When the atypical is typical

Biases in clinical research have compromised the medical treatment of women for decades

If there’s one thing a doctor loves, it is a symptom that is “classical”. At med school, we learned multiple lists of physical complaints and experiences that were neatly boxed into diagnostic criteria, which helpfully corresponded to multiple lists of clinical syndromes and diseases. We loved the “easy” diagnoses, like the chest-clutching, sweaty, overweight gentleman, keeling over in his early 60s just like his father before him, with his waxy yellow xanthelasma-covered eyelids closing dramatically as he clutches the last breath from his cigarette-heavy lungs. A heart attack waiting to happen, as the whispered voices around him declare. Simple.

We do not love, on the other hand, the “atypical presentations”. The diagnoses that lurk at the back of our minds.
Overlapping and intermingled signs and symptoms that could mean a brain tumour, or hypertension, or demyelination. Some of these we are regularly warned about – the ‘great pretenders’ such as syphilis, or lupus. The kind of illnesses that require head-scratching even from Dr House.

We are conscious that there are complicated pathological conundrums and we hope that we are wise enough to recognise the times when we know that we do not know. What if, however, the “atypical” presentation is one that occurs in more than half of the population? How could that possibly be? What if the classic Levine chest-clutching sign is only found in less than half of the population? In 2016, an article in the British Medical Journal pointed out that myocardial infarctions which present without pain, but instead with breathlessness and abdominal pain, take longer to diagnose and therefore treat, with a resultant increase in mortality.

It turns out that these symptoms are the most common presentation of cardiac ischaemia in women. In medicine we are programmed to consider the male patient as the norm, and the female as the anomaly. We are all familiar with the “standard” patient, the quintessential Norm. According to the International Commission on Radiological Protection’s 1974 definition, “Reference man is defined as being between 20-to-30 years of age, weighing 70kg, is 170cm in height, and lives in a climate with an average temperature of from 10°C to 20°C. He is a Caucasian and is a Western European or North American in habitat and custom.” When I see that written down, I am aghast at the ridiculousness of it.

Pharmaceutical companies have been using “standard” men in their clinical trials for decades. This has resulted in women and people of varied ethnicities and phenotypes being excluded and therefore the benefits and risks of a given drug or therapeutic intervention being insufficiently or improperly investigated. Drug companies have historically tested all of their new medications on groups of young white men, then marketed them to the full population without any recognition of the very high likelihood of variability in efficacy, metabolism, and side-effects between the genders and also between ethnic groups.

We have become more familiar with ethnicity-based therapeutic decision making when it comes to,
for example, hypertension and the use of ACE inhibitors, but we are presented with much fewer alternative pathways when we consider pharmaceutical interventions for men and women.

There is a particularly irritating cohort of humans when it comes to prescribing medication; those “women of child-bearing age”. Or, even worse, the pesky pregnant ones. However, pregnancy is a cinch therapeutically speaking – just tell them they can’t have any medications at all. Or if they really must insist on treating their potentially life-threatening infection or hyperemesis, tell them “we can’t say for definite if the drugs will work or are safe, but we think they probably are because other pregnant women have had to make the choice to take a tablet that has not been rigorously tested in pregnancy and most of those women were okay afterwards, as far as we know”.

Our old friend “anecdotal evidence” (an oxymoron if ever there was one). All those icky hormones and developing foetuses are very off-putting for the researchers, who would much rather ask Norm to pop in again to swallow a load of ondansetron, and see how his hyperemesis responds.

These gender gaps in research and data were highlighted by Caroline Criado-Perez in her book Invisible Women, where she also describes how car safety tests are all carried out using our friend Norm as a crash test dummy, meaning that women are 47 per cent more likely to be seriously injured in a car accident. Police stab vests, PPE, safety helmets, even mobile phones are all designed for a typical man, resulting in increased risks for other users.Is it time to erase the word “atypical” from our lexicon?