Anaëlle Monfort 1, Julia Macente 2, Martje Van Neste 3, Miao-Chan Huang 2, Nina Nauwelaerts 2, Getahun B. Abza 2, Ursula Winterfeld 4, Anne Smits 5,6,7, Karel Allegaert 3,5,7,8, Pieter Annaert 2,9, Monia Guidi 10,11,12, Alice Panchaud 1,13
1 Service of Pharmacy, Lausanne University Hospital and University of Lausanne (Lausanne, Switzerland), 2 Drug Delivery and Disposition Lab, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven (Leuven, Belgium), 3 Clinical Pharmacology and Pharmacotherapy, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven (Leuven, Belgium), 4 Swiss Teratogen Information Service, Service of Clinical Pharmacology, Lausanne University Hospital and University of Lausanne (Lausanne, Switzerland), 5 Child and Youth Institute, KU Leuven (Leuven, Belgium), 6 Neonatal Intensive Care Unit, University Hospitals Leuven (Leuven, Belgium), 7 Department of Development and Regeneration, KU Leuven (Leuven, Belgium), 8 Department of Hospital Pharmacy, Erasmus MC (Rotterdam, Netherlands), 9 BioNotus (Niel, Belgium), 10 Centre for Research and Innovation in Clinical Pharmaceutical Sciences, University Hospital and University of Lausanne (Lausanne, Switzerland), 11 Institute of Pharmaceutical Sciences of Western Switzerland, University of Geneva and University of Lausanne (Lausanne, Switzerland), 12 Service of Clinical Pharmacology, Lausanne University Hospital and University of Lausanne (Lausanne, Switzerland), 13 Institute of Primary Healthcare (BIHAM), University of Bern (Bern, Switzerland)
Introduction/Objectives: More than 50% of women take at least one medication during lactation. However, 54% of the drugs in the LactMed database lack lactation safety data, and only 2% have robust evidence (1). These findings highlight a significant gap in guidance for designing pharmacokinetic and safety studies for this population, despite Food and Drug Administration guidelines recommending clinical lactation studies. To address this, we identified key medication-related criteria essential for designing lactation studies that assess infant safety following systemic exposure during lactation. This led to the development of a pharmacokinetic-based decision tree, named Milk4baby, designed to guide researchers in selecting the most suitable methodological approach for each medication.
Methods: The Milk4baby decision tree was designed through a structured literature review and iterative discussions within an interdisciplinary panel of experts in clinical pharmacology, lactation, and pharmacometrics. Key factors influencing methodological selection were identified and organized into a systematic decision-making framework. The decision tree first considers the prevalence of medication use among women of childbearing age, used as a proxy for the lactating population, and categorizes it into three groups: low (<0.05%), intermediate (0.05-0.1%) or high (>0.1%) prevalence of use. Second, the safety profile of the medication in infants aged 0 to 2 years is evaluated using available data from infants, adults, and/or animals. Safety assessment is based on the type, severity and frequency of adverse effects and is classified into three categories: safe, moderately safe, or unsafe. Finally, the expected infant systemic exposure level is assessed by reconstructing the pathway of the medication from its administration to the mother to the observed infant plasma concentrations. This includes evaluation of maternal exposure using the medication’s oral bioavailability in adults, pattern of use and transfer into human milk, as well as infant exposure using medication’s oral bioavailability in infants and risk of medication accumulation. The expected infant systemic exposure is categorized as low, intermediate or high risk of exposure. The decision tree then recommends the most suitable methodological approach among case reports/case studies, physiologically based pharmacokinetic (PBPK) modelling and simulation, population pharmacokinetic (popPK) modelling, pharmacoepidemiologic studies or combinations of these methods.
Results: A preliminary application to six drugs was conducted to illustrate the operational use of the Milk4baby decision tree. For example, citalopram was classified as highly prevalent, with an expected prevalence in lactating women greater than 0.77%. It was categorized as having an intermediate safety risk due to the absence of data in infants younger than 7 years, despite mild to moderate adverse effects reported in adults. A high exposure risk was identified based on high adult oral bioavailability (≈80%), likelihood of transfer into human milk, and an accumulation ratio of 2.56, suggesting a potential risk of accumulation in neonates and infants. According to our Milk4baby decision tree, popPK modelling was identified as the most appropriate methodological approach to evaluate infant systemic exposure to citalopram. Verification of the decision tree was performed by three independent reviewers on 50 randomly selected medications from the LactMed and Le CRAT databases. PBPK modelling and case reports were recommended in 29 cases (58%), primarily due to the low prevalence of medication use and the presence of either a safety or exposure risk. PopPK alone was the second most frequently selected approach (9 cases, 18%) followed by a combination of case reports, popPK and PBPK in 5 cases (10%). Pharmacoepidemiologic studies were not selected, reflecting the low likelihood of identifying medications that simultaneously present high safety and exposure risk while being frequently prescribed to lactating women. Additional components must also be considered when designing robust lactation studies involving clinical samples, including the number of women-infant dyads to recruit, the types and timing of biological samples to collect, the number of samples required, and the expected pharmacokinetic variability, as reflected by coefficients of variation for parameters such as the area under the curve, clearance, volume of distribution, and bioavailability.
Conclusions: The Milk4baby decision tree aims to help researchers enhance the efficiency and accuracy of determining infant safety after systemic exposure to maternal medicine during lactation by choosing the most suitable pharmacokinetic method for lactation studies, ultimately supporting better-informed decisions for lactating women, their families and healthcare providers.
References:
References:
(1) Byrne JJ, Spong CY. “Is It Safe?” – The Many Unanswered Questions about Medications and Breast-Feeding. N Engl J Med. 2019 Apr 4;380(14):1296-1297. doi: 10.1056/NEJMp1817420. PMID: 30943334.
Reference: PAGE 34 (2026) Abstr 12272 [www.page-meeting.org/?abstract=12272]
Poster: Methodology - Study Design