Thromboembolic disease and the pill.
Authors: L F Nanni
Journal: BMJ (1970)

In a recent paper by Dr. W.H.W. Inman and his colleagues (25 April p. 203) an analysis is shown of 1305 reports of thromboembolism occurring during  time period 1 January 1965 and 30 June 1969 in women using oral   The conclusion made was the data...leave no doubt that there is a positive correlation between  risk of thromboembolism and  dose of oestrogen in oral contraceptives.  It is  purpose of this letter to point out reasons why this relationship cannot be proved by  data and methods used by  authors.  The study group was made up of cases of thromboembolism obtained from voluntary reports from  doctors to  Committee on Safety of Drugs.  As estimated by  authors this sample constituted less than 10% of  total number of cases that occurred during  time period.  A 10% sample would be more than adequate if it is either random or representative of  whole.  This sample is obviously not random and questionably representative.  Voluntary reports are known to be subjected to biases of all sorts.  In factthe sample appears to be biased in  direction of new drugs since  Committee instruct  doctors to report all  reactions to new products and only  serious reactions to  established ones.  No patient control data were used in this study.  Instead  expected number of occurrences of thromboembolism were determined from market research estimates of sales under  assumption of equal risks for all  products.  This departs from  acceptable procedure used in retrospective studies where in addition to using patient control data attempts are made to match them to  study group by characteristics such as predisposing conditions age parity  etc.  Additional uncertainties and biases arise from  use of market research estimate of sales as substitute for control data; patient change from product to product time lag between sales and occurrence of a disease etc.  The significance of  relation between thromboembolism and oestrogen dose levels was proved using a X2 test with one degree of freedom.  This test results from a modification of  test of significance of a slope under  assumptions that sampling errors in  expected frequencies are relatively negligible and that  total number of thromboembolism is small when compared  with  total sales.  Normally when  expected frequencies are not known  X2 test can still be applied with a reduced number of degrees of freedom.  This obviously does not apply here with only one degree of freedom available.  It is not clear what  effect of this uncertainty would be in  results obtained.  Four oestrogen dose levels: 50 Mug 75/80 Mug 100 Mug and 150 Mug were used in testing significant trends.  The last dose level represented by one out of  15 brands used in  study had a strong effect in  result.  It is fair to point out that if this dose level is eliminated no significant trend exists.  For instance when all  groups are combined  ratio of observed/expected for  dose levels of 50 Mug 75/80 Mug and 100 Mug are equal to 1.07 .78 .98 respectively which are not significantly different.  These values were obtained after adjustments were made in order to have  total differences exist between mestranol 100 Mug and ethinylestradiol 100 Mug (X2=2.7) and between mestranol 50 Mug and ethinylestradiol 50 Mug (X2=2.5).