The aftermath of a pill scare: regression to reassurance

In October 1995, following confidential exchanges of findings among investigators in several epidemiological studies, the UK Medicines Control Agency sent a 'Dear Doctor' letter to all clinical practitioners in the country. The letter alerted them to the possibility of an excess risk of venous thromboembolism among women taking combined oral contraceptives (OC) with the 'newer' progestins, notably desogestrel and gestodene. The communication provoked a major pill scare, not just in the United Kingdom but in other countries. The preliminary and unpublished findings from the four initial 1995-96 studies reported odds ratios (OR) ranging from 1.5 to 23 in the point estimates. These are very low relative risks but were communicated in a way that the public perceived as a 'doubling of the risks'. In the 3 years since the pill scare, additional research has been done. First, deliberate and careful analysis of some of the studies and replication of others have shown that the epidemiological investigations were affected by unavoidable systematic error. Three types of bias were demonstrated empirically, namely, prescription bias, referral bias and healthy user effect or attrition of susceptibles. All those biases would tend to drive OR spuriously upwards. Additional epidemiological studies have progressively shown lower ORs, some of them under the threshold of 1.0, i.e. 'no association'. Two major consensus assessments, one carried out by a World Health Organization Scientific Group and another undertaken by the International Federation of Fertility Societies, both attach little importance to differences between older (second generation) combined OC and newer ones (third generation). This paper is a synthesis of all published evidence since October 1995, at the time of the pill scare and in the 3 years since. In conclusion, all combined oral contraceptive pills are equally safe.