Presumptive false-positive amphetamine urine screen in a pregnant woman receiving α-methyldopa: A case report

Dear Editor,

Urine drug screening (UDS) is widely used in clinical and occupational evaluations because immunoassays provide rapid and cost-effective results.[1,2] However, these assays are susceptible to cross-reactivity with a variety of medications, potentially leading to presumptive false-positive results.[1,2] Although numerous medications have been reported to cause presumptive false-positive amphetamine results on UDS, pregnancy-related case reports remain scarce, with only a few cases described in pregnant women receiving labetalol, mexiletine, metoprolol, or imatinib.[3,4,5,6] In addition, computational and experimental studies have demonstrated that α-methyldopamine, the primary metabolite of α-methyldopa, may interfere with certain amphetamine immunoassays.[7] Large-scale analyses of electronic health records have further shown that numerous medication–assay cross-reactivities can be identified even in the absence of confirmatory testing by gas chromatography–mass spectrometry (GC–MS) or liquid chromatography–tandem mass spectrometry (LC–MS/MS).[7]

Here, we present a case of a pregnant woman with a presumptive false-positive urine amphetamine screen that was most likely associated with α-methyldopa therapy, highlighting its clinical implications.

A 29-year-old woman at 35 weeks’ gestation was referred to our outpatient psychiatric clinic as part of a pre-employment medical evaluation. She had no previous psychiatric diagnosis or treatment history. She denied tobacco, alcohol, and illicit drug use, and this history was corroborated by her family members. Physical examination, mental status examination, and psychometric assessments were all within normal limits. Her regular medications are summarized in Table 1.

Table 1.

Regular medications used by the patient during pregnancy

Medication	Indication	Dosage regimen
α-Methyldopa 750 mg/day*	Gestational hypertension	250 mg orally three times daily (08:00, 16:00, and 00:00)
Nifedipine 60 mg/day	Gestational hypertension	30 mg orally twice daily
Acetylsalicylic acid 100 mg/day	Preeclampsia prophylaxis	100 mg orally once daily
Pyridoxine, magnesium, and iron supplements	Vitamin and mineral supplementation during pregnancy

*On the day of the initial UDS, the patient reported inadvertently taking an additional morning dose of α-methyldopa. However, she was unable to recall the exact time at which the extra dose had been taken

Following the detection of a presumptive positive amphetamine result on the routine pre-employment UDS, the patient underwent a comprehensive reassessment for possible illicit substance use. After consultation with clinical biochemistry specialists and a review of the relevant literature, a second urine sample was obtained the following day, and the UDS was repeated. The results of the two UDS analyses are presented in Table 2.

Table 2.

Results of the first and second UDS tests*

Sample collection time	Urine creatinine	Urine specific gravity	Amphetamine concentration†	Test result (cutoff >500 ng/mL)
Day 1, 13:07	206.7 mg/dL	1.020	660 ng/mL	Positive
Day 2, 11:32	49.6 mg/dL	1.005	460 ng/mL	Negative

*UDS was performed using the EMIT® II Plus Amphetamines Assay (Syva®/Siemens Healthineers) on the Viva-ProE® analyzer, with a cutoff concentration of 500 ng/mL, corresponding to the Substance Abuse and Mental Health Services Administration (SAMHSA) initial screening cutoff.[1,2]. ^†The reported amphetamine concentration represents a semi-quantitative value derived from the calibration curve of the homogeneous enzyme immunoassay and does not constitute a quantitative measurement confirmed by mass spectrometry (GC–MS or LC–MS/MS)

To the best of our knowledge, no previous clinical case has reported a presumptive false-positive urine amphetamine result associated with α-methyldopa use during pregnancy. Because the potential for α-methyldopamine to interfere with amphetamine immunoassays has previously been demonstrated in computational and experimental studies, this case may represent a clinical illustration of that previously recognized analytical interference in pregnancy, although confirmatory testing was not performed.[7]

Furthermore, none of the patient’s concomitant medications has been reported to exhibit clinically relevant cross-reactivity with amphetamine immunoassays, making α-methyldopa the most plausible explanation for the presumptive false-positive screening result.

According to the manufacturer’s cross-reactivity data, α-methyldopa itself does not produce cross-reactivity with this immunoassay at concentrations up to 1,000 µg/mL. Therefore, the observed interference is more likely attributable to its metabolite, α-methyldopamine, rather than to the parent compound, a finding that is consistent with previous computational and experimental studies.[7]

Nevertheless, the decline of the second result below the assay cutoff may not be explained solely by a reduction in α-methyldopa/α-methyldopamine concentrations. The substantially greater dilution of the second urine specimen compared with the first may also have contributed to this finding. Although the urine creatinine concentration of 49.6 mg/dL does not meet the criterion for an excessively dilute specimen (<20 mg/dL), it indicates a clinically relevant difference in urine dilution that should be considered when interpreting the repeat test result.

In conclusion, this case suggests a possible association between α-methyldopa use during pregnancy and a presumptive false-positive urine amphetamine screening result, highlighting the need for cautious interpretation of positive immunoassay findings in the absence of confirmatory testing. A false-positive screening result may lead to inappropriate patient labeling, delays, or misdirection in medical care, and social stigma. Clinicians should therefore be aware of this potential interference and, whenever feasible, request confirmatory testing using GC–MS, LC–MS, or LC–MS/MS when interpreting positive amphetamine screening results.

Conflicts of interest

There are no conflicts of interest.

Funding Statement

Nil.