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SYMPOSIUM: EVIDENCE-BASED REPRODUCTIVE MEDICINE| Volume 26, ISSUE 3, P201-209, March 2013

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The early history of evidence-based reproductive medicine

Published:November 30, 2012DOI:https://doi.org/10.1016/j.rbmo.2012.11.010

      Abstract

      The origins of evidence-based medicine as understood today are traceable to 1972 and the publication of Archie Cochrane’s book Effectiveness and Efficiency: Random Reflections on Health Services. This book attempted to bridge the divide between scientific medicine and clinical judgment that had developed since the mid-19th century. Its genesis was stimulated by Cochrane’s experiences as a prisoner-of-war medical officer and of the demands placed after the 1939–1945 war on the UK National Health Service. In the 1960s, reproductive medicine was considered by the UK Medical Research Council to be relatively ‘unscientific’ in its approach to care delivery and was described as such by Cochrane in the 1970s. Evidence is presented here that reproductive medicine responded, becoming by 1989 a pioneering clinical discipline in the application of evidence to practice. This was achieved largely through the efforts of Iain Chalmers, who was a key player in the development of the systematic review and in the foundation of the Cochrane collection.
      Evidence-based medicine is considered as being the gold standard, combining the best available objective evidence with the individual skills and experience of the doctor attentive to the specific needs and cultural beliefs of each patient. This paper traces the origins of evidence-based medicine as understood today back to 1972 and the publication by Archie Cochrane of his book Effectiveness and Efficiency: Random Reflections on Health Services. This book attempted to bridge the divide between scientific medicine and clinical judgment that had developed since the mid-19th century. Its genesis was stimulated by Cochrane’s personal experiences as a prisoner-of-war medical officer and of the demands placed after the 1939–1945 war on the UK National Health Service. In the 1960s, reproductive medicine was considered by the UK Medical Research Council to be relatively ‘unscientific’ in its approach to care delivery and was described as such by Cochrane in the 1970s. Evidence is presented that reproductive medicine responded by becoming by 1989 a pioneering clinical discipline in the application of evidence to medical practice.

      Keywords

      Introduction

      Humans have used evidence to guide their decisions and actions since the beginnings of historical record keeping; indeed, the capacity to imply cause and effect from observation is integral to our understanding of what it is to be human. However, it is how we understand and interpret what constitutes reliable evidence that varies with circumstance and culture. Thus, in contemporary societies, evidence is used on a daily basis from a mix of revelatory, experiential, emotional, rational and scientific sources (
      • Barry C.A.
      The role of evidence in alternative medicine: contrasting biomedical and anthropological approaches.
      ,
      • Kaptchuk T.J.
      • Kerr C.E.
      Commentary: unbiased divination, unbiased evidence, and the patulin clinical trial.
      ). Each of these sources has validity to the person who is using them to fashion explanations, and so, regardless of whether that person is a patient or a doctor, all sources must be taken into account in any medical decision making (

      RCOG, 2011. How Evidence Can Influence Clinical Practice. Scientific Advisory Committee Opinion Paper 28, Royal College of Obstetricians and Gynaecologists, London.

      ). So where and when in this evidential melange did evidence-based medicine (EBM) appear and how has it developed in respect of reproductive medicine in particular?
      A tension between the relative value of clinical judgment and the scientific method has been a feature of Western medicine since the mid-to-late 19th century and the rise of the laboratory medical sciences with their emphasis on the experimental and ‘objective’ acquisition of ‘facts’ as evidence (
      • Bernard C.
      An Introduction to the Study of Experimental Medicine.
      ,
      • Porter T.M.
      Trust in Numbers: The Pursuit of Objectivity in Science and Public Life.
      ), which became embedded in the education of 20th-century US medical students as a result of the Flexner Report (
      • Flexner A.
      Medical education in the United States and Canada.
      ). Since these early attempts to free the practice of medicine from, at best, irrational beliefs and, at worst, quackery, this tension has tended to polarize the medical community. Academic medicine drove this notion of scientific medicine against the grain of medical practitioners who brought to their ‘art’ an authority of clinical judgment based on experience that was transmitted via apprentice-like training to the next generation (see
      • Strathern M.
      Afterword: accountability … and ethnography.
      , for discussion of similar tensions within academic life). The practitioner is focused on case-based clinical practice as set against the traditionally population-based nature of research evidence: a tension that may be easing in prospect through research evidence that facilitates ‘tailored’ treatment. Historically, the problem from the perspective of academic medicine has been how to convince medical practitioners to be more scientific in their approach, whilst practitioners viewed these attempts as incursions on their professional freedom of action and judgment.
      Evidence-based medicine aspires to resolve this tension.
      • Sackett D.L.
      • Rosenberg W.M.C.
      • Gray J.A.M.
      • Haynes R.B.
      • Richardson W.S.
      Evidence based medicine: what it is and what it isn’t.
      defined EBM as:… the conscientious, explicit, and judicious use of current best evidence in making decisions about the care of individual patients. The practice of evidence based medicine means integrating individual clinical expertise with the best available external clinical evidence from systematic research (our emphasis).
      They then go on to define the two pillars of EBM:By individual clinical expertise we mean the proficiency and judgment that individual clinicians acquire through clinical experience and clinical practice. Increased expertise is reflected in many ways, but especially in more effective and efficient diagnosis and in the more thoughtful identification and compassionate use of individual patients’ predicaments, rights, and preferences in making clinical decisions about their care.By best available external clinical evidence we mean clinically relevant research, often from the basic sciences of medicine, but especially from patient centred clinical research into the accuracy and precision of diagnostic tests (including the clinical examination), the power of prognostic markers, and the efficacy and safety of therapeutic, rehabilitative, and preventive regimens. External clinical evidence both invalidates previously accepted diagnostic tests and treatments and replaces them with new ones that are more powerful, more accurate, more efficacious, and safer.Good doctors use both individual clinical expertise and the best available external evidence, and neither alone is enough. Without clinical expertise, practice risks becoming tyrannised by evidence, for even excellent external evidence may be inapplicable to or inappropriate for an individual patient. Without current best evidence, practice risks becoming rapidly out of date, to the detriment of patients.
      However, whether EBM does resolve this tension, or simply rewords the problem generating it, remains the subject of intense debate (see, for example, critical responses to the
      • Sackett D.L.
      • Rosenberg W.M.C.
      • Gray J.A.M.
      • Haynes R.B.
      • Richardson W.S.
      Evidence based medicine: what it is and what it isn’t.
      paper at www.bmj.com/content/312/7023/71?tab=responses). In this paper, I first seek to establish the origins of EBM and of the randomized controlled trial (RCT) that conventionally occupies its evidential apex. I then look at the early application of EBM to reproductive medicine and record the general perception of its inadequacy and the putative role that ethical concerns had in generating this perception. Finally, I report the work, largely driven by Chalmers, in pioneering the application of EBM to reproductive medicine to propel it to the forefront of evidence-based clinical research.

      The birth of evidence-based medicine

      The birth of EBM as we understand it today is conventionally dated to 1972 (see, for example,
      • Enkin M.W.
      Systematic summaries and dissemination of evidence: the Cochrane Pregnancy and Childbirth Database.
      ) and the publication by Archie Cochrane (1909–1988) of his book Effectiveness and Efficiency: Random Reflections on Health Services (
      • Cochrane A.L.
      Effectiveness and Efficiency: Random Reflections on Health Services.
      ). Cochrane studied natural sciences at Cambridge University, followed by research for an uncompleted PhD at the Cambridge Physiological and Strangeways Laboratories studying tissue culture under Nevill Willmer (1902–2001;

      Obit, 2001. Professor Nevill Willmer. The Times (London), April 23rd.

      ), before training medically from 1934 to 1938 at University College Hospital, London. His period of clinical study was interrupted by a year’s volunteered service in the Spanish Medical Aid Committee’s Field Ambulance Unit in the Spanish civil war. This experience proved to be useful when, after a year as a house physician in London, he served from 1939 in the Royal Army Medical Corps, first in Egypt, then in Crete, where he was taken prisoner on 1 June 1941. There then followed 4 years as a prisoner-of-war medical officer in camps in Greece and Germany. He later described how his war experiences led him to acknowledge his ignorance and his need to have more objective knowledge:What I decided I could not continue doing was making decisions about intervening … when I had no idea whether I was doing more harm than good. I remember reading a pamphlet (I think from the BMA) extolling the advantages of the freedom of British doctors to do whatever they thought was best for their patients. … I would willingly have sacrificed all my medical freedom for some evidence … (
      • Cochrane A.L.
      • Blythe M.
      One Man’s Medicine.
      , pp.83–84).
      In this regard, Cochrane felt he had not been helped by his education at University College, of which he wrote:… teaching about diagnosis, and particularly treatment, was extremely dogmatic … A few of us used to plague the clinicians by asking them about the evidence in support of the treatment they were giving. Usually we were fobbed off with ‘in my clinical experience …’. When two physicians defended two different and seemingly opposing treatments for the same condition we inevitably became cynical (
      • Cochrane A.L.
      • Blythe M.
      One Man’s Medicine.
      ).
      In his influential 1972 book, Cochrane uses an evaluation of the UK National Health Service (NHS) to develop his ideas about to how to assess whether a given clinical intervention (or more strictly healthcare intervention) produced a clinically effective, efficient and fair outcome. These three outcome criteria may be understood through the following questions. (i) Effectiveness: does the intervention do more good than harm, whether assessed by the mortality or by the physical, social and emotional wellbeing of those compliant with the intervention? (ii) Efficiency: does the intervention really do more good than harm to those to whom it is offered (as opposed to those who take up that offer – a measure of the compliance gap) and does making it available make the best use of resources? (iii) Fairness: is the intervention made accessible to everyone in the community who can benefit from it?
      Cochrane had been a dedicated supporter of the NHS ideal since the 1930s and was concerned that, by 1970 when the NHS had been operating for just 21 years, the resources allocated to it should be used well: ‘[the NHS] could be seen as giving a blank cheque both to the demands of the patients [for help] and the wishes of the doctors [to be helpful]’ (
      • Cochrane A.L.
      Effectiveness and Efficiency: Random Reflections on Health Services.
      , p.9). Thus, the state provision of care focused his general interest on how best to measure care outcomes for both the individual and society at large. In his analysis, Cochrane draws on various sources of evidence to construct his ‘evidence base’, but of particular significance for him then was the prospective randomized trial.

      The randomized trial

      Histories of the prospective randomized trial dispute the primacy of the large, blind, placebo-controlled and randomized clinical trial (
      • Chalmers I.
      • Clarke M.
      Commentary: The 1944 patulin trial: the first properly controlled multicentre trial conducted under the aegis of the British Medical Research Council.
      ), as distinct from the many preceding, smaller, non-randomized, non-blinded and/or non-controlled trials (
      • Meldrum M.L.
      A brief history of the randomized controlled trial. From oranges and lemons to the gold standard.
      ). Some advocate the 1948 test of streptomycin for treating pulmonary tuberculosis (
      • MRC
      Medical Research Council streptomycin in tuberculosis trials committee.
      ;
      • Anon
      Legumes, lemons and streptomycin: a short history of the clinical trial.
      ), others citing an earlier trial that demonstrated the lack of effect of patulin on the common cold (
      • MRC
      Medical Research Council clinical trial of patulin in the common cold.
      ). But what links both is the involvement of the UK Medical Research Council (MRC). There was at that time a widespread belief that streptomycin was effective in treating tuberculosis, but the stimulus for the UK trial came from both the cost and limited availability of the drug. Neither condition applied to the same extent in the USA where the drug was produced. There, conducting a placebo-controlled trial was perceived as being ‘unethical’ by many clinicians, leading to their subversion of early trial attempts and the abandoning of the placebo arm (
      • Marks H.M.
      The Progress of Experiment: Science and Therapeutic Reform in the United States, 1900–1980.
      –119). The involvement of the MRC and nascent NHS was a critical determinant of the UK trial’s success, both because of their organizational effectiveness and for the impact of their findings on medical practice in the NHS. Thus, although there had been episodic reports of ‘controlled trials’ over the preceding 200 years (
      • Meldrum M.L.
      A brief history of the randomized controlled trial. From oranges and lemons to the gold standard.
      ), the scale of the studies was often small and the quality variable, and doubtful physicians showed little inclination to learn from them, preferring recourse to their own clinical judgment. In the post-war UK climate of the emergent state-organized and -funded NHS, the profession was becoming more receptive (whether or not willingly) to the idea of trials, which could be carried out on a sufficiently large scale and any findings applied. Moreover, and as a result of international debates during the 1930s, the development of medical statistics, notably by RA Fisher (1890–1962;
      • Fisher Box J.
      R.A. Fisher: The Life of a Scientist.
      ,
      • Hacking I.
      Telepathy: origins of randomization in the design of experiments.
      ,
      • Savage L.J.
      On rereading R.A. Fisher.
      ), and its practical application to medical trials, notably by the influential A Bradford Hill (1897–1991;
      • Armitage P.
      Bradford Hill and the randomized control trial.
      ,
      • Himsworth H.
      Bradford Hill and statistics in medicine.
      : and with whom Cochrane had trained 1945–46), there was increasing agreement about what features made a good study and what might weaken its usefulness (for contemporary discussion of these issues, see also
      • Strathern M.
      Afterword: accountability … and ethnography.
      ). It was in this more sympathetic environment (
      • Kaptchuk T.J.
      • Kerr C.E.
      Commentary: unbiased divination, unbiased evidence, and the patulin clinical trial.
      ) that the streptomycin trial for tuberculosis was reported (
      • MRC
      Medical Research Council streptomycin in tuberculosis trials committee.
      ). This trial influenced strongly the design of a similar trial in the USA, initiated in 1947, also by a federal body, the Public Health Service (
      • Marks H.M.
      The Progress of Experiment: Science and Therapeutic Reform in the United States, 1900–1980.
      ), although it was probably the Salk polio vaccine trial in 1950s USA (
      • Francis Jr., T.
      • Korns R.F.
      • Voight R.B.
      • Boisen M.
      • Hemphill F.M.
      • Napier J.A.
      • Tolchinsky E.
      An evaluation of the 1954 poliomyelitis vaccine trials.
      ) that finally convinced the US medical profession at large of the potential value of randomized control trials.
      Until 1950, most of the medical profession was not attracted to any form of clinical experimentation that challenged the personal judgment of physicians or seemingly threatened to treat patients as less than unique individuals. ‘Science’ was thought best confined to the laboratory where variability could be contained and physicians were best suited to delicately apply this knowledge within the context of ‘the art of healing’ (
      • Kaptchuk T.J.
      • Kerr C.E.
      Commentary: unbiased divination, unbiased evidence, and the patulin clinical trial.
      ).
      Interestingly, the USA Federal Food and Drug Agency (FDA) was relatively slow to demand RCTs, only doing so in 1970 (

      FDA, 1970. Federal Register 35 (May 8), pp. 7250–7253.

      ), despite its powers being strengthened in 1938 (

      FD Act, 1938. Public Law 717. Federal Food and Drug Act 75th Congress, Washington, USA.

      ) and further in 1962 (

      FDA, 1962. Drug Amendment of 1962, section 102. 2 Public Law 87–781, October 10th.

      ). This lag was largely due to a legacy of legal, commercial and professional wrangling (
      • Marks H.M.
      The Progress of Experiment: Science and Therapeutic Reform in the United States, 1900–1980.
      ).
      In conclusion, although the RCT now has a recognized place in the constellation of evidence that makes up a systematic review, it is a fairly recent tool in the armoury.

      Cochrane’s larger view

      Cochrane’s approach to evidence was distinguished by the fact that, whilst he acknowledged enthusiastically the importance of objective population data from RCTs, he also realized that the realities of patient, doctor and institutional variability and individuality must be recognized and that the total impact of interventions on care outcomes should be assessed in relation to the input costs (
      • Cochrane A.L.
      • Blythe M.
      One Man’s Medicine.
      , writing about the mid 1960s; pp.208–2009). For example, again writing from notes made in the mid 1960s, Cochrane says:One day, though, I wrote down my plans for making a start. To show that it is ethically acceptable and practically possible to randomize place of treatment between hospital and home, outpatients clinic and home, and hospital and outpatients clinic, length of stay in hospital (
      • Cochrane A.L.
      • Blythe M.
      One Man’s Medicine.
      ).
      Cochrane was even then contemplating an expanded range of evidence base extending well beyond that for drug trials.
      Cochrane was not developing these ideas in isolation, however. For example, at the same time, others were advancing comparable revolutionary ideas in the context of medical education. Thus, in 1966, McMaster University (Canada) introduced problem-based learning (PBL) into its medical school curriculum (
      • Camp W.
      Problem-based learning: a paradigm shift or a passing fad?.
      ), followed soon thereafter by universities in Maastricht (Holland), Newcastle (Australia) and New Mexico (USA). The PBL approach included several features of the ideas being articulated by Cochrane – in particular the responsibility of the physician to be up to date and in a continuous state of professional enquiry and challenge, as well as an approach to the medical student as a well integrated ‘whole’ professional. It is not therefore surprising that some of the earliest practitioners of EBM research were at McMaster University (
      • Spitzer W.O.
      • Sackett D.L.
      • Sibley J.C.
      • Roberts R.S.
      • Gent M.
      • Kergin D.J.
      • Hackett B.C.
      • Olynich A.
      The Burlington randomized trial of the nurse practitioner.
      ,
      • Spitzer W.O.
      • Feinstein A.R.
      • Sackett D.L.
      What is a health care trial?.
      ,
      • Sackett D.L.
      Screening for early detection of disease: to what purpose?.
      ,
      • Sackett D.L.
      • Holland W.W.
      Controversy in the detection of disease.
      ). The PBL approach to medical education, although initially resisted and slow to spread, has become widespread since the 1990s and forms at least one element of teaching in most medical schools. It is probably not coincidental, therefore, that the spread of PBL within medical education appears to have accompanied the wider espousal of EBM by medical practitioners. Paradoxically, PBL has been attacked as underemphasizing the scientific aspects of medicine at the expense of training in the ‘arts’ of medicine (McDermott, cited in
      • Ludmerer K.M.
      Time to Heal: American Medical Education from the Turn of the Century to the Era of Managed Care.
      , pp.305–306), almost a reversal of the attacks on EBM (albeit usually as a surrogate for PCTs) as being too impersonal. Both attacks are rooted in the same long-standing conflict between science and clinical judgment.

      Evidence-based reproductive medicine

      In his 1972 book, Cochrane refers to reproductive medicine in several places. Thus, in a section headed ‘Preventative medicine’, he laments both the lack of NHS research on population control (pp.28 and 78) and the widespread adoption of cervical smear testing in the absence of any controlled studies to assess its effectiveness – described interestingly as not pursued because ‘it was not considered ethical’ (p.27), a theme to which he returned later (
      • Cochrane A.L.
      • Blythe M.
      One Man’s Medicine.
      ). Further on in his 1972 book (pp.63–66), he writes about the ethical difficulty of undertaking midwifery research and the sad misuse of what data there were by the

      Peel Committee, 1970. Domiciliary Midwifery and Maternal Bed Needs. Report of the Sub-committee to the Department of Health and Social Security (Welsh Office). HMSO, London.

      , which had reported on home versus hospital deliveries. In a later essay,
      • Cochrane A.L.
      1931–1971: a critical review with particular reference to the medical profession.
      again drew particular attention to the absence of an evidence base in obstetrics and gynaecology, which he characterized as deserving ‘the wooden spoon’ as being the least scientific and evaluative of medical specialities (p.11). A similar perception is revealed in the 1960s’ archives of the MRC and the Royal College of Obstetricians and Gynaecologists (RCOG) (

      Macafee, 1962–1967. Macafee Report, The Training of Obstetricians and Gynaecologists in Britain, and Matters Related Thereto. The Report of a Select Committee to the Council of the Royal College of Obstetricians and Gynaecologists. RCOG, London, UK.

      ).

      The MRC and reproductive medicine in the UK

      An MRC Office report to Council (
      • MRC
      Report to the Council dated July 1969. MRC Folder 7/912.
      ) refers to a report made by the Secretary of the MRC to the Annual Review meeting of Council in November 1968 lamenting the limited MRC support in UK university departments of obstetrics and gynaecology. The RCOG through its Macafee committee (

      Macafee, 1962–1967. Macafee Report, The Training of Obstetricians and Gynaecologists in Britain, and Matters Related Thereto. The Report of a Select Committee to the Council of the Royal College of Obstetricians and Gynaecologists. RCOG, London, UK.

      ) had identified similar issues. Several barriers to academic research were identified in both reports, but these reduced in essence to the absence of a research culture or mentality and to the dominant position accorded to clinical training and practice. This cultural problem was considered to be self-perpetuating, attracting less-able students due to a lack of intellectual challenge and work overload, with few academic posts available in the specialty. Possible areas ripe for research that were identified included fertility control, hormonal control of the female tract, toxaemia and the non-pathological physiology of pregnancy, neonate and fetus. The report (
      • MRC
      Report to the Council dated July 1969. MRC Folder 7/912.
      ) also identified, without specifying its nature, a problem of ‘ethical objections to studies on the pregnant woman … While some academic obstetricians appear to despair of solving this general problem, others consider it a challenge which can be overcome’.
      These perceptions about reproductive medicine carry an ironic twist in that Cambridge scientist FHA Marshall (1878–1949;
      • Parkes A.S.
      Francis Hugh Adam Marshall. 1878–1949.
      ), who in his book of 1910 (
      • Marshall F.H.A.
      The Physiology of Reproduction.
      ) is widely credited with founding the modern discipline of reproduction, had specifically stressed the integrated nature of medical, as well as agricultural and scientific, elements of reproduction, a view shared by his influential Cambridge predecessor and colleague, Walter Heape (1855–1928;
      • Biggers J.D.
      Walter Heape, FRS: a pioneer in reproductive biology. Centenary of his embryo transfer experiments.
      ). However, neither Marshall nor Heape were medically trained and their main legacy, together with that of fellow younger Cambridge scientist John Hammond (1889–1964;
      • Slater W.K.
      • Edwards J.
      John Hammond, 1889–1964.
      ), was the foundation of rich schools of agricultural and physiological (including biochemical) reproduction (
      • Clarke A.E.
      Reflections on the reproductive sciences in agriculture in the UK and US, ca. 1900–2000+.
      ). But their links with mainstream obstetrics and gynaecology were more episodic, tenuous and often determined by the interests of a limited range of physicians. That this was the case is in part due to the perceived dubious ‘morality’ of applying to humans much of the reproductive research being done on animals (
      • Clarke A.E.
      Disciplining Reproduction: Modernity, American Life Sciences, and ‘the Problems of Sex’.
      ,
      • Clarke A.E.
      Reflections on the reproductive sciences in agriculture in the UK and US, ca. 1900–2000+.
      ).
      The deficiency of good research in obstetrics and gynaecology was recorded as not being restricted to the UK, as a section of the MRC report on US historical comparisons suggested. These criticisms echo those made in 1914 by J Whitridge Williams, head of the Johns Hopkins School of Medicine (Baltimore), who is reported by
      • Clarke A.E.
      Reproductive science 1913–1971.
      as launching a scathing attack on the American Gynecological Society for its failure to produce fundamental contributions to obstetrics or biochemical aspects of pregnancy, but instead to concentrate on technical virtuosity at the expense of extending knowledge, a criticism he repeated in 1925.
      • Clarke A.E.
      Disciplining Reproduction: Modernity, American Life Sciences, and ‘the Problems of Sex’.
      ,
      • Clarke A.E.
      Reflections on the reproductive sciences in agriculture in the UK and US, ca. 1900–2000+.
      also recorded how, in the USA, the same moral doubts about studying human reproduction had hampered and restricted obstetric and gynaecological research there. However, in the USA some encouraging progress was reported by the MRC as being made, due substantially to ‘a good deal of money – with no strings attached – being made available by the Macy Foundation (www.josiahmacyfoundation.org/about/history) to three academic departments of obstetrics’ (
      • MRC
      Report to the Council dated July 1969. MRC Folder 7/912.
      , p.3). The three institutions of Harvard, Colombia and Washington (St Louis) are described as training ‘men [sic] and having “seeded” obstetricians of scientific outlook across the country’. Also credited with stimulating research is the formation of a ‘Society of Gynaecologic Investigation during the 1950s’.
      However, the MRC report may understate the extent of interdisciplinary reproductive research encompassing medicine in the USA by this time. Thus, many other charitable foundations were supporting research in the USA from after World War I (
      • Clarke A.E.
      Disciplining Reproduction: Modernity, American Life Sciences, and ‘the Problems of Sex’.
      ). For example, a case study, not mentioned in the MRC report, is the reproductive research pursued and funded by the embryology department of the Carnegie Institution of Washington (attached to Johns Hopkins University), which built upon early foundations (1913–1955) laid by its medically qualified directors – Franklin P Mall (1862–1917; Director from 1906–1917;

      Sabin, F.R., 1934. Franklin Paine Mall 1962–1917. National Academy of Sciences USA Biographical Memoirs xvi, pp. 63–122.

      ), George Streeter (1837–1948; Director 1917–1940;

      Corner, G.W., 1954. George Linius Streeter 1873–1948. National Academy of Sciences USA Biographical Memoirs xxviii, pp. 259–287.

      ) and George Corner (1889–1981; Director 1940–1955;

      Ramsey, E.M., 1994. George Washington Corner 1889–1981. National Academy of Sciences USA Biographical Memoirs, pp. 56–93.

      ) – to build a towering reputation for research and teaching in reproduction. The work there included the study and expansion of its pioneering collection of human embryos, functional studies on the reproductive cycle (under the direction of Corner and Carl Hartman, 1879–1968), the use of primate models of human reproduction, and the development of improved contraception (
      • Clarke A.E.
      Reproductive science 1913–1971.
      ).
      It is further reported by the MRC that in the USA ‘As in this country, there are ethical problems associated with obstetric work, but it would not appear that these difficulties are so serious as to hamper advances in the field by those who are really competent to make them.’ The section on the USA ends with the statement ‘An approach which appears to be developing in some centres … is that obstetrics and gynaecology should be regarded as only part of a wider specialty of reproductive biology’ (
      • MRC
      Report to the Council dated July 1969. MRC Folder 7/912.
      , p.4).
      The MRC discussions of this report, despite its deficiencies regarding the situation in the USA, was accepted by Council on 16 February 1970 (
      • MRC
      Council Recommendations for the Development of Research in Obstetrics and Gynaecology (OG1/2) dated July 1970. MRC Folder 7/912.
      ) and led to several outcomes. First, a major focus on obstetrical and gynaecological research was agreed for phase II of the MRC Clinical Research Centre due to open in 1971 at Northwick Park (
      • MRC
      Council Recommendations for the Development of Research in Obstetrics and Gynaecology (OG1/2) dated July 1970. MRC Folder 7/912.
      ). Second, the creation of ‘multi-disciplinary units for work in reproductive biology’ that would ‘enable both clinical and non-clinical scientists, with minimal teaching and other responsibilities, to work in university departments of obstetrics and gynaecology with the assurance of long term careers’ and the adoption of ‘a more liberal policy … in the award of research grants’. This latter objective led directly during the 1970s to the formation of reproductive research units in Edinburgh and Cardiff (later moving to Oxford) under the direction of Roger Short and Alec Turnbull, respectively (Johnson and Franklin, unpublished observations). Third, and paradoxically, it led the MRC in 1971 to decline research funding to Edwards and Steptoe for their work developing IVF through to its application clinically (
      • Johnson M.H.
      • Franklin S.B.
      • Cottingham M.
      • Hopwood N.
      Why the Medical Research Council refused Robert Edwards and Patrick Steptoe support for research on human conception in 1971.
      ).

      Ethics and research in reproductive medicine

      The paradoxical nature of this failure to fund Edwards and Steptoe lies in the fact that, even by the 1960s, the publication of a series of papers was occurring that was to transform subsequent research and clinical practice in human reproductive biomedicine by generating the new field of assisted reproductive technology. The work of scientist Robert Edwards (1925–;
      • Johnson M.H.
      Robert Edwards: the path to IVF.
      ) in particular stood out as highly interdisciplinary, combining approaches from physiology, genetics and embryology with the explicit aim of developing human applications for the understanding and control of reproduction and development (
      • Edwards R.G.
      Maturation in vitro of human ovarian oocytes.
      ,
      • Johnson M.H.
      Robert Edwards: the path to IVF.
      ). Edwards, who was acknowledged in the MRC reports to be a first-rate scientist, was also distinctive in his cultivation of a close research partnership of equals with consultant Patrick Steptoe. Steptoe’s innovations in the field of laparoscopy (
      • Steptoe P.C.
      Laparoscopy in Gynaecology.
      ) were to prove crucial for the ability to pursue research on the reproductive tract in situ. Together these two pioneers can be credited with fostering a strong scientific approach to the study of areas of human reproduction hitherto not known for such rigorous research standards (e.g.
      • Shettles L.B.
      A morula stage of human ovum developed in vitro.
      ).
      The application to fund this work foundered for several reasons, but most substantially on ethical concerns, already highlighted generally by the MRC but not considered to be insuperable, as already discussed. Thus, the MRC report had mentioned ethical doubts about research into human pregnancy, but had not spelt out exactly what these were. They were articulated more explicitly in the request to Edwards and Steptoe to first perform IVF–embryo transfer on primates (
      • Johnson M.H.
      • Franklin S.B.
      • Cottingham M.
      • Hopwood N.
      Why the Medical Research Council refused Robert Edwards and Patrick Steptoe support for research on human conception in 1971.
      ). Thus, the possibility in 1971 that MRC-sponsored research might lead to the production of a deformed baby was too dangerous for them to contemplate. Of particular salience was the recent thalidomide tragedy, which had surfaced in medical journals late in 1961 (
      • McBride W.G.
      Thalidomide and congenital abnormalities.
      ) and hit the press headlines in 1962 and had rarely left them for most of the 1960s (
      • Knightley P.
      • Evans H.
      • Potter E.
      • Wallace M.
      Suffer the Children: The Story of Thalidomide.
      ). Then, in the late 1970s and early 1980s, as the MRC struggled to come to terms with the birth of Louise Brown and the change in policy towards funding IVF which that birth eventually stimulated (
      • Theodosiou A.A.
      • Johnson M.H.
      The politics of human embryo research and the motivation to achieve PGD.
      ), the MRC became immersed in a second media brouhaha over the ethics of its folate trial to test for the possible impact of this vitamin on spina bifida outcomes (
      • Beardlsey T.
      Spina bifida: MRC folate trials to start at last.
      ). Thus, the concerns expressed in the 1960s about the legitimacy of research to construct an evidence base for reproduction seemed in retrospect to be well founded – even if based on the fear of adverse publicity rather than ethical considerations per se!
      The evidence that the MRC was at best ambivalent about funding at least some types of reproduction research finds echoes in the USA. Thus, there is archival evidence that the National Institutes of Health in the USA took their cue from the MRC in reacting against funding of IVF research (
      • Johnson M.H.
      • Franklin S.B.
      • Cottingham M.
      • Hopwood N.
      Why the Medical Research Council refused Robert Edwards and Patrick Steptoe support for research on human conception in 1971.
      ). Indeed, an early reluctance in the USA to fund many areas of reproduction has been documented by
      • Clarke A.E.
      Disciplining Reproduction: Modernity, American Life Sciences, and ‘the Problems of Sex’.
      , as was the case for Pincus’ work on the pill (
      • Marsh M.
      • Ronner W.
      The Fertility Doctor.
      ). A reliance on wealthy private donors facilitated research on both the development of the oral contraceptive (
      • Fields A.
      Katharine Dexter McCormick: Pioneer for Women’s Rights.
      ,
      • Tuck S.L.
      McCormick, Katharine Dexter.
      ) and of IVF (
      • Johnson M.H.
      • Franklin S.B.
      • Cottingham M.
      • Hopwood N.
      Why the Medical Research Council refused Robert Edwards and Patrick Steptoe support for research on human conception in 1971.
      ).
      These doubts about the ethics of reproductive research played directly to the conflict between evidence base and professional autonomy, as is observed very clearly in the MRC’s rejection of the Edwards and Steptoe grant application. Most referees raised ethical concerns, either about the laparoscopic recovery of oocytes or about the placement of IVF-generated embryos into uteri. Every new treatment presents issues of risk and safety. The problem was that the MRC’s referees failed to recognize infertility as a serious health condition, as well as expressing doubt that IVF offered a realistic solution for its treatment. So the proposal was not seen as clinically relevant and patients are described as ‘purely’ research subjects (
      • Johnson M.H.
      • Franklin S.B.
      • Cottingham M.
      • Hopwood N.
      Why the Medical Research Council refused Robert Edwards and Patrick Steptoe support for research on human conception in 1971.
      ), a status ethico-legally very different to that of patients undergoing experimental treatments (
      • Landsborough Thomson A.
      Half a Century of Medical Research. The Programme of the Medical Research Council (UK), vol. 2.
      ). As one of the referees said: ‘From the ethical viewpoint, it is one thing to subject a woman to a course of gonadotrophin therapy and a laparoscopy in order to treat her infertility. But is it justifiable to carry out these procedures solely for the purposes of obtaining ova for in vitro experiments, which in themselves offer no immediate benefit to the patient?’ (
      • Johnson M.H.
      • Franklin S.B.
      • Cottingham M.
      • Hopwood N.
      Why the Medical Research Council refused Robert Edwards and Patrick Steptoe support for research on human conception in 1971.
      ). This distinction had been set out by the MRC in 1964:A distinction may legitimately be drawn between procedures undertaken as part of patient-care which are intended to contribute to the benefit of the individual patient, by treatment, prevention, or assessment, and those procedures which are undertaken either on patients or on healthy subjects solely for the purpose of contributing to medical knowledge and are not themselves designed to benefit the particular individual on whom they are performed. The former fall within the ambit of patient-care and are governed by the ordinary rules of professional conduct in medicine (
      • MRC
      Responsibility in investigations on human subjects: statement by Medical Research Council.
      ).
      Quite how the doctor was to ‘know’ that his treatment matched his intention ‘to contribute to the benefit of the individual patient’ was the issue raised by Cochrane and lies at the heart of discussions about EBM. However, it is clear that research in reproduction was hedged with both ethical and financial doubts that tended to reinforce the non-research culture about which the funding agencies were paradoxically wringing their hands. Each of these cultural, ethical and financial aspects probably contributed to the relatively poor performance and the relatively late entry of reproductive medicine to the research evidence base.

      Reproductive medicine then set the pace in the promotion of an evidence-based approach

      From these inauspicious beginnings, reproductive medicine then took the lead in the development of EBM, with obstetrics and related specialities featuring prominently among the earliest responders to Cochrane’s exhortations. Thus, within 2 years of his book’s appearance, plans were underway in Cardiff for the identification of controlled trials in perinatal medicine and a critical review of the effectiveness, efficiency and fairness of this medical discipline. The first substantial result of these endeavours was published in 1982 in the form of Effectiveness and Satisfaction in Antenatal Care, a multi–author volume edited by
      . In their introduction (pp.xi–xii), the editors questioned both the effectiveness and the efficiency of subjecting all pregnant women to a level of investigation that had been largely developed to deal with more problematic pregnancies, a theme developed by others throughout the volume. For example, Oakley (
      ) wrote about the development of the ‘reluctant consumer’ as a result of clinical interventions perceived by the patients to be unnecessary. Several authors questioned the value of applying technologies simply because they are available, and presented some evidential support for their doubts. In a concluding chapter,
      summarized many examples of how apparently innocuous interventions, such as blood tests and even simply giving advice, can have negative outcomes and, stating the issues in two questions, asked: ‘Are we doing more good than harm?’ and ‘Are we doing the best we can with what we have?’ They made a plea for a more systematic evaluation of the impact of a range of types of interventions by appropriately designed research. By 1987–1988, papers on meta-analyses of reproduction were being published (
      • Daya S.
      Efficacy of progesterone support in the luteal phase following in-vitro fertilization and embryo transfer: meta-analysis of clinical trials.
      ,
      • Dickersin K.
      Report from the panel on the Case for Registers of Clinical Trials at the Eighth Annual Meeting of the Society for Clinical Trials.
      ,
      • King J.F.
      • Grant A.
      • Keirse M.J.
      • Chalmers I.
      Beta-mimetics in preterm labour: an overview of the randomized controlled trials.
      ,
      • Kramer M.S.
      Determinants of low birth weight: methodological assessment and meta-analysis.
      ) and by 1989, Enkin and Chalmers answered their plea emphatically with three major publications (Table 1). Indeed, writing in July 1987, shortly before his death,
      • Cochrane A.L.
      Foreword.
      , in a foreword to one of these (Effective Care in Pregnancy and Childbirth;
      ) described this systematic review of RCTs of care during pregnancy and childbirth as ‘a new achievement … a real milestone in the history of randomized trials and in the evaluation of care’ and suggested that those methods used should be applied by other specialties. He ended: ‘I now have no hesitation whatsoever in withdrawing the slur of the wooden spoon from obstetrics’.
      Table 1Early history of Cochrane reviews.
      1978National Perinatal Epidemiology Unit, Oxford, UK established to assemble a register of controlled trials in perinatal medicine
      1982Effectiveness and Satisfaction in Antenatal Care (Enkin and Chalmers, 1982)
      1985Publication of classified bibliography of 3500 reports of controlled trials in perinatal medicine published between 1940 and 1984
      1989Output of collaborative work begins with publication of:
      Effective Care in Pregnancy and Childbirth (
      )
      A Guide to Effective Care in Pregnancy and Childbirth (
      )
      The Oxford Database of Perinatal Trials, version 1 (
      )
      1992Publication of Effective Care of the Newborn Infant
      1992 FebruaryThe Cochrane Centre opens in Oxford, UK
      1993 OctoberPregnancy and Childbirth Group registered
      Subfertility Group registered
      1993 MarchNeonatal Group registered
      1994 NovemberDiabetes Group registered
      1994 OctoberPeripheral Vascular Disease Group registered
      1994 AugustAcute Respiratory Infections Group registered
      1994 JuneOral Health Group registered
      Schizophrenia Group registered
      1994 MayInfectious Diseases Group registered
      1993 NovemberMusculoskeletal Group registered
      1993 AugustStroke Group registered
      2012 AprilOf 5000 Cochrane reviews, gynaecology makes up 7.2% (360), pregnancy and childbirth 8.5% (425), and neonatal care 5.8% (291)
      Adapted from the Cochrane Collaboration website: www.cochrane.org/about-us/history.
      This transformation was in large part due to the commitment of Iain Chalmers (
      • Enkin M.W.
      A paean to Iain Chalmers.
      ), who had arrived independently at a similar view to Cochrane. Chalmers describes how as a young physician, he became interested in evaluating the effects of health care in 1969 and 1970, while working for the United Nations in a Palestinian refugee camp in the Gaza Strip (where interestingly Cochrane’s father had been killed in 1917 and where Edwards had done war service between 1943 and 1948):It gradually dawned on me there that some things I had been taught in medical school were probably lethally wrong. This came as a very sobering realisation: how could it be that health professionals acting with the best of intentions could do more harm than good to those who looked to them for help? After a couple of years in Gaza I returned to Britain, to train in obstetrics, in Cardiff, the capital city of Wales. As a junior obstetrician I was confused by the conflicting opinions of senior doctors about when and how to intervene in pregnancy and childbirth. In 1972, however, a very readable little book came to my rescue. Effectiveness and Efficiency: Random Reflections on Health Services [
      • Cochrane A.L.
      Effectiveness and Efficiency: Random Reflections on Health Services.
      ] had been written by Archie Cochrane, [this] book and his subsequent friendship made me a lifelong sceptic about therapeutic claims unsupported by reliable evidence. It helped me to understand why some forms of research – particularly randomized controlled trials (RCTs) – were likely to generate more reliable information than others. In addition, I could identify strongly with Archie’s commitment to the decent principle of equitable access to (effective) health-care, and his emphasis on the need to provide humane and dignified (and thus effective) care when no effective cure was available (
      • Chalmers I.
      The pre-history of the first Cochrane Centre.
      ).
      As a result of his exposure to Cochrane’s book, Chalmers trained in social medicine and statistics, before returning to Cardiff obstetrics and gynaecology where in 1974 he embarked on a trawl for reports of perinatal controlled trials, spurred in part by criticisms from women about the UK maternity service (
      • Chalmers I.
      British debate on obstetric practice.
      ,
      ). As a result of the evidential uncertainties that his research uncovered, he identified the need to explore whether all trials were being reported (
      • Chalmers I.
      Underreporting research is scientific misconduct.
      ), whether all reported trials had equivalent value and whether the results of similar valuable trials (reported or not) could be combined to yield statistically more robust estimates of treatment effects (meta-analysis). In essence, what were being established were the guidelines for a high-quality systematic review of evidence (
      ). In 1978, Chalmers became the founding director of the National Perinatal Epidemiology Unit in Oxford funded by the NHS via the Department of Health (
      • Chalmers I.
      • Enkin M.W.
      • Keirse M.J.N.C.
      Preparing and updating systematic reviews of randomized controlled trials of health care.
      ,
      • Starr M.
      • Chalmers I.
      • Clarke M.
      • Oxman A.D.
      The origins, evolution, and future of the Cochrane Database of Systematic Reviews.
      ). His endeavours led in 1992 to the founding of the UK Cochrane Centre (also state funded) and ultimately to the Cochrane Collaboration (www.cochrane.org), the major source and repository of reliable evidence-based healthcare advice internationally and where, notably, the earliest special interest groups to be established were in reproductive medicine (Table 1).

      Conclusions

      Despite its late beginnings, reproductive medicine can quite reasonably consider itself a pioneer of EBM – largely due to the commitment and drive of Iain Chalmers, with major contributions from the McMaster team led by Murray Enkin (
      • Bryce R.I.
      • Enkin M.W.
      Six myths about controlled trials in perinatal medicine.
      ), who had first met Chalmers in 1978 (
      • Enkin M.W.
      A paean to Iain Chalmers.
      ). However, even today within reproductive medicine there remains a strong tradition of case-based reporting being given priority over solid research evidence (see
      • Chalmers I.
      Scientific inquiry and authoritarianism in perinatal care and education.
      for his early criticisms of such an approach). There is a role for both, but they inform in different ways about different aspects of health care. Indeed it is pertinent to ask ourselves: How would Cochrane view our approaches to EBM were he here today? After all, whilst the prospect of the then relatively new RCT excited him, as would surely the advances in meta-analysis, central to his vision of evidence was a multi-layered approach to health care in which he saw a key role for expert opinion and a clear focus on patient input and variability, aspects that RCTs can often ignore. Moreover, as we move into the age of personalized medicine, and the available patient cohorts for RCT become ever smaller, considerable rethinking about the structure (and value?) of the RCT may become necessary. These issues have been addressed by other contributors to the 2012 EBM Symposium. These are important questions because, when proponents of one type of evidence make excessive claims for it, patients (and indeed doctors) may suffer: exactly the situation that Cochrane sought to avoid.

      Acknowledgements

      I thank Sarah Franklin, Adele Clarke, Martin Richards and the RBMOnline referees for their helpful comments on drafts of this manuscript, for which, however, I alone take responsibility, and Margaret Wilson for help in locating some papers. This research was supported by Wellcome Trust (grant number 088708) and by a grant from the British Academy to Professor Sarah Franklin.

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