Manchester Intermittent Diet in Gestational Diabetes Acceptability Study (MIDDAS-GDM)

Non blinded randomised feasibility trial designed to assess the feasibility, safety, and acceptability of an intermittent low energy diet (ILED) vs best National Health Service (NHS) care in gestational diabetes.

Overall aim: To study the feasibility and acceptability and safety of an intermittent low-energy diet (ILED) amongst women with gestational diabetes (GDM). Also the feasibility of a randomised controlled trial (RCT) of ILED compared to best NHS care in these women. Background: Up to 16% of pregnant women in the UK develop GDM with rising rates due to increasing rates of obesity and maternal age. GDM affects both maternal and neonatal outcomes and is a high burden to patients and the NHS through frequent clinic visits, monitoring, and costly medications such as insulin. The National Institute for Health and Care Excellence (NICE) guidelines advocate healthy diet (with increased physical activity [PA]) as first-line therapy for GDM with approximately 30% progressing to metformin and/or insulin treatment. Women with GDM are keen for alternative dietary interventions to reduce their need for medications. It has been shown that intermittent low energy diets improve glycaemic control in type-2 diabetes. The investigators wish to test the utility of ILED in GDM. Aims: To explore the feasibility of using an ILED in the management of GDM with the objective of conducting a large, statistically powered RCT of ILED vs. best NHS care. Primary Objectives of the feasibility study: 1. Uptake, recruitment rate and retention to a RCT of ILED vs. best NHS care 2. Adherence to dietary allocation within the ILED and best NHS care groups. 3. Safety outcomes with ILED including episodes of maternal hypoglycaemia or ketonaemia 4. The suitability of progression to medication as a suitable endpoint for a future definitive study. Method: 48 women diagnosed with GDM and obesity (BMI ≥30kg/m2, or ≥27.5kg/m2 in high risk ethnic minority groups) will be randomized 1:1 to an ILED and physical activity intervention or best NHS Care (healthy diet and physical activity) for the third trimester of pregnancy. Both groups will receive the relevant diet and physical activity advice and fortnightly phone support by the study dietician until delivery. Participants will also undergo standard maternal and foetal assessments at baseline, delivery and 12 weeks post-delivery including weight and maternal metabolic parameters. Adherence to the diet and physical activity will be assessed using food records and a diet quality and physical activity questionnaires. The percentage of women in each group requiring metformin and/or insulin, and differences in capillary glucose profiles, HbA1c, insulin, c-peptide and HOMA-IR between the two groups will be analysed. Qualitative evaluation: Investigators will undertake qualitative analysis of the experiences and thoughts of 5 participants per group and healthcare professionals delivering the interventions. Anticipated impact and dissemination: This study will inform the feasibility and design of a definitive RCT of ILED versus best NHS care in GDM. Findings will be disseminated to health professionals and patients through published articles, conference presentations and patient networks in collaboration with the patient and public involvement and engagement panel.

Gestational Diabetes, Gestational Diabetes Mellitus in Pregnancy, Intermittent Fasting, Pregnancy Related, Diabetes, Diabetes in Pregnancy

Personalised advice and support from a diabetes dietician to follow NICE healthy eating diet and physical activity recommendations for GDM.

Two non-consecutive days of a food based 1000 kcal diet and five days of the NICE healthy eating diet and physical activity recommendations for the best NHS care group.

Uptake to trial will be measured as a percentage of eligible participants who consent to participate in the trial per month.

Retention rate will be measured as the percentage of participants who complete all scheduled 8 visits.

Self-reported adherence to the two low-calorie days per week completed expressed as a percentage of the potential low-calorie days in the intermittent low energy diet group.

The number of completed glucose (4 times a day) and ketone (3 times a day on two days of the week) measurements in both groups over the course of the study.

Overall diet quality will be assessed using the United Kingdom Diabetes and Diet Questionnaire (UKDDQ) at four time points within the study and changes in scores will be compared both within and between groups. The UKDDQ enables participants to state how often they eat specific foods and partake in particular eating behaviours, and gives each option a letter between A-F. The numbers of each letter are added up at the end of the questionnaire and this correlates with 'healthy', 'less healthy', and 'unhealthy' dietary choices (E and F = unhealthy, C and D = less healthy, A and B = healthy).

Scores recorded at four time points : 27-29 weeks' gestation, 31-33 weeks' gestation, and 36-37 weeks' gestation, and at 12-13 weeks postpartum

The number of episodes of hypoglycaemia (capillary blood glucose of <3.0 mmol/l) will be measured and compared between groups.

The number of episodes of ketonaemia (capillary ketones >1 mmol/l) will be measured and compared between groups.

Incidence of hyperbilirubinaemia/jaundice (defined as a total serum bilirubin level above 86 μmol/l) in neonates will be recorded in both groups.

Rates of admission to Special Care Baby Unit or Neonatal Intensive Care will be recorded in both groups.

A subset of participants in both groups (approximately 5 participants from each group) will be invited to an optional qualitative substudy which will involve one semi-structured interview at the end of the intervention. Participants will be asked about their experiences and thoughts regarding the intervention. Key themes will be identified using Braun and Clarke's thematic analysis to identify key issues around the acceptability of the test intervention.

Completion of scheduled patient contacts with the trial dietitian and gestational diabetes midwife will be recorded and compared between groups.

Participants will be asked to complete 4-day food diaries for 4 weeks of the trial at 24-28 weeks' gestation, 34-35 weeks' gestation, 36-37 weeks' gestation, and 12-13 weeks postpartum. They will also be given the option of recording diaries during the other weeks as this may help with their adherence. Completion rates of the food diaries each week across the whole intervention as a percentage of weeks in both groups will inform the utility of food diaries for tracking diet behaviour in both groups

4 day food diaries at 24-28 weeks' gestation, 34-35 weeks' gestation, 36-37 weeks' gestation, and 12-13 weeks postpartum.

Change in maternal weight (kg) from 27-29 weeks' gestation until final postpartum visit at 12-13 weeks postpartum will be measured and compared within and between groups

Recorded at 27-29 weeks' gestation, 31-33 weeks' gestation, 36-37 weeks' gestation, weight at delivery (on arrival at hospital and within 24 hours following delivery), and at 12-13 weeks postpartum.

Bloods will be taken at 27-29 weeks' gestation, 36-37 weeks' gestation, and at 12-13 weeks postpartum. Changes in HbA1c between these time points will be compared within and between groups and expressed in mmol/mol.

Bloods will be taken at 27-29 weeks' gestation, 36-37 weeks' gestation, and at 12-13 weeks postpartum. Changes in fasting glucose between these time points will be compared within and between groups and expressed in mmol/L.

Bloods will be taken at 27-29 weeks' gestation, 36-37 weeks' gestation, and at 12-13 weeks postpartum. Changes in insulin levels between these time points within and between groups will be compared and expressed in mU/L.

Oral Glucose Tolerance Test (OGTT) will be completed at 11-13 weeks postpartum. Fasting and 2 hour postprandial bloods will be measured and the percentage of women with a diagnosis of residual diabetes according to the World Health Organization (WHO) criteria will be reported in both groups.

HOMA-IR will be calculated from fasting glucose and insulin measurements [(fasting insulin mU/L x fasting glucose nmol/L)/22.5] assessed at 27-29 weeks' gestation, 36-37 weeks' gestation, and at 12-13 weeks postpartum. Changes in HOMA-IR between these time points will be compared within and between groups.

Health status (SF-36) questionnaires will be completed in both groups and scores compared both within and between groups. Scores range from 1-100; the lower the score the more the disability, the higher the score the more favourable the health state.

Recorded at 27-29 weeks' gestation, 31-33 weeks' gestation, 36-37 weeks' gestation, and at 12-13 weeks postpartum

Quality of life (WHOQoL-BREF) questionnaires will be completed in both groups and scores compared both within and between groups. This questionnaire measures four domains (physical health, psychological, social relationships and environment). Final scores range between 1-100; higher scores indicate a higher quality of life.

27-29 weeks' gestation, 31-33 weeks' gestation, 36-37 weeks' gestation, and at 12-13 weeks postpartum

Four-point capillary glucose profiles (four times daily) between 27-29 weeks' gestation and delivery will be compared within and between groups. The percentage of women within target ranges will be reported within and between groups (fasting <5.3 and 1 hour postprandial <7.8 mmol/l).

Inclusion Criteria: Pregnant women ≥18 years BMI of ≥30kg/m2 or a BMI ≥27.5 kg/m2 in high risk minority ethnic group (i.e. South Asian, Black African, African Caribbean) and <50 kg/m2 at booking appointment (8-12 weeks' gestation) Newly diagnosed GDM according to local diagnostic criteria (fasting glucose ≥5.3mmol/l and/or 2-hour postprandial glucose ≥8.5mmol/l in a 75g OGTT) scheduled to receive first line diet and physical activity (best NHS care) 24-28 weeks pregnant at screening appointment Exclusion Criteria: Pregestational type 1 or type 2 diabetes. Fasting glucose of ≥7 or 2-hour postprandial of ≥11 on OGTT (immediate intervention with medication would be required in this group of women) Current multiple pregnancy Maturity Onset Diabetes of the Young (MODY) Significant comorbid disease that in PI's opinion would preclude participation in the study e.g. chronic kidney disease, significant cardiac disease, history of disordered eating or severe psychological problems. Current participation in a GDM medication treatment trial People who are not capable of providing informed consent or adhering to the monitoring and safety protocols People who have previously had bariatric surgery for weight loss including gastric bypass and sleeve gastrectomy, and/or those prescribed weight loss medications (e.g. orlistat). Medications at the time of the OGTT that may interfere with results (e.g. high dose oral steroids, immunosuppressants) Previous history of intrauterine growth restriction Women who have lost more than 5% of their weight from booking appointment to screening appointment.

Patient identifiable data will not be shared. Anonymised trial data will be available on reasonable request to the investigators.

Data will be available following data analysis and publication, and will be accessible for 5-10 years.