Deuterium Oxide Dilution Method to Quantify Human Milk Intake Volume of Infants: Systematic Review – A Contribution from the ConcePTION Project

Background: Global health organizations recommend breastfeeding, but maternal pharmacotherapy can disrupt this due to safety concerns. Physiologically-based pharmacokinetic (PBPK) models predict medication transfer through breastfeeding, relying on validated milk intake volume data. However, literature mainly focused on different measurement methods, or such intake data were collected without systematic review. This systematic review therefore aims to gather data on human milk intake volume derived using the (dose-to-the-mother) deuterium oxide dilution method, allowing comparison with literature. Additionally, it aims to explore effects of maternal conditions on milk intake volume. Methods: PubMed, Embase, Web of science, Cochrane library, Scopus and CINAHL were searched for studies on the dilution method and breastfeeding in healthy infants. Risk of Bias was assessed using the Newcastle-Ottawa Scale (NOS) and the Risk of Bias 2 (RoB2) tool. Data on mean human milk intake volume were extracted and synthesized (mL/day and mL/kg/day) throughout infancy. Results: Sixty studies (34 countries) reported on milk intake volume of 5502 infants. This intake was best described by logarithmic regression y(mL/kg/day) = 149.4002 -0.2268*x -0.1365*log(x) (x=postnatal age, days). Maternal conditions showed no significant influence on human milk intake, except for maternal smoking (reduction). Conclusion: This function corresponds with previous literature, particularly between 1.5 to 12 months. Limited availability of early infancy data underscores the need for additional data in future PBPK modelling to enhance informed healthcare decisions and improved outcomes for mother and infant.