Evaluating Toxicology Testing Approaches in Pediatric Care: A Comprehensive Overview with Case Study Insights

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Introduction

This document summarizes a presentation by Dr. Rebecca Wilson, Assistant Professor at the University of Cincinnati College of Medicine and Director of Sendout Testing and Associate Director of Chemistry, Special Chemistry, and Urinalysis at Cincinnati Children's Hospital.

Her expertise lies in clinical chemistry, laboratory stewardship, and toxicology testing, particularly in pediatric, neonatal, and prenatal settings. The presentation critically evaluates the nuances, limitations, and ethical considerations of toxicology testing in these vulnerable populations, integrating methodologies, sample types, and interpretive challenges.

The Growing Crisis in Pediatric Toxicology

The United States is experiencing an alarming rise in drug exposures, overdoses, and poisonings among children and adolescents. Drug-related fatalities now represent the third leading cause of death in the pediatric population aged 1-19, surpassing cancer deaths in the last two years. This crisis is primarily driven by synthetic opioids, with fentanyl mortality surging four-fold from one death per 100,000 adolescents in 2018 to over four in 2021. This signifies a public health emergency where synthetic opioids dominate pediatric overdose mortality.

Parallel to this, there is a rising crisis in prenatal exposures, leading to a dramatic increase in Neonatal Abstinence Syndrome (NAS). NAS is caused by fetal exposure to drugs during pregnancy, including illicit drugs, prescription drugs (antidepressants, sedatives, opioids), and cannabis. Between 2010 and 2017, NAS rates increased nationally, with some states experiencing surges of over 283%. Infants with NAS face severe and far-reaching clinical consequences, including low birth weight, prematurity, neonatal seizures, congenital abnormalities, and long-term neurodevelopmental delays and behavioral challenges. The average hospital stay for an infant with NAS is three and a half times longer than for an unaffected infant, placing significant strain on healthcare systems.

Historical Context and Ethical, Social, and Legal Considerations

Toxicology testing has evolved significantly, initially driven by military needs in the 1960s and 70s, expanding into neonatal testing by the 1980s due to concerns about crack cocaine exposure. Legislation such as the Child Abuse Prevention and Treatment Act (amended in 2003) and the Comprehensive Addiction Recovery Act (2016) mandated states to notify Child Protective Services (CPS) of infants affected by prenatal substance exposure and provided funding for implementation. However, testing requirements vary considerably by state. For example, in Ohio, a drug test is not required for a pregnant person without consent, but a positive newborn drug test must be reported to CPS, unless it's for cannabis or prescribed methadone/buprenorphine.

Existing toxicology testing policies have faced significant criticism due to documented disparities in implementation, with evidence of disproportionate testing practices among racial/ethnic minorities, younger parents, and Medicaid-insured families. One study found Black infants were tested two to three times more frequently than white infants despite similar substance use rates. These disparities can lead to immediate consequences such as stigmatisation, damaged provider-family relationships, erosion of trust in healthcare, and potential psychological impacts on child development, even with negative results.

The three main drivers for toxicology testing are:

• Clinical: Guiding withdrawal management and safe discharge.
• Legal: Mandatory reporting to CPS.
• Social: Risk assessment for family stability, connecting families with support for addiction or mental health issues.

Critical Phases of Toxicology Testing

Toxicology testing involves three critical phases: pre-analytical, analytical, and post-analytical, each presenting unique challenges in pediatric populations.

• Pre-analytical Phase: Specimen Collection and Limitations Obtaining sufficient specimen volumes, especially from newborns, and handling complex matrices like meconium introduce significant variability. Specimen stability and collection techniques also impact reliability.

Common biological specimens and their characteristics include:

• Blood: Ideal for detecting acute exposure and providing quantitative concentrations, but difficult to obtain in pediatric patients and requires processing to remove interferences. There is a disparity in FDA-cleared screening assays for illicit drugs in blood compared to urine.
• Urine: Most tested due to ease of collection and relatively clean matrix. However, it provides limited information on exposure timing and is influenced by metabolic/hydration factors. Collection is challenging in patients with renal impairment, neonates, or young children (e.g., using cotton balls or gauze).
• Hair: Provides a longer detection window (months) but is infrequently used clinically due to complex extraction and poor temporal resolution; lacks standardization.
• Oral Fluid: Gaining popularity due to non-invasive collection but has lower analyte concentrations than urine and challenges in correlating with blood levels; lacks standardization.

For prenatal drug exposure, specimens are collected from both the birthing parent and newborn:

• Maternal Urine: Reflects recent drug use.
• Newborn Urine (first 24 hours): Primarily reflects exposure during the last few days to weeks of pregnancy.
• Umbilical Cord Tissue: Easy and non-invasive to collect, offers a comparable detection window to meconium (second and third trimesters), but is a newer matrix with less clinical experience and sparse data on expected drug concentrations.
• Meconium: Offers a longer detection window, typically covering the second and third trimesters, and is moderately established. However, it is non-homogeneous, and collection is not always possible (10% of neonates pass meconium during labor), with limited normative data.

There is wide variability in agreement between different prenatal specimen types, ranging from 44-66% for maternal and newborn urine, and as low as 40% for urine and meconium. Agreement between meconium and umbilical cord tissue is generally higher but can still be as low as 40% for some drug classes.

This variability is attributed to differences in drug class detection, matrix composition, extraction efficiencies, and testing methodology, as well as intrinsic biological differences in how drugs are deposited. Notably, for cocaine and its metabolites, umbilical cord concentrations were significantly lower than meconium in one study.

• Analytical Phase: Methodologies and Availability Toxicology testing falls into two categories:

Screening Methods (Immunoassay-based): Rapid, inexpensive, and readily available, providing qualitative (positive/negative) presumptive results based on manufacturer-designed cut-offs. They are susceptible to interferences and often use a single target analyte to represent a class, potentially leading to varied sensitivities for different drugs within that class.

Confirmatory Methods (Chromatography-Mass Spectrometry based): Verify screen results, quantify drug concentrations, and reduce false positives/negatives. These are highly accurate and precise but are more expensive, considered high-complexity laboratory-developed tests, and require specialized personnel and equipment. They often have longer turnaround times (days to weeks) and are not available in all laboratories.

A survey highlighted the widespread reliance on screening methods, with nearly 4,000 labs using immunoassays compared to only 421 having LC-mass spectrometry (LC-MS) based assays and even fewer for GC-mass spectrometry (GC-MS).

There is significant variability in test menus across laboratories. While over 4,000 labs perform opiate group immunoassay tests, only about 2,000 (50%) offer a separate fentanyl immunoassay. Crucially, most opiate group immunoassays do not detect fentanyl or its metabolites, and this is also true for other compounds like buprenorphine and oxycodone. This variability can dramatically impact patient care.

• Post-analytical Phase: Interpretation Results must be carefully reviewed by specialists and correlated with the patient's clinical presentation to avoid misdiagnosis or inappropriate interventions.

Case Study Insights and Test Discordance

The presentation highlighted several cases illustrating testing challenges:

• Case 1 (20-month-old with negative UDS but fentanyl poisoning): An initial immunoassay urine drug screen was negative, but comprehensive testing later identified fentanyl and norfentanyl, leading to diagnosis. This case exemplifies how common opiate immunoassays often miss fentanyl, necessitating more sophisticated methods for diagnosis.
• Case 2 (2-year-old with trouble breathing, stiff muscles, agitation): An immunoassay was positive for fentanyl, but a comprehensive GC-MS assay was negative. This discordance occurred because the GC-MS assay, designed for broader screening (up to 219 compounds) in "scan mode," sacrificed sensitivity for breadth, with a limit of detection (LOD) for fentanyl a thousand times higher than the immunoassay. This highlights that a "comprehensive" panel might miss clinically significant exposures detected by more sensitive targeted assays. The study showed that while immunoassay utilization decreased over time for general acute care, it remained stable or increased for pediatric acute care, where its broad screening capability is vital for unknown or polysubstance exposures.
• Case 3 (Infant with cocaine exposure discrepancies): Newborn urine and meconium were positive for cocaine, but maternal urine showed only a small peak below the cut-off, and the umbilical cord was negative. Such discrepancies are common due to varying concordance rates between specimen types for different drugs.

Test discordance is a critical issue:

• Immunoassays can miss cases detected by GC-MS (e.g., ~7% for amphetamines).
• Conversely, GC-MS can miss clinically significant exposures detected by immunoassays, especially for synthetic drugs like fentanyl, due to methodological differences and sensitivity settings. It is crucial to always correlate results with clinical suspicion.

Challenges and Opportunities

Current Challenges:

• Legal "patchwork": Inconsistent prenatal testing requirements across states.
• Ethical dilemmas: Mandatory reporting to CPS creates difficult situations for providers.
• Lack of standardization: No consensus guidelines for detection limits in neonatal specimens or for many laboratory-developed toxicology tests.
• Variable test menus: Significant differences in what institutions offer, especially concerning fentanyl screening.
• Clinical and public health gap: Rising pediatric exposures (e.g., 5,000% increase in fentanyl cases since 2016) and inconsistent follow-up for at-risk families.

Opportunities:

• Develop evidence-based guidelines: Especially for neonatal testing cut-offs.
• Advocate for equitable testing policies: Address disparities and optimize test utilization.
• Implement stewardship programs: Ensure the "right test for the right patient at the right time". Dr. Wilson's experience showed a hands-on approach (e.g., calling providers to switch orders for limited specimen types) was effective, leading to improved awareness among clinicians over time.
• Leverage newer technologies: High-sensitivity and specific assays like LC-MS/MS or accurate mass analyzers should ideally be available in all labs.
• Align stakeholders: Collaboration between labs, clinicians, and policymakers is essential to translate challenges into safer outcomes for children, particularly in the realm of child protection.

Discussion Points

During the Q&A, Dr. Wilson confirmed an increase in THC positivity in her hospital, particularly in prenatal testing and emergency department visits, linked to the legalization of cannabis in Ohio, Kentucky, and Indiana. This trend is expected to continue. When asked about histopathologic findings in autopsy cases related to drug exposure, Dr. Wilson noted she did not have specific pointers but found the question valuable for future research.

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