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Umbilical Cord Tissue: An Annotated Bibliography
Umbilical Cord Tissue: An Annotated Bibliography
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Compiled by: Beckymarie Christ, USDTL
—1989
The Connecting Stalk and Umbilical Cord
Williams, P., Warwick, R., Dyson, M., Bannister, L. (Eds.), Gray’s Anatomy, 37th edition, Churchill Livingstone, New York, 1989, p. 143.
Link to book
Figure
“A fetus of about 8 weeks, enclosed in the amnion, magnified about 2 1/2 diameters. A part of the chorion frondosum with its branching villous stems is shown in the lower part of the figure. The villous stems have been detached from the basal plate, which is not shown here.”
Implication of this Figure
Studying the anatomy of the umbilical cord shows that the umbilical cord is genetic material originating from the embryo, not from the mother. As genetic material of the mother, the ordering physician may order testing on behalf of the child without maternal consent.
—1993
Determination of Cocaine and Its Major Metabolite, Benzoylecgonine, in Amniotic Fluid, Umbilical Cord Blood, Umbilical Cord Tissue, and Neonatal Urine: A Case Study
Moore, C. M., Brown, S., Negrusz, A., Tebbett, I., Meyer, W., & Jain, L. (1993). Determination of cocaine and its major metabolite, benzoylecgonine, in amniotic fluid, umbilical cord blood, umbilical cord tissue, and neonatal urine: a case study. Journal of analytical toxicology, 17(1), 62-62.
DOI: 10.1093/jat/17.1.62
Abstract
Letter to the Editor; no Abstract.
Implication of this Study
Moore et al. (1993) demonstrates the critical capability to detect cocaine and benzoylecgonine in multiple maternal-fetal matrices, including amniotic fluid, umbilical cord blood/tissue, and neonatal urine, using advanced analytical methodologies.
—2006
Testing for fetal exposure to illicit drugs using umbilical cord tissue vs meconium
Montgomery, D., Plate, C., Alder, S. C., Jones, M., Jones, J., & Christensen, R. D. (2006). Testing for fetal exposure to illicit drugs using umbilical cord tissue vs meconium. Journal of Perinatology, 26(1), 11-14.
DOI: 10.1038/sj.jp.7211416
Abstract
Objective: We assessed the agreement of testing for fetal exposure to illicit drugs contrasting paired specimens of meconium vs umbilical cord tissue.
Methods: We obtained paired samples of meconium and umbilical cord tissue from 118 pregnancies with high suspicion of illicit drug use by the mothers. Each specimen was tested for amphetamines, opiates, cocaine, cannabinoids, and phencyclidine using drug class-specific immunoassays.
Results: The agreement of drug screening results between cord and meconium was above 90% for all drugs tested. Meconium identified 21 cases as positive for amphetamines. The paired cord identified 20 of these, and in addition identified three other positives that the meconium labeled as negative. Gas chromatography–mass spectrometry confirmed these three cord samples as methamphetamine positive. Meconium identified 97 samples that were negative for amphetamines, while the cord identified 94 of these as negative but three as positive. Agreement of cord with meconium for amphetamines was 96.6%. The concordance for opiates was 94.9%, for cocaine was 99.2%, and for cannabinoids was 90.7%
Conclusions: Umbilical cord tissue performs as well as meconium in assessing fetal drug exposure to amphetamines, opiates, cocaine, and cannabinoids. Results of studies using the cord may have a more rapid return to the clinician, because waiting for meconium to be passed sometimes requires several days. Moreover, in some cases the meconium is passed in utero making collection impossible, whereas cord should always be available for drug testing.
Implication of this Study
Montgomery et al. (2006) demonstrates that umbilical cord tissue provides comparable accuracy to meconium in detecting fetal exposure to amphetamines, opiates, cocaine, and cannabinoids, with agreement exceeding 90% across all drug classes.
—2008
Using umbilical cord tissue to detect fetal exposure to illicit drugs: a multicentered study in Utah and New Jersey
Montgomery, D. P., Plate, C. A., Jones, M., Jones, J., Rios, R., Lambert, D. K., … & Christensen, R. D. (2008). Using umbilical cord tissue to detect fetal exposure to illicit drugs: a multicentered study in Utah and New Jersey. Journal of Perinatology, 28(11), 750-753.
DOI: 10.1038/jp.2008.97
Abstract
Objective: We assessed umbilical cord tissue as a means of detecting fetal exposure to five classes of drugs of abuse.
Study Design: In a multicentered study in Utah and New Jersey, we collected umbilical cord tissue when high-risk criteria were met for maternal illicit drug use. The deidentified umbilical cord specimens were analyzed for five drug classes: methamphetamine, opiates, cocaine, cannabinoids and phencyclidine. For each umbilical cord specimen, an enzyme-linked immunosorbent assay (ELISA)-based screening test was compared with a ‘gold standard’ test, consisting of gas or liquid chromatography tandem mass spectrometry.
Results: A total of 498 umbilical cord samples were analyzed of which 157 (32%) were positive using mass spectrometric detection. The sensitivity and specificity of the ELISA-based test for each class of drugs tested were as follows: methamphetamine 97 and 97%, opiates 90 and 98%, cocaine 90 and 100%, cannabinoids 96 and 98% and phencyclidine (only 1 of the 498 umbilical cord sample was positive for phencyclidine) 100 and 100%.
Conclusions: We judge that the performances of the ELISA-based tests are sufficient for clinical testing of fetal exposure to methamphetamine, opiates, cocaine and cannabinoids. Studies obtained on umbilical cord tissue can result in a more rapid return to the clinician than meconium testing, because waiting for meconium to be passed sometimes requires many days. Moreover, in some cases the meconium is passed in utero making collection impossible, whereas umbilical cord tissue should always be available for drug testing.
Implication of this Study
Montgomery et al. (2008) established umbilical cord tissue as a viable alternative to meconium for detecting prenatal drug exposure, offering immediate specimen availability, simplified collection, and comparable detection windows (up to ~20 weeks). By validating cord tissue’s reliability across multiple clinical centers, the study pioneered its adoption in neonatal toxicology, enabling earlier identification of at-risk infants for conditions like neonatal abstinence syndrome (NAS). This work directly supported the subsequent development of expanded testing and standardized protocols now used nationwide.
—2008
McKnight v. State of South Carolina Appeals
State v. McKnight. 378 S.C. 33 (S.C. 2008), 661 S.E.2d 354. No. 26484. Supreme Court of South Carolina. Submitted April 1, 2008. Decided May 12, 2008.
Google Scholar Link
Implication of this Case
McKnight v. State was pivotal in legitimizing umbilical cord tissue testing as a forensic tool in legal cases involving alleged prenatal drug exposure. It advanced the scientific and legal framework for such testing, while also exposing important limitations and ethical concerns that continue to shape policy and practice in maternal-fetal medicine and the justice system.
—2009
Development and validation of a liquid chromatography mass spectrometry assay for the simultaneous quantification of methadone, cocaine, opiates and metabolites in human umbilical cord
de Castro, A., Concheiro, M., Shakleya, D. M., & Huestis, M. A. (2009). Development and validation of a liquid chromatography mass spectrometry assay for the simultaneous quantification of methadone, cocaine, opiates and metabolites in human umbilical cord. Journal of Chromatography B, 877(27), 3065-3071.
DOI: 10.1016/j.jchromb.2009.07.028
Abstract
A liquid chromatography mass spectrometric selected reaction monitoring mode (SRM) method for methadone, 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP), cocaine, benzoylecgonine (BE), 6-acetylmorphine, morphine and codeine quantification in human umbilical cord was developed and fully validated. Analytes were extracted from homogenized tissue (1 g) by solid phase extraction. Linearity was 2.5–500 ng/g, except for methadone (10–2000 ng/g). Method imprecision was <12.7%CV with analytical recovery 85.9–112.7%, extraction efficiency >59.2%, matrix effect 4.5–39.5%, process efficiency 48.6–92.6% and stability >84.6%. Analysis of an umbilical cord following controlled methadone administration and illicit drug use contained in ng/g, 40.3 morphine, 3.6 codeine, 442 BE, 186 methadone and 45.9 EDDP.
Implication of this Study
de Castro et al. (2009) catalyzed the adoption of umbilical cord tissue as a scientifically robust specimen for detecting in utero drug exposure, shaping both the technical standards and clinical protocols that are widely used today.
—2009
Determination of amphetamine and methamphetamine in umbilical cord using liquid chromatography–tandem mass spectrometry
Jones, J., Rios, R., Jones, M., Lewis, D., & Plate, C. (2009). Determination of amphetamine and methamphetamine in umbilical cord using liquid chromatography–tandem mass spectrometry. Journal of Chromatography B, 877(29), 3701-3706.
DOI: 10.1016/j.jchromb.2009.09.021
Abstract
The use of meconium as a drug-screening matrix for newborns has been the gold standard of care for the past two decades. A recent study using matched pairs of meconium and umbilical cord demonstrated a high degree of agreement. The use of liquid chromatography–tandem mass spectrometry as a means to confirm amphetamines presumptive positive umbilical cord specimens for amphetamine and methamphetamine is described here for the first time. The limit of detection for both compounds was 0.2 ng/g. The limit of quantitation for both compounds was 0.6 ng/g. The assay was linear for both compounds up to 100 ng/g.
Implication of this Study
Jones et al. (2009) was essential in establishing umbilical cord tissue testing using advanced LC-MS/MS methods—as a scientifically robust and legally defensible approach for detecting prenatal amphetamine and methamphetamine exposure. This led to widespread adoption in clinical and forensic settings, improved newborn care, and strengthened child protection protocols.
—2011
Agreement of umbilical cord drug and cotinine levels with maternal self-report of drug use and smoking during pregnancy
Wright, T. E., Milam, K. A., Rougee, L., Tanaka, M. D., & Collier, A. C. (2011). Agreement of umbilical cord drug and cotinine levels with maternal self-report of drug use and smoking during pregnancy. Journal of Perinatology, 31(5), 324-329.
DOI: 10.1038/jp.2010.132
Abstract
Objective: We undertook this study to assess the agreement between fetal umbilical cord drug levels and maternal self-report.
Study Design: Cord samples were collected from 103 placentas after delivery as a sub-project of the larger Pacific Research Center for Early Human Development (PRCEHD) study. These cord samples were then processed to obtain cord lysates and enzyme-linked immunosorbent assay (ELISA) performed for cotinine and illicit drugs. Levels of each of these substances were compared with clinical information
Results: We found fair agreement between self-reported smoking and cotinine levels (kappa = 0.26 (0.07–0.5)) as well as slight agreement with current drug use and positive drug levels (kappa = 0.19 (−0.05–0.4)). Compared with maternal self-report, sensitivity of cotinine levels was 27% and specificity was 98%. Sensitivity of positive cord illicit drug levels was 32% and specificity was 85%.
Conclusions: Umbilical cords provide another independent measure of maternal drug use and are readily available. To our knowledge, this is the first study to measure cotinine levels in the umbilical cord tissue.
Implication of this Study
Wright et al. (2011) stands out for its direct demonstration of the limitations of self-reported maternal drug use, providing compelling scientific justification for the routine use of umbilical cord tissue testing in both clinical and legal settings, highlighting the need for objective, reliable neonatal drug exposure assessment.
—2011
Ethyl-glucuronide and ethyl-sulfate in placental and fetal tissues by liquid chromatography coupled with tandem mass spectrometry
Morini, L., Falcón, M., Pichini, S., Garcia-Algar, O., Danesino, P., Groppi, A., & Luna, A. (2011). Ethyl-glucuronide and ethyl-sulfate in placental and fetal tissues by liquid chromatography coupled with tandem mass spectrometry. Analytical biochemistry, 418(1), 30-36.
DOI: 10.1016/j.ab.2011.06.038
Abstract
The aim of this study was to develop a method for the determination of ethyl-glucuronide (EtG) and ethyl-sulfate (EtS), two direct ethanol metabolites, in early placental and fetal human tissues, as potential biomarkers of transplacental ethanol transfer from the mother to the fetus. Placental and fetal tissue samples were obtained from women undergoing voluntary termination of pregnancy at 12 weeks of gestation. Samples were deproteinized and directly injected into a liquid chromatography coupled with tandem mass spectrometry (LC–MS/MS) system. Limits of detection of 13.0 and 23.0 pmol/g and lower limits of quantification of 22.0 and 40.0 pmol/g were reached for EtG and EtS, respectively. Inter- and intraday imprecision and accuracy were always lower than 15%. The method was applied to 70 samples (35 placentas and 35 fetal tissues). Of 35 samples, 4 samples collected from 4 women tested positive for EtG and EtS, always showing higher concentrations for EtG. The placenta/fetal tissue ratio for EtG was 2.9 ± 0.9, whereas EtS showed a ratio of 1.7 ± 0.7. Preliminary results suggest that these metabolites are present in both tissues. Further studies should now corroborate the hypothesis, not yet confirmed, that transplacental transfer of ethanol takes place not only for the parent compound but also for EtG and EtS.
Implication of this Study
Morini et al. (2011) provides the first validated, sensitive, and reproducible method for detecting direct ethanol metabolites in placental and fetal tissues, paving the way for the adoption of umbilical cord and placenta as practical, noninvasive matrices for assessing prenatal alcohol exposure. This has improved the ability of clinicians and researchers to identify at-risk newborns and has informed subsequent advances in both analytical methodology and our understanding of fetal alcohol exposure.
—2013
The Prevalence of Prenatal Opioid and Other Drug Use in Utah
Buchi, K. F., Suarez, C., & Varner, M. W. (2013). The prevalence of prenatal opioid and other drug use in Utah. American journal of perinatology, 30(03), 241-244.
DOI: 10.1055/s-0032-1323586
Abstract
Objectives: Determine the prevalence of prenatal opioid and other drug positivity among women delivering infants in Utah and compare the findings with national data.
Study Design: Umbilical cord tissue samples and nonidentifiable demographic data were collected anonymously in 13 labor and delivery units throughout Utah. Samples were analyzed for opioids, amphetamines, cannabinoids, cocaine, phencyclidine, barbiturates, benzodiazepines, propoxyphene, and alcohol biomarkers.
Results: Fifty-eight (6.8%) of 850 umbilical cord samples were positive for one or more substances. Opioids were the most frequently detected drugs (4.7%). Fewer samples were positive for alcohol (0.4%), methamphetamine (0.1%), cocaine (0.1%), and marijuana (0.4%).
Conclusion: Opioids were the most frequently detected drugs at delivery. Although some of the samples positive for opioids might have been a result of intrapartum exposure, a significant number were positive for opioids that are not given during labor. This parallels the increasing nonmedical use of prescription pain medications in the general population and has important implications for neonates because of the potential for significant morbidity secondary to neonatal abstinence syndrome.
Implication of this Study
Buchi et al. (2013) helped shift the paradigm towards routine, objective biological testing for prenatal drug exposure, particularly in areas heavily affected by the opioid crisis. Its methodological approach and clear demonstration of the burden of opioid exposure in newborns have been cited in subsequent research and public health reports, supporting efforts to improve maternal and neonatal outcomes through better surveillance, intervention, and policy development. It stands out for its pioneering use of umbilical cord tissue testing at a statewide level, its methodological rigor, and its direct impact on both scientific understanding and public health response to prenatal opioid exposure.
—2014
Detection of Neonatal Drug Exposure Using Umbilical Cord Tissue and Liquid Chromatography Time-of-Flight Mass Spectrometry
Marin, S. J., Metcalf, A., Krasowski, M. D., Linert, B. S., Clark, C. J., Strathmann, F. G., & McMillin, G. A. (2014). Detection of neonatal drug exposure using umbilical cord tissue and liquid chromatography time-of-flight mass spectrometry. Therapeutic Drug Monitoring, 36(1), 119-124.
DOI: 10.1097/ftd.0b013e3182a0d18c
Abstract
Background: A method for qualitative detection of 57 drugs and metabolites in umbilical cord tissue using liquid chromatography time-of-flight (TOF) mass spectrometry is described.
Methods: Results from 32 deidentified positive specimens analyzed by an outside laboratory using “screen with reflex to confirmation” testing were compared with TOF results. In addition, 57 umbilical cord tissue specimens paired with corresponding chart review data and 37 with meconium test results were analyzed by TOF. Urine drug test results from mother (n = 18) and neonate (n =30) were included if available. Cutoff concentrations, recovery, and matrix effects were determined by analyzing fortified drug-free cord tissue and negative specimens. Cutoffs (in nanograms per gram) ranged from 1 to 10 for opioids and opioid antagonists, 5–10 for benzodiazepines and nonbenzodiazepine hypnotics, 20–40 for barbiturates, 8 for stimulants, and 4 for phencyclidine. Adequate sensitivity for the detection of cannabis exposure could not be realized with this method.
Conclusions: Liquid chromatography time-of-flight mass spectrometry can provide accurate and sensitive detection of in utero drug exposure using umbilical cord tissue.
Implication of this Study
Marin et al. (2014) helped shift the paradigm from reliance solely on meconium to the broader adoption of umbilical cord tissue as a primary specimen for neonatal drug exposure testing. The study’s rigorous methodology and clear demonstration of LC-TOF-MS’s utility have made it a foundational reference for laboratories and clinicians seeking accurate, timely, and comprehensive drug exposure assessment in newborns.
—2016
Evaluating a switch from meconium to umbilical cord tissue for newborn drug testing: A retrospective study at an academic medical center
Palmer, K. L., Wood, K. E., & Krasowski, M. D. (2017). Evaluating a switch from meconium to umbilical cord tissue for newborn drug testing: a retrospective study at an academic medical center. Clinical biochemistry, 50(6), 255-261.
DOI: 10.1016/j.clinbiochem.2016.11.026
Abstract
Background: The objective of this study was to compare detection rates of newborn drug exposure at an academic medical center transitioning from meconium to umbilical cord tissue toxicology testing.
Methods: We performed an Institutional Review Board-approved retrospective chart review on all newborns (n = 2072) for whom newborn drug testing was ordered at our academic medical center between June 2012 and August 2015 (in August 2013, umbilical cord tissue became the preferred specimen).
Results: Meconium toxicology testing was positive for at least one compound in 221 cases (21.3% of 1037 total specimens), with non-medical drug use identified in 85 cases (8.2%). Umbilical cord tissue toxicology testing was positive for at least one compound in 302 cases (29.2%), with non-medical drug use identified in 107 cases (10.3%). Of the cases involving non-medical drug use, the most common compounds detected were tetrahydrocannabinol and amphetamines. Non-medical drug use did not differ significantly between meconium and umbilical cord tissue, either as a total or for classes of drugs such as amphetamines, cannabinoids, and opiates. Maternal non-medical use of tramadol (not tested for in meconium) was identified in 5 cases (0.4%). There were significant differences in rate of detection of iatrogenic medications. Specifically, morphine, lorazepam, phenobarbital, and codeine were more commonly detected in meconium, while oxycodone was more commonly detected in umbilical cord tissue.
Conclusions: Umbilical cord tissue toxicology testing yielded a similar detection rate compared to meconium testing. The use of umbilical cord tissue avoids detection of medications given to the neonate prior to meconium collection.
Implication of this Study
Palmer et al. (2016) provided evidence that helped shift clinical practice toward umbilical cord tissue testing by demonstrating its equivalence to meconium in detection rates, while offering clear advantages in collection and turnaround time.
—2018
Discordant Umbilical Cord Drug Testing Results in Monozygotic Twins
Alexander, A., Abbas, L., Jones, M., Jones, J., Lewis, D., & Negrusz, A. (2018). Discordant umbilical cord drug testing results in monozygotic twins. Journal of Analytical Toxicology, 42(5), e47-e49.
DOI: 10.1093/jat/bky009
Abstract
Our laboratory received segments of umbilical cord that originated from identical twins for routine toxicology analysis. The specimens were analyzed multiple times by liquid chromatography tandem mass spectrometry. The umbilical cord from newborn #1 was positive for hydromorphone only (1.06 ng/g), and the umbilical cord from newborn #2 was positive for hydromorphone (0.81 ng/g) and benzoylecgonine (5.41 ng/g). The hydromorphone results are consistent with maternal administration of hydromorphone; however, the cause of the discrepant benzoylecgonine results in the umbilical cords from the identical twins is unknown.
Implication of this Study
This Alexander et al. (2018) case study challenged the prevailing assumption that monozygotic twins, sharing identical genetic material and intrauterine environments, would have concordant umbilical cord drug testing results. The authors reported a case where one twin’s umbilical cord tested positive for both hydromorphone and benzoylecgonine (a cocaine metabolite), while the other tested positive only for hydromorphone, despite both being exposed to the same maternal environment. The cause of this discrepancy, particularly for benzoylecgonine, remained unexplained, highlighting previously underappreciated complexities in drug deposition and detection in umbilical cord tissue.
—2019
Umbilical Cord Tissue and Meconium May Not Be Equivalent for Confirming in Utero Substance Exposure
Colby, J. M., Adams, B. C., Morad, A., Presley, L. D., & Patrick, S. W. (2019). Umbilical cord tissue and meconium may not be equivalent for confirming in utero substance exposure. The Journal of pediatrics, 205, 277-280.
DOI: 10.1016/j.jpeds.2018.09.046
Abstract
In a retrospective study of 501 neonates with potential in utero substance exposure, the drug detection performance of a commercially available umbilical cord tissue toxicology test was evaluated against a commercially available gold standard meconium toxicology test. Drugs detected in paired meconium and umbilical cord tissue samples were often discordant.
Implication of this Study
Colby et al. (2019) has had a significant impact by challenging the assumption that umbilical cord tissue and meconium are equivalent for neonatal drug exposure testing. It highlights the importance of specimen selection, analytical methodology, and careful interpretation in clinical and forensic settings. In reference to this study, it is important to read the Letter to the Editor response by Dr. Adam Negrusz and Dr. Joe Jones which supports the study’s call for cautious interpretation of results and the development of best practice and addresses the inadequate sensitivity of analytical methodologies applied to testing of umbilical cord in the study.
—2019
Letters To the Editor: Testing umbilical cord tissue for drugs: Lower analytical limits, better concordance with meconium results
Negrusz, A., & Jones, J. (2019). Testing umbilical cord tissue for drugs: lower analytical limits, better concordance with meconium results. The Journal of Pediatrics, 209, 258-259.
DOI: 10.1016/j.jpeds.2019.01.009
Letter
To the Editor: Colby et al discussed the equivalency of umbilical cord and meconium testing to evaluate in utero exposure to drugs. The authors applied “commercial” umbilical cord tissue and
gold standard meconium toxicology tests for detection of several drugs in paired umbilical cord and meconium samples from 501 neonates. The results in both specimens were often
discordant. However, the overall prevalence of drugs in umbilical cord and meconium was similar for several groups, and the agreement between both specimens ranged from 80% to 100%. The sensitivity of umbilical cord tissue for cannabinoids was only 41%. The concentrations of drugs in umbilical cord are much lower than in meconium and require much lower limits of detection and/or cut-offs (Table). In our study on 371 matched umbilical cord-meconium pairs with the 11-Nor-9-carboxy-D9 -tetrahydrocannabinol (THC-COOH) cut-off in umbilical cord of 0.05 ng/g, the sensitivity and specificity were 88.5% and 93.8%, respectively, twice as high as in the study by Colby et al.
A review article coauthored by Colby shows the superiority umbilical cord tissue to meconium when testing for prenatal drug exposure. The main advantages of umbilical cord vs
meconium include availability in every birth, long window of detection (also true for meconium), large sample size, single collection ensuring integrity of cases requiring chain of custody, and drugs administered to a newborn not detected. By comparison, meconium may not be available for testing due being expelled in utero. This differs in neonates born preterm, term, and post-term averaging 5.1%, 16.5%, and 27.1%, respectively.
In conclusion, we believe that the discordant results of drug testing in umbilical cord vs meconium reported by Colby et al originated from inadequate sensitivity of analytical
methodologies applied to testing of umbilical cord for drugs of interest.
Implication of this Letter
Dr. Adam Negruz and Dr. Joe Jones’ Letter to the Editor in response to the Colby et al. (2019) study raised important considerations regarding the methodology and interpretation of results. Negrusz and Jones pointed out that differences in analytical sensitivity, specimen handling, and cutoff concentrations between tests could contribute to the observed discordance. They emphasized the need for standardized protocols and further research to clarify under what circumstances each specimen type may be preferable or more reliable. Their commentary underscores the complexity of neonatal drug testing and supports the study’s call for cautious interpretation of results and the development of best practices.
—2021
Patterns of Neonatal Co-Exposure to Gabapentin and Commonly Abused Drugs Observed in Umbilical Cord Tissue
Okoye, N. C., & McMillin, G. A. (2021). Patterns of neonatal co-exposure to gabapentin and commonly abused drugs observed in umbilical cord tissue. Journal of Analytical Toxicology, 45(5), 506-512.
DOI: 10.1093/jat/bkaa118
Abstract
Gabapentin was thought to have low abuse potential, but it is increasingly being abused by people with substance use disorder in an attempt to potentiate the euphoric effects from opioids and other CNS depressants. Additionally, infants co-exposed to gabapentin and opioids during pregnancy tend to exhibit prolonged and more severe neonatal abstinence syndrome. In this study, we describe positivity rates among commonly abused drugs and rates of co-medication with gabapentin in a large dataset of umbilical cord tissue specimens (n = 25,422) submitted routine newborn drug testing at a national clinical reference laboratory (ARUP Laboratories, Salt Lake City, UT, USA). Detection of prenatal drug exposure in umbilical cord tissue specimens was accomplished using a semi-quantitative liquid chromatography–tandem mass spectrometry assay designed to detect 47 specific drugs and drug metabolites including opioids, stimulants, sedative-hypnotics and hallucinogens. A positive result for at least one of the measured drugs or drug metabolites was reported in 7,054 (28%) of the umbilical cord tissues analyzed. Gabapentin had a positivity rate of ˜2% with 562 positive results. Of the 562 gabapentin-positive samples, 395 (70%) also had a positive result for at least one other drug or drug metabolite, with the highest co-positivity rate observed for norbuprenorphine (32%, n = 182) followed by amphetamine (15%, n = 84), buprenorphine (13%, n = 74), methamphetamine (12%, n = 68), morphine (11%, n = 64), fentanyl (10%, n = 54) and naloxone (10%, n = 54). Notably, the concentration of gabapentin in gabapentin-positive umbilical cord specimens was higher in buprenorphine-containing specimens as compared to specimens containing other opioids, stimulants or benzodiazepines. Identification of neonatal co-exposure to gabapentin and opioids, particularly buprenorphine, may guide clinicians in rapid initiation of monitoring and intervention for neonatal abstinence syndrome.
Implication of this Study
Okoye et al. (2021) is distinguished as a large-scale retrospective analysis of over 25,000 umbilical cord tissue specimens, providing robust data on the prevalence and patterns of neonatal exposure to gabapentin and its co-occurrence with other substances of use, offering new insights into the patterns and risks of neonatal co-exposure.
—2022
Umbilical Cord Drug Screening in Multiple Births: Experience from a Reference Laboratory and Academic Medical Center
Nelson, H. A., Wood, K. E., McMillin, G. A., & Krasowski, M. D. (2022). Concordance of umbilical cord drug screening in multiple births: experience from a reference laboratory and academic medical center. Journal of analytical toxicology, 46(6), 611-618.
DOI: 10.1093/jat/bkab077
Abstract
The objective of this study was to review the results of umbilical cord drug screening in twins and triplets (multiples) to compare the detected drug(s) and/or drug metabolite(s). Results that did not agree between multiples were considered mismatched and were investigated. A retrospective analysis was conducted using de-identified data from a national reference laboratory, and results were compared with data from an academic medical center, where detailed medical chart review was performed. Umbilical cord was analyzed for stimulants, sedatives, opioids and other drugs and metabolites. For the reference laboratory dataset, 23.3% (n = 844) of 3,616 umbilical cords from twins (n = 3,550) or triplets (n = 66) were positive for one or more drugs and/or metabolites. Of these, mismatched results were identified for 37 sets of twins (2.1%) and no sets of triplets. The most frequent mismatches were found in opioids (n = 24), with morphine (n = 5) being the most mismatched of any single analyte in the panel. Mismatches for the marijuana metabolite 11-nor-9-carboxy-delta-9-tetrahydrocannabinol (9-COOH-THC) in the reference laboratory dataset occurred in 6 of 737 sets of twins (0.8%) and no triplets. For the academic medical center dataset, 21.9% (n = 57) of 260 umbilical cords tested positive for one or more drugs and/or metabolite(s). Of these, four mismatches (3.2%) were identified, including 9-COOH-THC (n = 2), phentermine (n = 1) and oxycodone (n = 1), all involving twins. All involved cases where the discrepant analyte was likely present in the negative twin but either slightly below the reporting cutoff threshold or failed analytical quality criteria. Mismatched results of umbilical cord drug screening occur in less than 4% of twins and most often occur when the analyte is slightly above the reporting cutoff in just one infant.
Implication of this Study
Nelson et al. (2022) systematically evaluated the concordance of umbilical cord drug screening results in multiple births (e.g., twins, triplets) within both a reference laboratory and an academic medical center setting. This study stands out for its focused investigation on a previously underexplored population–multiple births–where questions about intrauterine drug exposure consistency are clinically relevant but rarely addressed in the literature.
—2022
The Identification of Prenatal Exposure to Mitragynine Using Umbilical Cord Tissue
Wright, M. E., Coy, D., Jones, J., Sukta, A., Racines, A., & Jones, M. (2022). The identification of prenatal exposure to mitragynine using umbilical cord tissue. American Journal of Analytical Chemistry, 13(4), 162-174.
DOI: 10.4236/ajac.2022.134011
Abstract
Objective: Kratom is widely available and literature exploring the effects of prenatal kratom exposure is lacking. This study aims to report a validated method for the detection of mitragynine in the umbilical cord and report our observations for specimens received at a national commercial reference laboratory.
Study Design: Assays were validated according to the recommendations of ANSI/ASB. A retrospective evaluation of records at a national reference laboratory was conducted to determine prevalence and co-exposure to other substances of abuse.
Result: Mitragynine was detected in 19 of 4456 specimens (0.43%) with concentrations ranging from 4 to >50 ng/g. Thirteen (13) of these specimens were positive for only mitragynine while the other 6 were also positive for either marijuana or opiates.
Conclusion: Umbilical cord is a suitable specimen type for the surveillance of maternal kratom use and can be used to identify exposed neonates for further investigations into short- or long-term health consequences.
Implication of this Study
Wright et al. (2022) demonstrated, for the first time, the feasibility of detecting prenatal exposure to mitragynine–the primary active alkaloid in kratom-using umbilical cord tissue as a biological matrix. It distinguishes itself by pioneering the detection of a novel and increasingly relevant substance in umbilical cord tissue, thereby enhancing the scope of prenatal drug exposure monitoring and setting a precedent for future research on emerging drugs of abuse in this matrix.
—2022
Using Umbilical Cord Tissue to Identify Prenatal Exposure to Fentanyl and Other Commonly Abused Drugs
Hariharan, S., Coy, D., & Jones, J. (2022). Using Umbilical Cord Tissue to Identify Prenatal Exposure to Fentanyl and Other Commonly Abused Drugs. Open Journal of Obstetrics and Gynecology, 12(5), 434-442.
DOI: 10.4236/ojog.2022.125039
Abstract
Background: Prenatal exposure to fentanyl may lead to Neonatal Abstinence Syndrome (NAS), a constellation of symptoms observed when newborns begin withdrawing from addictive substances such as opioids. The use of umbilical cord tissue segments (UC) for newborn toxicology has been increasing due to its apparent long detection window, sensitivity, and ease of collection. However, very little has been reported in the literature concerning the prevalence of in utero exposure to fentanyl and co-exposure with other commonly abused substances.
Specific Aim: The specific aims of this retrospective study are twofold. We will report prevalence of neonatal exposure to fentanyl for a nationwide high-risk population using UC submitted to a national reference laboratory for routine forensic toxicology analysis and the co-exposure patterns observed for these fentanyl-exposed neonates.
Methods: A secondary analysis was performed using historical data for UC received between January 1, 2020 and December 31, 2020 for routine forensic toxicology analysis.
Results: During the study period, our laboratory received 23,104 UC for analysis and 9667 (41.8%) of those UC were positive for at least one drug. The prevalence
of fentanyl detection was 1.9% (n = 429). Of these 429 specimens there were 407 UC where both fentanyl and norfentanyl were detected. There were
14 UC where only fentanyl was detected and 8 UC where only norfentanyl was detected. When detected, the median concentrations of fentanyl and
norfentanyl were 4029 pg/g (IQR: 1696, 9230 pg/g) and 10,756 pg/mg (IQR: 3925, 25,288 pg/g), respectively. Of the 429 positive fentanyl and/or norfentanyl
UC, 33 (7.7%) were only positive for fentanyl and/or norfentanyl. Of the 396 polypositive UC, morphine was the highest co-exposure with 243 UC (56.6%) being positive for both fentanyls and morphine. The second most prevalent co-exposure observed was methamphetamine/amphetamine (n = 173; 40.3%) followed by cannabinoids (n = 113; 26.3%) and benzoylecgonine (cocaine metabolite; n = 106; 24.7%).
Conclusions: Nonmedical use of fentanyl is an alarming trend in this country including this maternal demographic reported here. Fentanyl was typically found with other commonly abused substances.
Implication of this Study
Hariharan et al. (2022) systematically evaluated the use of umbilical cord tissue to identify in utero exposure to fentanyl and other commonly abused drugs in a large-scale retrospective analysis across a nationwide high-risk population.
—2023
Analysis of umbilical cord tissue as an indicator of in utero exposure to toxic adulterating substances
Midthun, K. M., Nelson, B. N., Strathmann, F. G., Browne, T., & Logan, B. K. (2023). Analysis of umbilical cord tissue as an indicator of in utero exposure to toxic adulterating substances. Frontiers in Pediatrics, 11, 1127020.
DOI: 10.3389/fped.2023.1127020
Abstract
In utero drug exposure is a significant public health threat to the well-being and normal development of the neonate. Recently, testing of umbilical cord tissue (UCT) has been employed to measure illicit drug exposure, as drugs used by the mother during the third trimester may be retained in the UCT. Focus has also been given to potential adverse health effects among drug users, resulting from exposure to pharmacologically active adulterants and cutting agents in the street drug supply. The in utero effects of these substances have not been well studied in humans, nor has their presence been demonstrated as a means for assessing adverse health effects in the neonate. Here, we describe the application of a novel test method to analyze UCT for the presence of more than 20 common adulterating/cutting substances via LC/Q-TOF. In total, 300 de-identified UCT samples were analyzed–all had previously tested positive for cocaine or opiates. Generally, the positivity rates of individual compounds were similar between the Cocaine and Opiates Subgroups, apart from levamisole, xylazine, dipyrone (metabolites), and promethazine. Many of the adulterants used in the street drug supply do have legitimate medicinal/therapeutic uses, including several of the compounds most frequently detected in this study. Caffeine and lidocaine were the most frequently identified compounds both individually (>70% each) and in combination with each other. Alternatively, levamisole, an adulterant with no legitimate therapeutic use, was present in 12% of cases. Importantly, this data demonstrates that the detection of traditional drugs of abuse may serve as indicators of potential in utero exposure to toxic adulterating substances during gestation. While there is cause for concern with respect to any unintentional drug exposure, illicit drug use during pregnancy, including uncontrolled dosing, poly-adulterant consumption, and the interactions of these drug mixtures, produces a significant public health threat to the neonate which warrants further study.
Implication of this Study
Midthun et al. (2023) demonstrates that umbilical cord tissue can be effectively used to detect not only traditional drugs of abuse but also a wide array of toxic adulterating and cutting agents to which fetuses may be exposed in utero. Using a novel LC/Q-TOF analytical method, the researchers screened 300 samples (previously positive for cocaine or opiates) for over 20 common adulterants, including both pharmacologically active and inactive compounds.
—2024
Using umbilical cord tissue to identify prenatal ethanol exposure and co-exposure to other commonly misused substances
Jones, J., Coy, D., Gidron, D., Hariharan, S., Jones, M., Patel, N., … & Brown, G. (2024). Using umbilical cord tissue to identify prenatal ethanol exposure and co-exposure to other commonly misused substances. Journal of Perinatology, 1-4.
DOI: 10.1038/s41372-024-02075-2
Abstract
Objective: Substance misuse during pregnancy can result in a variety of poor pregnancy outcomes. Objective data reporting the prevalence of neonates born with ethanol metabolites (evidence of prenatal ethanol exposure) in their fluids or tissues are limited.
Study Design: A secondary analysis of umbilical cord tissue specimens received for routine toxicological analysis was conducted. Prevalences of ethyl glucuronide (EtG), a long-term direct ethanol biomarker, were determined using a new laboratory tool, LDTDMSMS. Additionally, other commonly misused substances were determined using routine procedures.
Results: Of 12,995 specimens, 238 (1.8%) specimens contained EtG. Concentrations of EtG ranged from 5 ng/g to 6679 ng/g (median 47 ng/mg; IQR: 16 ng/g, 203 ng/g). Of those 238 EtG-positive specimens, nearly 58% (N = 138) contained additional substances or metabolites.
Conclusion: Self-report of substance use during pregnancy is under-reported. We have demonstrated co-exposure of substances with ethanol is higher than previous reports.
Implication of this Study
Jones et al. (2024) demonstrates that ethyl glucuronide (EtG), a direct and long-term biomarker of ethanol, can be reliably detected in umbilical cord tissue using advanced laboratory methods (LDTD-MS/MS and LC-MS/MS). This provides a more objective measure compared to self-reported substance use, which is often under-reported. It revealed a higher-than-expected prevalence of co-exposure to ethanol and other substances.
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