Milk Volume Outcomes Following Oral Nicotinamide Riboside Supplementation in Mothers of Extremely Preterm Infants

An adequate supply of a mother's own milk plays a critical role in optimizing health outcomes for at-risk infants, such as preterm and medically or surgically complex term infants. Despite this, insufficient milk production disproportionately affects the mothers of these infants. In the United States, metoclopramide is the only drug approved by the FDA for off-label use as a galactagogue. Nicotinamide riboside (NR), a niacin precursor, has been shown in a murine model to support lean body composition in lactating dams while augmenting high-quality milk production and enhancing cognitive and physical development of pups. Human testing with NR has been limited to long-term safety and bioavailability measures. This study aims to assess the feasibility of NR supplementation in mothers whose infants are admitted to the NICU for at least 4 weeks.

To address this gap, this study will enroll a small cohort of mothers with infants, either born preterm (\<32 weeks of gestation) or term infants with complex medical or surgical conditions, admitted to the NICU for at least four weeks.

This double-blinded, randomized, placebo-controlled pilot feasibility trial aims to investigate NR supplementation in mothers of infants who are hospitalized in the NICU for at least 4 weeks. The intervention period with maternal nicotinamide riboside supplementation/placebo and maternal milk, urine, and blood sampling will be 19 days, including an enrollment day.

We aim to establish the feasibility of conducting a supplementation study in mothers of hospitalized infants, with enrollment feasibility defined as enrolling ≥ 50% eligible mothers.

Secondary objectives include assessing feasibility metrics (supplement compliance, milk sample collection adherence, and withdrawal rates); protocol adherence; and the impact of nicotinamide riboside supplementation on milk volume, milk composition (including macro- and micronutrient composition, glycans, metabolites, lipidomics, and CCN3), and urinary metabolites. Remnant infant blood samples will be used to examine the relationship between infant feeding practices and neonatal insulin, glucose, and amino acid concentrations.

An optional component of the study is the collection of maternal blood to assess the impact of NR supplementation on the concentration of serum prolactin, AST, ALT, metabolites, and CCN3; plasma lipidomics; and whole blood concentration of NAD+ related precursors.

• Difference in mean milk volume of expressed milk (mL) between NR and placebo [Time frame: Volumes will be measured on study Day 0 + 3 days [baseline, pre-intervention], Study Day 10 ± 1 days [mid-intervention], and study Day 17 + 2 days [end of intervention].]
• Difference in human milk micronutrient concentrations between NR and placebo over time. [Time frame: Milk samples will be collected on study Day 0 + 3 days [baseline, pre-intervention], Study Day 10 ± 1 days [mid-intervention], and study Day 17 + 2 days [end of intervention].]
• Difference in amount and diversity of metabolites, including NAD+-related precursors and intermediates in milk between NR and placebo over time. [Time frame: Milk samples will be collected on study Day 0 + 3 days [baseline, pre-intervention], Study Day 10 ± 1 days [mid-intervention], and study Day 17 + 2 days [end of intervention].]
• Difference in human milk glycans (HMOs, glycoproteins, glycolipids) between NR and placebo over time. [Time frame: Milk samples will be collected on study Day 0 + 3 days [baseline, pre-intervention], Study Day 10 ± 1 days [mid-intervention], and study Day 17 + 2 days [end of intervention].]
• Difference in milk lipidomics in milk between NR and placebo over time. [Time frame: Milk samples will be collected on study Day 0 + 3 days [baseline, pre-intervention], Study Day 10 ± 1 days [mid-intervention], and study Day 17 + 2 days [end of intervention].]
• Difference in serum prolactin levels at day 18 and the change from the baseline between NR and placebo ( optional participation) [Time frame: Study Day 3 + 1/-3 days [baseline] and Study Day 18 + 2/-1 days [end of study visit]]
• Difference in plasma lipidomics between NR and placebo(optional participation). [Time frame: Study Day 3 + 1/-3 days [baseline] and Study Day 18 + 2/-1 days [end of study visit]]
• Difference in NAD+-related precursors and intermediates in K2 EDTA whole blood (optional participation) between NR and placebo over time. [Time frame: Study Day 3 + 1/-3 days [baseline] and Study Day 18 + 2/-1 days [end of study visit]]
• Difference in serum metabolites between NR and placebo (optional participation). [Time frame: Study Day 3 + 1/-3 days [baseline] and Study Day 18 + 2/-1 days [end of study visit]]
• Feasibility metrics include supplement compliance, milk sample collection adherence, and withdrawal. [Time frame: Total Day 18 + 2 days from the day of enrollment [Day 18-20]]
• Difference in the concentration of CCN3 in milk between NR and placebo over time. [Time frame: Milk samples will be collected on study Day 0 + 3 days [baseline, pre-intervention], Study Day 10 ± 1 days [mid-intervention], and study Day 17 + 2 days [end of intervention].]
• Difference in human milk protein, carbohydrate, and fat concentrations between NR and placebo over time. [Time frame: Milk samples will be collected on study Day 0 + 3 days [baseline, pre-intervention], Study Day 10 ± 1 days [mid-intervention], and study Day 17 + 2 days [end of intervention].]