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

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 haste