Follow-up at 1 year and beyond of women with gestational diabetes treated with insulin and/or oral glucose-lowering agents: a core outcome set using a Delphi survey

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The prevalence of gestational diabetes mellitus (GDM) is increasing worldwide and ranges between 5.2% and 40.4% across countries; this wide variability reflects multiple factors such as BMI, ethnicity, country income, and also the diagnostic criteria used [1]. Based on the International Association of Diabetes in Pregnancy Study Group (IADPSG) criteria, the European prevalence of GDM is approximatively 13% [2, 3]. Medical nutritional therapy (diet and exercise) is the first step in the treatment of GDM [4]. However, if the desired glycaemic goals are not achieved, pharmacological treatment will be required.

GDM is linked with a substantial lifetime risk of developing type 2 diabetes. A meta-analysis conducted on studies published over the last 50 years showed that women with a history of GDM have a higher risk of developing type 2 diabetes (RR 7.4) compared with women with normal glucose tolerance (NGT) in pregnancy [5]. Women with previous GDM are more likely to develop the metabolic syndrome [6] and cardiovascular disorders [7] in later life. Several studies have shown that women with GDM have a higher risk of developing postpartum depression [8, 9]. There is also a growing body of literature associating a history of GDM with the development of tumours, particularly breast and endometrial tumours [10].

Women with GDM should be screened for persistent diabetes or impaired fasting glucose and/or impaired glucose tolerance at 6–12 weeks postpartum using non-pregnancy criteria [11]. However, there is no standardised approach to the long-term follow-up of women with a previous GDM diagnosis. The results of clinical trials evaluating comparable interventions are usually summarised in systematic reviews and meta-analyses that provide the basis for guidelines and treatment recommendations. However, there is little consistency in outcome selection and reporting in clinical trials involving this population. This inconsistency raises concern for possible outcome selection bias, makes significant research synthesis difficult and limits the ability to combine the findings of individual studies into summary estimates. One way to overcome this is to develop a core outcome set (COS).

A COS is the minimum set of outcomes that should be consistently measured and reported in all clinical trials (and other studies). However, this does not restrict researchers from adding additional outcomes. A minimum set of outcomes will provide greater uniformity of reporting in clinical trials and more data to impact meta-analyses. Also, a COS will reduce study heterogeneity and the risk of reporting bias by consistently measuring and reporting these outcomes.

The Core Outcome Measures in Effectiveness Trials (COMET) initiative aims to standardise outcome reporting in trials, facilitates participation of diverse experts undertaking research and minimises duplication of work [12, 13]. The Core Outcome Set STAndards for Reporting (COS-STAR) is a checklist designed to be applicable regardless of the consensus methods used to develop the COS and the various participant groups [14]. The COS-STAR checklist provides guidance for minimal COS study reporting and its purpose is to promote the transparency and completeness of reporting in all COS studies. The CoRe Outcomes in Women’s and Newborn health (CROWN) initiative encourages the development of COSs in women’s and newborns’ health.

The aim of this study was to develop a COS for trials and other studies evaluating the long-term follow-up at 1 year and beyond of women with previous GDM treated with insulin and/oral glucose-lowering agents. This study focuses only on women with GDM treated with insulin and oral glucose-lowering agents as this population has more severe glucose abnormalities and are more likely to progress to type 2 diabetes, obesity and the metabolic syndrome [15, 16].

This study is registered in the COMET database [17]. Ethical approval for the study was obtained from the Galway University Hospitals Research Ethics Committee (reference CA 1905).

The three work packages of the study were: (1) a systematic review of literature that identified all the outcomes reported in clinical trials that involved the long-term follow-up of this population; (2) a Delphi survey in which all outcomes were scored and prioritised by key stakeholder groups to provide a preliminary list of final outcomes; and (3) a consensus meeting where the final list of outcomes was decided.

A total of 3344 titles and abstracts were identified. Following review of the title and/or abstracts, 62 full text papers were retrieved and assessed for eligibility. A further 37 papers were excluded following full text assessment, leaving 25 papers in the review (ESM Table 1). Following data extraction, 121 individual outcomes were identified. Following the SAG meeting, similar outcomes were combined, leaving a final 116 outcomes to be grouped and included in round 1 (ESM Fig. 1).

Round 3 was completed by 165 participants (86.8%). Similar to round 2, outcomes were brought forward when 70% or more participants scored the outcome as 7–9 and <15% participants scoring as 1–3. In total, 30 outcomes went through the consensus meeting (ESM Table 3).

This study used robust methods to develop the first COS relevant to the follow-up of women with previous gestational diabetes treated with insulin and/or glucose-lowering agents. A Delphi consensus panel with 20 representatives from ten countries agreed on nine outcomes to be included in the final COS. It is advised that all studies in this area use this COS to facilitate comparison among studies and limit heterogeneity and reporting bias. The application of agreed methods in developing a COS and the participation of multiple stakeholder groups assure the wide applicability and dissemination of this COS.

The wide applicability of the study was one of the main reasons why the outcomes ‘75 g oral glucose tolerance test’, ‘Blood glucose level at 2 h during the 75 g oral glucose tolerance test’, ‘Fasting glucose’ and ‘HbA_1c blood levels’ were combined into ‘Assessment of glycaemic status’; in so doing, the COS permits researchers the opportunity to assess glycaemic status according to their own national guidelines and resources. In addition, this COS identifies ‘what is to be collected’ and not ‘how it is to be collected’, which will be the subject of future work. Similarly, ‘Impaired fasting glucose’ and ‘Impaired glucose tolerance’ were combined as ‘Diagnosis of prediabetes since the index pregnancy’ to give the COS a worldwide applicability in light of the variability in diagnostic tools and criteria. However, while we would recommend that collection and reporting of all outcomes in the COS is mandatory, researchers can choose to collect any additional outcomes required for their study, including specific indices of glycaemic control.

Of importance, the COS consensus meeting had representation from a variety of health professionals/specialties, both local and international, and included women with a previous diagnosis of GDM. This stakeholder composition permitted both the health professionals and women to bring their experience and perspectives to the issues under discussion. Each participant was able to have an understanding of what was important to the other person and what was feasible. Ultimately, this resulted in shared decision-making in a study that will impact future research of women with gestational diabetes.

There are some limitations to our study. Currently, there are no methods for sample size calculation for this type of study. To minimise the potential for selection bias, participants were invited through international organisations and personal professional email lists. Only participants who completed each survey round were recorded. From the totality of initial emails sent before round 1, we had a 35% response. This response rate, however, included participants from 33 countries and five continents. We had a 34% drop-off rate between round 1 and round 2, but, impressively, 87% of participants who completed round 2 also completed round 3. There was a low response rate among primary care physicians (3.5%).

Another potential limitation of this study is the large number of items to be scored in rounds 1 and 2 of the online Delphi survey, which may have impacted negatively on the survey response rate.

We had a large percentage of international participants, including individuals from high-income, upper- and lower-middle-income countries. However, low-income countries were under-represented, and this may limit the generalisability of this COS to certain parts of the world. The participants at the consensus meeting tried to overcome this by rephrasing or combining outcomes in order to increase the worldwide applicability of the COS.

The access to service users was limited by data protection laws, so participants were recruited through the clinical facilities. Despite this, 30% of respondents in round 1 were international service users. At the consensus meeting, 50% of service user participants were non-Irish. We sought international participation for the COS to have global relevance. The service user representatives made important suggestions on all the outcomes discussed at the consensus meeting. Anonymous voting (via the electronic app during this meeting) aimed to prevent participants feeling compelled to vote in a certain way. It has been advocated that the views of health service users should be given greater value in the development of a COS [20] as outcomes reported for clinical studies might not reflect endpoints that are meaningful for them. Examples exist where health service users identified an outcome important to them as a group that might not have been considered by clinicians [21, 22, 23]. However, the responses from health service users and the responses from other stakeholder groups were generally concordant.

The strengths of the study include our use of robust methods in the COS development, including adherence to the COS-STAR statement, the thoroughness of the systematic review (six databases were searched for relevant studies), the high number of participants and the diversity of stakeholder groups participating at each stage of the COS.

Recent review papers have shown the degree of outcome reporting bias among studies, with the main outcome not being reported in up to 47% of the studies and inadequately reported in up to 76% of the studies reviewed [24, 25, 26]. Therefore, there is a cogent argument for creating and disseminating a COS to harmonise outcome reporting.

This is the first study to outline a COS for the long-term follow-up of women with previous GDM. We encourage all investigators undertaking research in this field to report, as a minimum, this COS to reduce reporting bias by allowing evidence synthesis across clinical studies. This will ultimately lead to improvements in the quality of research and delivery of evidence-based healthcare for women with GDM.