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Third-generation Pills

In October 1995 a warning letter was sent to doctors about an increased risk of thrombosis from 'third-generation' oral contraceptive pills. The estimate was that the risk of these events with new pills was about twice that with a previous 'generation' of pills. The result was much consternation - the media had the news before most GPs - and hype, with many women stopping using the pills or any contraception at all. Bandolier 21 did its own calculations showing risks to be very small.

It is educational, with that background, to read a paper from one of the authors of the key study which quietly and thoughtfully examines the possibilities of bias and causality, and comments rationally on how we may evaluate such information in future [1].

For new readers

The original information suggested that venous thromboembolism, which occurs in about 1 in 10,000 women on second-generation pills, happened twice as often with third-generation pills - an excess risk of 1 in 10,000. Most (99%) young women in whom this occurs are treated successfully, so the risk of any additional serious outcomes would be at most 1 in a million if there was an additional risk.

Spitzer looks at the additional risk (an odds ratio, or relative risk of about 2) and asks whether it could be produced by bias, and even if true whether it has credibility.


A number of different sources of bias could have occurred:

Spitzer argues that healthy user bias had an effect and that referral bias and prescription bias operated to drive the estimate of risk upwards. While the observed odds ratio was about 1.5, it was about 1.0 for new users of oral contraceptives.


Austin Bradford-Hill set out guidelines that have been used to elucidate causality from association [2]. The third-generation pill story was one of association, so asking questions about causality is useful in determining the underlying credibility of the association.

As the Table shows, applying the Bradford-Hill criteria gives an underwhelming conclusion as to causality.

Table: Causality and thromboembolism with third-generation oral contraceptives

Criterion Comment
Experiment No experiment was done, and no experiment could reasonably be done to test the association
Strength The odds ratios are weak (less than 2)
Consistency Relative risks are consistently weak, and some studies include no additional risk
Gradient Emerging evidence suggests that lower doses of ethinyl oestradiol have higher odds ratios for thromboembolism. The gradient is paradoxical
Biological plausibility There is none
Specificity The outcome is not specific for the intervention., Other factors (obesity, immobility, pregnancy) cause thromboembolism
Coherence There is none. Thromboembolism rates in second generation pills is lower now than 10 years ago
Temporality Not an issue
Analogy There are none


Spitzer's conclusions are that the clinical importance and public health significance of any differences among oral contraceptive products with respect to cardiovascular outcomes are trivial and undetectable because they occur so infrequently. His opinion is that all oral contraceptives on the market are safe and getting safer.

The importance of this paper is not just that it combines common sense and epidemiology so intelligently, but also because it makes issues of bias and causality so easily understandable. This is a classic teaching text which ought to be a must for any critical appraisal course.

For those who want a review of the association between oral contraceptive use and cardiovascular disease (myocardial infarction, stroke, thromboembolism), a useful paper is the 1998 review from Boston [3]. This examined epidemiological studies up to June 1997. No meta-analysis was done, and the numbers of women using oral contraceptives was small, but the conclusions indicate little or no increased risk for serious cardiovascular disease with oral contraceptives.


  1. WO Spitzer. Bias versus causality: interpreting recent evidence of oral contraceptive studies. Am J Obstet Gynecol 1998 197: S43-50.
  2. A Bradford-Hill. Principles of Medical Statistics, 9 th edition. Oxford University Press, 1971, pp 309-323.
  3. L Chasan-Taber, MJ Stampfer. Epidemiology of oral contraceptives and cardiovascular disease. Annals of Internal Medicine 1998 128: 467-477.
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