Breastmilk and the Link to Overweight/Obesity and Maternal Diet in the Mother-breastmilk-child Triad

The global obesity pandemic continues to escalate, with projections showing 1 in 5 women and 1 in 7 men obese by 2030. Maternal obesity raises the risk of childhood obesity by 264%, and overweight/obese children are more prone to become obese adults.

Obesity-associated metabolic dysfunctions (inflammation, insulin resistance, dyslipidemia) heighten morbidity and mortality risks. Breastfeeding mitigates overweight/obesity risks, yet mothers with overweight/obesity often encounter challenges in initiation, continuation, and altered milk composition, showing elevated levels of leptin, insulin, and n-6/n-3 fatty acids. However, findings on other components, like total fat, fatty acids, insulin, adipokines, carotenoids, and immune factors, remain inconsistent due to methodological limitations and lack of comprehensive analysis. Nonetheless, the potential pro-inflammatory and obesogenic properties of milk produced by mothers with overweight/obesity have been discussed. Recent systematic reviews link breastmilk protein, fat, leptin, and IL-6 to infant growth and adiposity. Findings for other components remain unclear due to small samples, methodological limitations, and lack of a systemic approach to analyze breastmilk as a complex biological system. Alterations in breastmilk composition may stem from disrupted de novo synthesis, transport across the blood-breastmilk barrier, or altered circulating levels. Recent studies showed impaired de novo synthesis of C15:0 and C16:1 fatty acids, probably caused by insulin resistance and reduced long-chain fatty acid transfer linked to inflammation (suppress lipoprotein lipase activity essential for transporting lipid compounds). Hence, poor cardiometabolic status may mediate altered breastfeeding outcomes and milk composition, but it requires further studies. Studies among non-lactating individuals suggested lifestyle and diet play crucial roles in mitigating overweight/obesity metabolic implications (e.g., metabolically healthy obese (MHO) and metabolically obese with normal weight (MONW) phenotypes). Maternal diet can influence breastmilk concentration of certain diet-dependent nutrients and bioactives (e.g., fatty acids, vitamins A, D, and carotenoids). Similarly, prohealthy/unhealthy dietary patterns seem to have beneficial/unfavorable effects on breastmilk composition and breastfeeding outcomes, but results remain inconclusive. Nonetheless, some suggest that diet may mitigate the effects of maternal overweight/obesity on breastmilk composition in mothers with overweight/obesity. The mechanisms linking obesity-related changes in breastmilk to infant development remain unclear. This study addresses this gap by studying the mother-breastmilk-infant triad, focusing on maternal cardiometabolic status, diet, breastmilk composition as a complex biological system, and anthropometric and metabolic outcomes.

This study aims to elucidate the intricate interplay between maternal adiposity, cardiometabolic status, diet, and breastmilk composition and to understand the role of breastmilk in the transmission of obesity and the shaping of infant metabolic health.

Our research questions will aim to determine/explore the following questions:

Q1. How does the maternal BMI category differentiate breastmilk composition from a systemic perspective? Q2. How does maternal cardiometabolic status mediate OW/OB-related alterations in breastmilk composition? Q3. Whether (and how) maternal diet moderates OW/OB-related alterations in breastmilk composition? Q4. Whether (and how) maternal OW/OB differentiates infant metabolomic profile? Q5. Whether (and how) OW/OB-related alterations in breastmilk composition influence infant outcomes and obesity risk? Q6. Whether (and how) maternal dietary patterns moderate adverse health outcomes of maternal OW/OB in infants?

The research hypotheses assume that:

H1. Maternal OW and OB are associated with pro-inflammatory properties and altered breastmilk metabolome via obesity-related low-grade inflammation, metabolic alterations, and oxidative stress, not dietary differences.

H2. Metabolically healthy OW and OB mothers produce less altered breastmilk than metabolically unhealthy mothers, as cardiometabolic status mediates between adiposity and breastmilk composition.

H3. A pro-healthy dietary pattern attenuates, and a westernized dietary pattern exacerbates obesity-related alterations in breastmilk composition due to differences in concentrations of pro-, anti-inflammatory, and antioxidant dietary compounds.

H4. Infants of OW and OB mothers have altered growth trajectories and metabolic pathways, higher fat mass, and oxidative stress compared to infants of NW mothers.

H5. Obesity-related changes in breastmilk composition determine alterations in infant outcomes.

H6. Maternal pro-health/westernized dietary patterns and metabolic health mitigate/exacerbate the adverse effects of overweight and obesity on infant outcomes.

The investigators will verify these hypotheses based on results collected using gold standards and novel body composition assessment and analytical methods (DXA scans, HPLC, GC-MS, ELISA, and LC-MS), nutrient-based and dietary pattern-based dietary assessment with biomarkers validation, in-depth evaluation of maternal cardiometabolic status and infant outcomes, and a systemic approach to breastmilk composition analysis. The findings will lay the foundation for tailored, evidence-based interventions to disrupt the intergenerational transmission of obesity. Furthermore. contribute to advancing the health sciences discipline and decreasing the global health burden of overweight and obesity, supporting the realization of WHO's Global Nutrition Goals.

Primary outcomes

• Difference between groups and change from 1 to 6 months postpartum in maternal body fat percentage [1, 3, and 6 months postpartum]: Assessment of changes in total body fat content, assessed by a bioelectrical impedance analysis (BIA) and a dual-energy X-ray absorptiometer (DXA). Results will be reported as a percentage (%).
• Difference between groups and change from 1 to 6 months postpartum in maternal fat-free mass percentage [1, 3, and 6 months postpartum]: Assessment of changes in fat-free mass, assessed by a bioelectrical impedance analysis (BIA) and a dual-energy X-ray absorptiometer (DXA). Results will be reported as a percentage (%).
• Difference between groups and change from 1 to 6 months postpartum in maternal Visceral Fat Area [1, 3, and 6 months postpartum]: Assessment of changes in visceral fat area, assessed by DXA. Results will be reported as square centimeters (cm\^2).
• Difference between groups and change from 1 to 6 months postpartum in maternal Subcutaneous Fat Area [1, 3, and 6 months postpartum]: Assessment of changes in subcutaneous fat area, assessed by DXA. Results will be reported as square centimeters (cm\^2).
• Difference between groups and change from 1 to 6 months postpartum in maternal Body Mass Index (BMI) [1, 3, and 6 months postpartum]: Weight and height will be combined to report BMI in kg/m\^2.
• Difference between groups and change from 1 to 6 months postpartum in maternal Waist-Hip Ratio (WHR) [1, 3, and 6 months postpartum]: Assessment of fat distribution calculated as the waist measurement divided by the hip measurement (dimensionless ratio).
• Difference between groups and change from 1 to 6 months postpartum in maternal Waist-to-Height Ratio (WHtR) [1, 3, and 6 months postpartum]: Assessment of fat distribution calculated as the waist measurement divided by height (dimensionless ratio).
• Difference between groups and change from 1 to 6 months postpartum in metabolic syndrome (MetS) incidence [1, 3, 6 months postpartum]: Assessment of MetS incidences diagnosed based on the occurence of three from five metabolic abnormalities diagnosed based on International Diabetes Federation-established cut-off points for women for waist circumference (≥80 cm), fasting blood glucose (≥100 mg/dL), triglicerides (≥150 mg/dL), HDL cholesterol (<50 mg/dL), blood pressure (systolic SBP ≥ 130 or diastolic ≥ 85 mmHg) as a marker of cardiometabolic health.
• Difference between groups and change from 1 to 6 months postpartum in maternal glycated haemoglobin (HbA1c) [1, 3, 6 months postpartum]: Assessment of changes in HbA1c (reported in %) as a marker of maternal cardiometabolic health.
• Difference between groups and change from 1 to 6 months postpartum in Homeostatic Model Assessment - Insulin Resistance (HOMA-IR) [1, 3, 6 months postpartum]: Assessment of HOMA-IR calculated as the product of fasting insulin \[µIU/mL\] and fasting glucose \[µIU/mL\] divided by 22.5 (dimensionless ratio) as an indicator of maternal cardiometabolic health.
• Difference between groups and change from 1 to 6 months postpartum in maternal serum leptin [1, 3, 6 months postpartum]: Assessment of maternal serum leptin assessed by the ELISA method as an indicator of maternal cardiometabolic health.
• Difference between groups and change from 1 to 6 months postpartum in maternal serum adiponectin [1, 3, 6 months postpartum]: Assessment of maternal serum adiponectin assessed by the ELISA method as an indicator of maternal cardiometabolic health.
• Difference between groups and change from 1 to 6 months postpartum in maternal serum and infant urine Retinol-Binding Protein-4 (RBP4) [1, 3, 6 months postpartum]: Assessment of maternal serum and infant urine RBP-4 assessed by the ELISA method as an indicator of maternal and infant cardiometabolic health.
• Difference between groups and change from 1 to 6 months postpartum in human milk macronutrients [1, 3, 6 months of postpartum]: Assessment of human milk macronutrients (fat, carbohydrate, dry material, protein, true protein) concentration assessed by mid-infrared (mid-IR) transmission spectroscopy method. Results will be reported in grams per 100 mL.
• Difference between groups and change from 1 to 6 months postpartum in human milk energy value [1, 3, 6 months of postpartum]: Assessment of human milk energy value assessed by mid-infrared (mid-IR) transmission spectroscopy method. Results will be reported in kcal per 100 mL.
• Difference between groups and change from 1 to 6 months postpartum in human milk secretory immunoglobulin A (S-IgA) [1, 3, and 6 months postpartum]: Assessment of human milk S-IgA assessed by Enzyme-Linked Immunosorbent Assay (ELISA) method. Results will be reported in grams per liter \[g/L\].
• Difference between groups and change from 1 to 6 months postpartum in human milk lactoferrin [1, 3, and 6 months postpartum]: Assessment of human milk lactoferrin assessed by ELISA method. Results will be reported in grams per liter \[g/L\].
• Difference between groups and change from 1 to 6 months postpartum in human milk leptin [1, 3, 6 months of postpartum]: Assessment of human milk leptin assessed by ELISA method.
• Difference between groups and change from 1 to 6 months postpartum in human milk adiponectin [1, 3, 6 months of postpartum]: Assessment of human milk adiponectin assessed by ELISA method.
• Difference between groups and change from 1 to 6 months postpartum in human milk insulin [1, 3, 6 months of postpartum]: Assessment of human milk insulin assessed by ELISA method.
• Difference between groups and change from 1 to 6 months postpartum in human milk High-Sensitivity C-Reactive Protein (hs-CRP) [1, 3, 6 months of postpartum]: Assessment of human milk hsCRP assessed by ELISA method.
• Difference between groups and change from 1 to 6 months postpartum in human milk interleukin 1 (IL-1) [1, 3, 6 months of postpartum]: Assessment of human milk IL-1 assessed by ELISA method.
• Difference between groups and change from 1 to 6 months postpartum in human milk interleukin 6 (IL-6) [1, 3, 6 months of postpartum]: Assessment of human milk IL-6 assessed by ELISA method.
• Difference between groups and change from 1 to 6 months postpartum in human milk Tumor Necrosis Factor-alpha (TNF-alfa) [1, 3, 6 months of postpartum]: Assessment of human milk TNF-alfa assessed by ELISA method.
• Difference between groups and change from 1 to 6 months postpartum in human milk fatty acid profile [1, 3, 6 months of postpartum]: Assessment of human milk fatty acid profile analyzed as methyl ester (FAME) by gas chromatography. Results will be reported as concentration within a total fat \[% wt/wt\].
• Difference between groups and the change from 1 to 6 months of life in infant anthropometric development [1, 3, 6 months of life]: Assessment of anthropometric development calculated as weight-, length-, BMI-, and head circumference z-scores for age and sex, analyzed based on WHO standards.
• Difference between groups and the change from 1 to 6 months of life in infant body fat-free mass percentage [1, 6 months of life]: Assessment of changes in total body fat-free mass content, assessed by the whole-body DXA scans with a vacuum cushion to prevent movement. Results will be reported as a percentage (%).
• Difference between groups and the change from 1 to 6 months of life in infant body fat percentage [1, 6 months of life]: Assessment of changes in total body fat content, assessed by the whole-body DXA scans with a vacuum cushion to prevent movement. Results will be reported as a percentage (%).

Secondary outcomes

• Difference between groups and the change from 1 to 6 months postpartum in the maternal resting metabolic rate (RMR) [1, 3, 6 months postpartum]: Assessment of the rate of maternal energy metabolism assessed by indirect calorimetry. Results will be reported as kilocalories per day \[kcal/d\].
• Difference between groups and the change from 1 to 6 months postpartum in maternal dietary intake [1, 3, 6 months postpartum]: Assessment of maternal dietary intake using 3-day food records.
• Difference between groups and the change from 1 to 6 months postpartum in maternal dietary habits [1, 3, 6 months postpartum]: Assessment of maternal dietary intake using a food frequency questionnaire (FFQ).
• Difference between groups and change from 1 to 6 months postpartum in maternal short- and long-term fatty acid status [1, 3, 6 months postpartum]: Assessment of serum blood and erythrocyte membranes fatty acids profile analyzed by gas chromatography. Results will be reported as concentration within a total fat \[% wt/wt\].
• Difference between groups and change from 1 to 6 months postpartum in maternal and human milk lipophilic antioxidants and vitamins [1, 3, 6 months postpartum]: Assessment of plasma and human milk carotenoids, retinol, and vitamin E, as well as serum vitamin D (25(OH)D) analyzed by high-performance liquid chromatography (HPLC). Results will be reported as micromoles per liter \[µmol/L\].
• Difference between groups and the change from 1 to 6 months of life in infant skin carotenoid status [1, 3, 6 months of life]: Assessment of skin carotenoids assessed by reflectance spectroscopy with Veggie Meter (Longevity Link, Ltd.). Results will be reported as a skin carotenoid score (SCS; 0-800, higher values mean more carotenoids)
• Difference between groups and change from 1 to 6 months postpartum in maternal and infant urine 8-isoprostane [1, 3, 6 months postpartum]: Assessment of maternal and infant urine 8-isoprostane analyzed by the ELISA as an indicator of oxidative stress. Results will be reported as picograms per milligram of creatinine \[pg per mg of creatinine\].
• Difference between groups and change from 1 to 6 months postpartum in maternal serum hsCRP [1, 3, 6 months postpartum]: Assessment of maternal serum hsCRP assessed by the ELISA method as an indicator of systemic inflammation.
• Difference between groups and change from 1 to 6 months postpartum in maternal serum IL-1 [1, 3, 6 months postpartum]: Assessment of maternal serum IL-1 assessed by the ELISA method as an indicator of systemic inflammation.
• Difference between groups and change from 1 to 6 months postpartum in maternal serum IL-6 [1, 3, 6 months postpartum]: Assessment of maternal serum IL-6 assessed by the ELISA method as an indicator of systemic inflammation.
• Difference between groups and change from 1 to 6 months postpartum in maternal serum TNF-alfa [1, 3, 6 months postpartum]: Assessment of maternal serum TNF-alfa assessed by the ELISA method as an indicator of systemic inflammation.
• Difference between groups and change from 1 to 3 months postpartum in human milk lipidomics [1, 3 months postpartum]: Assessment of human milk triacylglycerols (TG), diacylglycerols (DG), phosphatidylcholine (PC), sphingomyelin (SM), and phosphatidylethanolamine (PE) assessed by targeted lipidomic analysis using the LC-MS. Results expressed as the percentage relative amount of many lipid species.
• Difference between groups and change from 1 to 6 months postpartum in metabolomic profile of maternal serum blood and infant urine [1, 3, 6 months postpartum]: Assessment of the serum and urine non-targeted metabolomic profiles.

Other outcomes

• Difference between groups and change from 1 to 6 months postpartum in Bone Mineral Density (BMD) [1, 3, 6 months postpartum]: Assessment of changes in bone mineral density (BMD) using DXA.
• Difference between groups and change from 1 to 6 months postpartum in maternal hydration status [1, 3, 6 months postpartum]: Assessment of changes in hydration status, assessed by urine osmolality \[mOsm/kg\].
• Difference between groups and change from 1 to 6 months postpartum in maternal well-being [1, 3, 6 months postpartum]: Assessment of maternal well-being assessed using the WHO-5 Well-being Index. Results will be expressed as a percentage score from 0 to 100, with a higher score indicating a better quality of life.
• Difference between groups and change from 1 to 6 months postpartum in maternal fatigue [1, 3, 6 months postpartum]: Assessment of maternal fatigue using the Fatigue Assessment Scale (FAS). Results will be expressed as a FAS score ranging from 10 to 50, with higher scores indicating more severe fatigue.
• Difference between groups and change from 1 to 6 months postpartum in maternal perceived stress [1, 3, 6 months postpartum]: Assessment of maternal perceived stress assessed by the Perceived Stress Scale (PSS-10). Results will be expressed as a PSS-10 score ranging from 0 to 40, with higher scores indicating greater perceived stress.
• Difference between groups and change from 1 to 6 months postpartum in maternal postpartum depression [1, 3, 6 months postpartum]: Assessment of maternal postpartum depression risk assessed by the Edinburgh Postnatal Depression Scale (EPDS). Results will be expressed as an EPDS score ranging from 0 to 30, with higher scores indicating greater risk of postpartum depression, and values >=13 indicate probable depression.
• Difference between groups and change from 1 to 6 months postpartum in maternal breastfeeding self-efficacy [1, 3, 6 months postpartum]: Assessment of maternal breastfeeding self-efficacy assessed by the Breastfeeding Self-Efficacy Scale (BSES-SF). Results will be reported as a BSES-SF score ranging from 14 to 70, with higher scores indicating greater confidence in breastfeeding.

Sex: Female, ages: 19 Years to any, accepts healthy volunteers

Inclusion Criteria:

for mother:

* at least 19 years,
* plan of exclusively or predominantly breastfeeding for 6 months,
* consent to a sampling of biological material and participate in all planned procedures (for both mother and infant),
* willingness to finish the follow-up,
* well-understanding of the Polish language (for non-Polish nationalities); for infants:
* 1 month or less,
* clinically healthy,
* none or one formula feeding per day

Exclusion Criteria:

for mother:

* type 1 or 2 diabetes diagnosed before pregnancy,
* uncontrolled thyroid disease,
* breastfeeding more than 1 child or being a milk donor,
* tobacco/alcohol use during pregnancy or currently,
* inability to express a sufficient amount of milk; for infants:
* congenital disease,
* birth from a multiple pregnancy,
* preterm birth (<37 Hbd).

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