Effect of an individualised nutritional intervention on gestational diabetes mellitus prevention in a high-risk population screened by a prediction model: study protocol for a multicentre randomised controlled trial

The aim of this trial is to evaluate the effectiveness of an individualised nutritional intervention for the prevention of GDM among high-risk pregnant women screened by a novel risk prediction model in the first trimester. We hypothesise that providing individualised nutritional consultations at least once a month before the OGTT for high-risk pregnant women will reduce the prevalence of GDM and improve maternal and offspring perinatal outcomes.

The proposed study is a multicentre, open-label, parallel-group randomised trial. A total of 500 eligible women will be recruited from 3 different tertiary hospitals, including +/− 300 from the International Peace Maternity and Child Health Hospital, +/− 100 from Xinhua Hospital, and +/− 100 from Shanghai Fengxian District Central Hospital. A flowchart of participant recruitment, randomisation and follow-up is shown in Fig. 1 (see Additional file 1).

Women in early pregnancy who attend the antenatal clinics of three research centres will be identified by the GDM risk prediction model mentioned above. According to the multiple logistic regression model we previously established, the predictive probability of GDM development in our study population will be calculated with the formula 1/[1 + exp.(−β)], in which β equals (− 14.2334 + (0.0681*age) + (0.5005* blood triglyceride level in the first trimester, mmol/L) + (2.8165* fasting blood glucose level in the first trimester, mmol/L) + (1.1062*family history of diabetes in first-degree relatives) + (1.6925* HbA1c in the first trimester, %) + (0.4349*multiple pregnancy) + (2.6181* previous history of GDM). The area under the receiver operating characteristic curve of this model was 0.77 (95% CI 0.76–0.78). The optimum threshold probability was 0.13 with 59% sensitivity and 82% specificity when the Youden index was set at 0.41 [24]. Consequently, pregnant women with a calculated risk probability of GDM equal to or higher than 0.13 in the first trimester are considered high risk. Among them, pregnant women at less than 14 gestational weeks who are able to understand and provide informed consent and are ready to receive antenatal care and deliver at one of the research centres will be eligible to participate in our study.

We will exclude individuals if they have been diagnosed with the following disorders: pre-pregnancy essential hypertension, renal disease, HIV, hepatitis B or C, cardiac disease, thalassemia, cystic fibrosis, systemic lupus erythematosus or any other autoimmune disease, thyroid disease requiring medication, pregestational diabetes (including patients diagnosed with diabetes before conception; fasting blood glucose ≥7.0 mmol/L or HbA1c ≥ 6.5% in the first trimester; typical hyperglycaemic symptoms or hyperglycaemic crisis with optional blood glucose ≥11.1 mmol/L), or current prescription of medicines, such as metformin and glucocorticoids, that affect blood glucose values.

The research staff will verbally inform eligible pregnant women that the hospital is currently conducting a multicentre clinical trial to identify better preventive strategies for GDM and that they are eligible to participate. If they fully understand and are willing to join the study, they will meet the research staff in person at the hospital, sign an informed consent form and officially participate in the project prior to 14 gestational weeks. Baseline data, including sociodemographic characteristics and medical and maternal history, will be collected by standardised questionnaires. Each participant will be given a sequential study number by research staff. Subsequently, their basic information will be entered into an internet-based and password-protected clinical research management system (ResMan Research Manager, supported by West China Hospital, Sichuan University, China), which will automatically generate a research code and randomly allocate participants to the intervention group or the control group at a ratio of 1:1. The research assistants responsible for data collection, biostatisticians and data analysts will be masked to study group allocation. Given the nature of the intervention, the participants and investigators will be aware of the assignment.

For the intervention group, one-to-one nutritional counselling with the same dietician will be arranged 3 times before the OGTT (13–16 w, 17–20 w, 21–24 w). The average contact time with a dietician will be 30 min for each subject per visit. The primary intention of the nutritional intervention is to promote a long-term healthy dietary pattern and prevent excessive GWG throughout pregnancy, thereby potentially lowering the prevalence of GDM and resulting in better perinatal outcomes. Qualified dieticians from three centres will receive specific training with the aim of establishing a uniform set of intervention standards for the study. The proposed dietary strategies are based primarily on the International Federation of Gynaecology and Obstetrics (FIGO) endorsed guidelines for pregnant women and the Diagnosis and Therapy Guideline for Pregnancy with Diabetes Mellitus (2014) from the Chinese Medical Association (CMA) and Chinese Dietary Guidelines (2016) from the Chinese Nutrition Society [31‐33]. Macronutrient intake composition will be recommended to be in compliance with current clinical practice for patients diagnosed with GDM. Protein, fat and carbohydrates should account for 15–20%, 25–30%, and 45–50%, respectively, of the total energy intake. Low-glycaemic index (GI) foods (target GI ≤ 50) are recommended as carbohydrate sources due to their associations with appropriate GWG and ameliorated maternal glucose tolerance [34]. More specifically, the counselling will focus mainly on GWG management, food preparation techniques, meal timing, and proportions of whole grains, dark green leafy vegetables, nuts, fruits and lean protein consumption. Refined carbohydrate foods and other sugar-rich products will be restricted.

Compared with common dietary consultations, the greatest advantage of the intervention in this study lies in self-administered 3-day food records, a valid resource for nutritionists to pinpoint problems precisely and optimise dietary patterns individually. At enrolment, participants will be instructed by a trained research practitioner on how to record their diet diary in detail. A consecutive 3-day food record should cover 2 weekdays and 1 weekend day excluding special occasions (e.g., banquets, business trips, or tours). To obtain information that can represent participants’ usual dietary intakes, they are asked to truthfully record all foods and beverages consumed as accurately as possible. The food diary consists of consumption time, food category, preparation techniques and the accurate amount of raw ingredients in mixed dishes. To ensure a more precise and unified quantification of foods, participants will receive an 18-page colouring booklet that graphically shows commonly consumed local foods with serving sizes and different measurement tools. It is suggested that participants take pictures of foods for which it is difficult to estimate portion sizes themselves, which provides intuitive evidence for objective postcompletion revision by nutritionists. Before each appointment with a dietician, women assigned to the intervention group will be asked to complete a 3-day food record in advance. To ascertain whether their dietary patterns changed after the OGTT, 2 additional diet diaries will be required to be completed at 27–30 and 32–34 gestational weeks. During the study visits, food records will be entered by dieticians into nutritional analysis software (NutriStar Software, Zhending, China) based on the China Food Composition Tables (2018) [35], which will help to calculate energy and nutrient intake for in-depth quantified evaluation. Then, a tailored dietary prescription will be developed as mentioned above for further management in the intervention group. Subsequent visits will be scheduled by dieticians or research staff at the end of each consultation. Strategies have been established for retention of participants enrolled. A specific trained research staff will be responsible for follow-up and direct communications with all the participants at each trial centre. The research staff will not only remind them in person to fill in 3-day food records or to visit a dietician at designated gestational weeks, but also emphasize the benefits of the study to encourage them to complete follow-up. For convenience, study visits will be arranged in parallel with standard antenatal clinic visits. Additionally, priority access to ultrasound examinations during pregnancy will be provided. Adherence to the intervention is anticipated to be assessed comprehensively taking into consideration nutritional clinic attendance as required and the number of qualified 3-day food records. If needed, comparisons between nutrition prescriptions and actual diet records will be performed.

All the participants in both groups will attend standard antenatal care at their trial centre and will be provided with regular treatments if diagnosed with GDM. The control group will fill in five 3-day food records at designated gestational week periods (13–16 w, 17–20 w, 21–24 w, 27–30 w, 32–34 w) but will not be scheduled to see a study-specific dietician as part of the study. However, the control group participants will be allowed to visit nutritionists themselves for usual antenatal healthy diet advice in accordance with local health care provisions.

The participants will be informed clearly by investigators at enrolment that they may withdraw from the study at any period for any reason without penalty. Written consent will be obtained if the participant agrees to undergo continued follow-up for associated clinical outcomes after withdrawal.

The time schedule of recruitment, intervention, and outcome assessments is presented in Table 1 (see Additional file 2). All pregnant women will take a blood test assessing fasting glucose, HbA1c, and blood triglyceride levels in the first trimester. The number of foetuses will be determined by ultrasound in early pregnancy. After the required data are obtained, the recruiting staff will screen every single pregnant woman at antenatal clinics using the prediction model to determine their eligibility for the study and initiate recruitment as specified previously. Written informed consent, baseline information, and baseline blood pressure plus anthropometric measurements (body weight, height) will be obtained at recruitment. Fasting body weight measured in light clothing without shoes as well as blood pressure will be followed up at 1-month intervals during antenatal visits. The first 3-day food record will be distributed at first contact. Women in the intervention group will receive 3 nutritional consultations that will be paired with 3-day food records at 13–16, 17–20, and 21–24 gestational weeks before the OGTT and submit 2 more diaries after (27–30 w, 32–34 w). The participants in the control group will return their diaries directly to research staff 5 times throughout gestation (13–16 w, 17–20 w, 21–24 w, 27–30 w, 32–34 w). All the participants in both arms will be required to take a 75 g OGTT at 24–28 gestational weeks, the results of which will be the primary end point.

Ethical approval was obtained from the Medical Research Ethics Committees of the International Peace Maternity and Child Health Hospital (25 October 2019, GKLW 2019–11), Shanghai Fengxian District Central Hospital (19 November 2019, 2019-KY-11) and Xinhua Hospital (1 June 2020, XHEC-C-2020-086). All study procedures will comply with the Declaration of Helsinki. All participants will sign a written informed consent before participating in the trial. There were no protocol amendments.

Meetings will be held periodically for progress promotion and quality control. The completion of the study and publication of the results will be attributed to all study collaborators. The participants will receive feedback through open-access publications about the ultimate results of this trial. To reach the widest possible dissemination of the findings, open access publications in high impact journals, oral and poster presentations with interests in GDM prevention will be performed nationwide and internationally.