We assessed umbilical cord tissue as a means of detecting fetal exposure to five classes of drugs of abuse.
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.
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%.
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.
In a previous report, we provided preliminary evidence that assays of umbilical cord tissue can detect fetal exposure to illicit drugs.1 In that study we obtained paired samples of umbilical cord tissue and meconium, performed drug detection assays on both, and found >90% agreement between the paired specimens. Limitations of that study were that it was a single-centered study (Ogden, UT, USA), and that only about 100 samples were tested. The present study was undertaken to expand those findings by including four hospitals, three in Utah and one in New Jersey and testing 500 umbilical cord specimens.
The specific aim of the present study was to assess the performance of enzyme-linked immunosorbent assay (ELISA)-based tests on umbilical cord tissue for detecting amphetamines, opiates, cocaine, cannabinoids and phencyclidine, and to compare these results with the more time-consuming and expensive ‘gold standard’ liquid or gas chromatographic mass spectrometric detection methods. The study results, reported herein, lead us to conclude that the ELISA-based tests on umbilical cord tissue can indeed be used to assess fetal exposure to these classes of illicit drugs.
During a 15-month period (August 2006 through October 2007) a segment of approximately 10 cm was cut from the fetal end of each umbilical cord of a delivery at McKay-Dee Hospital Center, Ogden, UT, USA; Logan Regional Hospital, Logan, UT, USA and LDS Hospital, Salt Lake City, UT, USA and the University Hospital, University of Medicine and Dentistry of New Jersey, Newark, NJ, USA. The cord segments were stripped of blood, then lightly rinsed with sterile saline and placed in sterile containers in laboratory refrigerators. If any of the following criteria were met, the deidentified umbilical cord segment was submitted to the United States Drug Testing Laboratories (Des Plaines, IL, USA) for testing. If criteria were not met, the umbilical cord segment was discarded in the usual manner. Criteria for testing were: (1) a history of a previous pregnancy where drug abuse was proven, (2) maternal report of drug abuse during this pregnancy, (3) no prenatal care, (4) no permanent address, (5) sexually transmitted disease and (6) mother or father appearing intoxicated, ‘high’ or abusive or exhibiting inappropriate behavior.1
The umbilical cord specimens were stored at −20 °C and were batched for periodic research analysis. The results of these tests were not reported to the attending physician, but rather were treated as a deidentified, anonymous data set. No specimens were stored for more than 3 months before the assays were completed. The Intermountain Healthcare Institutional Review Board and the University of Medicine and Dentistry of New Jersey Institutional Review Board approved the study protocol.
The umbilical cord specimens were extracted by the procedures reported by Le et al.,2 and the extracts were analyzed for amphetamines, opiates, cocaine, cannabinoids and phencyclidine by ELISA assays (Immunalysis Corp., Pomona, CA, USA). Mass spectrometric analyses were made following procedures modified from Le et al.2
To arrive at the agreement values between the ELISA and the mass spectrometric analyses, it was necessary to determine cutoff values for the umbilical cord screening assays. This was performed by using receiver-operating characteristic (ROC) plots to assign a screening cutoff value for amphetamines, opiates, cocaine and cannabinoids.3
A total of 498 umbilical cord segments were obtained for drug testing. Each of the 498 samples successfully underwent both the mass spectrometric and the ELISA tests for all five drug classes under study. Of the 498 cord segments (32%), 157 tested positive using the mass spectrometric detection methods. The number of samples submitted from each of the four participating hospitals and the samples that tested positive by mass spectrometric methods are shown in Table 1.
ROC plots were generated for amphetamines, opiates, cocaine and cannabinoids, but could not be constructed for phencyclidine because only one phencyclidine-positive sample was detected during this study. From the ROC plots, cutoffs were chosen from the ELISA testing that yielded the best sensitivity and specificity for each drug-screening assay. Table 2 shows the results of the ELISA and mass spectrometric testing, demonstrating the sensitivity, specificity and positive and negative predictive values for the ELISA with respect to each of the five drug classes tested.
Rapidly detecting fetal exposure to illicit drugs can be of considerable medical value.4, 5, 6, 7, 8, 9, 10 For instance, such information can assist in making a diagnosis of neonatal drug withdrawal, and can help focus the treatment and the follow-up plans for the neonate.11 Currently, meconium is the most common source used for detecting fetal drug exposure,12, 13, 14, 15, 16 but meconium testing has certain drawbacks and limitations. For instance, in some cases the meconium has been passed before birth, making it unavailable for drug testing. In other cases, particularly among preterm infants, meconium is not passed for several days following delivery, thus delaying the diagnosis of fetal drug exposure. In yet other cases, particularly among term infants with a short hospital stay, meconium may not be passed in the hospital. For such cases, attempting to collect meconium at home, for drug testing, can be impractical.
An alternative means of detecting fetal exposure to illicit drugs involves testing of neonatal hair samples.17, 18, 19 Garcia-Bournissen et al.20 developed an analytical test in hair for cocaine and its metabolite benzoylecgonine. They found median cocaine concentrations 10-fold higher in the mother's hair than in her neonate's hair. They also found that when the mother's hair tested positive, only 60% of the paired neonatal samples tested positive. Practical problems with neonatal hair testing include inadequate hair to sample on some infants, parental objections to having their infant's hair shaved; and relative insensitivity of the test compared with meconium.17
To circumvent these difficulties in meconium and hair testing, we devised an alternative method using umbilical cord tissue.1 A segment of umbilical cord, stripped of blood and washed in sterile saline, is sent to the drug testing laboratory. Highly sensitive but expensive and time-consuming methods were developed for detecting illicit drugs in the umbilical cord tissue, using liquid or gas chromatographic and mass spectrometric detection. However, such testing is impractical for rapid clinical usage because of the expense and time required, thus more rapid and inexpensive alternative tests were developed using ELISA-based methodologies. Our present study was aimed at testing the umbilical cord tissue of 500 neonates who were judged to be ‘at risk’ for maternal illicit drug ingestion. Each of the 500 cord specimens were sent to the drug testing laboratory as ‘deidentified’ research specimens, to assure anonymity, and each cord was tested using both the gold standard mass spectrometric methods and the ELISA-based detection methods.
We found that the ELISA tests performed well. Their negative predictive values were outstanding, with values >98% for each drug class tested. This indicates that when the ELISA test is negative (no drug is detected in the sample) assurance is extremely high that none of the tested drug classes were present in that sample. The positive predictive values of the ELSIA tests were also very good, with all values exceeding 70%, and values as high as 95% for cocaine. Thus, when the ELISA test is positive, the specimen could be retested using mass spectrometric detection methods, thereby increasing the positive predictive value of the test to essentially 100%. The relative costs of testing umbilical cord, meconium, urine and hair were not directly calculated in this study, but the costs in commercial application should be similar, because the methods for receiving, preparing, assaying and results reporting of the various samples are similar.
The amount of maternal drug that must be ingested to be detected in meconium, hair or umbilical cord, and the timing of the ingestion during the pregnancy, are issues that are not yet resolved. Ostrea et al.21 reported cocaine in the meconium of three 17-week-old human fetuses, along with evidence that the concentration of cocaine in meconium is related to the amount and time of cocaine use prenatally. Using animal models of morphine administration, Silvestre et al.22 came to similar conclusions. Namely, the concentration of morphine in meconium is related to the amount ingested, it's timing relative to delivery and the duration of drug exposure. Although these general principals have been discovered, no exact methods are yet available for back-calculating the doses and timing of illicit drugs ingested by mothers, on the basis of the quantities of drugs or their metabolites in meconium, neonatal hair or umbilical cord tissue.
From our present and previous study findings,1 we maintain that umbilical cord tissue testing, using ELISA-based methods, can indeed be a useful way of detecting fetal exposure to illicit drugs. In certain cases, clinicians will find that cord testing has advantages over meconium and hair-based detection methods. In addition to its universal availability and rapid send-off time, umbilical cord testing is inherently more suitable than meconium or hair-based methods for anonymous epidemiologic screening studies for illicit drug use during pregnancy.
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We thank the nurses of the Labor and Delivery Units and the Neonatal Intensive Care Units at Logan Regional, McKay-Dee, LDS and University Hospital, UMDNJ, for their valuable assistance in collecting the umbilical cord specimens for this study. This work was supported by grant 2 R44 DA017412-02A1 from the National Institute of Drug Abuse.
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Montgomery, D., Plate, C., Jones, M. et al. Using umbilical cord tissue to detect fetal exposure to illicit drugs: a multicentered study in Utah and New Jersey. J Perinatol 28, 750–753 (2008). https://doi.org/10.1038/jp.2008.97
- drug abuse
- umbilical cord
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