Often when clinical laboratorians think of toxicology testing, forensic, pre-employment, or hurting management testing come to mind. Indeed these areas accept conventionally been the focus for establishing cutoffs, policies and procedures for drove and analysis, method validation, and interpreting results. Yet, with the increment in opioid abuse over the last decade, drug abuse during pregnancy also has risen speedily, boosting both the number of expectant mothers on opiate maintenance therapy and the incidence of neonatal forbearance syndrome (NAS) (1,2). As a upshot, assessing in utero drug exposure during pregnancy is emerging equally a crucial service hospital laboratories provide for both patient intendance teams and social services. This is causing clinical laboratories to take a critical look at their policies and procedures.

Neonatal toxicology testing is a unique area of laboratory stewardship that encompasses managing test utilization, educating stakeholders, interpreting results, and contributing to the evolution of audio institutional policies. In contrast to most other forms of toxicology testing, a provider who orders a neonatal drug examination is not the only individual acting on the result, which has cascading effects on treatments and social services. If a laboratory's expertise remains at the nucleus of testing, we can contribute beyond all disciplines to create better continuity of intendance.

Universal Versus Risk-Based Testing

There are ii major approaches to neonatal drug testing, and laboratories play a critical office in making sure that an organization's testing strategy is evidence-based to reduce the potential for biased pick. Universal screening ways consistently testing all newborns born at an institution. Take chances-based screening means testing neonates only when a mother or a neonate meets infirmary-defined criteria, which may include maternal history or signs of drug use, social risk factors, express or absent prenatal intendance, and symptoms of withdrawal in the neonate.

In that location are advantages and disadvantages to both approaches. A universal testing plan will generate more positive results that require follow-upwardly by both laboratories and patient care teams. As well, the number of unexpected results may increase, requiring significant resource to investigate. More positive results also lead to increased referrals to social services and may identify an undue burden on governmental agencies for relatively low-risk mothers.

Alternatively, risk-based testing may be perceived as unfairly profiling certain groups of patients, exposing an institution to potential legal bug. The hazard-based testing approach may too miss drug-exposed neonates if the policy doesn't adequately identify and exam for probable exposures. These and other factors make take chances-based testing policies more complicated to follow and monitor effectively. If gamble-based testing has been implemented, proper assessment of risk factors must be completed by the obstetrics-gynecology squad and communicated to the labor and delivery unit. The determination for or against testing must exist made prior to commitment to ensure proper collection of the desired specimen.

Currently the American College of Obstetricians and Gynecologists (ACOG) recommends routine screening for substance abuse disorder for all individuals, just screening is defined as questionnaires or patient interviews. The ACOG guideline states that routine laboratory testing of biological specimens is not required (3). This leaves in the hands of private institutions the determination to constitute advisable drug testing policies.

Specimen Selection and Collection

Neonatal toxicology testing presents distinctive pre-analytical challenges, most of which involve the difficulty in collecting adequate amounts of specimen to perform testing. For example, neonatal urine specimens may crave waiting several hours after delivery. As well, the entirety of a baby's meconium—the stool formed during gestation—must be collected even when passed in stages at several unlike times. Ofttimes laboratories receive an inadequate amount of meconium to perform necessary confirmatory testing, which may lead to testing being canceled due to quantity not sufficient. In the case of umbilical string testing, specimens must exist rinsed with saline to remove backlog claret, then dried and stored prior to analysis. Laboratories need to review their specimen treatment instructions for each specimen type used.

Laboratories besides play a role in ensuring that providers in labor and delivery, newborn nurseries, and neonatal intensive care units (NICU) are aware of their responsibilities in specimen collection. The choice of specimen dictates when and where it volition be nerveless: Umbilical cord tissue is collected during nativity, while neonatal urine must be nerveless presently after birth if the first void is desired. Meconium requires collection whenever it is passed, which may occur shortly after birth or be delayed upwards to 48 hours or even later in some instances. Meconium may also be unavailable entirely if passed in utero. Ease of collection and other logistical considerations frequently influence an establishment's choice of specimen.

specimen collection for neonatal drug testing table 1 CLN March 2018

Urine

Although urine is the most mutual specimen in adult toxicology testing, it is used less frequently in neonates due to pregnant limitations. Collecting urine from a neonate tin exist challenging and often requires specialized drove devices. Removing urine from a diaper may contaminate the specimen. In fact, most neonates produce very little urine in their first few days of life. A recent written report estimated urine output at 2.5 mL/kg/h or approximately 125 mL per 24-hour interval during the get-go 48 hours after birth. This explains why information technology can be nearly impossible to collect an adequate corporeality of specimen in a timely mode, fifty-fifty when using an appropriate collection device (4).

In addition to specimen collection problems, urine drug testing results can be of limited value in neonates. Urine typically provides a window of drug detection that spans only several days, and while this is extended slightly in neonates' first void, it has low sensitivity for more distant exposures. Due to their immature livers, neonates may also produce unique drug metabolites. In addition, most urine drug screens rely on immunoassays that react across broad drug classes and are targeted primarily to metabolites produced in adult populations. Neonatal metabolites may not be the target compounds for immunoassay screens, and limited cross-reactivity can lead to false-negative results (5).

Meconium

Meconium is i of the most commonly used specimens for neonatal drug testing and is considered the gold standard specimen. Although meconium begins to form around the 12th week of gestation, more than half of the material is produced in the last 8 weeks of pregnancy. Many waste products, including drugs and metabolites, accumulate in meconium (six). This leads to meconium's very long window of detection, which is estimated to include exposures in nearly of the third trimester, and in some cases, the afterwards part of the second trimester (7).

Despite meconium's long time use in neonatal testing, both laboratorians and other patient care team members face challenges in collecting it. Staff may encounter difficulties in obtaining adequate amounts of meconium and actually may not be able to if the meconium has been expelled in utero. Neonates may also pass meconium in stages, requiring multiple collections, and this passage may be delayed several days after birth. Considering meconium is heterogeneous, all collections must exist stored, combined, and mixed well prior to testing. Nevertheless, prolonged storage can as well touch the stability of drugs and metabolites. This makes proper meconium collection an onerous task for pa-tient care staff and sometimes leads to specimen mix-ups.

For these reasons, some institutions are exploring alternative types of specimens like umbilical cord tissue. Nevertheless, meconium is withal considered the gold standard specimen for assessing long-term drug exposure in newborns.

Umbilical String Tissue

Umbilical cord tissue is a relative newcomer in the field of neonatal toxicology testing, but information technology has been adopted by a growing number of institutions. Different meconium, cord tissue is bachelor immediately subsequently birth and the drove process is simple. Consequently, toxicology testing of string tissue often has a decreased fourth dimension-to-results relative to meconium (8).

Despite these benefits, the mechanism of drug deposition into string tissue is not well understood, and studies have found that drugs and metabolites do not accumulate in string tissue to the same ex-tent as in meconium (9). Not surprisingly, the window of drug detection using a cord tissue sample is shorter than meconium, and cord tissue may not capture as many exposures equally meconium (ix-xi).

Method Validation Requirements

There are no Food and Drug Administration-cleared or approved toxicology tests for meconium or umbilical cord tissue, so all tests in the marketplace are regulated as laboratory developed tests. For laboratories, this means increased demands during examination development and validation. Both cord tissue and meconium crave all-encompassing pre-analytical sample preparation that frequently includes some course of homogenization or tissue disruption. Attributable to the amount of labor required to process such specimens, these methods can be very expensive.

Several other issues further complicate method validation, including extensive sample cleanup and variable recovery of target analytes from circuitous mixtures like cord tissue and meconium. The limit of detection for a given drug likewise may vary essentially between laboratories.

The Importance of Turnaround Fourth dimension

Turnaround time for neonatal drug testing has an outsize touch on how a variety of stakeholders use neonatal toxicology results, equally it affects everything from discharge decisions to possible legal actions against a infant's parents. Labs must deliver neonatal toxicology test results quickly, ideally inside 48 hours of nascence. Delaying discharge until results are available is not always possible, and this may pose problems for both hospitals and neonates. For example, if results that suggest ongoing maternal substance corruption arrive afterwards a neonate has been discharged, this babe may experience additional preventable trauma before its female parent has been re-contacted, or be lost entirely to fol-low-up by providers and social services.

Most hospital laboratories offer aforementioned-day results when they test urine. However, more circuitous specimens such as meconium or umbilical cord tissue are often sent to outside laboratories for analysis. The increased turnaround time for sendout tests may have real consequences for diagnostic direction teams. Without timely neonatal toxicology results, providers assessing an infant for NAS symptoms may but have every bit a guide maternal history or maternal toxicology results.

Challenges in Event Interpretation

Providers often notice interpreting neonatal toxicology results particularly challenging: They must integrate multiple patient results (maternal and newborn) and multiple specimen types (urine, meconi-um, and umbilical cord), while too evaluating medication lists and the mother'due south cocky-reported history.

Moreover, providers must likewise integrate results from multiple testing laboratories that may have unlike methodologies or different limits of detection: A test consequence from ane laboratory is not necessarily interchangeable with a result from another. This may be particularly problematic in states that require reporting of positive results to local, county, or state health departments, which in plow interpret the findings. Furthermore, a more than sensitive analytical method may yield additional positive results, and if the effect of this on an institution's positivity rate is not appreciated, a hospital's population may announced to have a more substantial trouble with maternal drug use than is truly the case.

Frequently these multiple result streams do not agree. In these cases, clinical laboratorians troubleshoot unexpected results using their expertise in toxicology testing to provide critical evaluation of the full testing procedure.

Providers also confront challenges when they must deed on unconfirmed or presumptive positive results. If a laboratory performs drug screening in-firm and sends out the confirmation to a reference lab, providers must balance how and when to act on results. Presumptive positive results may trigger specific protocols to deal with NAS, but acting on an unconfirmed result may negatively affect the female parent-baby relationship and patient-provider relationship.

Chiefly, the renewed focus on the patient experience in hospitals also underscores the risk of faux positives, which tin can very negatively influence public perception of the quality of intendance.

Stakeholders and Effect Utilization

Neonatal drug testing programs require collaboration across a continuum of providers and stakeholders. The process of sample collection, the analytical performance of the test, and the composition of drugs detected all bear upon how stakeholders view the clinical performance. All providers—and clinical laboratorians—would prefer an affordable exam with 100% sensitivity and specificity with a rapid turnaround time. Notwithstanding, existent-world constraints dictate compromises related to sensitivity, cost, and turnaround time. Several publications have demonstrated that specimen type influences the specific drugs detected due to differences in distribution and deposition in the matrix (9).

Additionally, the analytical method and the limit of detection for target compounds prevent a specific specimen blazon or method from being ideal for all applications. Due to the current opioid epidemic, healthcare providers in NICUs and newborn nurseries may consider detection of opiates (illicit or prescribed) the most important component of the toxicology results profile. Adequate detection of opiates enables these stakeholders to apace triage infants who may develop NAS to the proper infirmary unit and provide therapeutic intervention as soon as possible. Conversely, providers in social services may be concerned with non-opiate drugs such equally cannabis, benzodiazepines, or gabapentin that accept potential for corruption but are not typically associated with NAS.

laboratory stewardship in neonatal drug testing sidebar CLN March 2018

Conclusion

Creating an effective neonatal testing program requires careful consideration of the preanalytic, analytic, and post-analytic phases of testing. The unique specimen types associated with neonates are singled-out from those used for other toxicology testing applications such equally hurting management. Laboratories need to examine these differences advisedly to ensure specimen quality and accurate timely results.

Neonatal testing is an opportunity for clinical laboratorians to assume a prominent role in the diagnostic direction squad for newborns, as laboratory testing has cascading impacts on treatment. Effective laboratory stewardship in this unique area highlights the role of laboratorians in providing constructive healthcare.

Jennifer M. Colby, PhD, is associate director for clinical chemistry and an assistant professor in the department of pathology, microbiology, and immunology at Vanderbilt Academy Medical Center in Nashville, Tennessee. +Email: [email protected]

Steven W. Cotten, PhD, is director for chemistry, immunology, toxicology, and betoken-of-care testing at the Ohio Country University Wexner Medical Center clinical laboratories and an assistant professor of pathology at Ohio State University in Columbus, Ohio. +Email: [email protected]

References

  1. Ohio Section of Health. 2015 Ohio drug overdose data report. http://world wide web.good for you.ohio.gov/-/media/HealthyOhio/ASSETS/Files/injury-prevention/2015-Overdose-Data/2015-Ohio-Drug-Overdose-Data-Report-Concluding.pdf?la=en (Accessed Dec 13, 2016).
  2. Ohio Department of Wellness. NAS summary report 2012-2014. http://www.healthy.ohio.gov/-/media/HealthyOhio/ASSETS/Files/injury-prevention/NAS-Summary-Written report-03-17b---Updated-03-22-2016-Final.pdf?la=en (Accessed Dec 13, 2016).
  3. Committee opinion no. 633: Alcohol abuse and other substance apply disorders ethical bug in obstetric and gynecologic practise. Obstet Gynecol 2015;125:1529.
  4. Kasamatsu A, Ohashi A, Tsuji S, et al. Prediction of urine volume shortly after birth using serum cystatin C. Clin Exp Nephrol 2016;764–9.
  5. Barakauskas VE, Davis R, Krasowski MD, et al. Unresolved discrepancies betwixt canna-binoid test results for infant urine. Clin Chem 2012;58:1364–7.
  6. Gray TR, LaGasse LL, Smith LM, et al. Identification of prenatal amphetamines exposure by maternal interview and meconium toxicology in the Infant Development, Surround and Life-manner (IDEAL) Study. Ther Drug Monit 2009;31:769–75.
  7. Himes SK, Tassiopoulos K, Yogev R, et al. Antiretroviral drugs in meconium: Detection for dif-ferent gestational periods of exposure. J Pediatr 2015;167:305–11.e3.
  8. Labardee RM, Swartzwelder JR, Gebhardt KE, et al. Method operation and clinical work-menstruum outcomes associated with meconium and umbilical cord toxicology testing. Clin Biochem 2017; doi:10.1016/j.clinbiochem.2017.09.016.
  9. Concheiro-Guisan A, Concheiro M. Bioanalysis during pregnancy: Recent advances and novel sampling strategies. Bioanalysis 2014;six:3133–53.
  10. Concheiro 1000, Lendoiro East, de Castro A, et al. Bioanalysis for cocaine, opiates, methadone, and amphetamines exposure detection during pregnancy. Drug Test Anal 2017;9:898–904.
  11. Colby JM. Comparing of umbilical string tissue and meconium for the confirmation of in utero drug exposure. Clin Biochem 2017;50:784–90.