Features of randomised trials designed by the NPEU Perinatal Trials Service during Adrian Grant’s directorship
Adrian Grant pioneered methodological innovations in the randomised trials organised by the Perinatal Trials Service established at the national Perinatal Epidemiology Unit in Oxford, UK. This Commentary discusses these innovations, and shows the wide range of trials designed under his directorship.
In his article recording Adrian Grant’s pioneering use of evidence synthesis in perinatal medicine between 1980 and 1992, Iain Chalmers  quoted from a 1984 letter published in The Lancet which Iain and I had co-authored with Adrian . In that letter we alluded to some of the additional principles - beyond the need for systematic review of existing evidence - which became methodological features of the wide range of randomised trials organised by the Perinatal Trials Service (PTS) established at the national Perinatal Epidemiology Unit (NPEU). The trials are listed in Appendix 1.
Our 1984 letter concluded with a warning that, to avoid the dangers of false inferences from non-randomised comparisons and small randomised trials, many perinatal controlled trials require sample sizes larger than any single unit can generate within a reasonable length of time. Although one centre was sufficient to obtain sufficient sample sizes to address some questions, for other questions, multicentre (often international) trials were needed.
Secure, random allocation
The NPEU PTS used a variety of contextually appropriate methods for secure random allocation - sequentially numbered sealed opaque envelopes, sequentially numbered drug vials, and central random allocation when there was sufficient time to make a call and where reasonable telecommunications existed.
Most of the trials used two-armed, individually randomised designs. Where appropriate, more complex designs were employed, including factorial trials and a cluster randomised trial.
Involving the views of care-givers and patients and their families
The PTS recognised that our work needed to address questions considered important by caregivers and families, so they were involved in deciding which questions to address, trial design and conduct, and dissemination of results. Taking account of families meant that many PTS trials investigated long term outcomes, such as pain, dyspareunia and incontinence for women, and disability for children.
A programme of randomised trials to support these methodological underpinnings needed an infrastructure and the PTS was established in 1982 “to provide a service to busy clinicians who wish to mount large simple-in-design randomized trials...[aiming] to identify moderate, but clinically useful, effects of promising treatments for the most important problems in perinatal care” .
The PTS had a flexible five-person core staff and others employed to work on specific trials. This continuity of staff enabled us to build standard operating systems. International trials needed particularly careful coordination, and the provision of trials materials in a number of languages. The eclampsia trial , for example was preceded by a pilot study in Argentina, with materials in Spanish.
Adrian Grant’s legacy for perinatal trials
Adrian Grant’s methodological innovations
• Identification and prioritisation of important questions
• Systematic reviews
• Alliance of patients, carers, and clinicians
• Efficient trial conduct
• Secure randomisation
• Appropriate design, outcomes, and size
• Support for participants
• Integral economic evaluation
• Embedded methodological research
• Long term follow up
• Feedback of trial results
Adrian continued to support trials in Aberdeen after his move to direct the Health Services Research Unit there (https://www.abdn.ac.uk/hsru) in 1994, and then for the National Institute for Health Research (http://www.nihr.ac.uk).
Many people are grateful for Adrian’s methodological rigor, his innovative approaches, and his generosity of support, mentoring and teaching. The lives of many babies and their families have been improved by Adrian’s pioneering work in perinatal trials, and the PTS that Adrian created has gone on to become a highly successful Clinical Trials Unit (https://www.npeu.ox.ac.uk/ctu).
DE is the sole contributor. The author read and approved the final manuscript.
Consent for publication
The authors declare that they have no competing interests.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
- 2.Chalmers I, Elbourne D, Grant A. Phenobarbitone and periventricular haemorrhage. Lancet. 1984;1:286.Google Scholar
- 12.Rotchell YE, Cruickshank JK, Phillips Gay M, Griffiths J, Stewart A, Farrell B, Ayers S, Hennis A, Grant AM, Duley L, Collins RE. Barbados low dose aspirin study in pregnancy (BLASP): a randomised trial for the prevention of pre-eclampsia and its complications. Br J Obstet Gynaecol. 1998;105:286–92.CrossRefPubMedGoogle Scholar
- 13.Olsen SF, Sorensen JD, Secher NJ, Hedegaard M, Henriksen TB, Hansen HS, Grant AM. Randomized controlled trial of the effect of fish-oil supplementation on pregnancy duration. The lancet. 1992. 1992;339(8800):1003–7.Google Scholar
- 19.Grant AM, O'Brien N, Joy M-T, Hennessy E, MacDonald D. Cerebral palsy among children born during the Dublin randomized trial of intrapartum monitoring. Lancet 1989;ii(8674):1233–1236.Google Scholar
- 27.Mahomed K, Grant AM, Ashurst H, James D. The Southmead perineal suture study. A randomized comparison of suture materials and suturing techniques for repair of perineal trauma. Br J Obstet Gynaecol 1989 1989;96(11):1272–1280.Google Scholar
- 32.Grant AM, Gordon B, Mackrodt C, Fern E, Truesdale A, Ayers S. The Ipswich childbirth study: one year follow-up of alternative methods used in perineal repair. Br J Obstet Gynaecol. 2001;108:34–40.Google Scholar
- 38.Ventriculomegaly Trial Group. Randomised trial of early tapping in neonatal posthaemorrhagic ventricular dilatation. Arch dis child. 1990. 1990;65(1):3–10.Google Scholar
- 39.Ventriculomegaly Trial Group. Randomised trial of early tapping in neonatal posthaemorrhagic ventricular dilatation: results at 30 months. Arch dis child. 1994. 1994;70(2):F129–36.Google Scholar
- 40.Collaborative Dexamethasone Trial Group. Dexamethasone therapy in neonatal chronic lung disease: an international placebo controlled trial. Pediatrics. 1991;88:421–7.Google Scholar
Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.