivors were affected by the limb damage which is characteristic of thalidomide. As a toxic nerve agent, it also caused devastating hidden damage. Johnson, Stokes and Arndt report the situation of Julie Lane, whose mother had been supplied with the drug. Outwardly, Julie only had minor hand damage. However, at a young age, she developed epileptic fits. In her teens, she lost the use of her legs and later on, her arms. She also gradually lost her hearing and her sight. As her epileptic brain activity was not typical, her symptoms were misdiagnosed as being psychosomatic, and not of physical origin. This caused her problems to be stigmatised. However, a post-mortem conducted after she died aged 44 showed evidence of major internal damage which had been there since birth.
  8. Survivors still wait for justice. Chemie Grunenthal, the company which patented thalidomide, has never been held to account. A trial was called in 1968 but later suspended, apparently on the basis that “public interest in a continuation of the criminal prosecution no longer exists” (p.131). In the UK, Distillers, the company which distributed the drug paid out some compensation following a lengthy legal battle. However, survivors in some other countries have never received compensation, and all survivors are still waiting for an apology from Chemie Grunenthal.
  9. Some countries protected their populations from thalidomide. Several countries which considered licensing thalidomide denied or significantly restricted the sale of the drug. These included Turkey, East Germany, the USA and France. In Turkey, Dr Aygun undertook tests involving tissue cultures and concluded the drug was unsafe in 1960. In East Germany, the relevant officials had concerns based simply on the information supplied in the patent. They noted that due to the structure of the molecule, an “embryo-toxic effect” (p124) was possible. They refused a licence. In the USA, Dr Frances Kelsey resisted significant pressure from the prospective American licensee company (Richardson Merrell) and managed to delay the approval of the drug until it was removed from sale in 1961. Her delay meant that only around 160 babies are estimated to have been affected by thalidomide in the USA. What these countries show is that the toxic properties of thalidomide were possible to identify using the technologies and processes of the time. Those governments which failed to prevent the distribution of thalidomide are partly to blame for the disaster, and should also be held to account.

 

In 2019, the generation of thalidomide survivors is turning 60. What “The Thalidomide Catastrophe” makes clear is this: the international sale of the drug was preventable. Its risks should have been identified by the company which patented the drug, those which distributed it and by the governments which allowed its sale. The damage which was initially caused has been extended over six decades by a failure to acknowledge and apologise for the harm that was caused. The need for an apology remains.

Tackling burnout in UK trainee doctors is vital for a sustainable, safe, high quality NHS: Our letter to the BMJ

In 2018, for the first time, the General Medical Council (GMC) included items on burnout in its National Training Survey. The survey was completed by 51,956 trainee doctors and 19,193 trainers, making it the largest burnout survey in UK doctors to date. The response rate was also extremely high – 96% of all doctors in training who were contacted completed it, as did 41% of all contacted trainers. As such, these results provide a reliable picture of the current situation in the medical workforce. The survey found that 24% of trainees and 21% of trainers feel burnt-out to a high degree or a very high degree (for the full report, see here).

When I read these results in the BMJ, I wasn’t surprised. Rates of stress and burnout are high in healthcare staff internationally; in the 2018 Medscape report on physician burnout and depression, out of 15,000 US doctors, 42% were burnt-out and 12% were categorised as ‘colloquially depressed’. I was also concerned: a growing body of research shows a strong and consistent link between higher staff burnout and poorer patient care. Papers I have authored and co-authored show:

• 70% of studies which have investigated burnout and patient safety in healthcare staff have found a significant link between the two (Hall et al., 2016).
• In nurses, higher burnout is linked with poorer perceptions of patient safety both at the level of the individual practitioner and the ward level (Johnson et al., 2017).
• GPs think that burnout affects the quality of patient care by reducing their abilities to emphathise, to show positive attitudes to patients and by increasing the number of inappropriate referrals made (Hall et al., 2017).

Together with Dr Maria Panagioti and Dr Christopher Bu, I decided to respond to the BMJ article on the survey findings to highlight the evidence that burnout in doctors affects patient care. In particular, our letter focused on a recently published systematic review and meta-analysis led by Dr Panagioti. The findings of the review are described in more detail in a previous blog post (see here), but in brief, the review reported that burnt-out doctors are at twice the risk of being involved in a patient safety incident and at twice the risk of having dissatisfied patients.

This research reinforces the importance of measuring burnout in the medical workforce and the need to reduce this. The best way to intervene is currently unclear; while evidence suggests that interventions which target organisations (for example, redesigning jobs) are more effective than those which target individuals (for example, delivering mindfulness courses; Panagioti et al., 2017), there are many interventions which blur this boundary. These include training interventions, which are delivered to individual practitioners but aim to support them in their work, rather than improve their personal coping skills. Evidence suggests these are effective for tackling burnout (Dreison et al., 2018). Clearly, more research is needed. However, while we wait for this, I would suggest that organisations respond to the expressed needs of their workforce, providing the interventions that are both requested and well utilised.

To read our letter to the BMJ, please see here.

To read my previous blog on tackling burnout, please see here.

Burnout in doctors and the quality of patient care: Our systematic review

There is increasing evidence that healthcare staff burnout is linked to a range of negative outcomes, including increased staff absences, higher rate of staff turnover, and poorer quality of patient care (see my previous blog on this here). In a systematic review I co-authored, we found that that 21 out of 30 (70%) studies looking at the link between higher staff burnout and poorer patient safety reported a significant association between the two (Hall et al., 2016). The review found hard evidence for what many clinicians could see happening in their wards and surgeries: when staff are hard pressed, patient care suffers. It was well received on social media and has since been cited dozens of times.

However, while this previous review found clear evidence for a link between staff burnout and patient safety, it seemed to me that two questions remained unanswered. The first was whether there is also a link between burnout and other aspects of patient care, such as patient satisfaction. The second was what the strength of this relationship is: that is, just how much do increases in burnout impact patient care?

So, when I was invited to contribute to a systematic review on the links between burnout and patient care in doctors by Dr Maria Panagioti, I jumped at the chance. The review led by Dr Panagioti aimed to answer both these questions. It gathered studies which investigated burnout in doctors in relation to a broader range of outcomes, including:

  1. Patient safety incidents, (e.g., adverse events, medication errors, diagnostic incidents)
  2. Low professionalism (e.g., adherence to treatment guidelines, quality of communication, malpractice claims, empathy)
  3. Low patient satisfaction

It also quantified the strength of these relationships using meta-analysis, which was not employed in the previous review.

Is burnout linked with patient safety incidents?

The review identified 21 studies which reported on the association between burnout and patient safety incidents. The results of the meta-analyses suggested that burnt-out doctors were twice as likely to be involved in a patient safety incident as those not suffering from burnout. All aspects of burnout (exhaustion, disengagement and low accomplishment) were associated with a significantly higher risk of being involved in a patient safety incident.

Is burnout linked with low professionalism?

28 studies were found which reported on the link between burnout and low professionalism (e.g., showing low empathy, having received a malpractice claim). The results of the meta-analyses suggested that burnt-out doctors were twice as likely to show low professionalism. When the different aspects of burnout were examined separately, disengagement was the aspect most linked with low professionalism. Doctors who were disengaged from their patients were 3-times as likely to exhibit low professionalism. Doctors high in emotional exhaustion or low in personal accomplishment were over 2.5-times as likely to exhibit low professionalism.

Importantly, the review found that the link between burnout and low professionalism was twice as high in trainee and early career doctors compared with more experienced doctors. This is particularly concerning when the recent GMC survey results showing that a quarter of trainee doctors are burnt-out are considered.

Is burnout linked with low patient satisfaction?

7 studies reported measures of patient satisfaction. It was found that burnt-out doctors were at twice the risk of having dissatisfied patients. Again, disengagement was the aspect of burnout most closely linked with low patient satisfaction, with disengaged doctors showing a 4.5-fold increased risk. Low personal accomplishment was also linked with twice the risk of low patient satisfaction. No link was found with emotional exhaustion.

Where now?

This review finds strong evidence that burnt-out doctors are at significantly higher risk of being involved in patient safety incidents, showing low professionalism and having dissatisfied patients. Having clarified the presence and size of the problem of burnout for patient care, the next step for us as researchers is to identify evidence-based solutions to this problem. While a number of interventions to reduce burnout have been proposed (see Panagioti et al., 2017), there is a need to identify 1) which interventions are most feasible and most effective, and 2) whether reducing burnout can improve patient care.

For my previous blog on tackling burnout, please see here.

The review described in this article was published in JAMA: Internal Medicine. To read it, please see here.

Can patient safety improvement still learn from the aviation industry?

As a clinical psychologist by background, starting out in patient safety research was a learning curve for me. Suddenly the outcomes being discussed weren’t mental health symptoms, they were avoidable patient deaths, medication errors and patient falls on wards. Another thing I began to hear about was the aviation industry. Practices from aviation had inspired early patient safety researchers and I came to understand that we had learned much from them. For example, they had introduced standardised reporting and embraced psychological approaches in order to understand the group behaviours that contribute to safety failures (Helmreich, 2000).

More recently, however, this idea has fallen from popularity. When Jeremy Hunt attended a hospital Q&A earlier this week, he used this analogy. @Dr_Sarah_H, an emergency doctor at the hospital, challenged him on it. She later tweeted the problems with this comparison, highlighting the relative complexity of healthcare to aviation, the lack of control staff often have over their workload and issues with understaffing in hospitals. Her string of tweets went viral (below).

 

A couple of days after seeing these tweets, I was contacted by an experienced RAF professional keen to share with me the things he believes aviation do which healthcare can still learn from. He said that the RAF:

  • Have both open and confidential reporting processes in place which are simple to use; with confidential reporting, should someone have a concern they feel they can’t raise through normal reporting channels, they can submit a confidential report which by-passes all channels and goes direct to the RAF’s Safety Centre where it will be investigated by an independent team whilst respecting the confidentiality of the reporter.

  • Reporting is viewed as the life-blood of the Safety Management System so some stations have introduced a monthly award scheme for the best report which is awarded by the senior officer on the station.This is aimed at those who report a ‘near miss’, even if it is due to their own honest mistake.

  • Every report is logged and investigated, with feedback provided to the reporter.

  • Everyone receives Human Factors training during which real-life case studies are used to draw out the key learning points.

  • To avoid ‘witch hunts’ which damage the reporting culture, all investigations take place under a strict ‘just’ culture by an independent team. Incidents are rarely found to have occurred due to a single factor; almost invariably a host of contributing factors are identified.

In summary, the aviation industry enables their staff to report in utter confidence and rewards staff for good reporting. I think it would be hard to deny that healthcare still has a long way to go to meet these standards. Perhaps the contention then, is not Jeremy Hunt’s point but his target audience: does he expect NHS emergency nurses and doctors to implement these changes? Unlikely. Telling staff working in underfunded services to achieve the safety levels seen in aviation will only engender frustration, the sense that they are not understood and that the impossible is being asked. As with the RAF, these changes will require leadership support, resource and buy-in from the highest levels.

What is the link between staff burnout and patient care?

Between January 2005 and March 2009, hundreds of patients died due to poor care at Stafford Hospitala. The public enquiry into what had happened at the hospital was launched in November 2010. I was living in nearby Birmingham at the time, and stories of the horrors that had occurred at the hospital were frequently broadcast on the local news. Surgical equipment such as clips and clamps which should have been single-use were being used multiple times; patients on wards were left without water and some became so desperate they drank from vases containing flowers. Food was taken to vulnerable patients but not fed to them, and patients could be heard crying out from their beds due to lack of pain relief.

How could this happen?
As an NHS employee in a neighbouring healthcare trust, I found it hard to fathom how this could have happened. The Francis Report, the final report from the inquiry into Stafford Hospital, was published in February 2013. It suggested the causes were complex. There were significant staff shortages caused by the cutting of jobs in an attempt to meet a £10m budget deficit. When concerns were raised by staff or visitors through relevant forums, these were ignored. Importantly, staff became disengaged at all levels, and this in itself became a hard-to-measure but important cause of suffering.

In one tv news report a former patient, Nicola Monti, describes how she returned to hospital with a bowel condition following the birth of her second baby. She became sicker in the squalid hospital conditions and contracted MRSA. As she speaks about how the nurse communicated this information to her, by throwing the test results down on the bed, tears spring to her eyes. The results meant continued isolation from her two children and intense feelings of loneliness, but it is clear that simply the callous manner in which the nurse told her was in itself a significant cause of pain.

These patterns play out in more muted ways
Staff disengagement had a key role in contributing to the terrible events that occurred in Stafford Hospital. Thankfully the Staffordshire hospital failings are an outlier, but in my experience these patterns can play out in more muted ways. In a service I worked in where bullying was rife and staff were miserable, patient care did not receive the enthusiasm and energy it should have. On the other hand, in services I’ve worked in where staff felt they were part of a functioning and effective team, the mood was more positive and patients received the best that service had to offer.

Time for research
While I had seen these patterns in services I worked in, I wanted to find evidence to back up my anecdote. I arrived in my current job as a Lecturer at the University of Leeds and Bradford Institute for Health Research in October 2013 with this as my focus.

Staff: The greatest asset of the NHS
The first thing I discovered when I began my reading in this area is that the workforce is the greatest asset of the NHS. The NHS is the world’s 5th biggest employer, employing 1.7m staff altogether, including 141,000 doctors and 329,000 nurses, midwives and health visitors. The annual bill for employing clinical staff is £43 billion, which is around half of NHS Trusts’ budgets (National Audit Office, 2016). 

Turnover
The second thing I discovered is the extent to which turnover and sickness absence –clear outcomes of elevated burnout and disengagement – are causing major problems for the NHS. Between 2011 and 2015 the number of staff leaving their jobs each year due to poor work-life balance doubled. Each time a staff member leaves, costs are incurred due to 1) employing temporary staff to fill their role until a replacement is found, 2) advertising, interviewing and recruiting a replacement staff member and 3) training the new staff member. I was unable to find cost estimates for the NHS, but the price of replacing a nurse has been estimated to be $20, 561 in the USA, $26, 652 in Canada, $23, 711 in New Zealand and $48, 790 in Australia (Duffield et al., 2014).

Sickness absence
NHS staff are off work due to sickness for twice the number of days as those working in the private sector. What is particularly concerning is that a significant proportion of these days are due to stress and anxiety. In doctors in acute trusts, 17% of all sickness absence days are in this category; in doctors in mental health trusts it is 26% (see my previous blog for more information on this). These absences can lead to delays and interruptions in care and divert NHS resources to paying for expensive agency cover. This problem is increasing: in 2010, £2.2 billion was spent on agency staff, but by 2015 the figure had risen to £3.3 billion. This leads to a vicious cycle: money that could be spent on enhancing services and supporting existing staff is diverted to agency fees. In turn, services suffer, staff are not as well supported and more leave and become unwell due to stress. This further increases the agency bill, and so on.

Impact on patient care
A large body of evidence shows that higher staff burnout is linked with poorer quality patient care. For example, in a study of emergency doctors published in 2015, those who were classed as suffering from burnout said they more frequently ordered extra tests, failed to treat pain in a timely manner, discharged patients to make the department manageable, did not discuss treatment options or answer patients’ questions, did not communicate important information in handovers and did not discuss treatment plans with appropriate staff (Lu et al., 2015).

This poorer care is reflected in lower patient satisfaction. In an analysis of the NHS staff surveys of 2009, 2010 and 2010 together with trust-level measures, patient satisfaction was higher when fewer staff worked extra hours, more staff felt valued by their colleagues, staff reported lower work pressure and higher levels of engagement (Powell et al., 2014).

The all-important question of patient safety
While there was a lot of research studies on the link between staff engagement, burnout and quality of care indicators, there was much less research on the link with patient safety outcomes. Exploring this was of key importance to me: in Stafford Hospital, patients weren’t just reporting low satisfaction, hundreds had died. Understanding and evidencing the link between staff engagement/burnout and patient safety was paramount to preventing this from happening again. When I told clinical colleagues of my plans, they told me not to bother: “It’s so obvious, of course staff wellbeing and patient safety are linked. You don’t need to research it”. I became slightly concerned I could be wasting my time, but decided to plough on anyway in the hope that like me, someone else might feel the need to evidence the obvious.

First step: A review of the literature
First we undertook the first systematic review of studies linking healthcare staff burnout and wellbeing with patient safety. Forty-six relevant studies were identified. The review found that 89% of the studies which measured wellbeing reported a significant association between wellbeing and patient safety, and 83% that measured burnout reported a significant association between burnout and patient safety. The review was led by Dr Louise Hall and published in PLOS One in 2016, and has since received over 100 citations according to Google Scholar metrics, making me glad that I didn’t heed the initial discouragement I received!

Which matters most – general mental wellbeing or burnout in particular?
The concept of more general mental wellbeing (e.g., depression) is distinct from burnout, which focuses specifically on negative work experiences and attitudes. I became interested in which of these areas may be most important to focus on in relation to patient safety. To address this we conducted a survey study in 323 nurses across 3 trusts. Participants completed measures of burnout, depression and perceptions of patient safety. Statistically speaking, we found that while both burnout and depression had direct individual associations with patient safety perceptions, the association between depression and patient safety was fully mediated by burnout. In other words, we found that depression IS linked with patient safety, but it is the portion of depression that overlaps with burnout that creates this link (See Figure 1). In short, burnout seems to be the more important concept to focus on. We concluded that interventions looking to improve patient safety may benefit from focusing on burnout in particular, for example using strategies to enhance staff engagement in work rather rolling out one-to-one therapy for depression. The study was published in Journal of Advanced Nursing.

Figure 1. It is the portion of depression that overlaps with burnout that is linked with poorer patient safety perceptions.

What are the mechanisms?
A final question we wanted to answer was into the mechanisms of this association: if a staff member is feeling burnt-out, how does this turn into poorer patient care? We addressed this in a qualitative study led by Dr Louise Hall, which was published in the Journal of Patient Safety. Five focus groups with 25 GPs were undertaken. GPs thought poor wellbeing and burnout affects care quality by reducing doctors’ ability to empathize, increasing their negative attitudes to patients and by increasing the likelihood that the GP will simply refer the patient on rather than manage them in clinic, even if the referral isn’t really appropriate. GPs thought that burnout impacts patient safety by reducing their mental functioning and decision making abilities and increasing their fatigue. As one GP said, when burnt-out, they may be less likely to ‘connect dots’ across time and realise that current symptoms may be indicative of a bigger picture indicating a more concerning problem; because of this they could risk missing an important diagnosis.

Interested in how healthcare staff burnout can be tackled? Please see this blog post.

This blog was written in conjunction with a talk given at the Practitioner Wellbeing Conference in Manchester on 14th June 2018. To download a copy of the slides, click here.

a The Francis report of February 2013 concluded that it would be unsafe to infer from these statistics that there was any particular number of avoidable or unnecessary deaths at the trust.