Lingering Norfentanyl: Considerations for Prolonged Clearance in Pregnancy Given Potential Clinical and Legal Implications

Abstract

How can elimination of fentanyl change during pregnancy? What are challenges clinicians face when interpreting drug testing results? When is it important for the clinical team to contact the laboratory toxicologist for consultation? The patient was a 33-year-old woman, Gravida 3 Para 2, established with an outpatient perinatal addiction program at 35 weeks’ gestation. Her history included tobacco use disorder, daily intravenous fentanyl use (last use 14 days prior to assessment), hepatitis C virus, and obesity (body mass index [BMI] 38.7 kg/m2 at 39 weeks’ gestation). She was initiated on buprenorphine and received regular urine toxicology testing. A series of urine drug tests were performed for this patient (Table 1). The initial urine drug screen (UDS) performed at an outside hospital 14 days after last reported fentanyl use was presumptive positive for buprenorphine, fentanyl, and opioids. Eleven days later, repeat testing using a point-of-care (POC) UDS cup was positive only for buprenorphine. No confirmatory testing was performed for either of those tests. On treatment day 13 (27 days since last reported fentanyl use), UDS remained fentanyl positive. Confirmatory liquid chromatography–tandem mass spectrometry (LC-MS/MS) testing reported fentanyl as <1.0 ng/mL, which was interpreted as negative for fentanyl. The norfentanyl level was not reported due to an interfering substance. After consultation, the toxicologist determined the total combined concentration of norfentanyl and the interfering substance was ≤4.1 ng/mL suggesting that the concentration of norfentanyl was very low as it was no more than 4.1 ng/mL. The identity and concentration of the interfering substance alone could not be determined by the LC-MS/MS assay used. For comparison, mean urine concentrations of norfentanyl in people wearing fentanyl transdermal patches range from 175 to 373 ng/mL depending on the patch dose which may range from 25 µg/h to 100 µg/h (1). Longitudinal urine drug testing grouped by days since last fentanyl use. aPOCT, point of care testing. bUnable to report due to interference with methodology. On treatment day 28 (42 days since last reported fentanyl use)—the day of scheduled cesarean section (CS)—a UDS collected upon arrival for the procedure again screened positive for fentanyl. Confirmatory LC-MS/MS reported fentanyl as <1.0 ng/mL and norfentanyl as 2.3 ng/mL. The patient received intrathecal fentanyl for pain control after collection of this specimen. Umbilical cord toxicology was negative. The care team debated whether toxicology findings reflected ongoing use or delayed elimination. Social work considered a Child Protective Services (CPS) report based on positive maternal UDS. Mirroring the general population, opioid use disorder among pregnant and postpartum patients has increased dramatically (2). Perinatal drug testing has clinical, ethical, and legal implications. Clinically, birth parents and infants may experience withdrawal after birth (2). Legally, families may face criminal sequelae and family separation. In the United States, clinicians must comply with federal and state law, which may include reporting the infant and birth parent to CPS. In some states, perinatal substance use as evidenced by a positive toxicology test is grounds for child abuse charges (3). Informed consent should be obtained prior to drug testing birthing parents. Some jurisdictions may not require informed consent for newborn toxicology testing. The implications of a positive toxicology test result should be discussed with birth parents (2). Sample options for toxicology testing in perinatal patients include maternal urine, infant urine, meconium, or umbilical cord tissue. Screening typically begins with immunoassay (IA) and can be followed by confirmatory testing. The IAs have high clinical sensitivity and are prone to false-positive results. The rate of false positives can vary by the drug class and vendor. Detection of a drug may be impacted by using a POC vs main laboratory assay, the cross-reactivity of the IA with the parent drug, its metabolites, or related compounds, and drugs administered during labor and delivery. POC tests for fentanyl often detect fentanyl, which is at lower concentrations in urine than norfentanyl, whereas main lab IAs may target norfentanyl, fentanyl, or both. Clinicians should be aware of limitations of toxicology tests. IA results should be considered presumptive. Best practice dictates that any unexpected positive or negative IA result should be verified using a confirmatory assay, either qualitative or quantitative (4). Mass spectrometry-based methods are generally used for confirmation and considered a definitive test. Clinicians should have a low threshold for consultation with the laboratory’s toxicologist when results are inconsistent with the clinical picture or patient report (4). Accurate interpretation of perinatal UDS is critical yet poses challenges (4). Physiologic changes during pregnancy can cause false-positive and false-negative results. Physiologic changes progress over the course of pregnancy, peaking in the third trimester, and affect all aspects of drug pharmacokinetics (5). A case report regarding delayed norfentanyl elimination in a pregnant women with opioid use disorder describes prolonged norfentanyl detection for up to 70 days after last fentanyl use (6). In comparison, the typical urine detection window in people entering treatment for fentanyl use was 7 to 13 days and people with overweight or obesity had longer detection windows (7). Possible contributing factors considered for our patient’s lingering norfentanyl concentrations include changes in enzymes and transporters, decreased albumin, increased renal blood flow, and an increase in the fat compartment (5). Reports on the effects of pharmacogenetics on fentanyl metabolism are conflicting. Pregnancy accelerates fentanyl metabolism via cytochrome P450 3A4 (CYP3A4) induction, which would hasten elimination, but the net effect on fentanyl exposure may be modulated by individual CYP3A4/3A5 and ABCB1 genotypes. Fentanyl is mainly metabolized by CYP3A enzymes. Polymorphisms in the related genes CYP3A4 (such as CYP3A4*22) and CYP3A5 (such as CYP3A5*3) can decrease the metabolic clearance of fentanyl (8). When this happens, fentanyl is metabolized more slowly, which may lead to prolonged or more intense drug effects. Additionally, the drug transporter p-glycoprotein, encoded by the ABCB1 gene, is a key efflux transporter at the blood–brain barrier and placenta, limiting the entry of fentanyl into the central nervous system and fetal circulation. The 3435C>T variant of the ABCB1 gene can lead to decreased ATP binding cassette subfamily B member 1 (ABCB1) expression, potentially resulting in higher fetal exposure to fentanyl (9). For our patient, changes in enzymes and transporters were considered unlikely given there was detectable norfentanyl and undetectable fentanyl, supporting adequate drug metabolism and elimination. Classic considerations for altered drug pharmacokinetics include protein binding and changes in renal function, both altered in pregnancy. About 88% of fentanyl is bound to protein, predominantly albumin (7). As albumin decreases during pregnancy, the amount of free drug increases, thus enabling increased metabolism of fentanyl to norfentanyl and excretion (10). Further, norfentanyl and fentanyl are predominantly eliminated by the kidneys. Therefore, in pregnancy, the lower albumin and increased renal blood flow would lean toward faster clearance of the drug, ruling these out as contributing factors for our patient’s lingering norfentanyl. Fentanyl is a small, highly lipophilic molecule, which increases its ability to cross plasma membranes and gives it a high volume of distribution (Vd) (7). Higher Vd is more pronounced in people with obesity and for drugs with higher lipophilicity (11). With chronic use, fentanyl moves out of the circulation into fat and muscle and accumulates in tissues (7). During pregnancy, the fat compartment increases, which will lead to a higher fentanyl Vd. This, paired with our patient’s gestational BMI and chronic fentanyl use, suggests she would have a higher fentanyl Vd. Chronic use of fat-soluble drugs can have delayed elimination over weeks; tetrahydrocannabinol (THC) metabolism is a well-known example of this (12). This mechanism likely contributed to our patient’s results. Secondary peaking is a phenomenon in drug elimination whereby sudden increases in drug concentration may occur during the elimination phase (7). Two mechanisms have been proposed: (a) enterogastric reabsorption, where the drug is held in the stomach by gastric cells and later reabsorbed in the intestine and (b) altered distribution pattern of the drug within the peripheral tissues (7). During pregnancy, gastrointestinal emptying is slower, which would theoretically reduce secondary peaking via the enterogastric reabsorption mechanism (7). For fentanyl distributed to fat and tissues, the release will occur due to changes in that compartment, which might be unpredictable. The most plausible explanation for our patient is delayed elimination due to prolonged release of fentanyl from the fat or other compartments. When monitoring drug use, urine toxicology is often used. Urine is prone to varying degrees of dilution. Different studies have evaluated normalizing the drug concentration to creatinine or specific gravity to manage dilution differences (4). There are limitations to normalization, but it may assist with following a patient’s trends. The specific gravity was available for our patient, though normalizing the norfentanyl concentrations to it did not provide additional information. For our patient, consultation with the laboratory toxicologist was essential to interpreting serial toxicology results. The patient’s care team concluded that prolonged clearance of norfentanyl was likely due to physiologic characteristics of pregnancy and obesity. This consensus was reached after a CPS report was made, though the interpretation of results was clarified with CPS. This family’s care could have been improved with awareness of nuances of perinatal toxicology interpretation. Screening immunoassays are presumptive results and should be confirmed using more specific methods before any punitive actions are taken. When available, ordering screening tests that reflex to confirmatory testing is recommended. Physiologic changes in pregnancy affect all aspects of drug pharmacokinetics and need to be considered for proper interpretation of screening and confirmatory drug results. There can be significant social or criminal implications associated with positive drug results surrounding pregnancy, even if mistakenly interpreted. Clinicians may have limited experience or expertise in interpreting drug results and a low threshold for consulting the laboratory toxicologist can be beneficial for patient care. Early collaboration amongst a multidisciplinary team could improve birth parent and baby patient outcomes when toxicology results are positive. Nonstandard Abbreviations: BMI, body mass index; UDS, urine drug screen; POC, point-of-care; CS, cesarean section; CPS, child protective services; IA, immunoassay; CYP3A4, cytochrome P450 3A4; ABCB1, ATP binding cassette subfamily B member 1; Vd, volume of distribution; THC, tetrahydrocannabinol. Human Genes: CYP3A4/3A5, cytochrome P450 family 3 subfamily A member 4 and 5; ABCB1, ATP binding cassette subfamily B member 1. Author Contributions: The corresponding author takes full responsibility that all authors on this publication have met the following required criteria of eligibility for authorship: (a) significant contributions to the conception and design, acquisition of data, or analysis and interpretation of data; (b) drafting or revising the article for intellectual content; (c) final approval of the published article; and (d) agreement to be accountable for all aspects of the article thus ensuring that questions related to the accuracy or integrity of any part of the article are appropriately investigated and resolved. Nobody who qualifies for authorship has been omitted from the list. Authors’ Disclosures or Potential Conflicts of Interest: Upon manuscript submission, all authors completed the author disclosure form. Research Funding: S Boden, E Cabacungan, and E Hovis received funding from the Maternal Health Innovation Program (Wisconsin Department of Health Services). Disclosures: L Smy has received consulting fees from Fluxergy and Navidx. K Ryan has received funding from the American Academy of Pediatrics for participation in the 2025 Safe Discharge Perinatal Quality Improvement Initiative, honoraria from the American Academy of Pediatrics and The Periscope Project, and serves as an editor for Elsevier for publications pertaining to newborn care and pediatrics. S Boden, E Cabacungan, and E Hovis received grant funding from the Wisconsin Department of Health Services Maternal Health Innovation Program. There are no additional conflicts of interest to disclose.

The authors' abstract, as published at the source. The Journal of Applied Laboratory Medicine, 2026 · DOI ↗