Nuns, prostitutes, witches and toads
In 1842, the Italian physician Domenico Antonio Rigoni-Stern noticed that nuns in Verona were more susceptible to breast cancer than other women. Ruminating on what aspect of convent living might explain the phenomenon, he concluded that the nun's corsets were too tight. This explanation was far wide of the mark but the initial observation was valid; we now know that having children makes a woman less likely to develop breast cancer.
But the Italian found another association. It seemed that the nuns were far less prone to cervical cancer than the rest of society. Furthermore, cervical cancer was unusually common amongst prostitutes. This observation provided the first clue to the real cause of the disease but it would take a further century and a half of confusion and dead-ends before the truth emerged.
The very earliest myth about cervical cancer emerged in early modern Europe where witches were believed to afflicted their victims with warts which ultimately led to a painful death. As we shall see, even this bizarre notion was not entirely without reason but, by the dawn of the 20th century, medicine had moved on and in 1901 The Lancet observed that cervical cancer was rare amongst Jewish women. Suspecting that the disease was caused by excess salt, the writer surmised that Jews were less susceptible because they did not eat bacon. An alternative explanation was offered when the subject was revisited in 1959, with a doctor speculating that circumcision reduced the risk (1). Neither were correct about the cause but, again, the association was real.
In the 1970s, epidemiological studies showed that cervical cancer was more common amongst women who had a history of herpes. It was therefore assumed that the cancer was caused by the herpes virus. It was not, but it was becoming clear that the disease was in some way connected with sexual activity. But just as science was getting closer it took a dramatic turn down a blind alley.
The suggestion that cancer of the cervix was caused by smoking was first made in 1977 and, by the end of the 1980s, the belief that passive smoking was also a risk factor had reached the pages of the Journal of the American Medical Association (2). A number of epidemiological studies had shown a small but consistent relationship between tobacco smoke and cervical cancer, and yet something strange seemed to be happening. Studies frequently showed that passive smoking carried as high or higher risk than active smoking. This was completely at odds with the expected dose-response relationship. The association with passive smoking was, as one researcher commented, "almost too strong".
Nevertheless, anti-smoking groups let it be known that smoking doubled a woman's risk of contracting cervical cancer and, with smoking now firmly in the frame, the observation that the disease was related to sex came under fire. In 1991, the British Journal of Obstetrics and Gynecology published an article by Malcolm Griffiths which flatly stated that Rigoni-Stern's research had been sloppy. There was, said Griffiths, no reason to believe that nuns had a lower rate of cervical cancer than the rest of the female population (3). The implication was obvious: cervical cancer was not related to sexual activity.
Griffith's theory took hold. In 2000, when the British Medical Journal reopened the debate, an exasperated professor wrote to ask:
To which a fellow doctor replied:
But, as was already becoming clear, sexual activity was very closely related to cervical cancer risk. By the end of the millennium, scientific - as opposed to statistical - evidence conclusively proved that the sexually transmitted human papillomavirus (HPV) was implicated in all cases of cervical cancers. HPV did not guarantee the onset of cervical cancer but it was impossible to contract the disease without first being infected with it. With this knowledge, the age-old observation of the nuns and prostitutes made perfect sense.
Biological evidence indicated that cervical cancer was no more caused by herpes than breast cancer was caused by tight corsets. The rarity of cervical cancer amongst Jewish women was, scientists now realised, due to the protective P53 gene which was far more common amongst Jews than other races. Salt had been a red herring. Even the old myth that cervical cancer was connected to witchcraft had some bearing in fact, since HPV causes warts to grow and in medieval society warts were associated with toads who were, in turn, associated with witches.
Smoking, like herpes, was not the cause of cervical cancer, it was simply more common amongst women who were sexually active and, therefore, more likely to be infected with HPV. Had the Italian doctor looked at tobacco use, he would have observed that smoking was more common amongst prostitutes than amongst nuns. He might also have noted that prostitutes were more likely to drink alcohol, have children and be atheists. But none of these things caused cervical cancer; they were just more common amongst prostitutes. The statistical correlations were real, but they were meaningless until the nature of HPV was understood.
The warning signs had always been there. For one thing, cervical cancer mortality had fallen by 80% in the second half of the 20th century, at a time when tobacco consumption had never been higher (5). This, in itself, strongly suggested that smoking was not a cause of the disease.
That smoking was correlated with sexual activity had been known for many years. In 1994, an article in the International Journal of Epidemiology had flagged up the issue:
Indeed it did. One epidemiological study (Nischan, 1988 (7)) had found a relative risk from smoking of 1.5, but, as the authors noted, "the risk for smokers depended significantly on number of sexual partners" - a telling observation that warranted closer scrutiny. Indeed, when they adjusted their figures in an effort to account for this mysterious confounder, the risk - already low - fell to just 1.2 (0.8-1.6) and was no longer statistically significant.
The real giveaway was that the risks for passive smokers were as high, or higher, than those found for smokers. Given the vastly lower dose of smoke inhaled by the former, this was a very peculiar finding which defied both common sense and the known dose-response relationship between amount smoked and risk to health. Another study (Scholes 1999 (8)) found a risk of 1.4 for both smokers and passive smokers and the study that attracted the most attention from the press (Slattery 1989 (9)) found a relative risk for smokers of 3.42. This was much higher than the association found in other studies but not quite as high as that found in the same study for passive smokers where a 3.43 risk was reported.
To take such findings at face value would require tearing up the toxicological text-book. It was hugely improbable that passive exposure to tobacco smoke in any setting was as harmful of smoking. What was much more likely was that cervical cancer was not a smoking-related disease at all and that the findings that suggested it was had been skewed by a confounding factor related to sexual activity.
That factor was the human papillomavirus. Once it was shown to be implicated in every case of cervical cancer, the long recognised correlation between sexual activity and cervical cancer made sense. And since smokers - taken as a group - were somewhat less likely to be celibate and somewhat more likely to be promiscuous, the correlation between smoking and cervical cancer had a rational explanation. Correlation, however, did not mean causation. Yes, there was an association between smoking and cervical cancer but the one did not in any way cause the other.
The association with passive smoking was more intriguing and had a unique explanation. Because HPV is carried by men and easily transmitted to women, a woman's risk of catching the virus depends as much on her partner's sexual history as her own. She may be a nonsmoker with no previous lovers but if her partner has slept with many women she remains at high risk. And since the smoking male tends to be have had more sexual partners than his nonsmoking counterpart, the woman who lives with him is at higher risk of contracting HPV, and therefore cervical cancer. Yes, living with a smoker slightly raises a woman's risk of cervical cancer but not because he smokes. Association is not causation.
Those researchers who had attempted to adjust for sexual history had made the mistake of only asking questions of the women. They had, of course, made every effort to find out about the man's smoking status but had neglected to enquire about his own sexual history which was far more important, considering his role as the HPV carrier.
As the role of HPV in cervical cancer became known, it became clear that smoking was not independently associated with the disease. HPV was the key and, by 2006, an effective vaccine against it was developed. Immunisation programmes were initiated by governments around the world and the possibility of wiping out cervical cancer within a few generations became a realistic proposition.
It was a rare breakthrough in the war against cancer and it had come about thanks to advancements in our understanding of biological science and was facilitated by the development of new drugs. It was, if you will, an 'old-fashioned' way of dealing with a public health problem. It owed nothing to the army of epidemiologists who were dominating popular science, nor to the proponents of the fashionable belief that cancers were caused by tobacco, diet, alcohol and environment. Not only had the social theorists missed the mark, but their preoccupation with smoking had sent researchers on a wild goose chase for more than two decades.
And yet, the anti-smoking organisations still had a slew of studies showing an association between smoking and cervical cancer. To admit these studies were worthless would be to accept the failure of their methods. To admit that cervical cancer was not a smoking-related disease would be to lose a weapon in their campaign to dissuade women from smoking. And so they carried on as if nothing had happened.
Today, the American Cancer Society maintains that smoking doubles the risk of cervical cancer (10). The fact that the organisation also claims that chlamydia, multiple pregnancies and oral contraceptives are also risk factors shows that the ACS has learnt nothing from the long history of mistaken cause-and-effect that has surrounded cervical cancer over the centuries. Chlamydia, multiple pregnancies and oral contraceptives - like herpes, warts and prostitution - are obviously associated with unprotected sex. It would be a truly extraordinary coincidence if these factors also happened to be independent risk factors but that is how they interpret the statistical data that show the correlations. Have I mentioned that correlation is not causation yet?
At least the ACS no longer claims that passive smoking raises the risk (according to its website). The same cannot be said of other anti-smoking groups. Rather than accepting that the studies had been flawed because they had failed to adjust for HPV infection, they continue to take them at face value.
What most excited them was the supposed finding that passive smoking was as hazardous, perhaps more hazardous, than smoking itself. A recent study on breast cancer had shown a higher risk for passive smokers than smokers. In truth, smoking of any kind was not a risk factor for breast cancer, as even the American Cancer Society accepted. Nonetheless, ASH released a press release titled 'Secondhand tobacco smoke more dangerous than smoking itself - implications for women especially frightening' (11) and Stanton Glantz described the finding as "the most important scientific development in the last 10 years" (12).
Discredited though they now were, the cervical cancer studies supported their bizarre belief that secondhand smoke was more deadly than smoking itself and the anti-smoking groups were quick to embrace it. Their motives were clear. Having banned smoking in virtually all indoor places, their attention turned to the outdoors but to ban smoking in the open air required persuading the public that secondhand smoke was exceptionally toxic. Further 'evidence' for this wacky idea appeared in the form of the Helena heart attack study (co-authored by Glantz) which claimed that heart attack incidence fell by a whopping 40% once smoking was banned in bars and restaurants. Not accepting for a minute that this study too might be fatally flawed, the anti-smoking groups used this as further evidence that secondhand smoke was far more dangerous than had been previously thought. Glantz also wrote an article titled 'Even a little secondhand smoke is dangerous' (13) and claimed that 30 seconds of exposure could kill.
In 2006, the Surgeon General told the American public that there was "no safe level" of secondhand smoke exposure. Secondhand smoke had become the most deadly entity known to man.
Christopher J. Snowdon is the author of Velvet Glove, Iron Fist: A History of Anti-Smoking
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(1) Dunn JE, Buell P. Association of cervical cancer with circumcision of sexual partner. J Natl Cancer Inst 1959;22:746–9.
(2) In January 1980, the American Journal of Epidemiology reported that there "an apparent connection, as yet unexplained, between smoking and cancer of the uterine"
(4) 'Screening and mortality from cervical cancer', Rapid responses; BMJ 1999; 319: 642 http://www.bmj.com/cgi/eletters/319/7210/642
(5) Cancer Research UK, 'UK Cervical Cancer mortality statistics'
(6) 'Cigarette smoking as a potential cause of cervical cancer; has confounding been controlled?', Andrew Phillips & George Davey Smith, International Journal of Epidemiology, 1994, Vol. 23, No. 1, pp.42-49
(7) 'Smoking and invasive cervical cancer risk: Results from a case-control study', Nischan et al. American Journal of Epidemiology, 1988, vol. 128, No. 1: pp. 74-77
(8)Scholes et al. Cancer Causes & Control, Vol, 10, No. 5, Oct. 1999 pp. 339-344 'The association between cigarette smoking and low-grade cervical abnormalities in reproductive-age women'
(9) JAMA, vol. 261, No. 11, 17/3/89, Slattery et al. 'Cigarette smoking and exposure to passive smoke are risk factors for cervical cancer'
(11) ASH press release, 2005 www.ash.org
(12) 'Lecture ties secondhand smoke to breast cancer', Michael Coburn, The Dartmouth News, 7.3.08