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

Not Applicable

Active, not recruiting

Interventions: Dietary Supplement: Very-low energy Diet (VLED)
Other: Standard of care (SOC)

Brief Summary: 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: 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.

Recruitment & Eligibility

Inclusion Criteria

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

Arm && Interventions

Group	Intervention	Description
Obese - Very low energy diet (VLED)	Very-low energy Diet (VLED)	Participants will adopt a very-low energy diet
Lean - Standard of care (SOC)	Standard of care (SOC)	Participants will receive the standard of care for lean women looking to become pregnant.
Obese - Standard of care (SOC)	Standard of care (SOC)	Participants will receive the standard of care for obese women looking to become pregnant.

Primary Outcome Measures

Name	Time	Method
Preconception weight loss	Baseline to post dietary intervention (16 weeks)	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).
Metabolome and inflammatory markers	Delivery	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).
Offspring body fat mass	Delivery	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).
Cord blood related to neonate outcomes	Before and after dietary intervention (16 weeks), delivery	The maternal metabolome (\~metabolites) will be related to neonate adiposity, gestational weight gain, pregnancy complications, and intrauterine fetal growth rate.
DNA methylation	Delivery	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.

Secondary Outcome Measures

Name	Time	Method
Fetal growth will be assessed by ultrasound	Each trimester of pregnancy (between 8-12 weeks, between 18-22 weeks, and between 28-34 weeks)	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.
Infant length and weight	Delivery to 12 month follow-up	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.
Metabolite levels	Each trimester of pregnancy (between 8-12 weeks, between 18-22 weeks, and between 28-34 weeks), delivery	Relationships between metabolite levels (\~2000 metabolites) in maternal blood at each trimester and cord blood mononuclear cell DNA methylation will be compared
Participant waist circumference in centimeters	Baseline and post dietary intervention (16 weeks), each trimester of pregnancy (between 8-12 weeks, between 18-22 weeks, and between 28-34 weeks)	The change in waist circumference (cm) will be assessed using a retractable, soft nylon measuring tape.