Maternal Metabolic and Molecular Changes Induced by Preconception Weight Loss and Their Effects on Birth Outcomes

Study Overview
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Brief Summary
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Our hypothesis is that aggressive preconception weight loss in obese women will improve the metabolic health of the mother and the intrauterine environment. An optimized developmental environment will normalize fetal growth and improve clinical fetal and infant outcomes, and theoretically reduce future susceptibility to obesity and cardiometabolic disease.

Detailed Description
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Further, our hypothesis is that the metabolic profiles in the mother and infant cord blood and epigenetic profiles in cord blood leukocytes will be improved in the very-low energy diet (VLED) group compared to standard practice nutrition counseling and support (SOC) group and approach the profiles found in normal weight (LEAN) individuals. We will relate these changes to the changes in the offspring clinical profiles. With these data in hand, we will develop a model to understand the potential molecular markers associated with offspring size and adiposity at birth, risk factors for later onset non-communicable diseases. We will use these insights to define, adopt and implement future interventions that mitigate the downstream risk of adiposity and cardiometabolic diseases.

Official Title
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Maternal Metabolic and Molecular Changes Induced by Preconception Weight Loss and Their Effects on Birth Outcomes

Conditions
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Obesity; Familial, Pregnancy Related

Intervention / Treatment
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* Dietary Supplement: Very-low energy Diet (VLED)
* Other: Standard of care (SOC)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: BMI > 30 ≤ 45 for obese participants OR BMI ≤ 25 for healthy body weight participants No known infertility No known risk factors for tubal disease Exclusion Criteria: Significant medical co-morbidities (e.g. heart, kidney, liver, autoimmune disease) Significant anemia Cancer other than minor skin cancers Conditions that would complicate pregnancy Recent use of anti-obesity drugs or appetite suppressants Previous bariatric surgery Endometriosis AFS (American Fertility Society classification class III or IV) Progesterone > 10 IU/ml Current pregnancy Use of sperm donor

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 40 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: Basic Science
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Obese - Very low energy diet (VLED)<br>Participants will adopt a very-low energy diet | Dietary Supplement: Very-low energy Diet (VLED)<br>* Structured, intensive dietary intervention using liquid meal replacements aimed at providing 800 kcal/day with a weight loss goal of 15% from baseline<br>|
| Other: Obese - Standard of care (SOC)<br>Participants will receive the standard of care for obese women looking to become pregnant. | Other: Standard of care (SOC)<br>* Standard consultation with registered dietitian to determine appropriate caloric deficit for a low calorie diet, education and advice to achieve weight loss in obese women. Standard of care for normal weight women<br>|
| Other: Lean - Standard of care (SOC)<br>Participants will receive the standard of care for lean women looking to become pregnant. | Other: Standard of care (SOC)<br>* Standard consultation with registered dietitian to determine appropriate caloric deficit for a low calorie diet, education and advice to achieve weight loss in obese women. Standard of care for normal weight women<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Preconception weight loss | Primary pre-specified outcome is BMI change (kg/m2) after dietary intervention. Trained staff will measure height and weight to the nearest .1cm and .1kg using a wall-mounted, precision stadiometer and calibrated digital scale. BMI will be calculated (kg/m2). | Baseline to post dietary intervention (16 weeks) | 
| Metabolome and inflammatory markers | Multivariate computational models will assess the association of maternal and neonate metabolite and inflammatory markers to fetal growth and newborn weight (g) and adiposity (g). | Delivery | 
| Offspring body fat mass | Percentage body fat (adiposity) in the offspring of women randomized to Very Low Energy Diet (VLED) compared to those randomized to Standard of Care (SOC). Body composition will be assessed by PeaPod (fat mass in grams). | Delivery | 
| Cord blood related to neonate outcomes | The maternal metabolome ( metabolites) will be related to neonate adiposity, gestational weight gain, pregnancy complications, and intrauterine fetal growth rate. | Before and after dietary intervention (16 weeks), delivery | 
| DNA methylation | Differences in site-specific DNA methylation ( 450,000 sites) in offspring cord blood mononuclear cells between the Standard of Care (SOC), Very Low Energy Diet (VLED) and lean groups will be assessed. | Delivery | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Participant waist circumference in centimeters | The change in waist circumference (cm) will be assessed using a retractable, soft nylon measuring tape. | Baseline and post dietary intervention (16 weeks), each trimester of pregnancy (between 8-12 weeks, between 18-22 weeks, and between 28-34 weeks) | 
| Fetal growth will be assessed by ultrasound | Gestational sac dimensions (mm), fundal height (mm), biparietal diameter (mm), head circumference (mm), and waist circumference (mm) will be assessed through ultrasound to determine fetal growth. | Each trimester of pregnancy (between 8-12 weeks, between 18-22 weeks, and between 28-34 weeks) | 
| Infant length and weight | Trained staff will measure infant length and weight to the nearest .1cm and .1kg using an infant length board and digital infant scale at delivery, 2-, 4-, 6-, 9-, and 12-months. Ponderal index will be calculated and used to assess change in growth. | Delivery to 12 month follow-up | 
| Metabolite levels | Relationships between metabolite levels ( 2000 metabolites) in maternal blood at each trimester and cord blood mononuclear cell DNA methylation will be compared | Each trimester of pregnancy (between 8-12 weeks, between 18-22 weeks, and between 28-34 weeks), delivery |