Links To And Excerpts From “False negative point‐of‐care urine pregnancy tests in an urban academic emergency department: a retrospective cohort study”

Today, I review, link to, and excerpt from False negative point‐of‐care urine pregnancy tests in an urban academic emergency department: a retrospective cohort study [PubMed Abstract] [Full-Text HTML] [Full-Text PDF]. J Am Coll Emerg Physicians Open. 2021 Jun; 2(3): e12427. Published online 2021 May 1. doi: 10.1002/emp2.12427

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Abstract

Study objective: To determine the prevalence of false negative point-of-care (POC) urine pregnancy tests among emergency department (ED) patients and among those with abdominal pain or vaginal bleeding.

Methods: We identified all female patients, ages 14-50 years without prior hysterectomy who had a negative POC urine pregnancy test (beta subunit of human chorionic gonadotropin [β-hCG]) performed by trained clinical staff in the ED between September 1, 2017 and December 31, 2018, as well as a subgroup we defined a priori as “high risk” for early pregnancy complications based on a triage chief complaint (text) of abdominal pain or vaginal bleeding. We identified those with a positive urine β-hCG, serum β-hCG >5 mIU/mL, or a diagnosis of pregnancy within 3 months of the initial ED visit (index visit). We used structured chart review with American College of Obstetrics and Gynecology guidelines to determine pregnancy diagnosis and outcomes (ectopic, intrauterine, abnormal including spontaneous abortion, and unknown), the date of conception, and whether the pregnancy was present at the index visit.

Results: Of 10,924 visits with a negative urine pregnancy test result that were screened for a pregnancy outcome, 171 (1.6%, 95% confidence interval [CI] = 1.4, 1.8) had a pregnancy present at the index visit. Diagnoses were ectopic (n = 12, 7.0%), intrauterine (n = 71, 41.5%), abnormal (n = 77, 45.0%), and unknown (n = 11, 6.4%). Of the 2732 patients with high-risk complaints, 97 (3.6%, 95% CI = 2.9, 4.3) had a pregnancy present at the index visit (relative risk of a pregnancy diagnosis 3.9, 95% CI = 2.9,5.3), including 10/12 ectopic (83%), 58/77 abnormal (75%), and 25/71 intrauterine pregnancies (35%). Serum β-hCG ranged from 2 mIU/mL to above assay (median = 119.5, interquartile range = 957.5).

Conclusion: Although false negative urine pregnancy tests were uncommon, multiple pregnancy diagnoses were missed, including ectopic pregnancies. False negatives were more common among patients with abdominal pain or vaginal bleeding. Concurrent serum β-hCG levels demonstrated a broad distribution.

Keywords: MESH; diagnostic errors; emergency medicine; false negative reactions; pregnancy tests.

© 2021 The Authors. JACEP Open published by Wiley Periodicals LLC on behalf of American College of Emergency Physicians.

1.3. Goals of this investigation

We sought to determine the prevalence of false negative urine pregnancy test results in a large urban ED to establish whether this test should appropriately be used to rule out pregnancy, both among a general population and among patients with symptoms concerning for early pregnancy complications. A high rate of false negative urine tests could inform clinician decisions as well as operational changes to support exclusive or more frequent serum testing. When available, we examined the concurrent serum β‐hCG level to evaluate the reason for false negative results. By identifying patients who had concurrent pregnancy testing (serum β‐hCG or ultrasound) as well as those who had pregnancy diagnosed in follow up from the ED visit, we aimed to provide a more accurate estimate of the performance of POC urine β‐hCG testing in routine clinical care.

Within this overall sample (n = 10,924), we used the Data Warehouse to identify for chart review all subjects who met inclusion criteria and also had possible evidence of pregnancy at the index visit or within 90 days (n = 383), including any positive urine β‐hCG test, any non‐zero serum β‐hCG test, any pelvic ultrasound, or any visit with an ICD‐10 diagnosis suggesting pregnancy (Table 1 and Figure 1).

5. DISCUSSION

We found that POC urine pregnancy testing yielded a false negative omission rate of 1.6%. Because we included patients who had concurrent pregnancy testing (serum β‐hCG or ultrasound) as well as those who did not have testing at the index visit, our study provides a more accurate and complete understanding of the limitations associated with using a POC urine β‐hCG approach to screen patients of childbearing potential for pregnancy. Our estimate is higher than the prior estimates of Griffey who reported a 0.34% false negative rate but only considered those with concurrent serum β‐hCG testing, ⁶ as well as Woo, ¹⁰ who found a false negative rate of 10.8% with a FOR of 0.9% (including follow‐up diagnoses within 3 months of the index visit).

The majority of concurrent serum results were above the stated limits of detection for urine testing and in the lower ranges of concentrations (Figure 2), confirming that POC assays may be susceptible to false negative results at low β‐hCG concentrations due to dilute urine samples. ²¹ Our results also show a second peak of concurrent high serum β‐hCG concentrations (>25,000 mIU/mL), consistent with the previously‐documented “hook effect” from excess β‐hCG fragments. ⁶ , ⁹ , ²² However, we also found a broad range of serum values, consistent with prior study of the FDA’s Manufacturer and User Facility Device Experience (MAUDE) database, which showed that most false negative results could not be attributed to the lower limit of detection or the hook effect. ²³ Although some false negative results may reflect process errors, such as faulty documentation or deviations from assay procedures, previous studies have shown equivalent false negative rates between POC and laboratory urine testing. ⁴

Clinical decisions around pregnancy testing should incorporate the indication for the test, the implications of a false negative result, the pre‐test suspicion for pregnancy, as well as test characteristics. For instance, urine testing meets current guidelines for most radiography and clinical trials, and some studies suggest that sensitivity may be further strengthened by history and clinical suspicion. ²⁴ , ²⁵ However, our results suggest that a urine POC testing strategy will miss a small but measurable number of pregnancy diagnoses, and failure to diagnose an early healthy pregnancy still risks harm via teratogenic medications, radiographic exposure, missed opportunities for prenatal care, and impacts to patient autonomy and trust of healthcare (as illustrated in Supporting Information Appendix 2).

Missed ectopic pregnancies have both higher mortality and medicolegal risks, as well as a documented higher risk of false negative urine results due to lower β‐hCG values. ²⁶ , ²⁷ We found a total of 12 ectopic pregnancies that presented with negative urine testing, consistent with prior studies and case reports. ⁶ , ⁷ , ⁸ In addition, we identified a priori a “high‐risk” subgroup of patients with symptoms suggestive of ectopic or other early pregnancy complications, including abdominal pain, pelvic pain and vaginal bleeding, who indeed had a higher rate of false negative urine tests (3.6% compared to 1.6% for the overall sample).

Given the anecdotal risks of false negative urine testing, many emergency physicians already use serum testing to exclude pregnancy. For instance, we found that the majority of false‐negative urine tests were recognized through serum testing at the index visit, implying that many clinical staff at our site employed a combined or serial testing strategy in which β‐hCG serum testing is performed for high‐risk patients despite a negative urine test. However, this practice is not universal or standardized, with even the most recent National Quality Forum Consensus Standards for Emergency Care (ED‐018‐08 ) only requiring that “women, ages 14–50 years old who present to the ED with a chief complaint of abdominal pain, have a pregnancy test (urine or serum) ordered in the ED” ¹⁵ (italics added). Although almost all patient encounters meet this standard, ⁹ our current results suggest that urine testing alone is not sufficient to rule out ectopic pregnancy, and that further decision tools or guidelines could benefit from the greater sensitivity of serum testing if high risk populations can be identified.

One reported benefit to urine POC testing is decreased length of stay and resource utilization in the age of overcrowding. ²⁸ One study of urine pregnancy tests did confirm that a POC test had a much shorter turnaround time, taking 7.6 versus 67.4 minutes for laboratory testing, although this does not include the highly‐variable time to obtain a urine sample. ²⁹ Although a POC approaches using both serum and capillary whole blood have been explored and validated, all of these studies have also reported similar negative predictive values for both whole blood and urine (97.9% and 97.6%, respectively). ²⁹ , ³⁰ Even the i‐Stat POC assay designed for use with whole blood has demonstrated false negatives due to a hook effect at high β‐hCG levels. ³¹ While further trials are ongoing, it may be impossible for an antibody‐driven, POC test to reach the sensitivity of quantitative serum laboratory testing.

6. CONCLUSIONS

We examined a large retrospective cohort of female patients of childbearing age who had negative POC urine pregnancy testing in our ED. We found that an important number of these results were falsely negative, including patients with ectopic, intrauterine, and abnormal pregnancies. The relative risk of false negative results was even greater among patients with abdominal pain or vaginal bleeding, a subgroup that included almost all of our ectopic cases. These false negative tests can contribute to diagnostic errors and pose a risk to patient safety and clinicians should use caution when relying on urine POC testing to rule out pregnancy. Serum β‐hCG testing, either as the initial screening test or obtained following a negative urine β‐hCG test, is the gold standard test for ruling out pregnancy in an ED patient of childbearing potential.

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