Fetal Programming of Inflammatory Responses and Body Fat by Maternal Obesity: Role of DHA in the Modulation of Epigenetic Markers of Obesity and Metabolic Disease.
Trial Snapshot
- Phase
- Not Applicable
- Status
- Completed
- Enrollment
- 247
- Locations
- 1
- Primary Endpoint
- Newborn body fat percentage
Study Overview
Brief Summary
According to the Chilean National Health Survey 2009-2010, 60% of woman in reproductive age are overweight or obese with detrimental consequences on women as well as offspring´s health at long term.
New efforts are required to clarify how increased maternal body fat and obesity previous and during pregnancy impinge an increased cardiometabolic and obesity risk in the progeny. Nowadays it is clear that obesity in adults constitute a chronic state of sub-clinical inflammation characterized by an increased infiltration of monocytes in the adipose tissue as well as an imbalance between increased pro- (M1) and decreased anti- (M2) inflammatory macrophage polarization. Increased inflammatory markers have been found in obese children as young as 3 years of age, but if these markers are present at birth is completely unknown.
Therefore, unveiling the mechanisms implicated in the capability of monocytes to differentiate into pro-inflammatory macrophages at birth would contribute to establish early markers of the potential risk to develop cardio-metabolic diseases. In this context, modulation of M1-M2 polarization seems to be crucial for the development of altered immune response, and this process would be tightly regulated by epigenetic mechanisms.
On the other hand, long chain polyunsaturated fatty acids (LCPUFAs) play a role as precursors of cellular membrane components and modifiers, and as precursors of a plethora of signaling molecules that participates in cardiovascular, metabolic and immune functions. Additionally, DHA regulates gene expression in monocytes and macrophages altering the M1/M2 polarization. The supplementation with DHA in a high risk population of pregestational obese mothers, with known low n-3 intake, would have an important impact on newborn and infant % body fat. An improvement in the n-6/n-3 LCPUFA ratio during pregnancy in humans could represent a primary prevention strategy to revert fetal and neonatal high body fat and a healthy immune system maturation.
The hypothesis of this proposal is that neonates born from obese mothers supplemented with DHA during pregnancy show a reduction in specific markers of high-risk of obesity. These markers would be evidenced as a lower percent of body fat at birth and at 4 months of age, as well as the reversion of functional and epigenetic changes in neonatal monocytes at birth, compared to neonates from obese mothers with low DHA intake.
Detailed Description
AIMS:
In neonates born from pregnant women with normal BMI (> 18.5 and <24,9) at the first prenatal visit (<14 weeks of gestation) (Reference Group) and with pre-gestational obesity (BMI >30 Kg/m2) with low (customary) DHA intake (200 mg/day) (MO Group) and pre-gestational obese women supplemented with a high dose of DHA (800 mg/day)(MO+DHA Group) we will:
- Analyze whether maternal DHA supplementation modifies the body composition in neonates and children at 4 months of age.
- Determine whether maternal supplementation with DHA during pregnancy modifies the balance of circulating pro- and anti-inflammatory cytokines and metabolic markers in the mother during pregnancy, the fetus, the placenta and the child at 4 months of age
- Determine whether the response of macrophages to inflammatory mediators associates with altered epigenetic markers in pro- and anti-inflammatory obesity-related-genes in fetal monocytes from obese mothers and if DHA maternal supplementation reverts this phenotype.
- Determine whether maternal obesity translates into changes in the genome-wide DNA methylation profile in fetal monocytes at birth and the impact of maternal DHA supplementation on this epigenetic effect.
METHODOLOGY. The EpiFat study, is a nested cohort in the Maternal obesity control ThrouGh Healthy nuTrition, MIGHT study (PI: Dr. Garmendia NCT02574767). MIGHT study randomized 1000 patients that began their prenatal care before 14 weeks of gestation to one of four parallel study arms: 2 groups received 200 mg/day DHA (based on Schizochytrium oil, 100% DHA, DSM) and 2 groups 800 mg/day DHA, each group had a group with and one without home-based diet and physical activity interventions.
Recruitment and follow up: At admission to the pre-delivery unit, midwives of the Dr. Sótero del Río Hospital invite all the pregnant women who fulfill eligibility criteria to participate in this study and carries out informed consent process.
Study Design
- Study Type
- Observational
- Observational Model
- Cohort
- Time Perspective
- Prospective
Eligibility Criteria
- Ages
- 24 Hours to 4 Months (Child)
- Sex
- All
- Accepts Healthy Volunteers
- Yes
Inclusion Criteria
- •Healthy term (> 37 weeks of gestation) newborns of: women with pregestational BMI ≥18,5 and <24,9 in the first prenatal visit (Reference Group); newborns of women with pregestational BMI ≥30 with customary DHA supplementation (200 mg/day) (Maternal obesity, MO Group); newborns from women with pregestational BMI ≥30 with 800 mg/day DHA supplementation (MO+DHA Group); all with singleton and healthy pregnancies.
Exclusion Criteria
- •Newborns with low birth weight (<2500 g), complications at delivery, or those requiring long-term hospital admission.
- •Newborns of women with preexisting diabetes, premature labor, gestational diabetes, preeclampsia, multiple gestation, chronic cardio-respiratory disorder or neurological o genetic defects of the fetus; any high risk pregnancy condition according to national guidelines,
Outcomes
Primary Outcomes
Newborn body fat percentage
Time Frame: 24 hours to 48 hours after birth.
Percentage of body fat obtained by skinfold measures and calculated using Catalano et al (1996) formula.
Infant body fat
Time Frame: 4 Months of age.
Percentage and fat mass obtained by Air Displacement Plethysmography (PEA POD)
Secondary Outcomes
- DHA antiinflammatory effects in neonatal monocytes(At birth)
- Epigenetic-driven inflammatory response of neonatal monocytes & macrophages in vitro.(At birth)