Thromboembolism and oral contraceptives.

Many of the medical statisticians involved in the above studies do not appear to have sufficiently appreciated the difficulty in diagnosing thromboembolic disease nor its frequency. Thromboembolic disease is very common in the hospital population. Thus, Freiman and associates33 found old or recent emboli in 64 per cent of a series of 61 consecutive adult autopsies. This work indicates that only a very small fraction of patients with pulmonary embolism present clinical manifestations, and while the majority of the embolizations are probably of no clinical significance, many of the more severe episodes are overlooked. More recently, Morrell and Dunnill34 reported finding pulmonary emboli in 52 per cent of 263 autopsy cases after methodical examination of one lung from each patient; the other lung was examined in the routine autopsy manner and pulmonary emboli were found in only 12 per cent. In other words, the diagnosis would have been missed in approximately 75 per cent of the cases if routine autopsies had been performed. These workers commented that perhaps pulmonary emboli should be regarded as almost universal in a hospital population. The incidence of pulmonary embolism has also been shown by many workers to be significantly higher than hitherto suspected in young, apparently healthy women by isotopic scanning techniques. That oral contraceptives might be implicated in thromboembolism was widely recognized by the medical profession in 1963. Thus any patient on the pill presenting with leg or chest pains would have been carefully examined for evidence of femoral thrombosis or pulmonary embolism. In these patients, special procedures such as venography, pulmonary angiography, isotopic scanning, and serum enzyme determinations were more likely to have been performed. If death occurred, the pathologist would have made a careful search specifically for these conditions. On the other hand, it is likely that leg pains in a woman not on the pill might have been dismissed as being merely due to leg cramps and a careful examination for evidence of femoral thrombosis would not have been carried out. If the patient suffered from respiratory distress with chest pain, influenzal pneumonia or some other viral pneumonic process would have been suspected and, unless a postmortem examination were performed, the diagnosis of a viral pneumonia would appear on the death certificate. In such circumstances, even if a post-mortem examination had been performed, it is probable, especially if the prosector is inexperienced or in the absence of a specific search, pulmonary emboli would be either overlooked or mistaken for postmortem clots. A high index of suspicion is important for the recognition of pulmonary embolism, not only during life but at autopsy. The knowledge that the patient was taking oral contraceptives, which was known to the general practitioner in all but two cases in the study of Inman and Vessey,2 would have led to serious consideration of thromboembolic disease even if the signs and symptoms were minimal. It follows that thromboembolic phenomena would have been recognized more frequently in women known to be on the pill, thus resulting in an apparent increase of incidence. Vessey and Doll3 were aware of this source of bias but argue that it was improbable because there was a stronger association between oral contraceptives and thromboembolism in those patients in whom the diagnosis was relatively certain than in the remainder. They state that if the history of the use of the pill led to recognition of the disease, the association should be stronger in those patients in whom the diagnosis was least evident as this group would contain patients whose condition was diagnosed only because they were known to be using oral contraceptives. But this is not necessarily true. As the index of suspicion was higher in a woman taking the pill, special diagnostic procedures were more likely to be deemed justifiable. Thus, if the history of pill ingestion had been responsible for consideration of the diagnosis of pulmonary embolism or thrombophlebitis in a woman with minimal signs and symptoms, special diagnostic procedures would probably have enabled the diagnosis to be excluded or confirmed as certain. Obviously the point is a debatable one, but it is the all-important one for on it hinges the whole validity of the hypothesis of an association. The results of retrospective studies are perhaps better explained on the hypothesis that the high index of suspicion generated by the knowledge that the patient is on the pill is the sole cause of the manyfold increase in the number of diagnosed cases of thromboembolic disease. This hypothesis is consistent with all the findings in the British studies. Thus Vessey and Doll3,4 found that the proportion of patients with thromboembolic disease who gave a previous history of this condition was significantly smaller among those who were using oral contraceptive (29 per cent) than among those who were not (40 per cent). Furthermore, in the Inman and Vessey2 series of 51 patients who died with pulmonary embolism and had predisposing causes, there was no significant increase in the percentage of pill users compared to the controls. Surely, if the pill plays a role in thromboembolic disease one would expect its effect to be greatest in those individuals who already had other predisposing causes. These otherwise inexplicable findings may be explained on the above hypothesis, since the presence of a predisposing cause will lead to a high index of suspicion probably of the same order of magnitude as that of a history of pill ingestion. The failure to recognize an increased incidence of coronary thrombosis among pill users is also readily explained. In the final analysis this diagnosis is dependent on objective data such as ECG and serum enzyme studies and a higher index of suspicion is unlikely to result in a significant increase in the number of cases diagnosed. Furthermore, as there were no early reports that the pill predisposed to coronary thrombosis the index of suspicion would not necessarily have been increased. The findings of an increased incidence of cerebral thrombosis are readily explained. Those referring physicians accepting the belief that the pill predisposes toward thrombosis would have favored the diagnosis of cerebral thrombosis if the differential diagnosis between this and cerebral hemorrhage was difficult as is often the case. This viewpoint receives some support from a recent study of strokes in women of childbearing age seen at the Mayo Clinic in which no evidence was found of an increase in incidence of cerebral infarction in the period from 1961 through 1966 compared to that of the previous sixteen years before oral contraceptives were in use.35 The findings of prospective studies give weighty confirmation to the hypothesis that the increase in thromboembolic disease in pill users observed in retrospective studies is only an apparent one. The prospective studies have not been acceptable to most statisticians because of their relatively poor design, but it is difficult to improve upon the design used in the recent study of Fuertes-de la Haba and associates21 in Puerto Rican women which revealed no differences. Of course, it could be argued that this particular study is only applicable to Puerto Rican women, but it would be indeed surprising if the pill did not produce the same alterations in clotting parameters in these women as observed in women else-where in the world. The other pieces of evidence implicating the pill which remain to be considered are the case reports in the literature. However, episodes of thromboembolic disease occurring in rare sites would only be likely to be published if the patient were taking oral contraceptives; thus this type of evidence is inherently biased and only useful in initially focusing attention on a possible association. To summarize, the general belief that oral contraceptives predispose towards thromboembolic disease is based on conclusions drawn from retrospective studies, certain hematologic findings, histological studies of blood vessels, and case reports. The hematological studies show changes in coagulation parameters such as apparent increases in factors VII and X, but such increases do not indicate hypercoagulability when this is defined as an increased tendency of the individual to thrombosis. Moreover, most, if not all, of these changes are seen during the last trimester of pregnancy but to a more pronounced degree; yet the incidence of the thromboembolic disease is decreased at this time. The histological lesions in the blood vessels— claimed as distinctive—were first observed long before the introduction of the pill and are seen in men. Case reports in themselves prove nothing. Although the retrospective studies were well designed and the results highly significant, the conclusions drawn from them and now widely accepted are in reality mere inferences masquerading as facts. An alternate hypothesis to explain the results of the retrospective studies is that the history of oral contraceptive ingestion leads to a high index of suspicion of thromboembolic episodes in pill users. Such a hypothesis explains why the pill in these studies did not increase the likelihood of thromboembolism in women with predisposing causes, because such a history would also result in a high index of suspicion. The hypothesis is also consistent with the results of prospective studies. Most of these have been criticized because of their relatively poor design, but such an objection is not applicable to the recent carefully controlled Puerto Rican study which also did not reveal any difference in incidence. It is therefore fair to conclude that the available evidence favors the opinion that oral contraceptives do not predispose towards thromboembolic disease.