Invisible Women: Exposing Data Bias in a World Designed for Men

by Caroline Criado Perez

  In 2014, the FDA released a database of ADR reports between 2004-13 which showed that women are far more likely than men to experience an ADR: more than 2 million were recorded for women compared to less than 1.3 million for men.127 Although around the same numbers of men and women die from an ADR, death is ninth on the list of most common ADRs for women, compared to first on the list for men. The second-most common ADR for women (after nausea) is that the drug simply doesn’t work at all, and data on the number of deaths that occur as a result of the drug failing to work is not available. We do know, however, that women are more likely to be hospitalised following an ADR,128 and more likely to experience more than one.129 A 2001 US study found that 80% of drugs that had been recently removed from the market caused more ADRs in women,130 while a 2017 analysis points to the ‘large number’ of medications and medical devices removed from the market by the FDA that posed greater health risks to women.131

  None of this should surprise us, because despite obvious sex differences, the vast majority of drugs, including anaesthetics and chemotherapeutics,132 continue with gender-neutral dosages,133 which puts women at risk of overdose.134 At a most basic level, women tend to have a higher body-fat percentage than men, which, along with the fact that blood flow to fat tissue is greater in women (for men it’s greater to skeletal muscle) can affect how they metabolise certain drugs.135 Acetaminophen (an ingredient in many pain relievers), for example, is eliminated by the female body at approximately 60% of the rate documented in men.136 Sex differences in drug metabolism is in part because women’s lower lean body mass results in a lower base metabolic rate,137 but it can also be affected by, among other things: sex differences in kidney enzymes;138 in bile acid composition (women have less);139 and intestinal enzyme activity.140 Male gut transit times are also around half the length of women’s, meaning women may need to wait for longer after eating before taking medications that must be absorbed on an empty stomach.141 Kidney filtering is also faster in men, meaning some renally excreted medications (for example digoxin – a heart medication) ‘may require a dosage adjustment’.142

  For millennia, medicine has functioned on the assumption that male bodies can represent humanity as a whole. As a result, we have a huge historical data gap when it comes to female bodies, and this is a data gap that is continuing to grow as researchers carry on ignoring the pressing ethical need to include female cells, animals and humans, in their research. That this is still going on in the twenty-first century is a scandal. It should be the subject of newspaper headlines worldwide. Women are dying, and the medical world is complicit. It needs to wake up.

  CHAPTER 11

  Yentl Syndrome

  In the 1983 film Yentl, Barbra Streisand plays a young Jewish woman in Poland who pretends to be a man in order to receive an education. The film’s premise has made its way into medical lore as ‘Yentl syndrome’, which describes the phenomenon whereby women are misdiagnosed and poorly treated unless their symptoms or diseases conform to that of men. Sometimes, Yentl syndrome can prove fatal.

  If I were to ask you to picture someone in the throes of a heart attack, you most likely would think of a man in his late middle age, possibly overweight, clutching at his heart in agony. That’s certainly what a Google image search offers up. You’re unlikely to think of a woman: heart disease is a male thing. But this stereotype is misleading. A recent analysis of data from 22 million people from North America, Europe, Asia and Australasia found that women from lower socio-economic backgrounds are 25% more likely to suffer a heart attack than men in the same income bracket.1

  Since 1989, cardiovascular disease has been the leading cause of death in US women and, following a heart attack, women are more likely to die than men.2 This disparity in deaths has been the case since 1984, and young women appear to be particularly at risk: in 2016 the British Medical Journal reported that young women were almost twice as likely as men to die in hospital.3 This may be in part because doctors aren’t spotting at-risk women: in 2016, the American Heart Association also raised concerns about a number of risk-prediction models ‘commonly used’ in patients with acute coronary syndrome, because they were developed in patient populations that were at least two-thirds male.4 The performance of these risk-prediction models in women ‘is not well established’.

  Common preventative methods may also not work as well in women. Acetylsalicylic acid (aspirin) has been found to be effective in preventing a first heart attack in men, but a 2005 paper found that it had a ‘nonsignificant’ effect in women aged between forty-five and sixty-five.5 Prior to this study, the authors noted, there had been ‘few similar data in women’. A more recent study from 2011 found that not only was aspirin ineffective for women, it was potentially harmful ‘in the majority of patients’.6 Similarly, a 2015 study found that taking a low dose of aspirin every other day ‘is ineffective or harmful in the majority of women in primary prevention’ of cancer or heart disease.7

  Perhaps the greatest contributor to the numbers of women dying following a heart attack, however, is that their heart attacks are simply being missed by their doctors. Research from the UK has found that women are 50% more likely to be misdiagnosed following a heart attack (rising to almost 60% for some types of heart attack8). This is partly because women often don’t have the ‘Hollywood heart attack’ as it’s known in medical circles (chest and left-arm pains).9 Women (particularly young women) may in fact present without any chest pain at all, but rather with stomach pain, breathlessness, nausea and fatigue.10 These symptoms are often referred to as ‘atypical’, a designation to which the British Medical Journal took exception in a 2016 article, saying that the term ‘may lead to the under-appreciation of risk associated with this presentation’.11 And under appreciation of the risk may in turn explain why a 2005 US study found that ‘only one in five physicians across multiple specialties was aware that more women than men die from cardiovascular disease each year, and most of these physicians did not rate themselves as effective in treating sex-tailored cardiovascular disease’.12

  Atypical or not, for certain types of heart attacks, women (and again especially young women) who present without chest pain are at particular risk of death13 – which makes it extremely concerning that current NHS England guidelines specify ‘acute cardiac sounding chest pain’ as part of the criteria for a patient being referred for primary percutaneous coronary interventions (PPCI) at one of the country’s specialist twenty-four-hour heart-attack centres.14 PPCI is an emergency treatment that restores blood flow during a heart attack, and which according to one doctor I spoke to has ‘massively improved survival and outcome’. But this treatment is only carried out at the twenty-four-hour heart-attack centres and, perhaps as a result, 75% of those who receive this treatment are men.15

  The tests doctors use to determine what’s wrong with a patient are also likely contributing to women’s higher death rates following a heart attack. Standard tests like the electrocardiogram or the physical stress test have been found to be less conclusive in women.16 A 2016 BMJ paper refers to recent work from Edinburgh which showed that the ‘normal’ diagnostic threshold for troponin (a protein released into the blood during heart damage) may be too high for women.17 And it’s not just about ‘standard’ levels for biomarkers being incorrect in women, we also need to establish new female-specific biomarkers.18 A biomarker is a biological characteristic (like troponin) whose presence can act as a diagnostic criteria for a specific disease, and a 2014 literature review of sex difference studies suggests that this may be a fruitful area to research.19 Unfortunately, it concludes that the work done so far is too limited to be able to say whether or not female-specific biomarkers will be found.

  Because women’s heart attacks may not only present differently, but may in fact be mechanically different, the technology we’ve developed to search for problems may not be suitable for female hearts.20 For example, a heart attack is traditionally diagnosed with an angiogram, which will show where there are obst
ructed arteries.21 But women often don’t have obstructed arteries, meaning that the scan won’t show up any abnormalities,22 and women who turn up at hospital with angina (chest pain) may simply be discharged with a diagnosis of ‘non-specific chest pain’ and told they have no significant disease.23 Except they do: women with ‘normal’ angiograms have gone on to suffer a heart attack or stroke shortly after being discharged from hospital.24

  Assuming a woman gets lucky and has her heart disease diagnosed, she must then navigate the obstacle course of male-biased treatment: sex differences have not generally been integrated either into ‘received medical wisdom’ or even clinical guidelines.25 For example, say a man and a woman are both diagnosed with a swollen aorta (the aorta is the main blood vessel that runs from the heart down through the chest and stomach). They are both suffering from an equal level of swelling – but their risk is not the same: the woman has a higher risk of rupture, which carries with it a 65% chance of death.26 And yet, in Dutch clinical guidelines, the thresholds for surgery don’t differ for each sex.27

  Diagnostic tests developed around male bodies are also a problem in other medical disciplines, even those where women are more at risk. Women have a higher risk than men of developing right-sided colon cancer, which often develops more aggressively,28 but the faecal blood test commonly used to detect colon cancer is less sensitive in women than in men.29 Meanwhile, because women have on average a longer and narrower colon than men, colonoscopies in women may be incomplete.30 Then there’s what the WHO calls the ‘frequent mistake’ of underestimating the importance of symptoms that can only occur in one sex, such as vaginal bleeding in dengue fever.31 When symptoms are listed in order of frequency for all patients rather than separated by sex, female-specific symptoms can be presented as less significant than they are in reality.

  The impact of such data gaps can snowball. When it comes to tuberculosis (TB), for example, a failure to account for how female social roles could make the disease more dangerous for women combines with a failure to collect sex-disaggregated data, leading to potentially deadly consequences.32 Men are more likely to have latent TB, but women are more likely to develop the active disease.33 Studies also suggest that women in developing countries who cook in poorly ventilated rooms with biomass fuels (as we’ve seen, this means millions of women) have impaired immune systems which leave them less able to fight off the bacteria.34 The result is that TB kills more women globally than any other single infectious disease. More women die annually of TB than of all causes of maternal mortality combined.35 But TB is nevertheless often considered to be a ‘male disease’, and as a result women are less likely to be screened for it.

  Even when women are screened, they are less likely to be diagnosed.36 Women may have a different immune response to TB resulting in different symptoms,37 and one study on why women are misdiagnosed found that TB lung lesions might not appear as severe in women.38 There is also evidence of sex differences in the sensitivity of commonly used screening tests.39 The standard way to test for TB in resource-limited settings is to get patients to cough up sputum and examine it under the microscope.40 But women with TB are less likely to have a sputum-producing cough, and even if they do have one their sputum is less likely to test positive for the disease.41 The sputum test is also problematic for social reasons: a study in Pakistan reported that women felt uncomfortable coughing up the mucus needed for the examination, and health workers weren’t explaining why they needed to. So they didn’t.42

  Medical practice that doesn’t account for female socialisation is a widespread issue in preventative efforts as well. The traditional advice of using condoms to avoid HIV infection is simply not practicable for many women who lack the social power to insist on their use. This also goes for Ebola, which can remain present in semen for up to six months. And although a gel has been developed to address this problem,43 it fails to account for the practice of ‘dry sex’ in certain parts of sub-Saharan Africa.44 A gel which also acts as a lubricant will not be acceptable in areas where women de-lubricate their vaginas with herbs in order to indicate that they are chaste.

  Failing to account for female socialisation can also lead to women living for decades with undiagnosed behavioural disorders. For years we have thought that autism is four times more common in boys than in girls, and that when girls have it, they are more seriously affected.45 But new research suggests that in fact female socialisation may help girls mask their symptoms better than boys and that there are far more girls living with autism than we previously realised.46 This historical failure is partly a result of the criteria for diagnosing autism having been based on data ‘derived almost entirely’ from studies of boys,47 with a 2016 Maltese study concluding that a significant cause of misdiagnosis in girls was ‘a general male-bias in diagnostic methods and clinical expectations’.48 There is also emerging evidence that some girls with anorexia may in fact be suffering from autism, but because it’s not a typical male symptom it’s been missed.49 Sarah Wild, head of Limpsfield Grange, the UK’s only state-funded residential school for girls with special needs, told the Guardian that ‘the diagnostic checklists and tests have been developed for boys and men, while girls and women present completely differently’.50 Meanwhile, a recently published draft of new NHS guidance on autism made no mention of women’s differing needs.51

  There are similar diagnostic problems when it comes to attention deficit hyperactivity disorder and Asperger’s. A 2012 survey by the UK’s National Autistic Society found that just 8% of girls with Asperger’s syndrome were diagnosed before the age of six, compared with 25% of boys; by the age of eleven the figures were 21% and 52%, respectively.52 Up to three-quarters of girls with ADHD are estimated to be undiagnosed – a gap which Dr Ellen Littman, the author of Understanding Girls with ADHD, puts down to the early clinical studies of ADHD having been done on ‘really hyperactive young white boys’. Girls tend to present less as hyperactive and more as disorganised, scattered and introverted.53

  More broadly, researchers suggest that because women are socialised to ‘take turns in conversation, to downplay their own status, and to demonstrate behaviors that communicate more accessibility and friendliness’, the traditional medical interview model may be unsuccessful in getting the information from women that is needed to diagnose them effectively.54 But sometimes – often – women are providing the information. It’s just that they aren’t being believed.

  American news website ThinkProgress reported the story of Kathy, whose heavy periods left her feeling so faint she couldn’t stand.55 But when it came to getting a diagnosis, Kathy faced the same problem encountered by Michelle in the previous chapter. Four different medical professionals thought it was in her head, that ‘she was simply struggling with anxiety and perhaps even had a serious mental health disorder’. Her primary-care doctor went so far as to tell her more than once, ‘All your symptoms are in your imagination.’

  But they weren’t in her imagination. In fact, Kathy turned out to have ‘potentially life-threatening uterine fibroids that required surgical intervention’, something that was only discovered after she demanded an ultrasound. She wasn’t anxious (although after nine months of being told she was crazy who could blame her if she was), she was anaemic.

  Rachael was also told she was imagining it. She had been trying to manage her severe pain and heavy periods with the pill for ten years by the time she collapsed at a gig. The hospital sent her home with painkillers and a diagnosis of stress. The next time she collapsed the hospital put her in the gastroenterology ward. ‘Six nights I was there, on a drip. There was a woman dying of bowel cancer in the bed opposite me. It was horrible.’ The doctors suspected kidney stones, so they ran multiple tests around her urinary system. They all came back negative. So did her blood tests. And the more tests that came back negative, the more Rachael sensed a shift in how she was being treated. ‘I started feeling they weren’t believing me. That they thought it was all in my head.’ Eventually a consultant s
hook his head as Rachael told him how much she hurt and told her, ‘We have to send you home. There’s nothing wrong with you.’

  But there was something wrong with her. Rachael was eventually diagnosed with endometriosis, a disease where womb tissue grows elsewhere in the body, causing extreme pain and sometimes infertility. It takes an average of eight years to diagnose in the UK,56 an average of ten years to diagnose in the US,57 and there is currently no cure. And although the disease is thought to affect one in ten women (176 million worldwide58) it took until 2017 for England’s National Institute for Health and Care Excellence to release its first ever guidance to doctors for dealing with it. The main recommendation? ‘Listen to women.’59

  This may be easier said than done, because failing to listen to female expressions of pain runs deep, and it starts early. A 2016 study from the University of Sussex played a series of cries to parents (twenty-five fathers and twenty-seven mothers) of three-month-old babies. They found that although babies’ cries aren’t differentiated by sex (sex-based pitch differences don’t occur until puberty) lower cries were perceived as male and higher cries perceived as female. They also found that when male parents were told that a lower-pitched cry belonged to a boy, they rated the baby as in more discomfort than when the cry was labelled female.

  Instead of believing women when they say they’re in pain, we tend to label them as mad. And who can blame us? Bitches be crazy, as Plato famously said. Women are hysterical (hystera is the Greek word for womb), crazy (if I had a pound for every time a man questioned my sanity in response to my saying anything vaguely feminist on Twitter I would be able to give up work for life), irrational and over emotional. The trope of the ‘crazy ex-girlfriend’ is so common it’s been satirised by Taylor Swift in her hit song ‘Blank Space’ and by Rachel Bloom in a whole Netflix series about a Crazy Ex-Girlfriend. Women are a ‘mystery’, explained renowned physicist Stephen Hawking,60 while Freud, who got rich and famous off his diagnoses of female hysteria, explained in a 1933 lecture that ‘Throughout history, people have knocked their heads against the riddle of femininity.’61