Reproductive BioMedicine Online (2013) 26, 201–209

www.sc iencedi rec t . comwww.rbmonl ine .com

SYMPOSIUM: EVIDENCE-BASED REPRODUCTIVE MEDICINE

The early history of evidence-basedreproductive medicine

Martin H Johnson

Anatomy School and Trophoblast Research Centre, Department of Physiology, Development and Neuroscience,Downing Street, Cambridge CB2 3DY, UKE-mail addresses: mhj@rbmonline.com, mhj21@cam.ac.uk.

Abstract The origins of e

1472-6483/$ - see front mathttp://dx.doi.org/10.1016/j

Martin H Johnson FRCOG, FBS, FMedSci is an editor of RBMOnline and Professor of Reproductive Sciences in thedepartment of physiology, development and neuroscience at the University of Cambridge, UK. He was, withRichard Gardner, Bob Edwards’ first graduate student (1966–1969) and opened the Nobel symposium on Bob’swork in Stockholm, 2010. He is author of Essential Reproduction (7th edition, 2013) and co-editor of SexualityRepositioned (2004), Death Rites and Rights (2007) and Birth Rites and Rights (2011). He has been Chair of theBritish Society for Developmental Biology (1984–1989), the first CIBA Foundation Public Debate Annual Lectureron human embryo research (Swansea, 1990), a member of the Human Fertilisation and Embryology Authority(1993–1999), treasurer and founding scientific member of the Cambridge Socio-legal group (2000–2012) andspecialist scientific advisor to the Joint Lords and Commons Committee scrutinizing the draft Human Embryosand Tissue Bill (2007).

vidence-based medicine as understood today are traceable to 1972 and the publication of Archie Cochra-ne’s book Effectiveness and Efficiency: Random Reflections on Health Services. This book attempted to bridge the divide betweenscientific medicine and clinical judgment that had developed since the mid-19th century. Its genesis was stimulated by Cochrane’sexperiences as a prisoner-of-war medical officer and of the demands placed after the 1939–1945 war on the UK National HealthService. In the 1960s, reproductive medicine was considered by the UK Medical Research Council to be relatively ‘unscientific’ inits approach to care delivery and was described as such by Cochrane in the 1970s. Evidence is presented here that reproductive med-icine responded, becoming by 1989 a pioneering clinical discipline in the application of evidence to practice. This was achievedlargely 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. RBMOnline

ª 2012, Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.

KEYWORDS: double-blind randomized controlled clinical trial, meta-analysis, Murray Enkin, problem-based learning (PBL), Robert Edwards

Introduction

Humans have used evidence to guide their decisions andactions since the beginnings of historical record keeping;indeed, the capacity to imply cause and effect from obser-vation is integral to our understanding of what it is to behuman. However, it is how we understand and interpretwhat constitutes reliable evidence that varies with circum-

ter ª 2012, Reproductive Healthcare Ltd..rbmo.2012.11.010

stance 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, 2006; Kaptchuk and Kerr, 2004). Each of thesesources has validity to the person who is using them to fash-ion explanations, and so, regardless of whether that personis a patient or a doctor, all sources must be taken intoaccount in any medical decision making (RCOG, 2011). So

Published by Elsevier Ltd. All rights reserved.

202 MH Johnson

where and when in this evidential melange didevidence-based medicine (EBM) appear and how has itdeveloped in respect of reproductive medicine in particular?

A tension between the relative value of clinical judgmentand the scientific method has been a feature of Westernmedicine since the mid-to-late 19th century and the riseof the laboratory medical sciences with their emphasis onthe experimental and ‘objective’ acquisition of ‘facts’ asevidence (Bernard, 1865; Porter, 1995), which becameembedded in the education of 20th-century US medical stu-dents as a result of the Flexner Report (Flexner, 1910).Since these early attempts to free the practice of medicinefrom, at best, irrational beliefs and, at worst, quackery, thistension has tended to polarize the medical community. Aca-demic medicine drove this notion of scientific medicineagainst the grain of medical practitioners who brought totheir ‘art’ an authority of clinical judgment based on expe-rience that was transmitted via apprentice-like training tothe next generation (see Strathern, 2000, for discussion ofsimilar tensions within academic life). The practitioner isfocused on case-based clinical practice as set against thetraditionally population-based nature of research evidence:a tension that may be easing in prospect through researchevidence that facilitates ‘tailored’ treatment. Historically,the problem from the perspective of academic medicinehas been how to convince medical practitioners to be morescientific in their approach, whilst practitioners viewedthese attempts as incursions on their professional freedomof action and judgment.

Evidence-based medicine aspires to resolve this tension.Sackett et al. (1996) defined EBM as:

. . . the conscientious, explicit, and judicious use of cur-rent best evidence in making decisions about the careof individual patients. The practice of evidence basedmedicine means integrating individual clinical expertisewith the best available external clinical evidence fromsystematic research (our emphasis).

They then go on to define the two pillars of EBM:

By individual clinical expertise we mean the proficiencyand judgment that individual clinicians acquire throughclinical experience and clinical practice. Increasedexpertise is reflected in many ways, but especially inmore effective and efficient diagnosis and in the morethoughtful identification and compassionate use of indi-vidual patients’ predicaments, rights, and preferencesin making clinical decisions about their care.By best available external clinical evidence we meanclinically relevant research, often from the basic sci-ences of medicine, but especially from patient centredclinical research into the accuracy and precision of diag-nostic tests (including the clinical examination), thepower of prognostic markers, and the efficacy and safetyof therapeutic, rehabilitative, and preventive regimens.External clinical evidence both invalidates previouslyaccepted diagnostic tests and treatments and replacesthem with new ones that are more powerful, more accu-rate, more efficacious, and safer.Good doctors use both individual clinical expertise andthe best available external evidence, and neither aloneis enough. Without clinical expertise, practice risks

becoming tyrannised by evidence, for even excellentexternal evidence may be inapplicable to or inappropri-ate for an individual patient. Without current best evi-dence, practice risks becoming rapidly out of date, tothe detriment of patients.

However, whether EBM does resolve this tension, or sim-ply rewords the problem generating it, remains the subjectof intense debate (see, for example, critical responses tothe Sackett et al. (1996) paper at www.bmj.com/con-tent/312/7023/71?tab=responses). In this paper, I first seekto establish the origins of EBM and of the randomized con-trolled trial (RCT) that conventionally occupies its eviden-tial apex. I then look at the early application of EBM toreproductive medicine and record the general perceptionof its inadequacy and the putative role that ethical concernshad in generating this perception. Finally, I report the work,largely driven by Chalmers, in pioneering the application ofEBM to reproductive medicine to propel it to the forefrontof evidence-based clinical research.

The birth of evidence-based medicine

The birth of EBM as we understand it today is conventionallydated to 1972 (see, for example, Enkin, 1995) and the pub-lication by Archie Cochrane (1909–1988) of his book Effec-tiveness and Efficiency: Random Reflections on HealthServices (Cochrane, 1972). Cochrane studied natural sci-ences at Cambridge University, followed by research foran uncompleted PhD at the Cambridge Physiological andStrangeways Laboratories studying tissue culture under Nev-ill Willmer (1902–2001; Obit, 2001), before training medi-cally from 1934 to 1938 at University College Hospital,London. His period of clinical study was interrupted by ayear’s volunteered service in the Spanish Medical Aid Com-mittee’s Field Ambulance Unit in the Spanish civil war. Thisexperience proved to be useful when, after a year as ahouse physician in London, he served from 1939 in the RoyalArmy Medical Corps, first in Egypt, then in Crete, where hewas taken prisoner on 1 June 1941. There then followed4 years as a prisoner-of-war medical officer in camps inGreece and Germany. He later described how his war expe-riences led him to acknowledge his ignorance and his needto have more objective knowledge:

What I decided I could not continue doing was makingdecisions about intervening . . . when I had no ideawhether I was doing more harm than good. I rememberreading a pamphlet (I think from the BMA) extolling theadvantages of the freedom of British doctors to dowhatever they thought was best for their patients. . . . Iwould willingly have sacrificed all my medical freedomfor some evidence . . . (Cochrane and Blythe, 1989,pp.83–84).

In this regard, Cochrane felt he had not been helped byhis education at University College, of which he wrote:

. . . teaching about diagnosis, and particularly treatment,was extremely dogmatic . . . A few of us used to plaguethe clinicians by asking them about the evidence in sup-port of the treatment they were giving. Usually we werefobbed off with ‘in my clinical experience . . .’. When two

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physicians defended two different and seemingly oppos-ing treatments for the same condition we inevitablybecame cynical (Cochrane and Blythe, 1989, p.17).

In his influential 1972 book, Cochrane uses an evalua-tion of the UK National Health Service (NHS) to develophis ideas about to how to assess whether a given clinicalintervention (or more strictly healthcare intervention) pro-duced a clinically effective, efficient and fair outcome.These three outcome criteria may be understood throughthe following questions. (i) Effectiveness: does the inter-vention do more good than harm, whether assessed bythe mortality or by the physical, social and emotionalwellbeing of those compliant with the intervention? (ii)Efficiency: does the intervention really do more good thanharm to those to whom it is offered (as opposed to thosewho take up that offer – a measure of the compliancegap) and does making it available make the best use ofresources? (iii) Fairness: is the intervention made accessi-ble to everyone in the community who can benefit from it?

Cochrane had been a dedicated supporter of the NHSideal since the 1930s and was concerned that, by 1970when the NHS had been operating for just 21 years, theresources allocated to it should be used well: ‘[the NHS]could be seen as giving a blank cheque both to thedemands of the patients [for help] and the wishes of thedoctors [to be helpful]’ (Cochrane, 1972, p.9). Thus, thestate provision of care focused his general interest onhow best to measure care outcomes for both the individualand society at large. In his analysis, Cochrane draws on var-ious sources of evidence to construct his ‘evidence base’,but of particular significance for him then was the prospec-tive randomized trial.

The randomized trial

Histories of the prospective randomized trial dispute theprimacy of the large, blind, placebo-controlled and ran-domized clinical trial (Chalmers and Clarke, 2004), as dis-tinct from the many preceding, smaller, non-randomized,non-blinded and/or non-controlled trials (Meldrum, 2000).Some advocate the 1948 test of streptomycin for treatingpulmonary tuberculosis (MRC, 1948; Anon, 2009), others cit-ing an earlier trial that demonstrated the lack of effect ofpatulin on the common cold (MRC, 1944). But what linksboth is the involvement of the UK Medical Research Council(MRC). There was at that time a widespread belief thatstreptomycin was effective in treating tuberculosis, butthe stimulus for the UK trial came from both the cost andlimited availability of the drug. Neither condition appliedto the same extent in the USA where the drug was pro-duced. There, conducting a placebo-controlled trial wasperceived as being ‘unethical’ by many clinicians, leadingto their subversion of early trial attempts and the abandon-ing of the placebo arm (Marks, 1997, p.117–119). Theinvolvement of the MRC and nascent NHS was a criticaldeterminant of the UK trial’s success, both because of theirorganizational effectiveness and for the impact of theirfindings on medical practice in the NHS. Thus, althoughthere had been episodic reports of ‘controlled trials’ overthe preceding 200 years (Meldrum, 2000), the scale of thestudies was often small and the quality variable, and doubt-

ful physicians showed little inclination to learn from them,preferring recourse to their own clinical judgment. In thepost-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 couldbe carried out on a sufficiently large scale and any findingsapplied. Moreover, and as a result of international debatesduring the 1930s, the development of medical statistics,notably by RA Fisher (1890–1962; Fisher Box, 1978; Hack-ing, 1988; Savage, 1976), and its practical application tomedical trials, notably by the influential A Bradford Hill(1897–1991; Armitage, 1992; Himsworth, 1982: and withwhom Cochrane had trained 1945–46), there was increasingagreement about what features made a good study andwhat might weaken its usefulness (for contemporary discus-sion of these issues, see also Strathern, 2000). It was in thismore sympathetic environment (Kaptchuk and Kerr, 2004)that the streptomycin trial for tuberculosis was reported(MRC, 1948). This trial influenced strongly the design of asimilar trial in the USA, initiated in 1947, also by a federalbody, the Public Health Service (Marks, 1997, p.121),although it was probably the Salk polio vaccine trial in 1950sUSA (Francis et al., 1955) that finally convinced the US med-ical profession at large of the potential value of randomizedcontrol trials.

Until 1950, most of the medical profession was notattracted to any form of clinical experimentation that chal-lenged the personal judgment of physicians or seeminglythreatened to treat patients as less than unique individuals.‘Science’ was thought best confined to the laboratory wherevariability could be contained and physicians were bestsuited to delicately apply this knowledge within the contextof ‘the art of healing’ (Kaptchuk and Kerr, 2004, p.247).

Interestingly, the USA Federal Food and Drug Agency(FDA) was relatively slow to demand RCTs, only doing soin 1970 (FDA, 1970), despite its powers being strengthenedin 1938 (FD Act, 1938) and further in 1962 (FDA, 1962). Thislag was largely due to a legacy of legal, commercial and pro-fessional wrangling (Marks, 1997, pp.74–96).

In conclusion, although the RCT now has a recognizedplace in the constellation of evidence that makes up a sys-tematic review, it is a fairly recent tool in the armoury.

Cochrane’s larger view

Cochrane’s approach to evidence was distinguished by thefact that, whilst he acknowledged enthusiastically theimportance of objective population data from RCTs, he alsorealized that the realities of patient, doctor and institu-tional variability and individuality must be recognized andthat the total impact of interventions on care outcomesshould be assessed in relation to the input costs (Cochraneand Blythe, 1989, writing about the mid 1960s;pp.208–2009). For example, again writing from notes madein the mid 1960s, Cochrane says:

One day, though, I wrote down my plans for making astart. To show that it is ethically acceptable and practi-cally possible to randomize place of treatment betweenhospital and home, outpatients clinic and home, and hos-pital and outpatients clinic, length of stay in hospital(Cochrane and Blythe, 1989, p.207).

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Cochrane was even then contemplating an expandedrange of evidence base extending well beyond that for drugtrials.

Cochrane was not developing these ideas in isolation,however. For example, at the same time, others wereadvancing comparable revolutionary ideas in the context ofmedical education. Thus, in 1966, McMaster University (Can-ada) introduced problem-based learning (PBL) into its medi-cal school curriculum (Camp, 1966), followed soonthereafter by universities in Maastricht (Holland), Newcastle(Australia) andNewMexico (USA). The PBL approach includedseveral features of the ideas being articulated by Cochrane –in particular the responsibility of the physician to be up todate and in a continuous state of professional enquiry andchallenge, as well as an approach to the medical student asa well integrated ‘whole’ professional. It is not therefore sur-prising that some of the earliest practitioners of EBMresearch were at McMaster University (Spitzer et al., 1974,1975; Sackett, 1975; Sackett and Holland, 1975). The PBLapproach to medical education, although initially resistedand slow to spread, has become widespread since the 1990sand forms at least one element of teaching in most medicalschools. It is probably not coincidental, therefore, that thespread of PBL within medical education appears to haveaccompanied the wider espousal of EBM bymedical practitio-ners. Paradoxically, PBL has been attacked as underempha-sizing the scientific aspects of medicine at the expense oftraining in the ‘arts’ of medicine (McDermott, cited in Lud-merer, 1999, pp.305–306), almost a reversal of the attackson EBM (albeit usually as a surrogate for PCTs) as being tooimpersonal. Both attacks are rooted in the same long-stand-ing conflict between science and clinical judgment.

Evidence-based reproductive medicine

In his 1972 book, Cochrane refers to reproductive medicinein several places. Thus, in a section headed ‘Preventativemedicine’, he laments both the lack of NHS research on pop-ulation control (pp.28 and 78) and the widespread adoptionof cervical smear testing in the absence of any controlledstudies to assess its effectiveness – described interestinglyas not pursued because ‘it was not considered ethical’(p.27), a theme to which he returned later (Cochrane andBlythe, 1989, pp.204–206). Further on in his 1972 book(pp.63–66), he writes about the ethical difficulty of under-taking midwifery research and the sad misuse of what datathere were by the Peel Committee (1970), which hadreported on home versus hospital deliveries. In a later essay,Cochrane (1979) again drew particular attention to theabsence of an evidence base in obstetrics and gynaecology,which he characterized as deserving ‘the wooden spoon’ asbeing the least scientific and evaluative of medical speciali-ties (p.11). A similar perception is revealed in the 1960s’archives of the MRC and the Royal College of Obstetriciansand Gynaecologists (RCOG) (Macafee, 1962–1967).

The MRC and reproductive medicine in the UK

An MRC Office report to Council (MRC, 1969) refers to areport made by the Secretary of the MRC to the AnnualReview meeting of Council in November 1968 lamenting

the limited MRC support in UK university departments ofobstetrics and gynaecology. The RCOG through its Macafeecommittee (Macafee, 1962–1967) had identified similarissues. Several barriers to academic research were identi-fied in both reports, but these reduced in essence to theabsence of a research culture or mentality and to the dom-inant position accorded to clinical training and practice.This cultural problem was considered to be self-perpetuat-ing, attracting less-able students due to a lack of intellec-tual challenge and work overload, with few academicposts available in the specialty. Possible areas ripe forresearch that were identified included fertility control, hor-monal control of the female tract, toxaemia and thenon-pathological physiology of pregnancy, neonate andfetus. The report (MRC, 1969, p.3) also identified, withoutspecifying its nature, a problem of ‘ethical objections tostudies on the pregnant woman . . . While some academicobstetricians appear to despair of solving this general prob-lem, others consider it a challenge which can be overcome’.

These perceptions about reproductive medicine carry anironic twist in that Cambridge scientist FHA Marshall(1878–1949; Parkes, 1950), who in his book of 1910 (Mar-shall, 1910) is widely credited with founding the modern dis-cipline of reproduction, had specifically stressed theintegrated nature of medical, as well as agricultural and sci-entific, elements of reproduction, a view shared by his influ-ential Cambridge predecessor and colleague, Walter Heape(1855–1928; Biggers, 1991). However, neither Marshall norHeape were medically trained and their main legacy,together with that of fellow younger Cambridge scientistJohn Hammond (1889–1964; Slater and Edwards, 1965),was the foundation of rich schools of agricultural and phys-iological (including biochemical) reproduction (Clarke,2007). But their links with mainstream obstetrics and gynae-cology were more episodic, tenuous and often determinedby the interests of a limited range of physicians. That thiswas the case is in part due to the perceived dubious ‘moral-ity’ of applying to humans much of the reproductiveresearch being done on animals (Clarke, 1998, 2007).

The deficiency of good research in obstetrics and gynae-cology was recorded as not being restricted to the UK, as asection of the MRC report on US historical comparisons sug-gested. These criticisms echo those made in 1914 by JWhitridge Williams, head of the Johns Hopkins School ofMedicine (Baltimore), who is reported by Clarke (2004,p.85) as launching a scathing attack on the American Gyne-cological Society for its failure to produce fundamental con-tributions to obstetrics or biochemical aspects ofpregnancy, but instead to concentrate on technical virtuos-ity at the expense of extending knowledge, a criticism herepeated in 1925. Clarke (1998, 2007) also recorded how,in the USA, the same moral doubts about studying humanreproduction had hampered and restricted obstetric andgynaecological research there. However, in the USA someencouraging progress was reported by the MRC as beingmade, due substantially to ‘a good deal of money – withno strings attached – being made available by the MacyFoundation (www.josiahmacyfoundation.org/about/his-tory) to three academic departments of obstetrics’ (MRC,1969, p.3). The three institutions of Harvard, Colombiaand Washington (St Louis) are described as training ‘men[sic] and having ‘‘seeded’’ obstetricians of scientific outlook

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across the country’. Also credited with stimulating researchis the formation of a ‘Society of Gynaecologic Investigationduring the 1950s’.

However, the MRC report may understate the extent ofinterdisciplinary reproductive research encompassing medi-cine in the USA by this time. Thus, many other charitablefoundations were supporting research in the USA from afterWorld War I (Clarke, 1998). For example, a case study, notmentioned in the MRC report, is the reproductive researchpursued and funded by the embryology department of theCarnegie Institution of Washington (attached to Johns Hop-kins University), which built upon early foundations(1913–1955) laid by its medically qualified directors –Franklin P Mall (1862–1917; Director from 1906–1917;Sabin, 1934), George Streeter (1837–1948; Director1917–1940; Corner, 1954) and George Corner (1889–1981;Director 1940–1955; Ramsey, 1994) – to build a toweringreputation for research and teaching in reproduction. Thework there included the study and expansion of its pioneer-ing collection of human embryos, functional studies on thereproductive cycle (under the direction of Corner and CarlHartman, 1879–1968), the use of primate models of humanreproduction, and the development of improved contracep-tion (Clarke, 2004).

It is further reported by the MRC that in the USA ‘As inthis country, there are ethical problems associated withobstetric work, but it would not appear that these difficul-ties are so serious as to hamper advances in the field bythose who are really competent to make them.’ The sectionon the USA ends with the statement ‘An approach whichappears to be developing in some centres . . . is that obstet-rics and gynaecology should be regarded as only part of awider specialty of reproductive biology’ (MRC, 1969, p.4).

The MRC discussions of this report, despite its deficien-cies regarding the situation in the USA, was accepted byCouncil on 16 February 1970 (MRC, 1970) and led to severaloutcomes. First, a major focus on obstetrical and gynaeco-logical research was agreed for phase II of the MRC ClinicalResearch Centre due to open in 1971 at Northwick Park(MRC, 1970). Second, the creation of ‘multi-disciplinaryunits for work in reproductive biology’ that would ‘enableboth clinical and non-clinical scientists, with minimal teach-ing and other responsibilities, to work in university depart-ments of obstetrics and gynaecology with the assurance oflong term careers’ and the adoption of ‘a more liberal policy. . . in the award of research grants’. This latter objective leddirectly during the 1970s to the formation of reproductiveresearch units in Edinburgh and Cardiff (later moving toOxford) under the direction of Roger Short and Alec Turn-bull, respectively (Johnson and Franklin, unpublished obser-vations). Third, and paradoxically, it led the MRC in 1971 todecline research funding to Edwards and Steptoe for theirwork developing IVF through to its application clinically(Johnson et al., 2010).

Ethics and research in reproductive medicine

The paradoxical nature of this failure to fund Edwards andSteptoe lies in the fact that, even by the 1960s, the publica-tion of a series of papers was occurring that was to trans-form subsequent research and clinical practice in human

reproductive biomedicine by generating the new field ofassisted reproductive technology. The work of scientist Rob-ert Edwards (1925–; Johnson, 2011) in particular stood outas highly interdisciplinary, combining approaches fromphysiology, genetics and embryology with the explicit aimof developing human applications for the understandingand control of reproduction and development (Edwards,1965; Johnson, 2011). Edwards, who was acknowledged inthe MRC reports to be a first-rate scientist, was also distinc-tive in his cultivation of a close research partnership ofequals with consultant Patrick Steptoe. Steptoe’s innova-tions in the field of laparoscopy (Steptoe, 1967) were toprove crucial for the ability to pursue research on the repro-ductive tract in situ. Together these two pioneers can becredited with fostering a strong scientific approach to thestudy of areas of human reproduction hitherto not knownfor such rigorous research standards (e.g. Shettles, 1955).

The application to fund this work foundered for severalreasons, but most substantially on ethical concerns, alreadyhighlighted generally by the MRC but not considered to beinsuperable, as already discussed. Thus, the MRC reporthad mentioned ethical doubts about research into humanpregnancy, but had not spelt out exactly what these were.They were articulated more explicitly in the request toEdwards and Steptoe to first perform IVF–embryo transferon primates (Johnson et al., 2010, p.2166). Thus, the possi-bility in 1971 that MRC-sponsored research might lead to theproduction of a deformed baby was too dangerous for themto contemplate. Of particular salience was the recent tha-lidomide tragedy, which had surfaced in medical journalslate in 1961 (McBride, 1961) and hit the press headlines in1962 and had rarely left them for most of the 1960s (Knight-ley et al., 1979). Then, in the late 1970s and early 1980s, asthe MRC struggled to come to terms with the birth of LouiseBrown and the change in policy towards funding IVF whichthat birth eventually stimulated (Theodosiou and Johnson,2011), the MRC became immersed in a second media brou-haha over the ethics of its folate trial to test for the possibleimpact of this vitamin on spina bifida outcomes (Beardlsey,1983). Thus, the concerns expressed in the 1960s about thelegitimacy of research to construct an evidence base forreproduction seemed in retrospect to be well founded –even if based on the fear of adverse publicity rather thanethical considerations per se!

The evidence that the MRC was at best ambivalent aboutfunding at least some types of reproduction research findsechoes in the USA. Thus, there is archival evidence thatthe National Institutes of Health in the USA took their cuefrom the MRC in reacting against funding of IVF research(Johnson et al., 2010, p.2167). Indeed, an early reluctancein the USA to fund many areas of reproduction has been doc-umented by Clarke (1998), as was the case for Pincus’ workon the pill (Marsh and Ronner, 2008, p.153). A reliance onwealthy private donors facilitated research on both thedevelopment of the oral contraceptive (Fields, 2003; Tuck,2000) and of IVF (Johnson et al., 2010, p.2168).

These doubts about the ethics of reproductive researchplayed directly to the conflict between evidence base andprofessional autonomy, as is observed very clearly in theMRC’s rejection of the Edwards and Steptoe grant applica-tion. Most referees raised ethical concerns, either aboutthe laparoscopic recovery of oocytes or about the placement

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of IVF-generated embryos into uteri. Every new treatmentpresents issues of risk and safety. The problem was thatthe MRC’s referees failed to recognize infertility as a serioushealth condition, as well as expressing doubt that IVFoffered a realistic solution for its treatment. So the proposalwas not seen as clinically relevant and patients are describedas ‘purely’ research subjects (Johnson et al., 2010), a statusethico-legally very different to that of patients undergoingexperimental treatments (Landsborough Thomson, 1975,p.29). As one of the referees said: ‘From the ethical view-point, it is one thing to subject a woman to a course ofgonadotrophin therapy and a laparoscopy in order to treather infertility. But is it justifiable to carry out these proce-dures solely for the purposes of obtaining ova for in vitroexperiments, which in themselves offer no immediate bene-fit to the patient?’ (Johnson et al., 2010, p.2166). This dis-tinction had been set out by the MRC in 1964:

A distinction may legitimately be drawn between proce-dures undertaken as part of patient-care which areintended to contribute to the benefit of the individualpatient, by treatment, prevention, or assessment, andthose procedures which are undertaken either on patientsor on healthy subjects solely for the purpose of contribut-ing to medical knowledge and are not themselvesdesigned to benefit the particular individual on whomthey are performed. The former fall within the ambit ofpatient-care and are governed by the ordinary rules ofprofessional conduct in medicine (MRC, 1964, p.178).

Quite how the doctor was to ‘know’ that his treatmentmatched his intention ‘to contribute to the benefit of theindividual patient’ was the issue raised by Cochrane and liesat the heart of discussions about EBM. However, it is clearthat research in reproduction was hedged with both ethicaland financial doubts that tended to reinforce thenon-research culture about which the funding agencies wereparadoxically wringing their hands. Each of these cultural,ethical and financial aspects probably contributed to therelatively poor performance and the relatively late entryof reproductive medicine to the research evidence base.

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

From these inauspicious beginnings, reproductive medicinethen took the lead in the development of EBM, with obstet-rics and related specialities featuring prominently amongthe earliest responders to Cochrane’s exhortations. Thus,within 2 years of his book’s appearance, plans were under-way in Cardiff for the identification of controlled trials inperinatal medicine and a critical review of the effective-ness, efficiency and fairness of this medical discipline.The first substantial result of these endeavours was pub-lished in 1982 in the form of Effectiveness and Satisfactionin Antenatal Care, a multi–author volume edited by MurrayEnkin and Iain Chalmers (1982). In their introduction(pp.xi–xii), the editors questioned both the effectivenessand the efficiency of subjecting all pregnant women to alevel of investigation that had been largely developed todeal with more problematic pregnancies, a theme devel-oped by others throughout the volume. For example, Oakley

(Enkin and Chalmers, 1982, p.18) wrote about the develop-ment of the ‘reluctant consumer’ as a result of clinicalinterventions perceived by the patients to be unnecessary.Several authors questioned the value of applying technolo-gies simply because they are available, and presented someevidential support for their doubts. In a concluding chapter,Enkin and Chalmers (1982, pp.266–290) summarized manyexamples of how apparently innocuous interventions, suchas blood tests and even simply giving advice, can have neg-ative outcomes and, stating the issues in two questions,asked: ‘Are we doing more good than harm?’ and ‘Are wedoing the best we can with what we have?’ They made aplea for a more systematic evaluation of the impact of arange of types of interventions by appropriately designedresearch. By 1987–1988, papers on meta-analyses of repro-duction were being published (Daya, 1988; Dickersin, 1988;King et al., 1988; Kramer, 1987) and by 1989, Enkin andChalmers answered their plea emphatically with threemajor publications (Table 1). Indeed, writing in July 1987,shortly before his death, Cochrane (1989), in a forewordto one of these (Effective Care in Pregnancy and Childbirth;Chalmers et al., 1989) described this systematic review ofRCTs of care during pregnancy and childbirth as ‘a newachievement . . . a real milestone in the history of random-ized trials and in the evaluation of care’ and suggested thatthose methods used should be applied by other specialties.He ended: ‘I now have no hesitation whatsoever in with-drawing the slur of the wooden spoon from obstetrics’.

This transformation was in large part due to the commit-ment of Iain Chalmers (Enkin, 1993), who had arrived inde-pendently at a similar view to Cochrane. Chalmers describeshow as a young physician, he became interested in evaluat-ing the effects of health care in 1969 and 1970, while work-ing for the United Nations in a Palestinian refugee camp inthe Gaza Strip (where interestingly Cochrane’s father hadbeen killed in 1917 and where Edwards had done war servicebetween 1943 and 1948):

It gradually dawned on me there that some things I hadbeen taught in medical school were probably lethallywrong. This came as a very sobering realisation: howcould it be that health professionals acting with the bestof intentions could do more harm than good to those wholooked to them for help? After a couple of years in Gaza Ireturned to Britain, to train in obstetrics, in Cardiff, thecapital city of Wales. As a junior obstetrician I was con-fused by the conflicting opinions of senior doctors aboutwhen and how to intervene in pregnancy and childbirth.In 1972, however, a very readable little book came to myrescue. Effectiveness and Efficiency: Random Reflectionson Health Services [Cochrane, 1972] had been written byArchie Cochrane, [this] book and his subsequent friend-ship made me a lifelong sceptic about therapeutic claimsunsupported by reliable evidence. It helped me to under-stand why some forms of research – particularly random-ized controlled trials (RCTs) – were likely to generatemore reliable information than others. In addition, Icould identify strongly with Archie’s commitment tothe decent principle of equitable access to (effective)health-care, and his emphasis on the need to providehumane and dignified (and thus effective) care when noeffective cure was available (Chalmers, 2003, p.243).

Table 1 Early history of Cochrane reviews.

1978 National Perinatal Epidemiology Unit, Oxford, UK established to assemble a register of controlled trials inperinatal medicine

1982 Effectiveness and Satisfaction in Antenatal Care (Enkin and Chalmers, 1982)1985 Publication of classified bibliography of 3500 reports of controlled trials in perinatal medicine published

between 1940 and 19841989 Output of collaborative work begins with publication of:

Effective Care in Pregnancy and Childbirth (Chalmers et al., 1989)

A Guide to Effective Care in Pregnancy and Childbirth (Enkin et al., 1989)

The Oxford Database of Perinatal Trials, version 1 (Sinclair and Bracken, 1992 Chalmers, 1989)

1992 Publication of Effective Care of the Newborn Infant1992 February The Cochrane Centre opens in Oxford, UK1993 October Pregnancy and Childbirth Group registered

Subfertility Group registered

1993 March Neonatal Group registered1994 November Diabetes Group registered1994 October Peripheral Vascular Disease Group registered1994 August Acute Respiratory Infections Group registered1994 June Oral Health Group registered

Schizophrenia Group registered

1994 May Infectious Diseases Group registered1993 November Musculoskeletal Group registered1993 August Stroke Group registered2012 April Of 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.

History of evidence-based reproductive medicine 207

As a result of his exposure to Cochrane’s book, Chalmerstrained in social medicine and statistics, before returning toCardiff obstetrics and gynaecology where in 1974 heembarked on a trawl for reports of perinatal controlled tri-als, spurred in part by criticisms from women about the UKmaternity service (Chalmers, 1976; Chard and Richards,1977). As a result of the evidential uncertainties that hisresearch uncovered, he identified the need to explorewhether all trials were being reported (Chalmers, 1990),whether all reported trials had equivalent value andwhether the results of similar valuable trials (reported ornot) could be combined to yield statistically more robustestimates of treatment effects (meta-analysis). In essence,what were being established were the guidelines for ahigh-quality systematic review of evidence (Chalmers andAltman, 1995). In 1978, Chalmers became the foundingdirector of the National Perinatal Epidemiology Unit inOxford funded by the NHS via the Department of Health(Chalmers et al., 1993; Starr et al., 2009). His endeavoursled in 1992 to the founding of the UK Cochrane Centre (alsostate funded) and ultimately to the Cochrane Collaboration(www.cochrane.org), the major source and repository ofreliable evidence-based healthcare advice internationallyand where, notably, the earliest special interest groups tobe established were in reproductive medicine (Table 1).

Conclusions

Despite its late beginnings, reproductive medicine can quitereasonably consider itself a pioneer of EBM – largely due tothe commitment and drive of Iain Chalmers, with majorcontributions from the McMaster team led by Murray Enkin

(Bryce and Enkin, 1985), who had first met Chalmers in 1978(Enkin, 1993). However, even today within reproductivemedicine there remains a strong tradition of case-basedreporting being given priority over solid research evidence(see Chalmers, 1983 for his early criticisms of such anapproach). There is a role for both, but they inform in dif-ferent ways about different aspects of health care. Indeedit is pertinent to ask ourselves: How would Cochrane viewour approaches to EBM were he here today? After all, whilstthe prospect of the then relatively new RCT excited him, aswould surely the advances in meta-analysis, central to hisvision of evidence was a multi-layered approach to healthcare in which he saw a key role for expert opinion and aclear focus on patient input and variability, aspects thatRCTs can often ignore. Moreover, as we move into the ageof personalized medicine, and the available patient cohortsfor RCT become ever smaller, considerable rethinking aboutthe structure (and value?) of the RCT may become neces-sary. These issues have been addressed by other contribu-tors to the 2012 EBM Symposium. These are importantquestions because, when proponents of one type of evi-dence make excessive claims for it, patients (and indeeddoctors) may suffer: exactly the situation that Cochranesought to avoid.

Acknowledgements

I thank Sarah Franklin, Adele Clarke, Martin Richards andthe RBMOnline referees for their helpful comments ondrafts of this manuscript, for which, however, I alone takeresponsibility, and Margaret Wilson for help in locating somepapers. This research was supported by Wellcome Trust

208 MH Johnson

(grant number 088708) and by a grant from the British Acad-emy to Professor Sarah Franklin.

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Declaration: The author reports no financial or commercialconflicts of interest.

Received 19 June 2012; refereed 23 October 2012; accepted 7November 2012.