Any environmental exposure a lactating woman experiences has the potential to transfer into her breast milk to some extent, potentially exposing the infant consuming milk to residual maternal substances. Simultaneously, pasteurized donor human milk (PDHM) serves as a lifeline for medically fragile infants in neonatal intensive care units (NICUs) when the mother’s own milk is unavailable [1, 2]. Subsequently, concerns have emerged regarding the potential risk of infant exposure to illicit and prescription drugs through PDHM [3, 4]. These concerns have been amplified by two trends: rising rates of substance use in the general population and the increasing potency of illicit substances, particularly synthetic opioids like fentanyl, which can “adulterate” the milk and cause adverse effects at minute concentrations. Though rare, documented cases exist of infant harm following exposure to maternal substances via the mother’s own milk, whether from medically supervised or illicit drug use [5]. For vulnerable NICU infants with immature metabolic and excretory systems, exposures to such residues pose risk, though these potential harms must be carefully weighed against the well-established benefits of human milk over commercial formula for this population. Although no cases of neonatal adverse effects from illicit or prescription drug exposure via PDHM have been reported in the medical literature, a comprehensive risk-benefit assessment requires empirical data quantifying drug adulterant prevalence, rather than reliance on theoretical concerns or reassurance from the absence of observed harm.

Substance use occurs in the lactating population. The prevalence of illicit drug use, specifically among breastfeeding women and milk donors, remains largely unknown, creating a critical knowledge gap. Cannabis is reported among approximately 5% of breastfeeding mothers according to Pregnancy Risk Assessment Monitoring System data from 2017, making it the most likely adulterant drug in human milk [6]. Other substance use documented in breastfeeding populations includes cocaine, opioids, and methamphetamine, all of which can transfer into breast milk as adulterant residues to varying degrees [7–9]. Medically supervised use of these and similar compounds (e.g., opioids, amphetamines) is less frequently posited as a concern, but also confers the same mechanistic risk to the infant.

Not-for-profit milk banks employ multi-layered strategies to mitigate potential risks of illicit and prescription drug residues in milk. Like blood banking [10], the cornerstone of these efforts is rigorous donor screening, which typically includes comprehensive health and medication histories, lifestyle questionnaires, serologic testing, and endorsement from a previously established healthcare provider [11, 12]. Importantly, these banks rely exclusively on voluntary, non-remunerated donors—a model that, again similar to blood banking [13], may attract individuals more committed to providing safe milk compared to paid donation models. Consequently, human milk obtained from carefully screened donors is designed to offer a supply with minimal risk of drug residues, providing a valuable option for medically vulnerable infants without access to a full diet of the mother’s own milk.

Beyond screening, the standard practice of combining milk from multiple donors (“pooling”) yields critical, strategic advantages that are often overlooked [12, 14]. Pooling facilitates standardization of nutritional composition across production batches, creates substantial dilution of any potential adulterants from individual contributors (reducing even theoretically significant concentrations to clinically insignificant levels), and mitigates “outlier effects” where idiosyncratic milk characteristics from a single donor might otherwise dominate. Furthermore, pooling enhances the immunological profile of batches by broadening the spectrum of bioactive components, including diverse antibodies, human milk oligosaccharides, vitamins, and other beneficial constituents essential for optimal infant development [15].

There is growing evidence supporting the effectiveness of these approaches. In a 2014 validation study, Escuder-Vieco et al. tested 400 pooled specimens from 63 donors using liquid chromatography tandem mass spectrometry (LC-MS/MS) and found no presence of caffeine, nicotine, morphine, amphetamines, cocaine, cannabis, methadone, or related metabolites, aligning with responses from donor screening questionnaires [11]. A follow-up study in 2016 confirmed the lack of substance use in 36 donors who reported no episodic or chronic use of the same substances during screening using two methodologies: (1) analysis of donor milk by LC-MS/MS, which indicated no drug use around the time of milk expression, and (2) hair sample testing by gas chromatography-mass spectrometry (GC-MS), which provided a longer retrospective view suggesting no illicit drug exposure during pregnancy and in the early stages of breastfeeding [16]. In their 2023 investigation, Ramos Santos et al used GC-MS to detect cocaine, nicotine, morphine, methadone, amphetamines, and ketamine (and metabolites) in breast milk. Notably, all of their 67 samples (unpooled) from a milk bank tested negative for the entire panel of analytes [17]. These studies each have potential methodological limitations, and the analytes quantified may not capture the most prevalent adulterants expected in our community.

Ideally, milk banks and NICUs would have access to an inexpensive, rapid, accurate, validated, and user-friendly test capable of detecting bioactive adulterant residues directly in milk. Among the available drug testing matrices—blood, breath, saliva, urine, sweat, and hair—only sweat and hair testing can provide a potential indication of drug use occurring more than several weeks prior [18]. In contrast to blood banking, no US Food and Drug Administration (FDA)-approved in vitro diagnostic assays currently exist for adulterant detection in human milk. Current enzyme-linked immunosorbent assay (ELISA) analytical methods for detecting adulterants in human milk are problematic [19]. ELISA assays marketed for milk banking are only internally validated for forensic use rather than any diagnostic purposes [20], presumably as manufacturers have not met FDA standards for validating the assays in the complex matrix of human milk. Further, ELISA testing in human milk typically requires sample processing that may demand specialized expertise or equipment beyond the routine capabilities of many milk banks. Consequently, milk testing practices vary significantly between milk banks with some facilities implementing forensic ELISA analytical milk testing in addition to donor screening protocols.

Given these considerations, a critical clinical question emerges: Under current donor screening protocols and milk processing practices, does infant-ready pooled PDHM contain illicit or prescription drug residues of concern at levels that might pose harm to medically fragile infants? This study addresses this knowledge gap by employing highly sensitive analytical methods to examine a large sample of PDHM from a not-for-profit milk bank accredited by the Human Milk Banking Association of North America (HMBANA) for these residues, generating evidence-based data to inform clinical practice and milk banking policies.