A two-arm non-blinded randomised feasibility protocol trial designed to assess the feasibility, safety, and acceptability of an intermittent low energy diet (ILED) vs best National Health Service (NHS) care in women with gestational diabetes and obesity in Greater Manchester.

Overall aim:

The aim of this trial is to test the safety, feasibility, and acceptability of an ILED in GDM to inform a future large-scale RCT.

Background:

Up to 16% of pregnant women in the United Kingdom 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. Our Patient and Public Involvement and Engagement work demonstrates that 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.

Primary Aim: to test the safety, feasibility, and acceptability of an ILED in GDM to inform a future large-scale RCT.

Primary Objectives:

• Uptake rate
• Recruitment rate
• Retention rate
• Adherence to the dietary interventions
• Completion of self-assessed glucose and ketone readings

Safety outcomes:

• Percentage of women following ILED/best NHS care with hypoglycaemia (episodes of blood glucose of <3.0mmol/mol)
• Percentage of women who develop significant ketonaemia in both groups (defined as ≥1.0mmol/L)
• Percentage of neonatal hypoglycaemic episodes requiring intervention, neonatal birth weight, gestational age at delivery, hyperbilirubinaemia/jaundice, and/or admission to Special Care Baby Unit or neonatal intensive care, and stillbirths
• The incidence and rate of other adverse events (e.g. headaches, lethargy, constipation, or complications requiring hospital admission) between the start of the trial intervention and delivery.

Secondary outcomes

• Completeness of collection of trial endpoints
• Fidelity of delivery of the interventions
• Qualitative analysis of the acceptability and implementation of the interventions

Exploratory outcomes The following outcomes will be explored without statistical inference.

1. Maternal outcomes:

   • The percentage of women requiring metformin and/or insulin
   • Four-point capillary glucose profiles during third trimester
   • Change in fasting blood test results between baseline measurements, 36-37 weeks' gestation, and 12 weeks post-delivery
   • Mode of delivery, development of preeclampsia, polyhydramnios (maximum liquor volume pool depth ≥8 cm)
   • Quality of life and health status questionnaires (WHOQoL-BREF and SF-36 questionnaires)

2. Foetal outcomes:

   • Foetal weight
   • Gestational age at delivery

Method:

We aim to recruit 48 women with GDM diagnosed between 24-30 weeks gestation from antenatal clinics at Wythenshawe and St Mary's hospitals, Manchester Foundation Trust, over 13 months starting in November 2022. Participants will be randomised (1:1) to ILED (2 low-energy diet days/week of 1000kcal and 5 days/week of the best NHS care healthy diet and physical activity advice) or best NHS care 7 days/week until delivery of their baby. Primary outcomes include uptake and retention of participants to the trial, and adherence to both dietary interventions. Safety outcomes will include birthweight, gestational age at delivery, neonatal hypoglycaemic episodes requiring intervention, neonatal hyperbilirubinaemia, admission to special care baby unit or neonatal intensive care unit, stillbirths, the percentage of women with hypoglycaemic episodes requiring third-party assistance, and significant maternal ketonaemia (defined as ≥1.0mmol/L) Secondary outcomes will assess the fidelity of delivery of the interventions, and qualitative analysis of participant and healthcare professionals' experiences of the diet. Exploratory outcomes include the number of women requiring metformin and/or insulin.

Qualitative evaluation:

Investigators will undertake qualitative analysis of the experiences and thoughts of approximately 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.

Inclusion Criteria:

1. Pregnant women ≥18 years
2. BMI of ≥27.5kg/m2 or a BMI ≥25 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)
3. 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)
4. 24-30 weeks pregnant at screening appointment

Exclusion Criteria:

1. Pregestational type 1 or type 2 diabetes.
2. Fasting glucose of ≥7 or 2-hour postprandial of ≥11 on OGTT (immediate intervention with medication would be required in this group of women)
3. Current multiple pregnancy
4. Maturity Onset Diabetes of the Young (MODY)
5. 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.
6. Current participation in a GDM medication treatment trial
7. People who are not capable of providing informed consent or adhering to the monitoring and safety protocols
8. 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).
9. Medications at the time of the OGTT that may interfere with results (e.g. high dose oral steroids, immunosuppressants)
10. Previous history of intrauterine growth restriction
11. 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.

To be confirmed

Non blinded (statistician and laboratory staff will remain blinded).