Antenatal Myo-inositol Supplementation in Pre-existing Diabetes (AMulet)

Antenatal Myo-inositol Supplementation in Pre-existing Diabetes to Promote Normal Neonatal Outcomes

This feasibility pilot study aims to gather data that can guide the design of a larger, more comprehensive trial to establish the effects of myo-inositol supplementation on supporting healthy outcomes in pregnancies complicated by Type 2 Diabetes Mellitus (T2DM). It seeks to assess myo-inositol's potential to support fetal and neonatal health, and optimise maternity outcomes as a complementary approach and adjuvant to existing diabetes mellitus therapies, as well as investigate the underlying biological mechanisms.

Study Overview

• Status: Recruiting
• Conditions: Perinatal and Neonatal Outcomes in Pregnancies With Type 2 Diabetes Mellitus (T2DM)
• Intervention / Treatment: Dietary supplement: Myo-inositol and folic acid supplement; Dietary supplement: Folic acid supplement

Detailed Description

The "Antenatal Myo-inositol supplementation in pre-existing diabetes to promote normal neonatal outcomes (AMulet)" pilot study aims to inform the design of a future double-blind randomised controlled trial which can assess the benefits of myo-inositol supplementation in pregnant women with T2DM. Despite provision of the international standard of care, pregnancies complicated by diabetes remain at high risk of adverse perinatal and neonatal outcomes. Offspring exposed to maternal diabetes in-utero also face increased risks of obesity and cardiometabolic diseases later in life. Myo-inositol supplementation has been trialled in pregnancy for the prevention and treatment of gestational diabetes, as well as in non-pregnant adults with T2DM, where improvements in glycaemic regulation and reduced insulin resistance have been observed with supplementation. However, myo-inositol supplementation has not yet been studied in pregnancies with T2DM. The primary aim of the AMulet trial would be to assess whether myo-inositol supplementation in pregnancies with T2DM can support normal fetal size and neonatal wellbeing. The present AMulet pilot study will assess the feasibility and acceptability of conducting such a trial and, additionally, seek to investigate the biological mechanisms through which myo-inositol may influence maternal and offspring health outcomes.

This pilot will recruit 182 pregnant women with T2DM between 12-16 weeks' gestation into a double-blind placebo-controlled randomized study. All participants will be randomly assigned to either an intervention group (receiving supplementation of myo-inositol with folic acid) or a control group (receiving supplementation with folic acid only). Supplementation will be in the form of similar looking capsules to be taken twice daily from recruitment until delivery.

Data and samples will be collected longitudinally across three study visits during pregnancy that will be arranged to coincide with routine antenatal clinic visits where possible, and a fourth visit soon after delivery. Additionally, there will be two re-supply visits and a post-delivery videoconference call. Other study data comprising antenatal, peripartum, fetal and neonatal outcomes will be extracted from medical records during pregnancy and post-delivery to assess the primary and secondary outcomes.

The binary composite primary outcome of normal fetal/neonatal size and wellbeing will be assessed by analyses on an intention-to-treat basis. Secondary outcomes, comprising maternity and other infant outcomes, will be assessed and quantified in terms of relative risk or mean differences between study groups. Adverse events, participant feedback as well as mechanistic understanding will be obtained.

This structured approach will inform the design of a future RCT by gathering data on feasibility and acceptability, identifying potential issues in protocols and data collection tools, and facilitating sample size calculations for the main trial which will aim to support the optimization of maternal and offspring health outcomes in pregnancies complicated by pre-existing T2DM.

• Study Type: Interventional
• Enrollment (Estimated): 182
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Gladys Woon, Bsc; Phone Number: +65 6516 4134; Email: gladys_woon@nuhs.edu.sg

Study Locations

• Singapore
  • Singapore
    • Singapore, Singapore, Singapore, 119228
      • Recruiting
      • National University Hospital
      • Contact: Gladys Woon, Bsc; Phone Number: +65 6516 4134; Email: gladys_woon@nuhs.edu.sg
      • Principal Investigator: Shiao-Yng Chan, MBBChir (UK), FRCOG (UK), PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria

• Pregnant women aged 21 years to 45 years old at the time of recruitment
• Ongoing, viable, singleton intrauterine pregnancy
• Between 12+0 days-16+6 days weeks' gestation at recruitment
• T2DM diagnosed by a documented 75g Oral Glucose Tolerance Test (OGTT) showing a fasting glucose of >7 mmol/L or 2h glucose >11.1 mmol/L, or an HbA1C >6.5%, either prior to pregnancy or during the first 16 weeks of the index pregnancy
• Intend to receive antenatal care and give birth at NUH
• Willing to provide written, informed consent
• Able to swallow capsules and comply with trial procedures

Exclusion Criteria

• Known or suspected fetal aneuploidy or genetic/structural anomaly
• Severe allergy to food items requiring carriage of an Epipen at all times

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Supportive Care
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Intervention (myo-inositol and folic acid supplement); Participants in the intervention arm will receive a total of 4 g/day of myo-inositol and 300 mcg/day of folic acid, divided into two daily doses.	Dietary supplement: Myo-inositol and folic acid supplement; Participants will take 4 capsules in the morning and 4 capsules in the evening, each capsule containing 500 mg of myo-inositol and 37.5 mcg of folic acid. Capsules are to be swallowed whole with a drink, starting from 12-16 weeks' gestation and continued until delivery.
Active Comparator: Control (folic acid supplement); Participants in the control arm will receive a total of 300 mcg/day of folic acid, divided into two daily doses.	Dietary supplement: Folic acid supplement; Participants will take 4 capsules in the morning and 4 capsules in the evening, each capsule containing 37.5 mcg of folic acid. Capsules are to be swallowed whole with a drink, starting from 12-16 weeks' gestation and continued until delivery.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Composite of fetal/neonatal wellbeing	Number and proportion of cases displaying all of the following outcomes of (1) being appropriately-grown-for-gestational-age (AGA; 10th-90th centile in weight) at birth; (2) delivered at term (37 weeks+0 days gestation or more); (3) no admission to the neonatal unit in the first 4 weeks of life; and (4) alive at delivery and at 4 weeks post-delivery. Results will also be presented as a relative risk with 95% confidence intervals, with and without adjustment for important covariates, as well as with and without stratification for baseline HbA1C (high/low), pre-pregnancy insulin treatment, duration since T2DM diagnosis (<1y, >1y), and in per-protocol analyses.	From birth until 4 weeks post-delivery

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Intrauterine fetal growth and wellbeing as assessed by antenatal serial ultrasound scans	Mean differences in cross-sectional comparisons and longitudinal changes in measured biometric parameters, derived size/weight estimates and Doppler assessments, as well as differences in the velocity of growth, peak/nadir in the velocity of growth and its gestational timing, and the fastest/slowest change in growth velocity and its gestational timing, with and without adjustment for important covariates.	Up to 38 weeks duration, from the earliest scan in pregnancy ~5-6 weeks' gestation until delivery of the baby between 22-42 weeks' gestation.
Neonatal anthropometry and body composition	Number and proportion, and relative risks, of macrosomia (birthweight >4000 g), low birthweight (<2500 g), Large-for-Gestational-Age (LGA; birthweight >90th centile), and Small-for-Gestational-Age (SGA; birthweight <10th centile), and mean differences or categorically-defined outcomes of birthweight, birth length, head circumference, abdominal circumference, mid-arm circumference, skinfold thickness, fat mass, fat-free mass, and percentage body fat (assessed by air displacement plethysmography, PEAPOD), with and without adjustment for important covariates. Continuous data to be standardised to z-scores, where appropriate.	Birth till 4-6 weeks post-delivery
Other perinatal and neonatal outcomes	Number and proportion, and relative risks, of neonatal respiratory distress (aetiology and treatment required), neonatal hypoglycemia, number of hypocount values <2.6 mmol/L, hyperbilirubinemia requiring phototherapy or exchange transfusion, neonatal sepsis (early and late onset, aetiology and treatment required), shoulder dystocia, birth trauma, hypoxic ischaemic encephalopathy/intracranial haemorrhage, neonatal unit admission, or stillbirth/neonatal death, as well as mean differences in the levels of glycaemia and bilirubinaemia, and in the duration of respiratory support, phototherapy and neonatal unit/hospital stay, with and without adjustment for important covariates. Continuous data to be standardised to z-scores, where appropriate.	Birth till 4-6 weeks post-delivery
Fetal (cord) insulinaemia and C-peptide	Number and proportion, and relative risks of fetal hyperinsulinaemia or high C-peptide concentration, and mean difference in insulin or C-peptide concentrations in umbilical cord blood (where obtainable); with and without adjustment for important covariates	At birth
Maternal glycaemic control	Mean differences and change in blood glucose levels (monitored through self-blood glucose monitoring or continuous glucose monitoring, CGM), other CGM parameters, markers of glycemic control, the frequency of participant-managed hypoglycemic episodes, proportional increases in metformin or insulin doses, and mean differences in daily insulin requirements per kilogram (kg) of body weight, proportion requiring other diabetes treatments, mean differences and change in HbA1C and HOMA-IR; with and without adjustment for important covariates. Continuous data to be standardised to z-scores, where appropriate.	Up to 100 weeks duration, from within a year before conception (last recorded before conception) or early pregnancy (between conception and recruitment between ~12-16 weeks gestation), until the delivery of the baby (between 22-42 weeks gestation).
Hypertensive disorders of pregnancy	Number and proportion, and relative risks, of pre-eclampsia/eclampsia, superimposed pre-eclampsia on chronic hypertension, and pregnancy-induced hypertension (as a composite and as individual complications), as well as difference in the gestational age of onset or diagnosis and severity of disorder, with and without adjustment for important covariates.	Between time of recruitment (~12 to 16 weeks of gestation) and 4-6 weeks post-delivery
Gestational age at delivery and preterm prelabour rupture of membranes (PPROM)	Number and proportion, and relative risks, of PPROM and preterm delivery (spontaneous and/or iatrogenic births), reasons for preterm birth, as well as the gestational ages at delivery and at PPROM will be presented, with and without adjustment for important covariates.	Between time of recruitment (~12 to 16 weeks of gestation) and delivery
Gestational weight gain	Mean differences in the total weight a woman gains during pregnancy, measured in kilograms (kg), as well as the rate of weight gain over the second and third trimesters of pregnancy (kg/week). Proportional differences in the categorisation of weight gain by the Institute of Medicine (IOM) guidelines as insufficient, appropriate, or excessive (considering the mother's pre-pregnancy BMI), with and without adjustment for important covariates	Up to 100 weeks duration; From pre-pregnancy (last recorded weight before conception) or earliest recorded weight in pregnancy (between conception and recruitment) to the last recorded weight before delivery (22-42 weeks gestation).
Maternal depressive and anxiety symptoms	Mean differences and change from baseline in scores of maternal depression and anxiety symptoms on validated questionnaires (Edinburgh Postnatal Depression Scale and State-Trait Anxiety Inventory), and proportional differences between groups in those with higher and lower scores, with and without adjustment for important covariates. Continuous data to be standardised to z-scores, where appropriate.	Between time of recruitment (~12 to 16 weeks of gestation) and 4-6 weeks post-delivery
Mode of delivery	Number and proportion, and relative risks, of caesarean section, primary caesarean section, emergency caesarean section, and instrumental delivery, with and without adjustment for important covariates.	At delivery
Postpartum blood loss	Number and proportion, and relative risks, of major postpartum haemorrhage (primary and secondary), and mean differences in the volume of blood loss (primary and secondary), with and without adjustment for important covariates.	At delivery and up to 4-6 weeks post-delivery
Other antenatal and peripartum events	Number and proportion, and relative risks, of antenatal complications such as intrahepatic cholestasis, placental abruption and antepartum haemorrhage, and peripartum events encompassing type of onset/induction and progress of labour, requirement for labour augmentation, non-reassuring cardiotocography suggestive of fetal compromise, meconium-stained liquor, shoulder dystocia, perineal trauma, admission to high-dependency/intensive care unit, and other relevant complications, as well as mean differences in the duration of each stage of labour and entire labour, and length of maternal HDU/ICU/hospital stay, with and without adjustment for important covariates.	From conception to 4-6 weeks post-delivery
Circulating, urinary and placental inositol and inositol-metabolite concentrations	Mean differences in cross-sectional comparisons and longitudinal changes from baseline in maternal circulation and urinary concentrations of myo-inositol and the other 4 inositol isomers, and inositol metabolites, as well as mean differences in circulating fetal/cord concentrations of these inositols/inositol-metabolites at birth, and in placental and fetal membrane tissues; with and without adjustment for important covariates.	Between time of recruitment (~12 to 16 weeks of gestation) and delivery
Multi-Omic Profiling	Differences in the characteristics and quantities of each element/class of the biochemical, metabolic, metabolomic, hormonal, chemoadipocytokine, proteomic, lipidomic, genomic, epigenomic and transcriptomic profiles as well as tissue tensile strength (where applicable) in maternal blood & urine, fetal (umbilical cord) blood & tissue, placenta and fetal membranes.	Between the time of recruitment (~12 to 16 weeks of gestation) and delivery
Stool microbiota composition and activity	Descriptive and quantifiable differences in metagenomics and metatranscriptomics, reflecting microbial diversity, the relative abundance of key bacterial species, and metabolic activity in maternal and neonatal stool. Continuous data to be standardised to z-scores, where appropriate.	Between the time of recruitment (~12 to 16 weeks of gestation) and 4-6 weeks post-delivery

Collaborators and Investigators

• Sponsor: National University Hospital, Singapore
• Collaborators: National University of Singapore
• Investigators: Principal Investigator: Shiao-Yng Chan, MBBChir (UK), FRCOG (UK), PhD, National University of Singapore, National University Hospital Singapore, Institute for Human Development and Potential (A*STAR)

Study record dates

Study Major Dates

• Study Start (Estimated): December 1, 2025
• Primary Completion (Estimated): August 31, 2028
• Study Completion (Estimated): August 31, 2029

Study Registration Dates

• First Submitted: September 18, 2025
• First Submitted That Met QC Criteria: November 16, 2025
• First Posted (Estimated): November 21, 2025

Study Record Updates

• Last Update Posted (Estimated): December 9, 2025
• Last Update Submitted That Met QC Criteria: December 2, 2025
• Last Verified: October 1, 2025

More Information

Terms related to this study

• Keywords: Diabetes; Pregnancy; Folic acid; Prematurity; Dietary Supplement; Stillbirth; Neonatal Death; Myo-inositol; Neonatal Complications; Birthweight; Neonatal Intensive Care Unit Admission; Maternity Complications
• Additional Relevant MeSH Terms: Urogenital Diseases; Endocrine System Diseases; Pathologic Processes; Female Urogenital Diseases and Pregnancy Complications; Metabolic Diseases; Body Weight; Obstetric Labor, Premature; Obstetric Labor Complications; Pregnancy Complications; Glucose Metabolism Disorders; Death; Fetal Death; Pathological Conditions, Signs and Symptoms; Nutritional and Metabolic Diseases; Signs and Symptoms; Premature Birth; Birth Weight; Stillbirth; Diabetes Mellitus; Perinatal Death; Organic Chemicals; Carbohydrates; Alcohols; Sugar Alcohols; Inositol
• Other Study ID Numbers: 2024-4610

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No