Review
Drugs of abuse testing in meconium

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Abstract

Prenatal substance abuse is an ongoing concern with significant impact on neonatal health and development across socioeconomic lines. Meconium, passed by neonates during their first post-natal bowel movements, is a matrix unique to the developing fetus and contains a long history of prenatal metabolism. Over the last two decades, the use of meconium as a matrix for assessing prenatal exposure to drugs of abuse has yielded methods exhibiting higher sensitivity, easier collection, and a larger window of detection than traditional matrices. Recently, a method has been developed for the analysis of fatty acid ethyl esters in meconium as a biomarker of fetal alcohol exposure, potentially facilitating the future diagnosis of Fetal Alcohol Spectrum Disorder in situations where gestational alcohol consumption history is unknown. Screening for prenatal exposure to illicit and abused licit drugs in meconium is possible by use of a variety of immunoassay methods with conformational analysis usually occurring by GCMS or LCMS. In spite of increased sample preparation time relative to blood and urine, the long metabolic history, coupled with the ease and wide window of collection of meconium make it the ideal matrix for determining fetal drug exposure.

Introduction

Prenatal substance abuse is an ongoing concern, with significant impact on neonatal health and development [1], [2], [3], [4], [5], [6], [7], [8], [9], [10], [11]. Drug abuse in pregnancy exists across socioeconomic lines and has been consistently confirmed in numerous prevalence studies over the last decade [12], [13]. Rates of prenatal drug use have been determined by maternal report, urine analysis, blood analysis, and meconium analysis ranging from 3.4–31% for cocaine, 1–12% for cannabis, 1.6–21% for opiates, and 0.1–4% for ethanol in general and high-risk populations [13], [14], [15], [16], [17]. Over the last two decades, the use of meconium as a matrix for assessing prenatal drug exposure has yielded a method exhibiting higher sensitivity, easier collection, and a larger window of detection than other traditional matrices [18], [19]. In addition to its clinical utility in neonatal intervention and follow-up, the capability of meconium analysis to detect drugs of abuse and their multiple metabolites [20] provides a powerful research tool, assisting in the study of maternal–fetal drug disposition and metabolic capabilities specific to the fetus [21], [22], [23].

Section snippets

Meconium

Meconium comprises the neonate's first several bowel movements, identified most commonly by its dark green/black colour and a lack of odour usually inherent to regular feces. It is a highly complex matrix consisting of water, desquamated epithelial cells from the gastrointestinal tract and skin, lanugo (fine neonatal hair), fatty material from the vernix caseosa, bile acids and salts, cholesterol and sterol precursors, blood group substances, enzymes, mucopolysaccharides, sugars, lipids,

Cocaine

Cocaine crosses the placenta via passive diffusion [38]. The metabolism of cocaine has been shown to be highly variable, with little consistency in the relative amounts of cocaine and its metabolites among specimens [5], [20]. This fact, in combination with the potential augmentation of cocaine and metabolites in meconium by urine contamination in the diaper, has created difficulty in establishing a genuine dose–response relationship [39], [40]. In spite of this, there is solid evidence

Opiates

Animal studies have shown that opiates distribute readily across the placenta, resulting in peak fetal blood levels occurring relatively quickly post-intravenous administration as studied with meperidine, methadone and morphine [32]. Morphine distributes widely and variably into many fetal tissues, independent of administered dose [19]. Correlations have been demonstrated between higher dose, longer duration and later gestational timing of exposure and increased levels of morphine in meconium

Cannabinoids

The plant Cannabis sativa produces over fifty unique compounds known as cannabinoids, with Δ9-tetrahydrocannabinol (THC) being the most prevalent and psychoactive. Both human and animal studies have shown that cannabinoids cross the placenta, resulting in peak fetal levels after approximately two hours post-inhalation [32]. Levels in the maternal circulation remain higher than those on the fetal side at all times after smoke inhalation, presumably due to extensive protein binding [32], [57].

Amphetamines/phencyclidine

Amphetamines and phencyclidine are used in pregnancy, although less extensively relative to other drugs of abuse [15], [55], [60]. Methamphetamine has been shown to cross the placenta within thirty seconds of intraperitoneal injections in animal studies. Peak concentrations are lower on the fetal side, but slower elimination results in prolonged fetal exposure relative to the mother [61]. While no dose–response relationship has been established for amphetamines in meconium, individual case

Current trends in illicit drug detection

ELISA is rapidly becoming the favored method for screening. While the assay sensitivity can be as low as 5 ng/g of meconium when 0.5 g of meconium is used for the analysis, the cutoff for the positive values is still kept rather high: 80–100 ng/g for cocaine, benzoylecgonine, opiates and amphetamines and 10 ng/g for PCP and cannabinoids.

For confirmation, LCMS is gaining in popularity, due to the fact that there is no need for derivatization and in most cases LCMS has a higher sensitivity than

Ethanol

Ethanol is a small molecule that distributes rapidly into total body water and passes readily across the placenta. Ethanol is cleared rapidly from the blood following pseudo-zero order kinetics [63] resulting in a limited window of detection in blood and urine. The use of multiple maternal markers for alcoholism was found to be ineffective in accurately detecting prenatal alcohol abuse [64], warranting the need for a biomarker specific for pregnancy and directly related to fetal exposure.

Fatty

Clinical implications

The clinical effects of prenatal exposure to cocaine are not conclusive. While some studies have claimed neuroteratogenicity as an adverse outcome related to prenatal exposure [75], later systematic reviews could not detect long-term developmental consequences directly attributable to cocaine [76]. Associated effects such as dose-related decrease in fetal weight and head size [2], prolonged hospitalization [77], and increased early life problems [6] may not be due to cocaine itself, but rather

Conclusion

While detecting neonatal withdrawal is one objective commonly listed in favour of neonatal drug screening, one study demonstrated that only 10% of screened infants with ‘withdrawal symptoms’ tested positive for drugs of abuse, with 75% of infants with positive screens being asymptomatic [37]. In many cases, the benefit of screening lies mainly in the potential for intervention based on the developmentally detrimental lifestyle factors associated with prenatal drug abuse [40]. It is important to

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