Ear/v Human Development, 10 (1985) 171-191 Elsevier

171

EHD 00614

Promoting perinatal health: is it time emphasis in research?

for a change of

Iain Chalmers a,* and John C. Sinclair b ’ National Perinatal Epidemiology Unit, Radcliff Infirmary Oxford OX2 6HE, United Kingdom, and ’ Department of Paediatrics, McMaster University Medical Centre, 1200 Main Street West, Hamilton,

Ontario, Canada

Accepted for publication 31 July 1984

clinical science; research methods; collaborative clinical trials; research funding

“We always say, ‘What is the treatment of this disease? rather than ‘Is there a treatment for this disease? Even the expression ‘effective treatment’ is a quaint one. We do not talk of ‘mobile motorcars’, we assume that they move, because that is their purpose and function. Logically we should not give treatment unless it is effective. “Deriving from this I obtain an uncomfortable concept which I believe to be true but which I find too depressing to accept. This is it.. ‘It is better to believe in therapeutic nonsense, than openly to admit therapeutic bankruptcy’. Better, in the sense that a little credulity makes us better doctors, though worse research workers. “I find this one of the most uncomfortable concepts that logical reasoning leads me to. If you admit to yourself that the treatment you are giving is frankly inactive, you will inspire little confidence in your patients unless you happen to be a remarkably gifted actor, and the results of your treatment will be negligible. But if you believe fervently in your treatment even though controlled tests show that it is quite useless, then your results are much better, your patients are much better, and your income is much better, too. I believe this accounts for the remarkable success of some of the less gifted, but more credulous members of our profession, and also for the violent dislike of statistics and controlled tests which fashionable and successful doctors are accustomed to display. It is an almost insoluble problem, and the majority of worthwhile doctors are driven to a compromise in which they muster enough genuine belief in their treatment to keep their patients happy and maintain their own self-respect, while preserving enough doubt to admit their inadequacy during transient bouts of uncomfortable honesty” [l].

As Richard Asher observes, there is an inevitable tension between the certainty and self-confidence required to sustain day-to-day clinical practice and the uncer- tainty and questioning attitudes which are prerequisites for evaluating clinical practice scientifically. He might have added that not only are the majority of worthwhile doctors driven to a compromise, but so also are most of their patients. Just like the perinatologists caring for them and their baby, for example, the parents

* To whom all correspondence should be addressed.

0378-3782/85/$03.30 0 1985 Elsevier Science Publishers B.V. (Biomedical Division)

172

of a compromised 800 g fetus must be confident that the caesarean section which has been prescribed for them represents the best course of action. Parents and clinicians alike resist any tendency to question the decision to pursue a particular course of clinical management which, to a less involved observer, may appear questionable. They must believe in what they are doing in the hope of achieving the peace of mind to face whatever consequences may ensue.

The day-to-day clinical decisions made by those involved in perinatal practice are probably influenced relatively little by the results of research [15,51]. Certainly there is a great deal of evidence that medical and surgical practice in general are shaped by a wide variety of influences. But we believe that we must at least try to address the ‘almost insoluble problem’ identified by Asher. There are three principal reasons why we hold this view. Firstly, intervention in the perinatal period has had unintended and harmful consequences in the past: those practising perinatal medi- cine should be concerned to use research to help minimize such consequences in their current and future practice. Secondly, in a field in which development is so rapid and diverse it is important to distinguish real from apparent advances: this should help to maxim&e the numbers of mothers and babies who can benefit from changes in practice. The last of our reasons for wishing to see a closer relationship between perinatal research and perinatal practice is that perinatal medicine is expensive. If its practitioners wish to secure an appropriate share of the necessarily limited resources available, it is becoming clear that they will have to convince others that they can deploy their allocation as least as effectively as competitors in other sections of the health and social services [49]. If perinatal practice is to move towards fulfilling these conditions, however, we believe there must be a change of emphasis within perinatal research.

Problems in evaluating perinatal practice

“The perinatal field can be characterised as one which is replete with observed associations, many of which are ripe for testing in randomized controlled trials” [40].

In evidence to the Social Services Committee of the House of Commons in 1980, the British Medical Research Council estimated that it was spending over 4 million pounds per year supporting projects of relevance to the perinatal field [37]. Perusal of the list of projects supported suggests that under 5% of this sum was being invested in controlled trials of clinical practice. That the British MRC is not exceptional among sponsors of research in this respect is reflected in the very small proportion of published research in obstetrics and paediatrics which relates to the results of controlled trials of perinatal practice (Table I).

The case series, case-control and cohort analytic studies which have dominated the perinatal research literature have made important contributions to knowledge about the frequencies and interrelationships of variables of interest, and about etiology, natural history and prognosis. But we would suggest that it is only exceptionally that they have provided unambiguous evidence upon which to develop or modify perinatal practice. Indeed, the difficulties in interpreting the meaning of

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174

the associations which have been observed can be used to “justify” almost every extreme in the astonishing range of clinical policies which exists in perinatal practice. Each clinician’s certainty about the correctness of his or her own approach-how- ever different it may be from that of colleagues-is thus insured against serious challenge by the difficulties inherent in interpreting observational data.

There do seem to be good reasons for concern about the quality of clinical research in the perinatal field. In a systematic evaluation of all 86 reports of therapeutic studies in the perinatal field published in four major journals during 1979, Tyson and his colleagues [68] concluded that in only 10% were the recom- mendations for clinical practice justified by the evidence presented. But in the light of the rather anarchic way in which perinatal practice has developed and continues to develop, should we be concerned about this? Our specialty’s reliance on a combination of clinical impressions and observational research has, after all, been associated with some striking achievements.

Our own reason for proposing a re-evaluation of the relation between perinatal research and practice is that, in other fields, striking success has also been associated with more systematic attempts to assess practice. The treatment of the leukaemias and lymphomas, for example, has been developed within the framework of an ongoing series of randomized controlled trials. This planned, step-by-step approach to the development of practice has contributed both directly, and, perhaps even more importantly, indirectly, to avoiding introducing harmful treatments unwit- tingly, while at the same time fostering the development of ever more effective therapies.

If, in the perinatal field, we had in the past made determined efforts to implement comparable programmes of treatment evaluation, but failed, we might be able to claim justifiably that we must be content with our current approach to the develop- ment of clinical practice. As a research community, however, investigators in the perinatal field have not made a sustained effort to develop systematic programmes of treatment evaluation. We feel there is therefore no alternative but to acknowledge that such a strategy might be more effective in evaluating practices than the “free wheeling” approach on which we have come to place so much reliance.

The fact that controlled trials of therapy have not flourished in the perinatal field to the same extent as in some other branches of medical practice may be partly due to the complexity and ambiguity of the outcome measures we use. One quandary facing those who wish to evaluate perinatal (and particularly neonatal) practice is the same today as it was a quarter of a century ago. It was recognized then that to prevent both retrolental fibroplasia and neonatal death, it was necessary to practice medicine on a tight rope. This is nowhere better illustrated than in the controlled trial of intensive neonatal care conducted by Kitchen and his colleagues [33] in which a reduction in the risk of death with intensive care was achieved at the cost of an increase in the risk of surviving profoundly handicapped.

The intensive care which was evaluated in Kitchen’s study is often dismissed by neonatologists as primitive by today’s standards. This observation is true but it is irrelevant to the main lesson from the trial. The results are a reminder that, like oxygen administration, perinatal interventions have the potential for affecting the

175

risks of death and the risks of surviving handicapped in a reciprocal manner. If one further complicates the evaluative quandary by remembering that perinatal interven- tions made on behalf of fetuses and neonates can have adverse immediate and long term effects on their parents and vice versa, then it should become clear that evaluation of perinatal practice is more complex than assessing the effect of streptomycin on early pulmonary tuberculosis.

Quite apart from the inherent complexity of assessing the effects of perinatal practice, the search for meaningful outcome measures is a problem which continues to confront most of those involved in perinatal research. Unambiguous adverse outcomes such as death or major handicap of likely perinatal origin are fortunately very rare. For this reason, surrogate measures such as low birthweight, preterm delivery, low Apgar score, aspects of acid-base status, neurobehavioural assessments and brain ultrasound, have been used in treatment evaluations. Variations in these surrogate measures are sometimes difficult to reconcile with each other and are often of uncertain significance with respect to less ambiguous outcomes. A number of examples could be cited to illustrate the quandaries and paradoxes presented by the use of surrogate outcome measures: the fact that high-protein supplements taken during pregnancy result in restricted fetal growth without any evidence that the fetuses are compromised in any less ambiguous respects [54]; the fact that fetal weight gain can be promoted by both bed rest [55] and anti-malarial drugs [44] without any evidence that any other benefit accrues to the fetus from these treatments; the fact that disturbances of acid-base status in the perinatal period are of unknown prognostic significance for long term status in childhood; the fact that some of the most dramatic intraventricular haemorrhages visualized on ultrasound appear to be less strongly predictive of subsequent death than more moderate bleeds [66], and so on.

The danger of extrapolating from effects on intermediate outcome measures such as those we use in perinatal research has been well-illustrated in the attempts to mitigate and prevent coronary disease and stroke with drugs which alter the factors known to be associated with an increased risk of these diseases. Raised serum cholesterol is one such factor; it can be lowered by administering clofibrate, but this drug appears to lead to an increase in moitality from non-cardiovascular disease, including cancer [50].

Another reason that we have not evolved more systematic research strategies for evaluating perinatal practice may be quite simply that the incentives have not been great enough. In contrast to the experience of those involved in the treatment of leukaemia, for example, obstetricians and paediatricians have always expected the vast majority of their patients to survive - whatever treatment they have been offered. Similarly, the steady fall in perinatal mortality rates everywhere can be, and has been used to endorse any or all of the developments in clinical practice with which this welcome trend has been associated.

We believe, however, that the history of perinatal practice holds some lessons for those who seek reassurance in such observations. Our reliance on observational data has led us to make a number of far-reaching mistakes in the past [58]. Take, for example, the treatment comparisons made using observational data which led

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investigators to claim that the use of stilboestrol and ethisterone in diabetic preg- nancy reduced the intrauterine death rate from 80% to 30% [72]. A randomized controlled trial mounted to assess this claim in a scientifically more rigorous manner provided strong negative evidence with which to refute it [18]. Furthermore, al- though the trial was not designed to identify long term effects of the treatment, the enduring value of this well-designed experiment has been illustrated by the follow-up, 27 years later, of the cases and controls entered into the study as pregnant women [4] and fetuses [5] (Table II).

Who would have predicted that male fetuses exposed to stilboestrol would be half as likely as controls to be married at the age of thirty? Whether this possible effect is seen as good or bad, the data should be a sobering reminder of both the potential for long term effects of perinatal practices and the need to carry the evaluation of these practices beyond our usual obsession with perinatal mortality. What, for example, are the likely long term effects of chronic fetal exposure to the beta sympatho- mimetic drugs which are currently being prescribed during pregnancy [31]? What are the long term consequences of fetal exposure to ultrasound [46]? What are the effects on subsequent relationships between parents and children who have been involved in

TABLE II

Randomised placebo-controlled trial of stilboestrol and ethisterone in pregnant diabetic women

Stilboestrol/ ethisterone (n = 76)

Placebo (n=72)

Shorr - term outcome * No. cases Mothers

Albuminuria 16 Poor diabetic control 4

Fetuses Abortions 6 Stillbirths 9 Infant deaths 9 Later deaths 2

Follow - at 2 7 up years Mothers **

Breast cancer 4 Benign tumours 10

Daughters *** Benign tumours 2 Infertility 2 average No. of children 1.15

Sons *** Genitourinary infections 3 Unmarried 17

* Conference on Diabetes in Pregnancy [18]. ** Beral and Colwell [4].

*** Beral and Colwell [S].

No. cases

13 1

6 7

11 0

1 2

0 0 1.62

1 8

intensive neonatal care over an extended period [7]? These questions are important not because it is probable that dramatic adverse consequences will affect a high proportion of those exposed, but because such large numbers of individuals are being exposed that even if the risk of important adverse outcomes is increased only slightly, the absolute number of people affected may be considerable.

In non-randomized treatment comparisons, it is difficult to control for confound- ing factors even if a wealth of descriptive data is available for attempting to adjust statistically for differences in pre-treatment risks. This problem is nowhere more elegantly illustrated than in a randomized, placebo-controlled trial to assess the effect of a cholesterol-lowering drug on fatal myocardial reinfarction rates [20]. Men offered the active preparation had a similar 5-year mortality to those offered the placebo. However, within the placebo group the men who complied with instructions to take their pills had considerably lower mortality rates than non-compliers! When the predictive power of this risk factor-compliance-was compared with that of 40 other ‘previously known’ risk factors for early reinfarction, the relatively weak explanatory power of the known risk factors was demonstrated. It seems very likely that our own attempts to use classic perinatal risk factors (birthweight and gesta- tional age, for example) to achieve statistical control of selection bias in non-rando- mized treatment comparisons must also sometimes fail to achieve the control of bias required. As Percy Malpas, a British obstetrician, noted 30 years ago, “the object of all clinical investigations should be so to understand the conditions of each enquiry as to reduce the need for statistical control to a minimum” [35]. Randomization overcomes these difficulties by controlling for both known and unknown risk factors.

Reducing imprecision in comparisons of alternative treatments

The fact that researchers in the perinatal field employ randomization relatively rarely to control for selection biases in comparing alternative treatments does not mean that they are unfamiliar with its methodological advantages compared with statistical manipulation of observational da&: the Register of Controlled Trials in Perinatal Medicine set up by the National Perinatal Epidemiology Unit [28] contains references to nearly 3,000 reports of controlled trials. Although some exemplary treatment evaluations are included in this total, however, many of the trials suffer from gross methodological weaknesses. In particular, the small sample sizes studied have resulted in estimates of treatment differences which, although unbiassed, are imprecise [77].

As Table III shows, there are two important consequences of conducting trials that are too small. Firstly, real and clinically significant differences between treat- ments may be incorrectly dismissed because they fail to achieve statistical signifi- cance. Secondly, if statistically significant differences are observed, these will tend to result in an overestimate of true differences. The confusion which can be created by such imprecision can be illustrated using the trials which have been mounted in an attempt to assess the role of phenobarbitone in preventing periventricular haemorr-

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TABLE III

Two ways in which small trials can give misleading results

If, in rruth, adverse outcome occurs in 50% of cases who received treatment A and 40% of cases who received treatment B, then a trial with 400 in each group should give:

A 200 B 160 P -=z 0.01

and a trial with 40 in each group should give: A 20 B 16 P N.S.

Conchmion 1. True differences tend to be ascribed to chance in small trials.

But, in practice, clinical trials comparing treatments A and B give estimates of the true difference in adverse outcome following the two treatments. Thus, trials with 400 in each group may yield:

A 190 195 200 210 220 B 170 165 160 150 140 P N.S. < 0.05 < 0.01 < 0.001 < 0.001

and trials with 40 in each g&p may yield: A 19 20 21 22 23 24 B 17 16 15 14 13 12 P N.S. N.S. N.S. N.S. < 0.05 -c 0.05

Conclusion 2. Statistically significant differences observed in small trials tend to overestimate true differences.

hage. In view of the small size of the four trials reported so far [3,19,27,73), it is not surprising that the play of chance has led investigators to arrive at different conclusions about the value of phenobarbitone. Whitelaw and his colleagues [74], however, made the important observation that in every study so far reported there have been fewer parenchymal haemorrhages among phenobarbitone-treated infants than among controls. The data to which this statement refers are presented in Table IV.

The summary relative risk of parenchymal haemorrhage in babies given pheno- barbitone (0.36) using data from all four trials suggests that the incidence of this most serious form of periventricular haemorrhage may be substantially reduced by

TABLE IV

Distribution of 21 cases of parenchymal haemorrhage in four trials mounted to evaluate the role of phenobarbitone in preventing intraventricular haemorrhage

Phenobarbitone Control

Goldstein et al. [27] 2/58 3/64 Cooke et al [19] 4/30 8/30 Bedard et al. [3] o/21 2/21 Whitelaw et al. [73] o/30 2/30

Summary relative risk (and 95% confidence limits) of parenchymal haemorrhage after phenobarbitone = 0.36 (0.12-1.09).

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prophylactic phenobarbitone [14]. This important possibility can only be addressed satisfactorily by mounting larger trials to reduce the imprecision of current estimates of these and other treatment differences.

The need for multicentre collaboration

We must stress again that much reliable knowledge has come, and will continue to come from basic research and from uncontrolled clinical observations. But it is only when the difference between one treatment and another is large that it may be reasonable to disregard the moderate biases that may be engendered by non-rando- mized comparisons. When, as is often the case, the effects of treatment are likely to be either moderate but worthwhile, or negligibly small and not worthwhile, reliable distinction between “moderate” and “negligible” effects implies reliable avoidance of both moderate biases and moderate random errors. It is in these commonly encountered circumstances that randomized comparisons using large samples are required.

There are important practical implications of these considerations. Individual centres may well be able to mount trials large enough to detect treatment effects on some of the intermediate outcome measures to which we have referred earlier. But there is often no hope of a centre which has decided to ‘go it alone’ accumulating in a reasonable time period sufficient cases to compare treatment effects on outcomes of unambiguous importance. Quite simply, if we wish to obtain unbiassed and precise estimates of treatment differences in terms of outcomes such as death and severe disability then randomized trials must be mounted on a collaborative, multicentre basis.

As other perinatal research workers have already pointed out [42], multicentre collaboration will only be achieved if independent investigators show a greater willingness to share their data and the other rewards of their efforts. The dividends which have resulted from the emergence of just such a spirit of collaboration within cardiovascular research over the past decade give some feeling for the benefits which might flow from fostering a similar spirit within perinatal research. But such collaboration requires a fairly radical change in the way that credit is accorded to individual researchers and the clinical departments in which they work. A competi- tive spirit fuelled by the value our society places on individualism has no doubt played its part in generating good perinatal research. But it has also resulted in a plethora of uninterpretable observations resulting from poorly designed research based on samples of inadequate size. If perinatal research is to develop in the same direction as research in the cardiovascular and cancer fields, then collaboration in well-designed multicentre trials is required.

There are undoubted difficulties confronting those who wish to foster multicentre collaboration. Credit for the success of a multicentre trial is shared by large numbers of people who must often remain relatively anonymous. Although group authorship is often the most equitable basis for dealing with the complex question of authorship credits in the published reports of multicentre trials, for example, it can undoubtedly

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pose problems both for individuals who may need a publication record for subse- quent promotion and for collaborating institutions which, for a variety of reasons, may need to be seen to be actively engaged in their own research. This problem can be and has been minimized in trials such as the Coronary Drug Project and the Diabetic Retinopathy Study which have used an approach involving the conduct of ancillary studies and both group and individual authorship depending on the type of paper involved [41]. In addition, however, wholehearted collaboration in important multicentre trials must become a criterion by which individuals and institutions which have contributed to the success of the trial should be credited by the research community and others.

Even with extensive multicentre collaboration, it will be impossible to assemble samples of sufficient size to achieve acceptable precision in estimating some of the effects of some perinatal practices. But there are many instances in which multi- centre collaboration could result in scientifically more rigorous evaluation of peri- natal practice than is usual at present. This fact is not lost on the consumers of research results. Clinicians, patients and others involved in decisions about health services have been warned to demand evidence from controlled trials. We would predict that there is likely to be growing impatience with a research establishment which appears to ignore the need to raise the standards of clinical research and the evidence on which clinical practice is based. For example, it is now more than 4 years since the first neonate was entered into the first trial mounted to assess the effect of phenobarbitone on the incidence of periventricular haemorrhage. This treatment may have both short-term [73] and long term adverse effects [25,29,30], but it may also reduce the risk of the devastating handicaps which are sometimes associated with being born pre-term. The anxiety and confusion caused by the conflicting results of trials using small sample sizes are adverse effects of inadequate research design with which the research community must become increasingly concerned.

Science and clinical research

“The idea that clinical medicine has no intellectual content, with nothing worthy of science, nothing that can be considered a research challenge, is what has kept the state of clinical practice in its current state of intellectual decrepitude and servitude” [26].

Clinical research in the perinatal field, like clinical research in general, is a victim of what Silverman [60] has called “ the divisive effect of reductionist snobbery”. The reductionist, Silverman observes, when faced with Newton’s problem to discover the source of gravity, cuts open the apple and looks inside. This approach to complex problems can undoubtedly be a powerful strategy; but in the perinatal field and more generally it is too often seen as the be-all and end-all of research. If perinatal researchers are to persuade outside observers that they are taking seriously the important practical objectives we outlined earlier, then research at subcellular, clinical and social levels must be more equally valued. The inequitable distribution of research funds between these different levels of investigation is an eloquent

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reflection of the inflated reverence with which the reductionist approach is regarded. We do not propose this shift of emphasis solely because we feel that researchers

should be concerned to address the practical questions facing clinicians. We also believe that there too often seems to be an assumption that better understanding of biological and pathological mechanisms will come exclusively from research pursued within a reductionist framework. Important insights into those mechanisms can and do arise from observations made in clinical trials. The observation that aspirin prevented stroke more effectively in men than in women experiencing transient ischaemic attacks [ll], for example, provided the foundation for subsequent labora- tory research related to the possible mode of action of aspirin [6.5]. The sex-related differences observed in the clinical trial were confirmed by thrombosis experiments performed in rabbits [32] and pharmacokinetic studies done in rabbits and man [lo], although subsequent trials in humans suggest that any difference is not as large as originally suggested.

Clinical studies to assess the effects of diethylstilboestrol administration during pregnancy illustrate the scope for a more imaginative view of the role of clinical research in unravelling basic biological mechanisms. Case-control studies of vaginal adenocarcinoma provided the first evidence that transplacental carcinogenesis was occurring in human beings. Data derived from follow-up of the cases entered into placebo-controlled trials have provided evidence of more subtle effects (morphologi- cal, functional and behavioural) which are of relevance to a better understanding of the biology of human development.

We believe that researchers have underestimated the role which pragmatic clinical trials could play in elucidating pathological mechanisms. To take one example, an association between maternal cigarette smoking and low birthweight was observed nearly 30 years ago [61]. Since then vast amounts of effort and resources have been directed at trying to tease out the effects of smoking during pregnancy by mounting and analysing observational studies. Not surprisingly, given the nature of the data, there has been disagreement about the meaning of the associations which have been observed. It was not until 20 years after the original observation that the hypothesis it generated was tested in an experiment mounted to assess the effects of anti-smok- ing advice in pregnancy [24]. At a purely pragmatic level such trials are important to assess whether or not anti-smoking advice given to women during pregnancy is effective in persuading them to give up cigarettes. At a more fundamental level, however, it is obviously important to know what impact smoking withdrawal before and at different times during pregnancy has on the fetal outcomes which we are concerned to influence. Just as clinical trials of breast cancer therapy have provided important insights into the pathology of that disease, so also are smoking withdrawal trials [57] beginning to throw light on the nature of the associations which have been so extensively documented between smoking in pregnancy and a variety of adverse outcomes.

The selection of independent and dependent variables in perinatal research also reflects the perspective from which researchers view their work. From a medical perspective, for example, we are used to measuring the outcome of clinical interven- tion in terms of death and acute or long-term morbidity. The effects of medical

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practice, however, can be viewed from perspectives other than a purely medical one. Users of the maternity and child health services, for example, have given important expression to their concerns about the possible social consequences of current perinatal practices. Not only should research workers incorporate social outcomes into evaluative research in the perinatal field [47], but they should exploit opportuni- ties to contribute to the small but suggestive body of research evidence concerning the effects of social intervention on biological outcomes [48].

Another non-medical but increasingly important perspective is that funds for health care are limited and those responsible for budgets are looking for cost-effective treatments. This perspective has led to formal attempts at economic evaluation of programmes aimed at treatment and prevention of myocardial infarction [21], oestrogen use in postmenopausal women [71], management of hypertension [64], and chronic renal failure. Recently, the approach has also been applied in the evaluation of neonatal intensive care of very low birthweight babies [9]. A variety of techniques of economic evaluation have been used, including cost-effectiveness analysis, cost- utility analysis, and cost-benefit analysis [62]. Cost-utility analysis, for example, involves determining patients’ or society’s preference for different health states. For example, randomly sampled parents of children of school age were asked to declare their preference for various health states in childhood: not surprisingly perhaps, parents rated some chronic dysfunctional states as worse than death [67]. Thus a perinatal programme that increases survival rate but also increases the rate of survival of handicapped individuals may be judged using cost-utility analysis to have had a negative impact. All these techniques of social and economic evaluation require a comparison of one programme (or manoeuvre) with another, and so are appropriate as outcome measures in randomized controlled trials. Furthermore, as long as the results are presented in sufficient detail, readers who would prefer a different set of costs to be associated with the various possible outcomes can determine whether their conclusions would have been different.

Research funding agencies and collaborative perinatal trials

Whatever the focus of the outcome measures used in perinatal research, little research effort is currently invested in statistically powerful clinical trials mounted to evaluate perinatal practices. This may be partly because such research can rarely be planned and implemented within a single centre. The practicalities of generating proposals for research with a reductionist emphasis present fewer problems to applicants than those for multicentre trials which, as with the Cervical Cerclage Trial mounted under the joint auspices of the British Medical Research Council and the Royal College of Obstetricians and Gynaecologists, may involve as many as 150 collaborating obstetricians. Within perinatal medicine, no body exists comparable to, for example, the Co-ordinating Committee on Cancer Research or the Intema- tional Committee on Thrombosis and Haemostasis. Perhaps a change of emphasis within perinatal research must await the formation of an equivalent grouping by those who believe that collaborative perinatal trials can help perinatal practice to

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become more firmly guided by the results of scientific research. Quite apart from the fact that there is no such professional grouping within

perinatal medicine, there is currently no framework or established mechanism for mounting collaborative trials of perinatal practice comparable to the arrangements which exist in the cancer and cardiovascular fields. This reflects the confusion which often seems to exist concerning which of the research funding agencies should be regarded as responsible for fostering collaborative trials. One possible explanation for this confusion is the often artificial distinction which has been drawn between ‘biomedical’ and ‘health services’ research. There would seem to us to be persuasive reasons for regarding controlled trials of clinical practices as essential elements of health services research, and indeed the British Medical Research Council has argued that trials should be viewed in this way [38].

Of the public agencies within Britain it is the Department of Health and Social Security (DHSS) that is primarily responsible for commissioning ‘health services research’. Although some proposals for controlled trials of perinatal practices have arisen within the DHSS during recent years, however, at least five of these have been referred to the Medical Research Council because they were deemed to fall within the ‘biomedical’ sphere. Unlike the DHSS, the British MRC, although it suggests that randomized controlled trials should be seen as health services research, does not generally see it as its role to take active ‘commissioning initiatives in trials in perinatal care. Asked by the Chairman of the Social Services Committee whether it was part of the Council’s function to stimulate research in the perinatal field, a British MRC witness answered that the current policy was “to wait for applications to come in and judge whether they are scientifically excellent and whether the group proposing them are of good quality” [37]. The new director of the U.S. National Institutes of Health appears to take a similar, though less extreme view [74].

The delays which result from the sort of confusion described above can be, and have been crucial in determining the ultimate fate of proposals for important controlled trials. Because perinatal researchers cannot look to charitable bodies for funding on the scale provided for their colleagues working in some other fields of research [56], the lack of a coherent strategy for using public funds to promote controlled trials is particularly serious. Success in mounting collaborative trials often seems to depend on the efficiency with which researchers and funding agencies respond to opportunilies created by clinical or public interest in a particular subject at a particular moment in time [34]. If these opportunities are not grasped imagina- tively and effectively, the chances of reliable evaluation may be lost indefinitely.

The Canadian MRC, in a statement of its policy towards clinical trials in general [39], has recognized the need for flexibility in its methods for considering applica- tions for trials. In practice this flexibility has meant a greater interaction between the Council and applicants. This offers opportunities to improve the initial protocol, if necessary by using Council funds for planning complex trials, including convening meetings of prospective participants. These principles have led the Canadian MRC to take important initiatives in fostering trials in the perinatal field and it has established a ‘Committee for Promotion of Clinical Trials in Perinatology’ [40]. Whether this mechanism will lead to more collaborative trials in the perinatal field

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in Canada than in Britain and the United States remains to be seen. But there can be no doubt that there is considerable scope for reducing the inefficiency with which proposals for multicentre trials are currently handled.

Not only are proposals for multicentre trials subject to the delays inherent in any large bureaucracy, however, they often have to run the gauntlet of an assessment process dominated by referees who may have little or no practical experience of mounting such studies themselves and scant sympathy for research which lacks any overt reductionist component. One view of the response of the British MRC to an opportunity to mount a randomized trial to assess the efficacy and safety of ultrasound in pregnancy when this technology was being introduced into obstetric practice in the early 1970’s is illustrative [43]. Although some clinicians had reservations about withholding the postulated benefits of ultrasound from controls, a pilot study demonstrated that a randomized clinical trial would be feasible. When, 3 years after discussions had been initiated, the proposal for the main study was considered by the MRC’s Cell Board it was opposition from laboratory scientists, not clinicians, which led to its rejection. This seems to have dealt a double blow: if a British trial had been mounted successfully it seemed likely at the time that this example would have been followed in North America [43].

A decade after this initiative for a randomized trial of ultrasound in pregnancy was nipped in the bud in this way, we are beginning to regret our ignorance about both the extent to which the postulated benefits of ultrasound examination during pregnancy in fact exist, and what hazards, however rare, may be associated with its current use in millions of pregnancies every year. Biological effects of ultrasound may include reduction in immune response, change in sister chromatid exchange frequencies, cell death, change in cell membrane functions, degradation of macro- molecules, free radical formation and reduced cell potential [46]. The relevance of these observations to the use of ultrasound in obstetrics is unknown, but as a recent consensus statement by the National Institutes of Health observes, “long-term follow-up of infants involved in a randomized trial would help clarify questions about the effects of ultrasound on development in humans” [46]. Had the proposal put to the British MRC a decade ago not been a victim of an assessment process dominated by individuals with no experience of or sympathy for multicentre trials, not only would there be better information on the efficacy of obstetric ultrasound, but two large randomized cohorts of lo-year-old children with contrasting exposure to ultrasound during fetal life would now be available for both testing and generating specific hypotheses about possible adverse effects. It is particularly sad that this opportunity was not grasped by the MRC in the light of its record of imaginative handling of research related to diethylstilboestrol use in pregnancy: within 12 months of a meeting convened by the MRC at which the need for a randomized trial had been acknowledged, several centres were entering cases into a collaborative experiment, and these have been profitably studied again 30 years after recruitment [4,5]. It is often not easy to understand the variations in funding agency responses to proposals for collaborative perinatal .trials which, to all appearances, are of comparable scientific merit. This difficulty can be addressed (and has been in some places) by encouraging a more open approach to the assessment process.

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Three recent developments illustrate the scope which exists for imaginative initiatives by the research community and the charitable and public institutions to which they look for assistance in promoting research to evaluate the efficacy and safety of clinical practices. Firstly, the formation, in 1978, of the Society for Clinical Trials in North America and the International Society for Clinical Biostatistics in Europe, and the subsequent publication of quarterly journals under the auspices of each (Controlled Clinical Trials and Statistics in Medicine respectively), have promo- ted methodological research with an emphasis on the design, organization, operation and analysis of large randomized controlled trials. These issues are rarely addressed at medical meetings or in medical periodicals, even in reports of trials. The creation of an accessible literature on these subjects should help to promote the development of sound principles and practices in mounting multicentre randomized trials.

Secondly, it is being increasingly acknowledged that there is a need for ‘data centres’ staffed by individuals whose main skills lie in the efficient design, manage- ment and analysis of multicentre trials. These centres require funding in their own right and should not be dependent on funds tied to specific research projects. Indeed, unless the resource which such centres represents becomes more widely available to clinical researchers, opportunities to mount large collaborative trials will continue to be lost forever because of organizational inertia and inefficiency. The Cancer Research Campaign, for example, has funded a Clinical Trials Centre which houses the basic facilities for the organization of large-scale prospective clinical trials in cancer [56]. The centre provides both office space and expertise where such trials can be run efficiently. Although each project is responsible for providing its own funding to cover the salaries of a co-ordinator and secretary together with essential office equipment and running expenses, the Cancer Research Campaign, in addition to providing the physical facilities, has also funded three permanent members of staff who can give advice on the initial setting up of studies and train those appointed to administer them. The scope for cost-effective management of large collaborative randomized trials is also well-exemplified by the Clinical Trials Service Unit in Oxford [76]. A staff of eight, half of which is clerical/administrative, provides a central randomization facility and data entry, management and analysis service for over 20 different trials at any one time. This level of activity can only be sustained if trial protocols are kept simple and this emphasis is much to the advantage of all concerned. If treatments are to be widely practicable, then simple treatment protocols are possible; if they are to be evaluated in terms of major end points, then simple follow-up protocols are also possible.

A third example of initiatives which will foster multicentre collaboration in clinical trials concerns the creation of trial registers. The British Medical Research Council, for example, has agreed to support a U.K. Cancer Trials Register set up under the aegis of the Co-ordinating Committee on Cancer Research and the British Association of Surgical Oncology [69]. The Register has been established to provide up-to-date and readily accessible information for clinicians and others involved in running trials, and it is hoped that it will reduce the number of small, unproductive studies and any unnecessary duplication of trial protocols. Similar initiatives with similar objectives have been taken in other fields. For nearly 10 years, the Registry

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of the International Committee on Thrombosis and Haemostasis has listed ongoing trials that evaluate the clinical efficacy of anticoagulants, defibrinating agents, thrombolytic agents, inhibitors of the fibrinolytic system, substances inhibiting certain platelet functions and systematic haemostatic agents [70]. The National Perinatal Epidemiology Unit’s Register of Controlled Trials in Perinatal Medicine [28], which is supported by the World Health Organization, is also moving in this direction. It is to be expanded to include unpublished and ongoing trials as well as references to published reports as at present.

Scientific journal editors and the quality of clinical research

If the quality of controlled trials in perinatal medicine is to improve, we believe that the editors of scientific journals must impose more stringent requirements on those who conduct and report research in the perinatal field. We agree with Spodick’s view [63] that the onus of ensuring appropriate design of clinical trials should be on the editors of scientific journals-both because others in authority are not insisting on it, and because publication is virtually always necessary for investigators to thrive. Unfortunately, although details of appropriate scientific standards for reports of evaluative research have been proposed [16,22,45,77], it is clear that some editors remain far from persuaded that there is anything to be worried about. The editors of one of the obstetric journals evaluated by Tyson and his colleagues [68], for example, were obviously offended by the aspersions cast on the scientific integrity of their organ. Without either the permission or knowledge of the authors they republished Tyson’s article, attacked it in an editorial [52] and limited the right of reply of both the authors and others.

Although this example of editorial reaction to criticism is, as far as we know, exceptional, we would single out one other editorial practice which we believe to be misguided. This concerns the double standard operated in respect of reports of ‘negative’ and ‘positive’ results: as the British Medical Journal put it, ‘negative results have never made riveting reading’ [S]. The ,Archives of Disease in Childhood, for example, in its instructions to authors, offers only 400 words to those who wish to report the results of ‘negative’ trials. The concept of a ‘negative’ trial is misconceived. It refers to studies in which statistically significant differences have not been demonstrated. This should not be the basis on which to reject trials any more than the demonstration of statistically significant differences should be a reason for accepting them. What editors should be concerned about is the statistical power of the studies submitted to them and whether the authors have calculated and discussed the implications of the confidence limits surrounding their estimates of treatment differences. Small trials which suggest beneficial effects of an innovative treatment are almost certainly more likely to reach publication than trials in which no statistically significant differences have been demonstrated. The influence of this probable selection bias in determining the overall content of the scientific literature is that important information may remain inaccessible. As Table III demonstrates, it will encourage a tendency to overestimate the real differences between treatments

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because of selective publication of those in which the differences observed are statistically significant.

The central role of clinicians in promoting better clinical research

Finally, what part should clinicians - whether they regard themselves as re- searchers or not - play in seeking better evidence upon which to base perinatal practice? The double standard by which haphazard variations in practice and informal treatment comparisons are accepted and systematic variations in practice and formal treatment comparisons are resisted needs exposure and discussion [12]. Stressing the importance of a step-by-step approach to advancing the knowledge of breast cancer, for example, a surgeon has remarked that “a large number of doctors have the naive idea that progress in treatment is made by a series of major breakthroughs and that they merely have to stand on the sidelines applauding the breakthroughs, which are then adopted as standard practice”. He suggests that “ this attitude is parasitic” and that “it is the responsibility of all clinicians treating patients to participate in clinical trials when the opportunity presents” [12].

As we indicated at the outset of this paper, however, clinicians find randomiza- tion threatening [59]. There is a peace of mind which comes from being certain that the treatment one offers to one’s patient is the best available. Even if one can admit to oneself that it is not known which treatment is best, deciding clinical management ‘by the toss of a coin’, let alone admitting to the patient that that is what is happening, runs counter to the authoritarian atmosphere in which most doctors have been trained. As Claude Bernard suggested more than a century ago, “Many physicians attack experimentation, believing that medicine should be a science of observation”. “But”, he pointed out, “physicians make therapeutic experiments daily on their patients so this inconsistency cannot stand careful thought. Medicine by its nature is an experimental science, but it must apply the experimental method systematically” [6].

More than 60 years ago the need for collaborative experiments was recognized in our own field by the President of the American Gynecology Society. He said this:

“We should take stock of unnecessary operating. Such stock-taking should begin with our own clinics, for the least excusable of unnecessary suffering is that on women-and particularly mothers of young children.. what serious study has ever been made beating upon the harm or harmlessness of the variety of procedures, or concerning the failure or effectiveness of each? To achieve this there is a need for collective experimentation since no man is likely to have a large experience” [23].

During the years since Dr. Dickinson made his perceptive remarks there have been repeated calls for application of the risk-minimizing research strategy of randomized controlled trials in perinatal medicine [13,17,36,53]. Today, the calls are increasingly coming from outside our specialty and from outside the medical profession [49]. Controlled trials are not the be-all and end-all of perinatal research any more than is any other methodological framework. But the strengths and limitations of collaborative controlled trials in providing evidence with which to guide practice cannot be identified clearly without greater experience than currently

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exists in trying to mount these studies. We believe that it is time that perinatologists and the organizations responsible for fostering clinical research stopped complaining about difficulties which have been confronted successfully by research workers in other fields and faced up to these challenges more squarely than they have done so far.

Acknowledgements

An earlier draft of this paper was discussed at a Symposium on the Effects of Perinatal Care on Mortality, Morbidity and Handicap held in Bristol, U.K. during the Spring of 1982. We wish to thank the National Birthday Trust Fund and the Department of Health and Social Security for sponsoring this symposium: it provided an important opportunity to exchange views on the subject we have discussed in this paper and many other issues of current interest in the perinatal field. In addition, we are grateful to the many individuals who have commented on previous drafts of the manuscript, and to Lesley Mierh and Jini Hetherington who have typed them. Iain Chalmers is supported by a grant from the Department of Health and Social Security.

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