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16: 535- 54 1, 1979
Interpretation of Data by the Clinician Joseph W. Goldzieher Division of Clinical Sciences and Reproductive Biology, Southwest Foundation for Research and Education, San Antonio, T exas, USA
ABSTRACT
Goldzieher J W (Division of Clinical Sciences and Reproductive Biology, Southwest Foundation for Research and Education, San Antonio, TX, USA). Interpretation of data by the clinician. lntj Gynaecol Obstet 16: 535- 541, 1979 The cardinal challenges to every practicing physician are to interpret clinical data correctly and to place them in proper perspective. Clinical investigations frequently lack the rigidly coi1trolled conditions and the careful experimental designs usually found in preclinical animal studies, and this deficiency is partially attributable to the inherent complexities of clinical medicine. Consequently~ a great deal of controversy results from conflicting interpretations, extrapolations and overextension. of limited data that are often equivocal. More careful appraisal of data and increased awareness of the well-known pitfalls found in retrospective and prospective studies, in which biostatistical design and clinical relevance are often incompatible, are emphasized, and personal biases and the flagrant sensationalism expounded by the media are condemned. The clinician is cautioned to sift through the data, consider the benefit/risk ratio for each patient and then. to subordinate the role of critical scientist and assume the role of physician, exercising good judgment in light of the existing evidence and the immediate problems at hand.
INTRODUCTION We are about 20 years into the modern era of contraception. One of the new contrivances, the contraceptive steroid, has been the subject of more scientific publications than any other drug in history. Yet, it is still controversial, and the controversy surrounding its use seems to proliferate with the passage of time. Controversy is nothing new to science and medicine. In part it is the continuous testing process to which the search for truth must always be subjected. In part it is a reflection of the Portions of this presentation w ill appear in Controversies in Contraception, Moghissi, © 1979, Th e Williams and Wilkins Co, Baltimore, MD, USA .
contemporary environment, especially its sociocultural attitudes. It is necessary to sort out some of the underlying factors which generate these controversies, for without this the merit of various views is difficult to assess. Sometimes access to a desired answer is either impossible or impractical. In order to decide whether certain events, which normally occur very rarely, are increased in frequency by contraceptive hormones, it would be necessary to select a representative sample of some tens of thousands of women by a carefully designed, unbiased procedure, segregate them for 10- 20 years in an environment whi ch represents a cross section of the national environ ments, permit none to enter or to leave, assign th em in truly random fashion to the experimental maneuvers in question and observe the results. We might then get some believable data about the relationship of contraceptive steroids to breast cancer, uterine cancer, liver tumors and other rare events. Some other very immediate problems have equally impractical solutions. It is often asked whether combination and sequential pills, or highdose and low-dose pills, are "equally effective." If we were looking for a tenfold difference in effectiveness, this might not be difficult to answer, but if we were seeking to detect a twofold difference (ie, a 100% increase or decrease in effectiveness), the problem becomes formidable. If we assume tha t half of the pregnancies which occur with oral contraceptive (OC) use are due to human error (a reasonable, and probably low, estimate), calculations tell us that a t least 58 000 cycles of use would be required with each drug to give us a 95 % level of confidence that the observed twofold difference did not occur by random chance. Moreover, this number of cycles assumes that the subjects were perfectly randomized and that there was no dropout or any other source of data loss. If we assume that 90% of pregnancies are due to human error and only 10% are due to a difference between the two drugs, the number of cycles required becomes astronomical , and so does the cost. In the laboratory, where controlled conditions, genetic homogeneity, random assignment ofmaneuln t J G)'IJaeco l Obstet 16
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vers and freedom from clinical ethical constraints are possible, sophisticated biostatistical procedures let us optimize our experimental designs and accurately evaluate our findings. However, clinical investigation is an infinitely more difficult discipline whose chief current problem appears to be that clinicians do not understand the complexities of biostatistics and biostatisticians do not understand the complexities of clinical medicine. The upshot is, occasionally, a major disaster, such as the large and costly University Group Diabetes Program which has been criticized by both clinicians and biostatisticians. Perhaps, the most useful recommendation for all active investigators and for all those who read and evaluate such investigations is to read the essays of Alvan Feinstein (8, 9) on the architecture of clinical investigation-and then to pass them on to their statistician and epidemiologist colleagues. I suspect that this would cause much planned clinical and epidemiologic research to be returned to the drawing board for reconsideration .
PROBLEMS OF INTERPRETING DATA If all of the pertinent data on some subject were precise and unambiguous, controversy would still arise from conflicting perceptions of their context. But, as we all know, the data themselves are never complete, almost never black-or-white, rarely unambiguous and inevitably subject to change as new data appear. An excellent example of the need to examine data carefully is found in a publication by Janerich et al (15), which has been used to suggest that the administration ofOC steroids inadvertently during early gestation , or the use of these steroids as a quick pregnancy test, might be associated with limb-reduction defects in the offspring. On the basis of this and other reports, the US Food and Drug Administration removed the pregnancy-test pills from the market, and some investigators have advised postponement of efforts at conception for some months after discontinuing contraceptive steroids. Examination of the data, however, shows that the incidence of limb-reduction defects in pill users was no greater than that in the controls; but when these data were lumped together with all other sorts of data on hormone administration during early gestation, the inci-
dence of defects was significantly higher than that in the controls. How one derives scientifically meaningful conclusions from the lumping of such disparate data, and what this implies in terms_of the endocrinologic expertise involved in this investigation , merits a moment's thought. More recent stud-
lntj Gynaecol Obstet 16
ies by Rothman and Louik, on a very large material, have in fact concluded that "oral contraceptives present no major teratogenic hazard" (25). When data appear to be unequivocal, when they are the result of a well-designed, straightforward experiment, their interpretation may still present serious problems. Consider the following example: Experiment: Equal numbers of well-dressed men and women are asked to walk over a long stretch of rough ground. Observations: Women stumbled much more often than men. Statistical evaluation: Correlation between stumbling and being female shows a significant association : x2 = 6.6; p < o.o1. Possible causal inferences: l. Women are genetically less stable than men.
2. Estrogens cause disorders of the middle ear and/or the cerebellum; androgens may be protective. 3. Chronic lipstick use is toxic; it weakens leg muscles. 4. Male clothes have an antigravitational effect. 5. High heels are not good on rough ground. Logical errors of interpretation have been made regarding the effects of contraceptive steroids on lipid metabolism: plasma triglycerides are elevated by these agents, even to a level above the "normal range" in a small percentage of subjects. Furthermore, epidemiologic studies have claimed that there is a statistical association between idiopathic elevation of triglycerides (among other things) and atherogenic cardiovascular disease. Is it then acceptable to interpret this, as Wynn and Doar have done (29), to indicate that OCs will cause heart disease? Should one not instead ask other questions? For example: Is idiopathic hypertriglyceridemia causally related to atherogenic heart disease, or is it merely a manifestation of a common underlying process? Do hypertriglyceridemias of whatever origin have the same prognostic significance? If elevated triglycerides "cause" heart disease, is this related to the level of hypertriglyceridemia? What other factors influence this relationship? And so forth. As we all know, the relationship of the various hyperlipidemias to cardiovascular disease is extremely complex, and such simplistic views are likely to generate more heat than light. Clinical investigation rarely permits the luxury of a precisely controlled experiment, with all that that implies in terms of design, randomization, etc. Nevertheless, the realities of life require that operational decisions be made on some basis. Nowadays one has recourse to the discipline of epidemiology, which often proceeds on the premise of "better to use bad
Eva luation of data on OC hazards
data than to do nothing" and which bristles with thorny mathematical formulations and sophisticated computer technology. Some, like Feinstein, have suggested that a transition from old pre-science to modern pseudoscience does not necessarily represent progress. The simplest nonexperimental (ie, epidemiologic) type of investigation is the recording of anecdotal information such as adverse-reaction reports. This is a valuable procedure which acts as an early-warning alert. The classical example of its utility is, of course, the case of thalidomide. Drawing inferences from case reports is an extremely risky business, open to a great variety of logical errors of which the post-hoc fallacy is the most common and most flagrant. Today, the prestige of setting up an adverse-effect registry and maybe getting some grant funds lends added attractiveness to case-collecting. Considering the high overall probability that the occurrence of a symptom during the use of some drug is merely a matter of coincidence, it takes an extremely optimistic individual to undertake such an enterprise. A relevant example of the problem with anecdotal case reports is the question of chromosomal and congenital anomalies associated with OC use. A report by Carr (6), based on eight abortuses, and another by Nora and Nora (21) on congenital anomalies, generated a great deal of concern about .the use of contraceptive steroids in women who become pregnant inadvertently during their use. A large amount of information has accumulated rapidly since then (for a review, see Benagiano and Goldzieher (4] and Rothman and Louik (25]) and has failed to substantiate the existence of such hazards. Similarly, an anecdotal report in 1973 by Baum et al (3) on liver tumors caused hundreds of unreported cases, some in OC users, to come out of the woodwork. A careful case-control study by the US Public Health Service's Center for Disease Control and the Armed Forces Institute of Pathology has shown a statistically significant association with OC use, especially with use for prolonged periods, and this question is now under active investigation. Whether or not a causal relationship is found, the number of cases must be exceedingly small: l. The Royal College of General Practitioners (20) found no .cases in 200 000 woman-years' experience. 2. An Oxford study (28) found no cases in 50 000 woman-years' experience. 3. A California study (23) found no cases in 46 000 woman-years' experience. 4. The Boston Surveillance Program (19) found only one case in nine years. 5. The Scottish National Diagnostic Index in-
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eluded no cases among 5 million women, 19681974. A more complex procedure used by epidemiologists is to collect a series of events, such as cerebrovascular accidents or chromosomal anomalies, and work backward in time with this pseudocohort of subjects toward a presumed cause. Research customarily works forward in time from action to effect. Therefore, Feinstein (9) has called this backward procedure " trohoc" research - trohoc being "cohort" spelled backwards. A typical example of this type of investigation is the work of Mann and Inman (16) on myocardial infarction (MI) and pill use. In their first MI study ( 16), these epidemiologists examined every second death certificate from women in the appropriate age group, ascertained the frequency of pill use and compared this to the rate in so-called "control" subjects. (Epidemiologists often study a disease by giving precise numerical values to these diagnoses or to the " vital statistics" derived from them and then applying rigorous statistical procedures to these numbers.) The frequency of factors predisposing to MI in the cases vs the controls was ignored. Clinicians who examine Table I might come to their own conclusions about the validity of calculations of relative risk, etc, based on comparisons of two groups with such dissimilar prognoses. The studies of Mann and Inman (16) and Mann et al (I 7) also concluded that there was a su bstantially greater hazard of fatal heart attacks in pillusing women over the age of 40- a relative risk of 4. 7 compared to one of 2.8 in the under-40 women (Table II) . This information was widely publicized by the British and American news media and was the subject of a television spectacular by the US Food and Drug Administration. Without a doubt, many women in the over-40 age group have since been systematically encouraged to change to less effective methods of contraception. Subsequently, Mann et al (17) did examine the other half of the
Table I. Factors predisposing to myocardial infarction (MI) in OC users suffering Mls and in controls. Predisposing Factor
Smoking Hypertension Diabetes Obesity History of preeclampsia Type II hyperlipidemia
Ml Patients
Controls
(%)
(%)
76.3 18.3 6.7 23.3 30.0 41.0
52.9
3.5 0.0 9.9 11.2 0.0
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Table 11. British myocardial infarction (MI) studies: Mann and Inman (1 e> and Mann et al (1 7). Age (years)
Difference c
MI death certificates, and they found no increased risk at all in the over-40 pill users in this part of the sample. When the two sets of data are combined, as in the bottom of Table II, there is no difference in the relative risk of older vs younger women. However, their retraction is buried in a London fog of epidemiologic verbiage and did not become the object of corrective media coverage or a TV spectacular. Mann et al (18) had also made similar claims from their morbidity data on MI, but little was said about the important differences in the frequency. of predisposing factors in the infarction patients vs the controls and the possible confounding role of cigarette smoking was ignored. It took a complete reanalysis of the data, performed independently by Jain of the Population Council (14) and Ory (22) of the Center for Disease Control to show that the calcula tions were completely confounded by the smoking habits of the subjects and that, .in fact, nonsmoking pill users had no greater relative risk of MI than nonsmoking nonusers. Another major hazard in the interpretation of " trohoc" studies is the problem of extrapolation. Consider the well-publicized " trohoc" study of Sartwell and his colleagues (27) on thromboembolism a nd the pill. To obtain their base data, they examined the records of nearly 40 East Coast university and public hospitals and identified 2648 cases with the diagnosis of thromboembcrlism in ma rried women of the appropriate age group. In order to minimize extraneous factors and deal only
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with idiopathic disease, they eliminated all cases with predisposing factors and, after matching these with controls, they were left with 175 pairs, or about 7% of the original charts. After making a ratio of 70 of these 175 case-control pairs in a certain manner, they concluded that there was a 4.4-fold relative risk of thromboembolism associated with pill use. All other methodologic questions aside (11), one must ask how this highly selected subset of records from hospitals which have a population of patients quite unrepresentative of American women as a whole can be used to estimate the "relative risk of pill use" in the USA or elsewhere? This, however, is precisely what is implied by the inclusion of such relative risks in the product information that accompanies commercial OCs. Whether it is even remotely relevant to populations with different ethnic and social structures, as in the developing world, is a question of overriding importance which has not been sufficiently appreciated by various regulatory agencies. The classical prospective study, which identifies a population of subjects at the outset and then observes them over the passage of time in a specified manner, avoids some of the fundamental pitfalls of trohockery; indeed, it is frequently the second epidemiologic step after the identification of an association by a "trohoc" study. Prospective studies have their own pitfalls, many of which were perceptively discussed in the introduction to the pill study of the Royal College of General Practitioners (26) . One of the unavoidable biases in a prospective
Evaluation of data on OC hazards
study of pill-related adverse reactions is the bias introduced by self-selection. It has been amply demonstrated that women who select pills as their contraceptive differ in important ways from women who select other modalities, and this bias cannot be eliminated by stratification of the data since we have no idea a priori of all of the stratifiable variables that may be relevant. In any event, when the conclusions of a prospective study in which selfselection occurred are at variance with the conclusions of a prospective study in which the subjects were randomly assigned to alternative contraceptive modalities (as in the case of the Royal College of General Practitioners study vs the Fuertes de Ia H a ba et a l study [10) in Puerto Rico) , the amber light of caution should glow brightly. Indeed , after a questionnaire survey of 37 292 women in the Boston area, Hoover et al (13) concluded : The use of OCs varies with socia l and reproducti ve characteris tics that are risk indicators for ma'!Y diseases. OC use was associa ted with increased risk of hospita liza ti on for thromboembolic disease, men ta l illness, hyperth yro idism, hypert ension, a nd cancer of the cervix. OC users were hospitalized for ma'!)l non-life threatening conditions 20 to 40 percent more frequently than non-users.
As a matter of fact, the whole notion of a causal relationship between thromboembolic disease and OC use, so avidly pursued by epidemiologists and the news media alike, has been shaken to its roots by investigators of cardiovascular disease who have used modern di agnostic technology. As early as 1972, Hicks ( 12) discussed the problems in the di agnosis of thromboembolic disease in the light of an ongoing study sponsored by the British Medical Research Council. He noted that st udies with definitive methods such as radiolabeled fibrinogen suggested that not more than 20%-40 % of deep leg vein thrombosis is evident clinically and diagnosed , a nd in his specific trial, only 22 % of all venous thromboses were diagnosed clinically (12). Moreover, there was also a significant percent age of false-positive clinical diagnoses. Such figures put the clinical diagnosis of thromboembolic disease on shaky ground indeed and suggest that statistical arithmetic applied to such data might be equally shaky. In this regard, it is interesting to note that the name of M . B. Vessey is mentioned among the acknowledgments in Hicks' publication (12). The point has since been conclusively substantiated by Barnes et al (2), who used the noninvasive technique of Doppler ultrasound, checked for reliability against isotope phlebography. They found that the clinical diagnosis of leg vein thrombosis was confirmed by ultrasound in only 30.7% of cases in non pill-users and in only 16.7% of pill-users. The figure
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confirm the enormous amount of clinica l misdiagnosis a nd the statistically significant higher misdi agnosis in the contraceptors. The same appears to be the case with pulmonary embolism, where Robin (24) recently concluded that " pulmona ry embolism is being ex tensively overdiagnosed and overtreated, especially in normal patients, a nd more especially in the previously norm a l women on oral contraceptives." If accurate diagnostic methods indicate that only a bout 20 % of thromboembolism diagnosis in OC users is correct, one can only conclude that all statistics based on clinical diagnosis of this disease are meaningless and that no conclusions whatever can be drawn from them regarding the relationship to OC use. Further doubts have been raised by publicat ions such as that of DeGennes et al (7), which reexamined the cases of OC users who suffered episodes of vascular disease (30 cerebrovascular accidents, seven cases of coronary artery disease and seven cases of thromboembolic disease) and found that 74% of these cases had previously unsuspected hyperlipoproteinemia, an obvious predisposing factor. R ecently, the British group has tried to expand the thromboem bolic and myocardia l disease problem to encompass a variety of cardiovascular disorders. Beral's transnational study of vital statistics a nd OC use (5) has been severel y criticized by Belsey of the World Health Organization on factual and methodologic grounds, and the recent vital statistics from the USA and elsewhere a lso contradict her hypoth esis. Data from th e Oxford study (28), which reported nine deat hs in 49 681 woman-years of OC use compared to no deaths in 39 146 woman-years of use of six other form s of contraception, look less impressive when the actual diagnoses are inspected (Table III) : The cardiovascular deaths in the Royal College of General Practitioners study (26) are also so few in number and with such a distribution (Table IV) th at few clinicians would be willing to draw any conclusions whatever.
Table Ill. Causes of death (number) in Oxford oral contraceptive prospective study (28). Cause of Death
No. of Deaths
Mitral valve disease Congenital heart disease Cardiomyopathy Subarachnoid hemorrhage Cerebrovascular accidents (" toxemia") Myocardial infarction (" toxemia") Myocardial infarction (off OCs 11 months)
1 1 1 1 1 2 1
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Table IV. Deaths from cardiovascular disease (CVD) among 23 000 OC users and 23 000 non-OC contraceptors (totaling 200 000 woman-years of observation) in the Royal College of General Practitioners study (26). No. of Deaths from CVD Cause of Death Malignant hypertension Myocardial infarction Subarachnoid hemorrhage Cerebral thrombosis
OC Users 0 6
Former Users
Nonusers
2
0
1
28
5
4
1
0
0 3
• Differences are not statistically significant.
NEWS MEDIA SENSATIONALISM At the subprofessional level, the news media have thrived on the controversies surrounding contraception and have aggravated them in the sense that their souped-up stories come to the attention of those segments of the medical and professional communities which are not directly involved in the field of contraception and which cannot take the time to examine the original data sources. Even professionals are not immune to the McCarthyite dogma of " where there's smoke, there's fire." Unfortunately, some members of the profession have even used media sensationalism for self-serving ends. One may also wonder a little about the pathology registries which spring up at the first hint of a drug-related histologic lesion . The debate about the relative safety of high-dose vs low-dose OCs in England was sensationalized by the media with the shocking consequences (1): At the national level, the confusion resulting from misinterpretation of the statement by the Committee on Safety of Drugs in December 1969 concerning ora l contraceptives containing oestrogens, aided a nd abetted by ad verse publicity in the television programme "The Frost Report ," undoubtedly led to large numbers of women discontinuing ora l contraception and almost certainly resulted in many thousands of unintended pregnancies. Indeed the Chief Medical Officer (1972) has estimated that perhaps 20,000 unintended births resulted.
In the USA, the Nelson hearings in Congress were said to have resulted in perhaps 200 000 unplanned " Nelson babies."
CONCLUSION As with most other things, we must consider the benefit/risk or benefit/cost ratio of the debate about
lntj Gy naecol Obstet 16
contraceptive modalities. The benefit/risk ratio is not something that can be calculated in a vacuum. It is the moment of truth when the physician must take off his critical-scientist's hat and put on his doctor's hat: the point at which all of the scientific doubts and questions must be resolved face-to-face with one particular human being whose unique problem must be dealt with right then and there. The multiplicity of factors which influence the final judgment in that particular instance represent a situation which the practicing physician deals with every day, but it is beyond the ability of computers and probably outside the ken of epidemiologists. Therein lies much of the difficulty and much of the confusion . As we have said, controversy and debate are necessary constituents of the scientific process-an inherent feature of the continued reassessment of the state of our knowledge. However, there is a high price to be paid for public controversy-perhaps too high a price. The widespread fears aroused in the public by incautious statements of professionals, which in turn are sensationalized by the media, create a pressure on public officials. It is politically impossible simply to say that these questions are currently unanswerable and that, in any event, only a very small number of people are likely to be harmed. Therefore, we see large sums of money being spent on case-control investigations, prospective surveys and other highly visible but scientifically second-class activities. The health budget being finite, this means that experimental science, which might eventually provide much more meaningful insights, is that much the poorer. The point is not a trivial one: the Walnut Creek (23) and the University Group Diabetes Program studies cost millions, and no one has yet come forth with what it cost to screen thousands of records in 40 hospitals so that Sartwell and his colleagues could calculate a risk ratio based on 70 case-control pairs of a nonrepresentative population . Nor can these controversies be ignored by regulatory agencies concerned with public health. Since they must, by their very nature, operate on a " worstcase" basis, the constraints they place on drug development and drug utilization become inevitably more stringent, to a point of excess which is of great concern to all of us. The consequences for new drug development and availability have been far-reaching and devastating. Consider, for example, the implications of the decision of health officials in India who have barred the use of Depo-Provera (medroxyprogesterone acetate, The Upjohn Co., Kalamazoo, Ml, USA) because of its controversial tumorigenic effects in beagle dogs, in the perspective
Eva luation of data on OC hazards
of a society where deaths from childbirth number in the thousands per million births. The effects of the recent negative decision of the FDA will no doubt become evident also in the next few years. Controversy is not merely the stuff of science. It no longer occurs in the quiet halls of academia, between professionals aware of the qualifications and constra ints of th eir da ta and conclusions. M edical controversy is now part of the public domain, and its exploita tion is rampant and demonstrably injurious. Where is the accountability? Will D a vid Frost be fa ther to the 20 000 unpla nned children his TV perform a nce helped beget? Will there be a Nelson University to educate the 200 000 " Nelson babies"? Wh a t will V essey and Mann say to a woman over 40 who gave up the pill for a less effective method a nd had a mongoloid baby? Will certain of my ca ncerophobe colleagues accept responsibility for the traged y of a 14-year-old San Antonio girl who nearl y lost her life from complications of her unwanted pregnancy and eventual cesarean section, and when asked why she didn 't use the pill , replied , " I hear it causes ca ncer"? Let us all try to remember, as we each grind our axe, that it is th e innocent who often get hurt.
REFERENCES I. Badaracco M , Vessey MP, Wi ggins P: The effect of the sta tement by the Commiu ee on Sa fety of Drugs concernin g ora l contracepti ves cont a ining oestrogens on the cont racepti ve prac tices of women a ttending two famil y pl anning clinics. J O bstet Gynaecol Br Com monw 80:353, 1973. 2. Ba rnes R W , Kra pf T , Hoa k JC: Erroneous clini ca l diagnosis of leg vein thrombosis in women on ora l contracepti ves. O bstet G ynecol 5 1:556, 1978. 3. Bau m JK, Holt z F, Bookstein JJ, Klein EW : Possible associa tion between benign hepatomas and ora l contracepti ves. La ncet 2:926, 1973. 4. Benagia no G, Goldzieher JW : Contraception. In Adva nces in Perina tology. Raven Press, New York, 1979. 5. Bera l V : Ca rdiovascula r disease morta lity trends a nd ora l contraceptive use in young women. Lancet 2: 1047, 19 76. 6. Carr DH : C hromosomes a ft er ora l contracepti ves. La ncet 2:830, 1967. 7. DeGennes .J L, Turpin G, Truffert .J: Vascula r disease a nd ora l cont raceptives: fa milia l hyperlipoproteinemia as a predisposin g factor. Diabete Metab 2:81 , 1976. 8. Feinstein AR : Clinical Biostat istics. C . V . Mosby, StLouis, 1977. 9. Feinstein AR : C linica l biosta tistics: X X . T he epidemiologic trohoc, the a bl a ti ve risk ra tio a nd "retrospecti ve research." C lin Pha rm acal T her 14:29 1, 1973. 10. Fu ertes de Ia Haba A, Curet JO, Pelegrina I, Ba ngdi wa la 1: T hrombophlebitis among ora l a nd nonora l contraceptive users. O bstet Gynecol 38:259, 1971 . 11 . Goldzieher .JW, Dozier T S: Ora l contracepti ves and throm-
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boembolism : a reassessment. Am J Obstet Gynecol 123:878, 19 75. 12. Hicks BH : The value of clinical criteria for epidemiologic di agnosis of deep vein thrombosis. Milba nk Mem Fund Q 50: 16 1, 1972. 13. Hoover R , Ba in C , Cole P, M acM a hon B: Ora l contracepti ve use: associa tion with frequency of hospita lizat ion and chro nic disease risk indicators. Am J Public Health 68:335, 19 78. 14. J a in AK : C igarette smokin g, use of oral contracep ti ves and myocardi a l infa rction . Am J Obstet Gy necol 126:30 I, 1976. 15 . .Janerich DT, Pi per JM , G1eba tis OM : Ora l contraceptives a nd congenita l limb-reduction defects. N Engl J Med 291: 697, 19 74. 16. M a nn Jl , Inma n W : Ora l contraceptives and death from myocardi a l infa rcti on. Br Med J 2:245, 19 75. 17 . M an n .JI , Inman W , Thorogood M : O ra l contraceptive use in older wo men and fa ta l myocardia l infa rcti on . Br Med J 2:445, 1976. 18. M a nn JI , Vessey MP, Thorogood M , Doll R : M yocardi a l infarction in youn g women with specia l reference to ora l cont race pti ve prac tice. Br Med J 2:24 1, 1975. 19. M orrison A, Jick H , Ory HW : Ora l contracepti ves and hepa titis: a report from the Boston Colla bora ti ve Drug Surve illance Progra m. Lancet / : 11 42, 1977. 20. Morta lity a mong oral-contracepti ve users: Royal College of Genera l Pract itioners' O ra l Contraception Stud y. Lancet 2: 72 7, 1977. 2 1. Nora JJ, Nora AH: Birth defects and ora l contrace pti ves. La ncet / :94 1, 1973. 22. Ory HW : Associa tion between ora l contraceptives and myocardia l infa rction . J AM A 237:26 19, 1977. 23. Ramcha ra n S (ed): T he Wa lnu t C reek Contracepti ve Drug Stud y: A Prospecti ve Survey of the Side Effects of O ra l Cont racepti ves, Vol 2: Additiona l Findings in O ra l Contracepti ve Users and Nonusers. Center for Popula tion Research M onogr, DHEW Pub! No. (NIH) 76-563. US Government Printing Office, Washington , DC, 1976. 24. Robin ED : O verdiagnosis a nd overtreatment of pulmona ry embolism: the Emperor may have no clothes. Ann Int ern Med 87: 77 5, 19 77. 25. Rothma n KJ , Louik C: O ra l contracepti ves a nd birth defects. N E ng! J M ed 299:522, 1978. 26. Royal College of Ge nera l Pract itioners: O ra l Contrace ptives a nd H ealth. Pitman Medical, London, 19 74. 27. Sartwell PE, Masi AT, Arthes FG, Greene GR , Smith H E: T hromboembolism a nd ora l contraceptives: an epidem iologic case-control study. Am J Epidemiol 90:365, 1969. 28. Vessey MP , McPherson K , J ohnson B: Morta lity a mong wo men participating in the Oxford/ Famil y Pla nning Associa tion contraceptive stud y. Lancet 2:73 1, 1977 . 29. Wynn V, Doar J : Some effects of ora l contracepti ves on carbohydra te metabolism. La ncet 2:76 1, 1969.
Address for reprints: Joseph W. Goldzieher Director, Division of Clinical Sciences and Reproductive Biology Southwest Foundation for Research and Education
PO Box 28147
San Antonio, TX 78284 USA
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J Gynaccol Obstct
16: 535- 54 1, 1979
Interpretation of Data by the Clinician Joseph W. Goldzieher Division of Clinical Sciences and Reproductive Biology, Southwest Foundation for Research and Education, San Antonio, T exas, USA
ABSTRACT
Goldzieher J W (Division of Clinical Sciences and Reproductive Biology, Southwest Foundation for Research and Education, San Antonio, TX, USA). Interpretation of data by the clinician. lntj Gynaecol Obstet 16: 535- 541, 1979 The cardinal challenges to every practicing physician are to interpret clinical data correctly and to place them in proper perspective. Clinical investigations frequently lack the rigidly coi1trolled conditions and the careful experimental designs usually found in preclinical animal studies, and this deficiency is partially attributable to the inherent complexities of clinical medicine. Consequently~ a great deal of controversy results from conflicting interpretations, extrapolations and overextension. of limited data that are often equivocal. More careful appraisal of data and increased awareness of the well-known pitfalls found in retrospective and prospective studies, in which biostatistical design and clinical relevance are often incompatible, are emphasized, and personal biases and the flagrant sensationalism expounded by the media are condemned. The clinician is cautioned to sift through the data, consider the benefit/risk ratio for each patient and then. to subordinate the role of critical scientist and assume the role of physician, exercising good judgment in light of the existing evidence and the immediate problems at hand.
INTRODUCTION We are about 20 years into the modern era of contraception. One of the new contrivances, the contraceptive steroid, has been the subject of more scientific publications than any other drug in history. Yet, it is still controversial, and the controversy surrounding its use seems to proliferate with the passage of time. Controversy is nothing new to science and medicine. In part it is the continuous testing process to which the search for truth must always be subjected. In part it is a reflection of the Portions of this presentation w ill appear in Controversies in Contraception, Moghissi, © 1979, Th e Williams and Wilkins Co, Baltimore, MD, USA .
contemporary environment, especially its sociocultural attitudes. It is necessary to sort out some of the underlying factors which generate these controversies, for without this the merit of various views is difficult to assess. Sometimes access to a desired answer is either impossible or impractical. In order to decide whether certain events, which normally occur very rarely, are increased in frequency by contraceptive hormones, it would be necessary to select a representative sample of some tens of thousands of women by a carefully designed, unbiased procedure, segregate them for 10- 20 years in an environment whi ch represents a cross section of the national environ ments, permit none to enter or to leave, assign th em in truly random fashion to the experimental maneuvers in question and observe the results. We might then get some believable data about the relationship of contraceptive steroids to breast cancer, uterine cancer, liver tumors and other rare events. Some other very immediate problems have equally impractical solutions. It is often asked whether combination and sequential pills, or highdose and low-dose pills, are "equally effective." If we were looking for a tenfold difference in effectiveness, this might not be difficult to answer, but if we were seeking to detect a twofold difference (ie, a 100% increase or decrease in effectiveness), the problem becomes formidable. If we assume tha t half of the pregnancies which occur with oral contraceptive (OC) use are due to human error (a reasonable, and probably low, estimate), calculations tell us that a t least 58 000 cycles of use would be required with each drug to give us a 95 % level of confidence that the observed twofold difference did not occur by random chance. Moreover, this number of cycles assumes that the subjects were perfectly randomized and that there was no dropout or any other source of data loss. If we assume that 90% of pregnancies are due to human error and only 10% are due to a difference between the two drugs, the number of cycles required becomes astronomical , and so does the cost. In the laboratory, where controlled conditions, genetic homogeneity, random assignment ofmaneuln t J G)'IJaeco l Obstet 16
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vers and freedom from clinical ethical constraints are possible, sophisticated biostatistical procedures let us optimize our experimental designs and accurately evaluate our findings. However, clinical investigation is an infinitely more difficult discipline whose chief current problem appears to be that clinicians do not understand the complexities of biostatistics and biostatisticians do not understand the complexities of clinical medicine. The upshot is, occasionally, a major disaster, such as the large and costly University Group Diabetes Program which has been criticized by both clinicians and biostatisticians. Perhaps, the most useful recommendation for all active investigators and for all those who read and evaluate such investigations is to read the essays of Alvan Feinstein (8, 9) on the architecture of clinical investigation-and then to pass them on to their statistician and epidemiologist colleagues. I suspect that this would cause much planned clinical and epidemiologic research to be returned to the drawing board for reconsideration .
PROBLEMS OF INTERPRETING DATA If all of the pertinent data on some subject were precise and unambiguous, controversy would still arise from conflicting perceptions of their context. But, as we all know, the data themselves are never complete, almost never black-or-white, rarely unambiguous and inevitably subject to change as new data appear. An excellent example of the need to examine data carefully is found in a publication by Janerich et al (15), which has been used to suggest that the administration ofOC steroids inadvertently during early gestation , or the use of these steroids as a quick pregnancy test, might be associated with limb-reduction defects in the offspring. On the basis of this and other reports, the US Food and Drug Administration removed the pregnancy-test pills from the market, and some investigators have advised postponement of efforts at conception for some months after discontinuing contraceptive steroids. Examination of the data, however, shows that the incidence of limb-reduction defects in pill users was no greater than that in the controls; but when these data were lumped together with all other sorts of data on hormone administration during early gestation, the inci-
dence of defects was significantly higher than that in the controls. How one derives scientifically meaningful conclusions from the lumping of such disparate data, and what this implies in terms_of the endocrinologic expertise involved in this investigation , merits a moment's thought. More recent stud-
lntj Gynaecol Obstet 16
ies by Rothman and Louik, on a very large material, have in fact concluded that "oral contraceptives present no major teratogenic hazard" (25). When data appear to be unequivocal, when they are the result of a well-designed, straightforward experiment, their interpretation may still present serious problems. Consider the following example: Experiment: Equal numbers of well-dressed men and women are asked to walk over a long stretch of rough ground. Observations: Women stumbled much more often than men. Statistical evaluation: Correlation between stumbling and being female shows a significant association : x2 = 6.6; p < o.o1. Possible causal inferences: l. Women are genetically less stable than men.
2. Estrogens cause disorders of the middle ear and/or the cerebellum; androgens may be protective. 3. Chronic lipstick use is toxic; it weakens leg muscles. 4. Male clothes have an antigravitational effect. 5. High heels are not good on rough ground. Logical errors of interpretation have been made regarding the effects of contraceptive steroids on lipid metabolism: plasma triglycerides are elevated by these agents, even to a level above the "normal range" in a small percentage of subjects. Furthermore, epidemiologic studies have claimed that there is a statistical association between idiopathic elevation of triglycerides (among other things) and atherogenic cardiovascular disease. Is it then acceptable to interpret this, as Wynn and Doar have done (29), to indicate that OCs will cause heart disease? Should one not instead ask other questions? For example: Is idiopathic hypertriglyceridemia causally related to atherogenic heart disease, or is it merely a manifestation of a common underlying process? Do hypertriglyceridemias of whatever origin have the same prognostic significance? If elevated triglycerides "cause" heart disease, is this related to the level of hypertriglyceridemia? What other factors influence this relationship? And so forth. As we all know, the relationship of the various hyperlipidemias to cardiovascular disease is extremely complex, and such simplistic views are likely to generate more heat than light. Clinical investigation rarely permits the luxury of a precisely controlled experiment, with all that that implies in terms of design, randomization, etc. Nevertheless, the realities of life require that operational decisions be made on some basis. Nowadays one has recourse to the discipline of epidemiology, which often proceeds on the premise of "better to use bad
Eva luation of data on OC hazards
data than to do nothing" and which bristles with thorny mathematical formulations and sophisticated computer technology. Some, like Feinstein, have suggested that a transition from old pre-science to modern pseudoscience does not necessarily represent progress. The simplest nonexperimental (ie, epidemiologic) type of investigation is the recording of anecdotal information such as adverse-reaction reports. This is a valuable procedure which acts as an early-warning alert. The classical example of its utility is, of course, the case of thalidomide. Drawing inferences from case reports is an extremely risky business, open to a great variety of logical errors of which the post-hoc fallacy is the most common and most flagrant. Today, the prestige of setting up an adverse-effect registry and maybe getting some grant funds lends added attractiveness to case-collecting. Considering the high overall probability that the occurrence of a symptom during the use of some drug is merely a matter of coincidence, it takes an extremely optimistic individual to undertake such an enterprise. A relevant example of the problem with anecdotal case reports is the question of chromosomal and congenital anomalies associated with OC use. A report by Carr (6), based on eight abortuses, and another by Nora and Nora (21) on congenital anomalies, generated a great deal of concern about .the use of contraceptive steroids in women who become pregnant inadvertently during their use. A large amount of information has accumulated rapidly since then (for a review, see Benagiano and Goldzieher (4] and Rothman and Louik (25]) and has failed to substantiate the existence of such hazards. Similarly, an anecdotal report in 1973 by Baum et al (3) on liver tumors caused hundreds of unreported cases, some in OC users, to come out of the woodwork. A careful case-control study by the US Public Health Service's Center for Disease Control and the Armed Forces Institute of Pathology has shown a statistically significant association with OC use, especially with use for prolonged periods, and this question is now under active investigation. Whether or not a causal relationship is found, the number of cases must be exceedingly small: l. The Royal College of General Practitioners (20) found no .cases in 200 000 woman-years' experience. 2. An Oxford study (28) found no cases in 50 000 woman-years' experience. 3. A California study (23) found no cases in 46 000 woman-years' experience. 4. The Boston Surveillance Program (19) found only one case in nine years. 5. The Scottish National Diagnostic Index in-
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eluded no cases among 5 million women, 19681974. A more complex procedure used by epidemiologists is to collect a series of events, such as cerebrovascular accidents or chromosomal anomalies, and work backward in time with this pseudocohort of subjects toward a presumed cause. Research customarily works forward in time from action to effect. Therefore, Feinstein (9) has called this backward procedure " trohoc" research - trohoc being "cohort" spelled backwards. A typical example of this type of investigation is the work of Mann and Inman (16) on myocardial infarction (MI) and pill use. In their first MI study ( 16), these epidemiologists examined every second death certificate from women in the appropriate age group, ascertained the frequency of pill use and compared this to the rate in so-called "control" subjects. (Epidemiologists often study a disease by giving precise numerical values to these diagnoses or to the " vital statistics" derived from them and then applying rigorous statistical procedures to these numbers.) The frequency of factors predisposing to MI in the cases vs the controls was ignored. Clinicians who examine Table I might come to their own conclusions about the validity of calculations of relative risk, etc, based on comparisons of two groups with such dissimilar prognoses. The studies of Mann and Inman (16) and Mann et al (I 7) also concluded that there was a su bstantially greater hazard of fatal heart attacks in pillusing women over the age of 40- a relative risk of 4. 7 compared to one of 2.8 in the under-40 women (Table II) . This information was widely publicized by the British and American news media and was the subject of a television spectacular by the US Food and Drug Administration. Without a doubt, many women in the over-40 age group have since been systematically encouraged to change to less effective methods of contraception. Subsequently, Mann et al (17) did examine the other half of the
Table I. Factors predisposing to myocardial infarction (MI) in OC users suffering Mls and in controls. Predisposing Factor
Smoking Hypertension Diabetes Obesity History of preeclampsia Type II hyperlipidemia
Ml Patients
Controls
(%)
(%)
76.3 18.3 6.7 23.3 30.0 41.0
52.9
3.5 0.0 9.9 11.2 0.0
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Table 11. British myocardial infarction (MI) studies: Mann and Inman (1 e> and Mann et al (1 7). Age (years)
Difference c
MI death certificates, and they found no increased risk at all in the over-40 pill users in this part of the sample. When the two sets of data are combined, as in the bottom of Table II, there is no difference in the relative risk of older vs younger women. However, their retraction is buried in a London fog of epidemiologic verbiage and did not become the object of corrective media coverage or a TV spectacular. Mann et al (18) had also made similar claims from their morbidity data on MI, but little was said about the important differences in the frequency. of predisposing factors in the infarction patients vs the controls and the possible confounding role of cigarette smoking was ignored. It took a complete reanalysis of the data, performed independently by Jain of the Population Council (14) and Ory (22) of the Center for Disease Control to show that the calcula tions were completely confounded by the smoking habits of the subjects and that, .in fact, nonsmoking pill users had no greater relative risk of MI than nonsmoking nonusers. Another major hazard in the interpretation of " trohoc" studies is the problem of extrapolation. Consider the well-publicized " trohoc" study of Sartwell and his colleagues (27) on thromboembolism a nd the pill. To obtain their base data, they examined the records of nearly 40 East Coast university and public hospitals and identified 2648 cases with the diagnosis of thromboembcrlism in ma rried women of the appropriate age group. In order to minimize extraneous factors and deal only
Jnt j Gynaecol Obstet 16
with idiopathic disease, they eliminated all cases with predisposing factors and, after matching these with controls, they were left with 175 pairs, or about 7% of the original charts. After making a ratio of 70 of these 175 case-control pairs in a certain manner, they concluded that there was a 4.4-fold relative risk of thromboembolism associated with pill use. All other methodologic questions aside (11), one must ask how this highly selected subset of records from hospitals which have a population of patients quite unrepresentative of American women as a whole can be used to estimate the "relative risk of pill use" in the USA or elsewhere? This, however, is precisely what is implied by the inclusion of such relative risks in the product information that accompanies commercial OCs. Whether it is even remotely relevant to populations with different ethnic and social structures, as in the developing world, is a question of overriding importance which has not been sufficiently appreciated by various regulatory agencies. The classical prospective study, which identifies a population of subjects at the outset and then observes them over the passage of time in a specified manner, avoids some of the fundamental pitfalls of trohockery; indeed, it is frequently the second epidemiologic step after the identification of an association by a "trohoc" study. Prospective studies have their own pitfalls, many of which were perceptively discussed in the introduction to the pill study of the Royal College of General Practitioners (26) . One of the unavoidable biases in a prospective
Evaluation of data on OC hazards
study of pill-related adverse reactions is the bias introduced by self-selection. It has been amply demonstrated that women who select pills as their contraceptive differ in important ways from women who select other modalities, and this bias cannot be eliminated by stratification of the data since we have no idea a priori of all of the stratifiable variables that may be relevant. In any event, when the conclusions of a prospective study in which selfselection occurred are at variance with the conclusions of a prospective study in which the subjects were randomly assigned to alternative contraceptive modalities (as in the case of the Royal College of General Practitioners study vs the Fuertes de Ia H a ba et a l study [10) in Puerto Rico) , the amber light of caution should glow brightly. Indeed , after a questionnaire survey of 37 292 women in the Boston area, Hoover et al (13) concluded : The use of OCs varies with socia l and reproducti ve characteris tics that are risk indicators for ma'!Y diseases. OC use was associa ted with increased risk of hospita liza ti on for thromboembolic disease, men ta l illness, hyperth yro idism, hypert ension, a nd cancer of the cervix. OC users were hospitalized for ma'!)l non-life threatening conditions 20 to 40 percent more frequently than non-users.
As a matter of fact, the whole notion of a causal relationship between thromboembolic disease and OC use, so avidly pursued by epidemiologists and the news media alike, has been shaken to its roots by investigators of cardiovascular disease who have used modern di agnostic technology. As early as 1972, Hicks ( 12) discussed the problems in the di agnosis of thromboembolic disease in the light of an ongoing study sponsored by the British Medical Research Council. He noted that st udies with definitive methods such as radiolabeled fibrinogen suggested that not more than 20%-40 % of deep leg vein thrombosis is evident clinically and diagnosed , a nd in his specific trial, only 22 % of all venous thromboses were diagnosed clinically (12). Moreover, there was also a significant percent age of false-positive clinical diagnoses. Such figures put the clinical diagnosis of thromboembolic disease on shaky ground indeed and suggest that statistical arithmetic applied to such data might be equally shaky. In this regard, it is interesting to note that the name of M . B. Vessey is mentioned among the acknowledgments in Hicks' publication (12). The point has since been conclusively substantiated by Barnes et al (2), who used the noninvasive technique of Doppler ultrasound, checked for reliability against isotope phlebography. They found that the clinical diagnosis of leg vein thrombosis was confirmed by ultrasound in only 30.7% of cases in non pill-users and in only 16.7% of pill-users. The figure
539
confirm the enormous amount of clinica l misdiagnosis a nd the statistically significant higher misdi agnosis in the contraceptors. The same appears to be the case with pulmonary embolism, where Robin (24) recently concluded that " pulmona ry embolism is being ex tensively overdiagnosed and overtreated, especially in normal patients, a nd more especially in the previously norm a l women on oral contraceptives." If accurate diagnostic methods indicate that only a bout 20 % of thromboembolism diagnosis in OC users is correct, one can only conclude that all statistics based on clinical diagnosis of this disease are meaningless and that no conclusions whatever can be drawn from them regarding the relationship to OC use. Further doubts have been raised by publicat ions such as that of DeGennes et al (7), which reexamined the cases of OC users who suffered episodes of vascular disease (30 cerebrovascular accidents, seven cases of coronary artery disease and seven cases of thromboembolic disease) and found that 74% of these cases had previously unsuspected hyperlipoproteinemia, an obvious predisposing factor. R ecently, the British group has tried to expand the thromboem bolic and myocardia l disease problem to encompass a variety of cardiovascular disorders. Beral's transnational study of vital statistics a nd OC use (5) has been severel y criticized by Belsey of the World Health Organization on factual and methodologic grounds, and the recent vital statistics from the USA and elsewhere a lso contradict her hypoth esis. Data from th e Oxford study (28), which reported nine deat hs in 49 681 woman-years of OC use compared to no deaths in 39 146 woman-years of use of six other form s of contraception, look less impressive when the actual diagnoses are inspected (Table III) : The cardiovascular deaths in the Royal College of General Practitioners study (26) are also so few in number and with such a distribution (Table IV) th at few clinicians would be willing to draw any conclusions whatever.
Table Ill. Causes of death (number) in Oxford oral contraceptive prospective study (28). Cause of Death
No. of Deaths
Mitral valve disease Congenital heart disease Cardiomyopathy Subarachnoid hemorrhage Cerebrovascular accidents (" toxemia") Myocardial infarction (" toxemia") Myocardial infarction (off OCs 11 months)
1 1 1 1 1 2 1
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Table IV. Deaths from cardiovascular disease (CVD) among 23 000 OC users and 23 000 non-OC contraceptors (totaling 200 000 woman-years of observation) in the Royal College of General Practitioners study (26). No. of Deaths from CVD Cause of Death Malignant hypertension Myocardial infarction Subarachnoid hemorrhage Cerebral thrombosis
OC Users 0 6
Former Users
Nonusers
2
0
1
28
5
4
1
0
0 3
• Differences are not statistically significant.
NEWS MEDIA SENSATIONALISM At the subprofessional level, the news media have thrived on the controversies surrounding contraception and have aggravated them in the sense that their souped-up stories come to the attention of those segments of the medical and professional communities which are not directly involved in the field of contraception and which cannot take the time to examine the original data sources. Even professionals are not immune to the McCarthyite dogma of " where there's smoke, there's fire." Unfortunately, some members of the profession have even used media sensationalism for self-serving ends. One may also wonder a little about the pathology registries which spring up at the first hint of a drug-related histologic lesion . The debate about the relative safety of high-dose vs low-dose OCs in England was sensationalized by the media with the shocking consequences (1): At the national level, the confusion resulting from misinterpretation of the statement by the Committee on Safety of Drugs in December 1969 concerning ora l contraceptives containing oestrogens, aided a nd abetted by ad verse publicity in the television programme "The Frost Report ," undoubtedly led to large numbers of women discontinuing ora l contraception and almost certainly resulted in many thousands of unintended pregnancies. Indeed the Chief Medical Officer (1972) has estimated that perhaps 20,000 unintended births resulted.
In the USA, the Nelson hearings in Congress were said to have resulted in perhaps 200 000 unplanned " Nelson babies."
CONCLUSION As with most other things, we must consider the benefit/risk or benefit/cost ratio of the debate about
lntj Gy naecol Obstet 16
contraceptive modalities. The benefit/risk ratio is not something that can be calculated in a vacuum. It is the moment of truth when the physician must take off his critical-scientist's hat and put on his doctor's hat: the point at which all of the scientific doubts and questions must be resolved face-to-face with one particular human being whose unique problem must be dealt with right then and there. The multiplicity of factors which influence the final judgment in that particular instance represent a situation which the practicing physician deals with every day, but it is beyond the ability of computers and probably outside the ken of epidemiologists. Therein lies much of the difficulty and much of the confusion . As we have said, controversy and debate are necessary constituents of the scientific process-an inherent feature of the continued reassessment of the state of our knowledge. However, there is a high price to be paid for public controversy-perhaps too high a price. The widespread fears aroused in the public by incautious statements of professionals, which in turn are sensationalized by the media, create a pressure on public officials. It is politically impossible simply to say that these questions are currently unanswerable and that, in any event, only a very small number of people are likely to be harmed. Therefore, we see large sums of money being spent on case-control investigations, prospective surveys and other highly visible but scientifically second-class activities. The health budget being finite, this means that experimental science, which might eventually provide much more meaningful insights, is that much the poorer. The point is not a trivial one: the Walnut Creek (23) and the University Group Diabetes Program studies cost millions, and no one has yet come forth with what it cost to screen thousands of records in 40 hospitals so that Sartwell and his colleagues could calculate a risk ratio based on 70 case-control pairs of a nonrepresentative population . Nor can these controversies be ignored by regulatory agencies concerned with public health. Since they must, by their very nature, operate on a " worstcase" basis, the constraints they place on drug development and drug utilization become inevitably more stringent, to a point of excess which is of great concern to all of us. The consequences for new drug development and availability have been far-reaching and devastating. Consider, for example, the implications of the decision of health officials in India who have barred the use of Depo-Provera (medroxyprogesterone acetate, The Upjohn Co., Kalamazoo, Ml, USA) because of its controversial tumorigenic effects in beagle dogs, in the perspective
Eva luation of data on OC hazards
of a society where deaths from childbirth number in the thousands per million births. The effects of the recent negative decision of the FDA will no doubt become evident also in the next few years. Controversy is not merely the stuff of science. It no longer occurs in the quiet halls of academia, between professionals aware of the qualifications and constra ints of th eir da ta and conclusions. M edical controversy is now part of the public domain, and its exploita tion is rampant and demonstrably injurious. Where is the accountability? Will D a vid Frost be fa ther to the 20 000 unpla nned children his TV perform a nce helped beget? Will there be a Nelson University to educate the 200 000 " Nelson babies"? Wh a t will V essey and Mann say to a woman over 40 who gave up the pill for a less effective method a nd had a mongoloid baby? Will certain of my ca ncerophobe colleagues accept responsibility for the traged y of a 14-year-old San Antonio girl who nearl y lost her life from complications of her unwanted pregnancy and eventual cesarean section, and when asked why she didn 't use the pill , replied , " I hear it causes ca ncer"? Let us all try to remember, as we each grind our axe, that it is th e innocent who often get hurt.
REFERENCES I. Badaracco M , Vessey MP, Wi ggins P: The effect of the sta tement by the Commiu ee on Sa fety of Drugs concernin g ora l contracepti ves cont a ining oestrogens on the cont racepti ve prac tices of women a ttending two famil y pl anning clinics. J O bstet Gynaecol Br Com monw 80:353, 1973. 2. Ba rnes R W , Kra pf T , Hoa k JC: Erroneous clini ca l diagnosis of leg vein thrombosis in women on ora l contracepti ves. O bstet G ynecol 5 1:556, 1978. 3. Bau m JK, Holt z F, Bookstein JJ, Klein EW : Possible associa tion between benign hepatomas and ora l contracepti ves. La ncet 2:926, 1973. 4. Benagia no G, Goldzieher JW : Contraception. In Adva nces in Perina tology. Raven Press, New York, 1979. 5. Bera l V : Ca rdiovascula r disease morta lity trends a nd ora l contraceptive use in young women. Lancet 2: 1047, 19 76. 6. Carr DH : C hromosomes a ft er ora l contracepti ves. La ncet 2:830, 1967. 7. DeGennes .J L, Turpin G, Truffert .J: Vascula r disease a nd ora l cont raceptives: fa milia l hyperlipoproteinemia as a predisposin g factor. Diabete Metab 2:81 , 1976. 8. Feinstein AR : Clinical Biostat istics. C . V . Mosby, StLouis, 1977. 9. Feinstein AR : C linica l biosta tistics: X X . T he epidemiologic trohoc, the a bl a ti ve risk ra tio a nd "retrospecti ve research." C lin Pha rm acal T her 14:29 1, 1973. 10. Fu ertes de Ia Haba A, Curet JO, Pelegrina I, Ba ngdi wa la 1: T hrombophlebitis among ora l a nd nonora l contraceptive users. O bstet Gynecol 38:259, 1971 . 11 . Goldzieher .JW, Dozier T S: Ora l contracepti ves and throm-
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boembolism : a reassessment. Am J Obstet Gynecol 123:878, 19 75. 12. Hicks BH : The value of clinical criteria for epidemiologic di agnosis of deep vein thrombosis. Milba nk Mem Fund Q 50: 16 1, 1972. 13. Hoover R , Ba in C , Cole P, M acM a hon B: Ora l contracepti ve use: associa tion with frequency of hospita lizat ion and chro nic disease risk indicators. Am J Public Health 68:335, 19 78. 14. J a in AK : C igarette smokin g, use of oral contracep ti ves and myocardi a l infa rction . Am J Obstet Gy necol 126:30 I, 1976. 15 . .Janerich DT, Pi per JM , G1eba tis OM : Ora l contraceptives a nd congenita l limb-reduction defects. N Engl J Med 291: 697, 19 74. 16. M a nn Jl , Inma n W : Ora l contraceptives and death from myocardi a l infa rcti on. Br Med J 2:245, 19 75. 17 . M an n .JI , Inman W , Thorogood M : O ra l contraceptive use in older wo men and fa ta l myocardia l infa rcti on . Br Med J 2:445, 1976. 18. M a nn JI , Vessey MP, Thorogood M , Doll R : M yocardi a l infarction in youn g women with specia l reference to ora l cont race pti ve prac tice. Br Med J 2:24 1, 1975. 19. M orrison A, Jick H , Ory HW : Ora l contracepti ves and hepa titis: a report from the Boston Colla bora ti ve Drug Surve illance Progra m. Lancet / : 11 42, 1977. 20. Morta lity a mong oral-contracepti ve users: Royal College of Genera l Pract itioners' O ra l Contraception Stud y. Lancet 2: 72 7, 1977. 2 1. Nora JJ, Nora AH: Birth defects and ora l contrace pti ves. La ncet / :94 1, 1973. 22. Ory HW : Associa tion between ora l contraceptives and myocardia l infa rction . J AM A 237:26 19, 1977. 23. Ramcha ra n S (ed): T he Wa lnu t C reek Contracepti ve Drug Stud y: A Prospecti ve Survey of the Side Effects of O ra l Cont racepti ves, Vol 2: Additiona l Findings in O ra l Contracepti ve Users and Nonusers. Center for Popula tion Research M onogr, DHEW Pub! No. (NIH) 76-563. US Government Printing Office, Washington , DC, 1976. 24. Robin ED : O verdiagnosis a nd overtreatment of pulmona ry embolism: the Emperor may have no clothes. Ann Int ern Med 87: 77 5, 19 77. 25. Rothma n KJ , Louik C: O ra l contracepti ves a nd birth defects. N E ng! J M ed 299:522, 1978. 26. Royal College of Ge nera l Pract itioners: O ra l Contrace ptives a nd H ealth. Pitman Medical, London, 19 74. 27. Sartwell PE, Masi AT, Arthes FG, Greene GR , Smith H E: T hromboembolism a nd ora l contraceptives: an epidem iologic case-control study. Am J Epidemiol 90:365, 1969. 28. Vessey MP , McPherson K , J ohnson B: Morta lity a mong wo men participating in the Oxford/ Famil y Pla nning Associa tion contraceptive stud y. Lancet 2:73 1, 1977 . 29. Wynn V, Doar J : Some effects of ora l contracepti ves on carbohydra te metabolism. La ncet 2:76 1, 1969.
Address for reprints: Joseph W. Goldzieher Director, Division of Clinical Sciences and Reproductive Biology Southwest Foundation for Research and Education
PO Box 28147
San Antonio, TX 78284 USA
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