(S-100) Understanding How Low Calorie Sweeteners Pass from Mother to Infants Through Breastmilk – Insights from Population Pharmacokinetic Modeling

Allison Sylvetsky, PhD – Department of Exercise and Nutrition Sciences – George Washington University; Janae Kuttamperoor, BA – Department of Exercise and Nutrition Sciences – George Washington University; Hongyi Cai, PhD – Clinical Mass Spectrometry Lab – National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institutes of Health (NIH),; Peter Walter, PhD – Clinical Mass Spectrometry Lab – National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health (NIH); John Van Den Anker, MD PhD – Division of Clinical Pharmacology – Children's National Hospital; Jeanne Murphy, PhD, CNM – School of Nursing – George Washington University; Kathleen Arcaro, PhD – Department of Veterinary and Animal Sciences – University of Massachusetts Amherst; Dina Daines, CNM DNP – Department of Obstetrics and Gynecology – George Washington University; Mathangi Gopalakrishnan, MPharm PhD – Center for Translational Medicine – University of Maryland Baltimore School of Pharmacy

Objectives: Forty-four percent of lactating women report consuming beverages containing low-calorie sweeteners (LCS) in a given week [1,2]; yet, in vitro and rodent studies, as well as observational studies in humans, suggest that early life LCS exposure may have potential negative effects on infant health [6–10]. Despite these concerns, evidence-based guidelines for maternal LCS intake during lactation are lacking. This research aims to characterize the pharmacokinetics of ace-K and sucralose in mothers and infants using data from infant plasma, maternal breast milk, and maternal plasma collected after maternal LCS beverage consumption.

Methods: This prospective pharmacokinetic (PK) study included 40 exclusively breastfeeding mothers, 4–24 weeks postpartum, and their infants. Each mother consumed 20 oz of Ocean Spray Diet Cranberry™, containing 17.4 mg ace-K and 94.8 mg sucralose. Rich plasma and breast milk samples were collected serially from mothers, and a heel-stick blood sample was also collected from each infant at designated times post-ingestion of breast milk.
Ace-K and sucralose concentrations were quantified using LC-MS [11]. Nonlinear mixed-effects modeling was performed jointly on plasma and breast milk data [12], using Pumas v2.0 [13]. Maternal covariates (age, weight, postpartum age) were tested. Infant models were derived by physiologically scaling maternal models and fit to infant concentrations via post hoc prediction. Simulations of real-world maternal consumption patterns estimated infant exposure.

Results: Pharmacokinetic analysis included 488 maternal plasma, 360 breast milk, and 40 infant plasma observations for both ace-K and sucralose. Ace-K PK was described by a one-compartment model with simultaneous zero- and first-order absorption and first-order elimination. The breast milk volume was fixed physiologically, and a fixed transfer rate of 0.01 h⁻¹ from milk to plasma enabled estimation of the milk entry rate (1 h⁻¹). Mean apparent clearance and volume estimates were 10 L/h and 30 L, respectively.
Sucralose PK was described by a two-compartment model with zero-order absorption and first-order elimination. An additional breast milk compartment, with volume fixed to physiological capacity [14], and transit compartments were added to capture the lag between plasma and milk concentrations. Mass transfer to milk was assumed negligible. Postpartum age decreased milk transfer over time. The mean apparent clearance central volume was 130L/h and 770 L, respectively.

Infant models were scaled using allometry and maturation functions for clearance and volume (total body water). Simulations across ages and weights, based on CDC growth charts and age-appropriate milk intake, showed that daily maternal consumption of 1–3 LCS beverages resulted in infant exposures >5-fold lower than levels associated with harm in animal studies.

Conclusions: In conclusion, the pharmacokinetics of ace-K and sucralose were adequately characterized in the breast milk and plasma of lactating mothers and infants. Findings contribute to a better understanding of LCS exposure during lactation and will help inform evidence-based recommendations on maternal LCS consumption while breastfeeding.

Citations: Citations:
[1] Fein SB, Labiner-Wolfe J, Shealy KR, Li R, Chen J, Grummer-Strawn LM. Infant Feeding Practices Study II: Study Methods. Pediatrics 2008;122:S28–35. https://doi.org/10.1542/peds.2008-1315c.
[2] Huang Q, Murphy J, Smith ER, Sylvetsky AC. Diet Beverage Intake during Lactation and Associations with Infant Outcomes in the Infant Feeding Practices Study II. Nutrients 2021;13:3154. https://doi.org/10.3390/nu13093154.
[3] Sylvetsky AC, Rother KI. Trends in the consumption of low-calorie sweeteners. Physiol Behav 2016;164:446–50. https://doi.org/10.1016/j.physbeh.2016.03.030.
[4] Sylvetsky AC, Dietz WH. Nutrient-Content Claims — Guidance or Cause for Confusion? N Engl J Med 2014;371:195–8. https://doi.org/10.1056/NEJMp1404899.
[5] Baker-Smith CM, de Ferranti SD, Cochran WJ, COMMITTEE ON NUTRITION SOG HEPATOLOGY, AND NUTRITION, Abrams SA, Fuchs GJ III, et al. The Use of Nonnutritive Sweeteners in Children. Pediatrics 2019;144:e20192765. https://doi.org/10.1542/peds.2019-2765.
[6] Archibald A, Dolinsky V, Azad M. Early-Life Exposure to Non-Nutritive Sweeteners and the Developmental Origins of Childhood Obesity: Global Evidence from Human and Rodent Studies. Nutrients 2018;10:194. https://doi.org/10.3390/nu10020194.
[7] Olivier-Van Stichelen S, Rother KI, Hanover JA. Maternal Exposure to Non-nutritive Sweeteners Impacts Progeny’s Metabolism and Microbiome. Front Microbiol 2019;10:1360. https://doi.org/10.3389/fmicb.2019.01360.
[8] Plows JF, Morton-Jones J, Bridge-Comer PE, Ponnampalam A, Stanley JL, Vickers MH, et al. Consumption of the Artificial Sweetener Acesulfame Potassium throughout Pregnancy Induces Glucose Intolerance and Adipose Tissue Dysfunction in Mice. J Nutr 2020;150:1773–81. https://doi.org/10.1093/jn/nxaa106.
[9] Simon BR, Parlee SD, Learman BS, Mori H, Scheller EL, Cawthorn WP, et al. Artificial Sweeteners Stimulate Adipogenesis and Suppress Lipolysis Independently of Sweet Taste Receptors. J Biol Chem 2013;288:32475–89. https://doi.org/10.1074/jbc.M113.514034.
[10] Zhang G-H, Chen M-L, Liu S-S, Zhan Y-H, Quan Y, Qin Y-M, et al. Effects of Mother’s Dietary Exposure to Acesulfame-K in Pregnancy or Lactation on the Adult Offspring’s Sweet Preference. Chem Senses 2011;36:763–70. https://doi.org/10.1093/chemse/bjr050.
[11] Sylvetsky A.C., Walter P.J., Garraffo H.M., Robien K., Rother K.I. Widespread sucralose exposure in a randomized clinical trial in healthy young adults. Am. J. Clin. Nutr. 2017;105:820–823. doi: 10.3945/ajcn.116.144402.
[12] Salman S, Sy SKB, Ilett KF, Page-Sharp M, Paech MJ. Population pharmacokinetic modeling of tramadol and its O-desmethyl metabolite in plasma and breast milk. Eur J Clin Pharmacol 2011;67:899–908. https://doi.org/10.1007/s00228-011-1023-6.
[13] Rackauckas C, Ma Y, Noack A, Dixit V, Mogensen PK, Elrod C, et al. Accelerated Predictive Healthcare Analytics with Pumas, A High Performance Pharmaceutical Modeling and Simulation Platform. Pharmacology and Toxicology; 2020. https://doi.org/10.1101/2020.11.28.402297.
[14] Kent JC, Mitoulas LR, Cregan MD, Ramsay DT, Doherty DA, Hartmann PE. Volume and Frequency of Breastfeedings and Fat Content of Breast Milk Throughout the Day. Pediatrics 2006;117:e387–95. https://doi.org/10.1542/peds.2005-1417.

Keywords: Low Calorie Sweeteners (LCS), Maternal-infant exposure, Population PK