Progesterone

A protocol with explicitly defined objectives, formal consensus development methods, criteria for participant identification and selection, and statistical methods was developed. The study was prospectively registered with the Core Outcome Measures in Effectiveness Trials (COMET) initiative (registration number 603 available online at www.comet-initiative.org/studies/details/603). The ethics board of the Academic Medical Center, Amsterdam, The Netherlands, advised that ethical approval was not required (reference number E2-172) because this project should be considered as service evaluation and development.
The target of the core outcome set was to capture important outcomes for individual studies, systematic reviews, and guidelines for preterm birth prevention in asymptomatic woman. For our purposes, preterm birth was defined as neonates born alive before 37 weeks of gestation.^{5 (link)} An asymptomatic woman was defined as one without symptoms of preterm labor (e.g increased uterine contractions, menstrual cramps of backache, color change of vaginal discharge, prelabor rupture of membranes). Preventive treatment of preterm birth was defined as one started before any symptoms of preterm labor were present. This preventive strategy could be pharmacologic (e.g. progesterone, marine oils, probiotics) or non-pharmacologic (e.g. cerclage, pessary, lifestyle interventions and alternative therapies).
A Project Steering Committee was established to give guidance to the different phases of this project consisting of two obstetricians (Irene de Graaf, Khalid S. Khan), two neonatologists (Timo de Haan, Stephen Kempley), two midwives (Felipe Castro, Birgit van der Goes), two patient representatives (Aoife Ahern, Mandy Daly) and three methodologists with experience in formal consensus and/or core outcome set methods (James Duffy, Brent Opmeer, and Paula Williamson).
A systematic literature review was undertaken searching the Cochrane Pregnancy and Childbirth Group's (PCG) Trials Register.¹ The Pregnancy and Childbirth Group register is maintained by monthly searches of the Cochrane Central Register of Controlled Trials and weekly searches of EMBASE and MEDLINE and hand-searches of 30 journal and conference proceedings (from January 1997 to January 2011). The register was searched utilizing the register’s codes for preterm birth. Two reviewers (S.M. and Z.A.) independently screened titles and abstracts. They critically reviewed the full text of selected studies and extracted reported outcomes. Any discrepancies were resolved by discussion. In addition, all delegates (n=168) of the First European Spontaneous Preterm Birth Congress (Svendborg, Denmark, May 24–25, 2014), mainly representing obstetricians and researchers, but also midwives, neonatologists and members of industry, were requested via e-mail to recommend potential outcomes.
Patient representatives and parents were invited through social media (Twitter and patient forums on Facebook) to participate in an online questionnaire to share their opinions regarding outcomes relevant to preterm birth. Members of patient organisations including the European foundation for the Care of Newborn Infants, their partner organizations, and parental forums of neonatal baby units were e-mailed by their own organization including an invitation for the online questionnaire through an electronic newsletter. Patients also contributed their opinions through in-person semistructured interviews conducted by one of the authors (J.v.t.H.).
The Project Steering Committee identified outcomes that were duplicated as a result of varied terminologies used by different stakeholders and for grouping closely related outcomes into overarching domains. This outcome inventory of 29 outcomes was entered into a Delphi process (Figure 1).
We used a two-round electronic Delphi survey design, a well-established method to elicit consensus based on an iterative process with anonymous consultation and with controlled feedback and quantified analysis of the responses.⁶ A priori we agreed the important methodological features for our Delphi process: [1] composition of the group; [2] anonymity; [3] how to assess the importance of outcomes; [4] method of feedback of results to participants; [5] how consensus would be reached; [6] how to assess possible attrition bias.
The setting for the Delphi survey was multinational involving stakeholders from middle- and high-income countries. A formal written invitation was e-mailed to all members of the Cochrane Pregnancy and Childbirth group (n=30), the Core Outcomes in Women’s Health initiative (n=77), the European Preterm Birth Congress (n=168), and the Global Obstetrics Network (n=237). Most members of these organizations are researchers (methodologists), obstetricians (mainly specialized in maternal fetal medicine) or neonatologists. The European foundation for the Care of Newborn Infants approached their members themselves, including their partner organizations in Australia, Belgium, Bulgaria, Canada, Chile, Croatia, Cyprus, Denmark, Finland, France, Germany, Greece, Hungary, Ireland, Israel, Italy, Lithuania, Mexico, the Netherlands, Norway, Poland, Portugal, Spain, Turkey, United Kingdom, and the United States. All midwifes from ‘Barts Health Nursing and Midwifery’ (n=132) and some midwifes of the School of Nursing and Midwifery (Galway, Ireland) and the Dutch Consortium for Healthcare Evaluation in Obstetrics and Gynaecology were approached. With this approach we aimed to targeted midwifes who were active in research (50%) and midwifes who were not active in research (50%). In total 337 obstetricians, 152 midwives, 174 researchers, 75 neonatologists, and an unknown number of parents (through the previously mentioned patient organizations) were invited.
We used LimeSurvey for the Delphi survey. The survey was piloted first by eight people representing every stakeholder group. No changes were needed after the pilot. The official survey had a closing date of 5 weeks after the date of invitation for every Delphi round. An e-mail reminder was sent to participants on days 7, 14, 21, and 28. Nonresponders in the first round were not invited to participate in the subsequent round.
Participants were asked to rate the importance of each outcome on a 9-point Likert scale anchored between 1 (‘limited importance’) and 9 (‘critical importance’). The scale is recommended by the Grading of Recommendations Assessment, Development and Evaluation working group: 1–3: limited importance; 4–6: important but not critical; 7–9: critical.^{7 (link)} Participants were invited to recommend additional potential outcomes for consideration at the end of the survey using free-text responses.
The individual, stakeholder group and total results from the first round were relayed back to participants by e-mail; the individual responses directly after filling in the first round questionnaire, the stakeholder group, and total group responses were fed back anonymously 1 day prior to the invitation to the second round of the Delphi survey. Furthermore, participants of the second survey were able to see the mean value of the total group responses from the first Delphi round while completing the survey. Participants were asked to score all the individual outcomes again using the same 9-point Likert scale. No outcomes were excluded in this round to ensure a holistic approach to scoring in round 2.
The Delphi survey responses were analyzed using SPSS version 21.0. For each outcome the median and interquartile range were calculated. Frequency tables of all scores were generated, as well as boxplots for visualization (that were used to relay back the whole and stakeholder group responses). We defined consensus a priori. Core outcomes required at least 70% of participants in each stakeholder group scoring the outcome as ‘critical’ and less than 15% of participants in each stakeholder group scoring the outcome as ‘limited importance’.^{8 (link)} Outcomes which should not be included in a core outcome set required at least 70% of participants in each stakeholder group scoring the outcome as ‘limited importance’ and less than 15% of participants in each stakeholder group scoring the outcome as ‘critical’. If outcomes did not meet either criteria they were classified as outcomes with no consensus. Attrition bias (e.g. a selective group did not respond to the second round of the survey or a selective group participated in the consultation meeting) was assessed by 1) comparing the distribution of median first round scores across the outcomes for those not participating in the second round with those who did; and 2) comparing the distribution of median round 2 scores across the outcomes for those participating in the consultation meeting compared with those who did not.
The final phase of the study was a face-to-face consultation meeting with participants of the Delphi exercise representing all stakeholder groups (Washington, DC, November 9, 2014). This meeting was organized within a meeting for a prospective individual participant data analysis project for studies on the use of pessary in the prevention of preterm birth in asymptomatic women. Eleven participants of this prospective individual patient data project did also took part in the Delphi survey earlier. They mainly represented the stakeholder groups of obstetricians and methodologists. Representatives from the other stakeholder groups (parents, midwives and neonatologists), who were living close to the location of the consultation meeting, were invited for this consultation meeting as well. In total 23 obstetricians, 10 researchers, two neonatologists, two patient representatives, and one midwife were invited to attend this meeting. Information material on the purpose of the consultation meeting and the Delphi round 2 results were sent to participants before the meeting. A plenary presentation on the Delphi survey outcomes was complemented by small group sessions (mixed groups) where participants expressed their views on the candidate outcomes. Only outcomes that did not reach full consensus in the Delphi exercise were presented to the attendees of the meeting with an anonymous voting using electronic touchpads. Consensus in the consultation meeting required a majority of 70% of participants from each stakeholder group approving an individual outcome as ‘critical’ according to the 1–9 Likert scale. With the permission of the participants the consultation meeting was recorded.