Nutritional Intervention Preconception and During Pregnancy to Maintain Healthy Glucose Metabolism and Offspring Health

Study Overview
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Brief Summary
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The study aims to assess whether a nutritional drink taken before conception and continuing through pregnancy, assists in the maintenance of healthy glucose metabolism in the mother and promotes offspring health.

Detailed Description
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It is known that maternal insulin resistance and high blood glucose levels in early pregnancy alter the functioning of the placenta in ways that persistently affect the supply of nutrients and fat in the unborn baby. There is an increasing focus on the need to optimise preconception nutrition but as yet, limited preconception interventions that are recognized as promoting health for the mother and her child. The Investigators will recruit up to 1800 women, aged 18-38 years, who are planning a pregnancy in the United Kingdom, Singapore and New Zealand with the aim of securing 600 or more pregnancies. The participants will be randomly allocated to receive the standard nutritional drink or the study nutritional drink. Women who conceive between one and twelve months after starting the nutritional drink will be followed through pregnancy and studied with their babies for three years after delivery. Various testing will be carried out at relevant time points. Mothers will undergo blood, urine, hair and cheek swab sampling, dual-energy X-ray absorptiometry (DXA) scans along with body measurements and health and lifestyle questionnaires. Infants will undergo hair, cheek swab, urine and stool sampling along with body measurements, measurements of body composition and a DXA scan. Placental, cord and other perinatal tissues/samples will be collected. The data collected will allow identification of the contributions of nutritional and lifestyle factors, social and economic status, ethnicity, genetics and metabolomics and gut microbes to maintaining healthy glucose metabolism in pregnancy, enhancing fertility, mood and reproductive outcomes in the mother, and promoting healthy growth, body composition and wellbeing in the children. The effect of the intervention on the primary outcome will be examined in two special interest groups; i) women who are overweight or obese prior to conception & ii) women with documented evidence of dysglycemia prior to conception.

Official Title
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Nutritional Intervention Preconception and During Pregnancy to Maintain Healthy Glucose Metabolism and Offspring Health (NiPPeR)

Conditions
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Hyperglycemia

Intervention / Treatment
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* Dietary Supplement: Study nutritional drink
* Dietary Supplement: Standard nutritional drink


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Women aged 18-38 years Planning to conceive within 6 months Able to provide written, informed consent In Singapore: Chinese, Malay and Indian ethnicity or mixed Chinese/Malay/Indian ethnicity Exclusion Criteria: Pregnant or lactating at recruitment Assisted fertility, apart from those taking clomiphene or letrozole alone Pre-existing diabetes (type 1 or type 2) Oral or implanted contraception currently or in the last month, or with an Intrauterine Contraceptive Device (IUCD) in situ On metformin or systemic steroids currently or in the last month Known serious food allergy Not able to give informed consent Women on anticonvulsants (who are treated with high dose B vitamins in pregnancy) currently or in the last month On treatment for Human Immunodeficiency Virus (HIV), Hepatitis B or C currently or in the last month The partners of the women (over 16 years of age) will also be invited to participate in the study. After having gained written informed consent, fathers will have blood, urine, hair sampling, cheek swabs and body measurements taken and will complete a health and a lifestyle questionnaire at one of the visits during pregnancy. The mother will consent for their babies to have body measurements, buccal, hair, stool samples and allergy testing from birth to 3.5 years.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 38 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Intervention (study nutritional drink)<br>Study nutritional drink comes in the form of a sachet to mix with water & take twice a day (once in the morning and once in the evening). The drink will be taken before the participant becomes pregnant (for up to 1 year) and throughout pregnancy. | Dietary Supplement: Study nutritional drink<br>* Study nutritional drink containing a mix of micronutrients, probiotics and myo-inositol.<br>|
| Active Comparator: Control (standard nutritional drink)<br>Standard nutritional drink comes in the form of a sachet to mix with water & take twice a day (once in the morning and once in the evening). The drink will be taken before the participant becomes pregnant (for up to 1 year) and throughout pregnancy. | Dietary Supplement: Standard nutritional drink<br>* Standard nutritional drink containing a mix of micronutrients.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Glucose tolerance during pregnancy |  | Pregnancy Oral Glucose Tolerance Test (OGTT) measurement at 24 - 32 weeks gestation | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Duration of gestation |  | Up to 43 weeks, derived from estimated date of conception from menstrual and ultrasound scan data and date of delivery | 
| Pregnancy weight gain and body composition |  | Up to 36 weeks, between date of first pregnancy visit and late gestation | 
| Postpartum weight retention and body composition |  | Up to 2 years, between date of delivery and 6,12 and 24 months postpartum | 
| Change in body composition before, during and after gestation |  | Up to 4 years, between preconception, pregnancy and 2 years postpartum | 
| Clinical pregnancy, pregnancy loss and live birth rates, including median time to conception of those who conceive during the treatment period and proportions conceiving within 3 months, 6 months and a year of commencing the NiPPeR drink |  | Between recruitment and delivery | 
| Gestational diabetes frequency |  | Pregnancy OGTT measurement at 24 - 32 weeks gestation | 
| Hypertensive disorders of pregnancy (pregnancy-induced hypertension and pre-eclampsia/eclampsia) |  | Up to 49 weeks, between conception derived from estimated date of conception from menstrual and ultrasound scan data and date of delivery, and up to 6 weeks after delivery | 
| Nausea and vomiting frequency |  | Up to 36 weeks, between 7 weeks of gestation and delivery | 
| Other antenatal, perinatal and postnatal complications |  | Up to 49 weeks, between conception from estimated date of conception derived from menstrual and ultrasound scan data, and up to 6 weeks after delivery | 
| Preconception and antenatal maternal wellbeing/mood (Edinburgh Post-natal Depression Scale and State-Trait Anxiety Inventory) |  | Up to 2 years, between preconception and delivery | 
| Postnatal maternal wellbeing/mood (Edinburgh Post-natal Depression Scale and State-Trait Anxiety Inventory) |  | Up to 52 weeks, between date of delivery and infant age 1 year | 
| Mode of labour onset and delivery |  | Delivery | 
| Neonatal complications and admission to neonatal care facilities |  | Up to 4 weeks post-delivery | 
| Preconception maternal micronutrient status (blood analysis) |  | Date of second preconception visit up to 1 year before pregnancy | 
| Antenatal maternal micronutrient status (blood analysis) |  | Up to 30 weeks, between 7 weeks gestation and 37 weeks of gestation | 
| Preconception maternal gut microbiota composition and activity profile (analysis of sequencing and transcription data) |  | Up to 6 weeks from the start of intervention, date of preconception visit 2 which is up to 1 year before pregnancy | 
| Antenatal and postnatal maternal gut and epithelial microbiota composition profile (analysis of sequencing data) |  | Up to 18 months, between 7 weeks gestation and post-delivery visits | 
| Maternal preconception biochemical, metabolic and molecular profiles |  | Up to 6 weeks from the start of intervention, date of second preconception visit which is up to 1 year before pregnancy | 
| Maternal antenatal biochemical, metabolic and molecular profiles |  | Up to 30 weeks, between 7 weeks gestation and 37 weeks of gestation | 
| Placental and cord tissue, and their cellular derivatives: biochemical, metabolic and molecular profiles |  | Birth | 
| Maternal postnatal biochemical, metabolic and molecular profiles |  | 6 months after delivery | 
| Maternal preconception epigenetic profile |  | Preconception to up to 1 year before pregnancy | 
| Maternal antenatal epigenetic profile |  | Up to 30 weeks, between 7 weeks gestation and 37 weeks of gestation | 
| Maternal postnatal epigenetic profile |  | 6 months after delivery | 
| Breast milk macronutrient profile (subsample) |  | Up to 1 year, between date of delivery and 1 year postpartum | 
| Breast milk micronutrient profile (subsample) |  | Up to 1 year, between date of delivery and 1 year postpartum | 
| Breast milk immune factor profile (subsample) |  | Up to 1 year, between date of delivery and 1 year postpartum | 
| Breast milk epigenetic profile (subsample) |  | Up to 1 year, between date of delivery and 1 year postpartum | 
| Breast milk biochemical, metabolic, microbiome and molecular profiles (subsample) |  | Up to 1 year, between date of delivery and 1 year postpartum | 
| Healthy lactogenesis |  | Up to 1 year, between date of delivery and 1 year postpartum | 
| Maternal and infant transcriptomics (including of breastmilk) |  | Up to 34 months, between preconception, pregnancy and 1 year postpartum | 
| Intrauterine growth and wellbeing as assessed by antenatal serial ultrasound scans |  | Up to 30 weeks, between 7 weeks gestation and 37 weeks of gestation | 
| Offspring birthweight and size at birth |  | At birth | 
| Offspring size for gestational age at birth, less than the 10th, 10th - 90th, and above the 90th percentiles for gestational age |  | At birth | 
| Offspring size for gestational age and sex at birth (percentile and standard deviation scores) |  | At birth | 
| Offspring adiposity (skinfold thicknesses, regional, total and percentage fat mass) |  | Up to 3.5 years, between date of delivery and 3.5 years postpartum | 
| Adiposity gain, body composition and linear growth during infancy and childhood |  | Up to 3.5 years, from birth to infant age 3.5 years | 
| Cord blood C-peptide |  | At delivery | 
| Offspring cardiometabolic profile |  | Up to 3.5 years, from birth to infant age 3.5 years | 
| Offspring allergic wellbeing |  | Up to 3.5 years, from birth to infant age 3.5 years | 
| Offspring biochemical, metabolic and molecular profiles |  | Up to 3.5 years, from birth to infant age 3.5 years | 
| Offspring epigenetic profile |  | Up to 3.5 years, from birth to infant age 3.5 years | 
| Infant gut microbiota composition and activity |  | Up to 3.5 years, from birth to infant age 3.5 years | 
| Influence of parental and offspring genotype, sociodemography, body composition, metabolism, lifestyle and diet on the above primary and secondary outcomes at baseline and with the intervention |  | Up to 5.5 years, between preconception, pregnancy and 3.5 years postpartum | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Nutrition, Glucose metabolism, Body composition