Abstract
Consumption of drugs of abuse, tobacco and alcohol throughout pregnancy is a serious public health problem and results in an important economic cost to the health system. Drug and/or metabolites determination in biological matrices from mother and newborn is an objective measure of in utero drug exposure. We reviewed methods published for the determination of in utero drug exposure from 2007 to 2014, with special focus on meconium, placenta, umbilical cord and newborn hair. Accurate bioanalytical procedures are essential to obtain high-quality data to perform interventions and to establish correlations between analytical measures and clinical outcomes. We included a brief overview of clinical implications of in utero drug exposure to better understand the importance of this serious health issue.
Papers of special note have been highlighted as: •• of considerable interest
References
- 1 . The effect of controlled drugs on the unborn child and fetus. J. Cin. Forensic Med. 8, 129–139 (2001).
- 2 . Consequences of prenatal substance use. Int. J. Adolesc. Med. Health 24, 105–112 (2012).
- 3 . Women, pregnancy and methadone. Heroin Add. Rel. Cin. Probl. 2, 1–8 (2000).
- 4 . Drug abuse's smallest victims: in utero drug exposure. Forensic Sci. Int. 128, 20–30 (2002).
- 5 . Risk factors for early pregnancy loss. Epidemiology 1, 382–385 (1990).
- 6 Drogas y Teratogenia. Adicciones 18(1), 1–18 (2006).
- 7 Substance Abuse and Mental Health Services Administration. Results from the 2012 National Survey on Drug Use and Health: Summary of National Findings. Substance Abuse and Mental Health Services Administration, MD, USA (2013).
- 8 Observatorio Español de la Droga y las Toxicomanías. Informe 2011. Situación y tendencias de los problemas de la drogas en España. www.pnsd.msssi.gob.es.
- 9 Estimates of illicit drug use during pregnancy by maternal interview, hair analysis, and meconium analysis. J. Pediatr. 138, 344–348 (2001).
- 10 Assessment of exposure to drugs of abuse during pregnancy by hair analysis in a Mediterranean island. Addiction 107, 1471–1479 (2012).
- 11 . Bioanalytical procedures for monitoring in utero drug exposure. Anal. Bioanal. Chem. 388, 1455–1465 (2007).
- 12 Biological matrices for the evaluation of in utero exposure to drugs of abuse. Ther. Drug Monit. 29, 711–734 (2007).
- 13 . The role of alternative specimens in toxicological analysis. Biomed. Chromatogr. 22, 795–821 (2008).
- 14 Effects of addictive substances during pregnancy and infancy and their analysis in biological materials. In: Reviews of Environmental Contamination and Toxicology, Volume 227. Whitacre DM (Ed.). Springer International Publishing, Switzerland, 55–77 (2014).
- 15 . In utero alcohol exposure, epigenetic changes, and their consequences. Alcohol Res. 35(1), 37–46 (2013).
- 16 . Comitee on substance abuse and Comitte on Fetus and Newborn. Prenatal substance abuse: short and long-term effects on the exposed fetus. Pediatrics 131(3), e1009–10024 (2014).
- 17 Ethanol cytotoxic effect on trophoblast cells. Toxicol. Lett. 225(2), 216–221 (2014).
- 18 . Neonatal abstinence syndrome. Pediatrics 134, e547 (2014).•• Complete description and analysis of the neonatal abstinence syndrome from a clinical and toxicological point of view.
- 19 . Chronic opioid use during pregnancy: maternal and fetal implications. Clin. Perinatol. 40(3), 509–524 (2013).
- 20 Methadone dose and neonatal abstinence syndrome-systematic review and meta-analysis. Addiction 105(12), 2071–2084 (2010).
- 21 . Observations on heroin and methadone withdrawal in the newborn. Pediatrics 48(3), 353–358 (1971).
- 22 . The use of psychotropic medication during pregnancy: how about the newborn? Neuropsychiatr. Dis. Treat. 9, 1257–1266 (2013).
- 23 . Neonatal and longer term management following substance misuse in pregnancy. Early Hum. Dev. 89(11), 887–892 (2013).
- 24 Neonatal abstinence syndrome after methadone or buprenorphine exposure. N. Engl. J. Med. 363(24), 2320–2331 (2010).
- 25 Effects of prenatal methamphetamine exposure on behavioral and cognitive findings at 7.5 years of age. J. Pediatr. 164(6), 1333–1338 (2014).
- 26 . Systematic review of prenatal cocaine exposure and adolescent development. Pediatrics 131(6), e1917–e1936 (2013).
- 27 . A review of the effects of prenatal cocaine exposure among school-aged children. Pediatrics 125(3), 554–565 (2010).
- 28 . Effects of prenatal cocaine/polydrug exposure on substance use by age 15. Drug Alcohol Depend. 134, 201–210 (2014).
- 29 Altered reward processing in adolescents with prenatal exposure to maternal cigarette smoking. JAMA Psychiatry 70(8), 847–856 (2013).
- 30 . The impact of exposure to addictive drugs on future generations: physiological and behavioral effects. Neuropharmacology 76, 269–275 (2014).
- 31 Child Welfare Information Gateway. U.S. Department of Health and Human Services. (2012). www.childwelfare.gov/systemwide/laws_policies/statutes/drugexposed.pdf.
- 32 Alternative matrices for cocaine, heroin, and methadone in utero drug exposure detection. Ther. Drug Monit. 35(4), 502–509 (2013).•• Comparison of maternal hair, meconium, placenta and umbilical cord for the detection of in utero drug exposure and description of multi-analyte methods.
- 33 Correlations of maternal buprenorphine dose, buprenorphine, and metabolite concentrations in meconium with neonatal outcomes. Cin. Pharmacol. Ther. 84, 604–12 (2008).
- 34 Detection of cocaine exposure in the neonate. Analyses of urine, meconium, and amniotic fluid from mothers and infants exposed to cocaine. Arch. Pathol. Lab. Med. 118, 988–93 (1994).
- 35 . Opioid detection in maternal and neonatal hair and meconium: characterization of an at-risk population and implications to fetal toxicology. Ther. Drug Monit. 32, 318–323 (2010).
- 36 Methamphetamine detection in maternal and neonatal hair: implication for fetal safety. Arch. Dis. Child Fetal Neonatal Ed. 92, 351–355 (2007).
- 37 Methadone, cocaine, opiates, and metabolites disposition in umbilical cord and correlations to maternal methadone dose and neonatal outcomes. Ther. Drug Monit. 33, 443–452 (2011).
- 38 Umbilical cord monitoring of in utero drug exposure to buprenorphine and correlation with maternal dose and neonatal outcomes. J. Anal. Toxicol. 34, 498–505 (2010).
- 39 Testing for fetal exposure to illicit drugs using umbilical cord tissue vs meconium. J. Perinatol. 26, 11–14 (2006).
- 40 Determination of cocaine and its major metabolite, benzoylecgonine, in amniotic fluid, umbilical cord blood, umbilical cord tissue, and neonatal urine: a case study. J. Anal. Toxicol. 17(1), 62 (1993).
- 41 Detection of cocaine and its metabolites in amniotic fluid and umbilical cord tissue. J. Anal. Toxicol. 21, 97–104 (1997).
- 42 Maternal methadone dose, placental methadone concentrations, and neonatal outcomes. Clin. Chem. 57, 449–458 (2011).
- 43 Maternal buprenorphine dose, placenta buprenorphine, and metabolite concentrations and neonatal outcomes. Ther. Drug Monit. 32, 206–215 (2010).
- 44 Maternal hair testing for the assessment of fetal exposure to drug of abuse during early pregnancy: comparison with testing in placental and fetal remains. Forensic Sci. Int. 218, 92–96 (2012).
- 45 Confirmation of gestational exposure to alprazolam by analysis of biological matrices in a newborn with neonatal sepsis. Cin. Toxicol. 45, 295–298 (2007).
- 46 Neonatal withdrawal syndrome after chronic maternal drinking of mate. Ther. Drug Monit. 29, 127–129 (2007).
- 47 Prenatal exposure to arecoline (areca nut alkaloid) and birth outcomes. Arch. Dis. Child Fetal Neonatal Ed. 90, F276–F277 (2005).
- 48 US Department of Health and Human Services, Food and Drug Administration. Mass Spectrometry for Confirmation of the Identity of Animal Drug Residues. (2003). www.fda.gov/downloads/AnimalVeterinary/GuidanceComplianceEnforcement/GuidanceforIndustry/ucm052658.pdf.
- 49 European Union Decision 2002/657/EC (17/8/2002). Off. J. Eur. Commun. 221, 8–36 (2002).
- 50 Scientific Working Group for Forensic Toxicology (SWGTOX). Standard practices for method validation in forensic toxicology. J. Anal. Toxicol. 37, 452–474 (2013).•• Complete guidelines for analytilcal method validation.
- 51 Quantification of fatty acid ethyl esters (FAEE) and ethyl glucuronide (EtG) in meconium from newborns for detection of alcohol abuse in a maternal health evaluation study. Anal. Bioanal. Chem. 396, 2469–2477 (2010).
- 52 Fatty acid ethyl esters (FAEEs) as markers for alcohol in meconium: method validation and implementation of a screening program for prenatal drug exposure. Forensic Sci. Med. Pathol. 9, 287–295 (2013).
- 53 Validation of a novel method to identify in utero ethanol exposure: simultaneous meconium extraction of fatty acid ethyl esters, ethyl glucuronide, and ethyl sulfate followed by LC–MS/MS quantification. Anal. Bioanal. Chem. 406(7), 1945–1955 (2014).•• Challenging method for the simultaneous determination of the alcohol biomarkers ethyl-glucuronide, ethyl-sulfate and fatty acid ethyl esters in meconium.
- 54 A new method for quantifying prenatal exposure to ethanol by microwave-assisted extraction (MAE) of meconium followed by gas chromatography-mass spectrometry (GC–MS). Anal. Bioanal. Chem. 404, 147–155 (2012).
- 55 An improved method for rapidly quantifying fatty acid ethyl esters in meconium suitable for prenatal alcohol screening. Alcohol 45, 193–199 (2011).
- 56 Ethyl glucuronide determination in meconium and hair by hydrophilic interaction liquid chromatography-tandem mass spectrometry. Forensic Sci. Int. 196, 121–127 (2010).
- 57 Determination of eight fatyy acid ethyl esters in meconium samples by headspace solid-phase microextraction and gas chromatography-mass spectrometry. J. Sep. Sci. 33, 2115–2122 (2010).
- 58 Quantitation of fatty acid ethyl esters in human meconium by an improved liquid chromatography/tandem mass spectrometry. J. Chromatogr. B 878, 1871–1874 (2010).
- 59 Quantification of fatty acid ethyl esters (FAEE) and ethyl glucuronide (EtG) in meconium from newborns for detection of alcohol abuse in a maternal health evaluation study. Anal. Bioanal. Chem. 396, 2469–2477 (2010).
- 60 Liquid chromatography with tandem mass spectrometric detection for the measurement of ethyl glucuronide and ethyl sulfate in meconium: new biomarkers of gestational ethanol exposure. Ther. Drug Monit. 30, 725–732 (2008).
- 61 . Effect of hydrolysis on identifying prenatal cannabis exposure. Anal. Bioanal. Chem. 397, 2335–2347 (2010).
- 62 Confirmation of cannabinoids in meconium using two-dimensional gas chromatography with mass spectrometry detection. J. Chromatogr. B 858, 59–64 (2007).
- 63 Quantitation of benzodiazepines in urine, serum, plasma, and meconium by LC–MS–MS. J. Anal. Toxicol. 32, 491–498 (2008).
- 64 . Development and validation of a liquid-chromatography-atmospheric pressure chemical ionization-tandem mass spectrometry method of simultaneous analysis of 10 amphetamine-, methamphetamine- and 3,4-methylenedioxymethamphetamine-related (MDMA) analytes in human meconium. J. Chromatogr. B 867, 194–204 (2008).
- 65 Simultaneous quantification of amphetamine and methamphetamine in meconium using ISOLUTE® HM-N-supported liquid extraction columns and GC–MS. J. Anal. Toxicol. 32, 485–490 (2008).
- 66 . Validation and application of a method for the determination of buprenorphine, norbuprenorphine, and their glucuronide conjugates in human meconium. Anal. Chem. 80, 246–252 (2008).
- 67 Development and practical application of accelerated solvent extraction for the isolation of cocaine/crack biomarkers in meconium samples. J. Chromatogr. B 957, 14–23 (2014).
- 68 Simultaneous determination of codeine, morphine, hydrocodone, hydromorphone, oxycodone, and 6-acetylmorphine in urine, serum, plasma, whole blood, and meconium by LC–MS/MS. J. Anal. Toxicol. 31, 1–14 (2007).
- 69 Nicotine and metabolites in paired umbilical cord tissue and meconium specimens. Ther. Drug Monit 33, 80–85 (2011).
- 70 . Quantification of nicotine, cotinine, trans-3′-hydroxycotinine, nornicotine and norcotinine in human meconium by liquid chromatography/tandem mass spectrometry. J. Chromatogr. B 863, 107–114 (2008).
- 71 A rapid assay for the simultaneous determination of nicotine, cocaine and metabolites in meconium using disposable pipette extraction and gas chromatography-mass spectrometry (GC–MS). J. Anal. Toxicol. 38, 31–38 (2014).
- 72 Cocaine and opiates use in pregnancy: detection of drugs in neonatal meconium and urine. J. Anal. Toxicol. 33, 351–355 (2009).
- 73 . A liquid chromatography tandem mass spectrometry method for the simultaneous quantification of 20 drugs of abuse and metabolites in human meconium. Anal. Bioanal. Chem. 393, 1977–1990 (2009).
- 74 Development of a new immunoassay for the detection of ethyl glucuronide (EtG) in meconium: validation with authentic specimens analyzed using LC–MS/MS. Preliminary results. Clin. Chem. Lab. Med.
doi: 10.1515/cclm-2013–1087 (2014) (Epub ahead of print). - 75 . Drugs of abuse detection in meconium: a comparison between ELISA and biochip microarray. J. Anal. Toxicol. 35, 40–45 (2011).
- 76 Comparison of drugs of abuse detection in meconium by EMIT®II and ELISA. J. Anal. Toxicol. 33, 148–154 (2009).
- 77 Broad-spectrum drug screening of meconium by liquid chromatography with tandem mass spectrometry and time-of-flight mass spectrometry. Anal. Bioanal. Chem. 398, 925–935 (2010).
- 78 Transplacental transfer and metabolism of buprenorphine. J. Pharmacol. Exp. Ther. 300(1), 26–33 (2002).
- 79 . Drug transfer and metabolism by the human Placenta. Clin. Pharmacokinet 43(8), 487–514 (2004).
- 80 Simultaneous determination of opiates, methadone, amphetamines, cocaine, and metabolites in human placenta and umbilical cord by LC–MS/MS. Anal. Bioanal. Chem. 405(12), 4295–4305 (2013).
- 81 The detection and quantification of ethyl glucuronide in placental tissue perfusate by headspace solid-phase microextraction coupled with gas chromatography-mass spectrometry. J. Popul Ther. Cin. Pharmacol 19(3), e473–e482 (2012).
- 82 Ethyl-glucuronide and ethyl-sulfate in placental and fetal tissues by liquid chromatography couple with tandem mass spectrometry. Anal. Biochem. 418, 30–36 (2011).
- 83 . Simultaneous quantification of buprenorphine, norbuprenorphine, buprenorphine glucuronide, and norbuprenorphine glucuronide in human placenta by liquid chromatography mass spectrometry. Anal. Bioanal. Chem. 394, 513–522 (2009).
- 84 Gas chromatography-mass spectrometry assay for the simultaneous quantification of drugs of abuse in human placenta at 12th week of gestation. Forensic Sci. Int 196, 38–42 (2010).
- 85 Simultaneous quantification of methadone, cocaine, opiates, and metabolites in human placenta by liquid chromatography-mass spectrometry. J. Anal. Toxicol. 33, 243–252 (2009).
- 86 . Umbilical cord. In: Encyclopedia of Reproduction, Volume 4. Knobil E, Neil J (Eds). Academic Press, CA, USA, 915–923 (1999).
- 87 . Simultaneous quantificatification of buprenorphine, norbuprenorphine, buprenorphine-glucuronide and norbuprenorphine-glucuronide in human umbilical cord by liquid chromatography tandem mass spectrometry. Forensic Sci. Int 188, 144–151 (2009).
- 88 Determination of amphetamine and methamphetamine in umbilical cord using liquid chromatography-tandem mass spectrometry. J. Chromatogr. B 877, 3701–3706 (2009).
- 89 Development and validation of a liquid chromatography mass spectrometry assay for the simultaneous quantification of methadone, cocaine, opiates and metabolites in human umbilical cord. J. Chromatogr. B 877, 3065–3071 (2009).
- 90 Detection of in utero marijuana exposure by GC–MS, ultra-sensitive ELISA and LC–TOF–MS using umbilical cord tissue. J. Anal. Toxicol. 37, 391–394 (2013).
- 91 Detection of neonatal drug exposure using umbilical cord tissue and liquid chromatography time-of-flight mass spectrometry. Ther. Drug Monit 36, 119–124 (2014).
- 92 . State of the art in hair analysis for detection of drug and alcohol abuse. Clin. Chim. Acta 370, 17–49 (2006).
- 93 Maternal hair analysis for the detection of illicit drugs, medicines, and alcohol exposure during pregnancy. Ther. Drug Monit 35, 296–304 (2013).
- 94 Cocaine use during pregnancy assessed by hair analysis in a Canry Islands cohort. BMC Pregnancy Childbirth 12, 2–8 (2012).
- 95 Role of LC–MS/MS in hair testing for the determination of common drugs of abuse and other psychoactive drugs. Bioanalysis 5(15), 1919–1938 (2013).
- 96 Hair ethyl glucuronide levels as a marker for alchol use and abuse: a review of the current state of art. Drug Alcohol Depend. 134, 1–11 (2014).
- 97 Society of Hair Testing, Statement 2011. (2014). www.soht.org/index.php/statements/9-nicht-kategorisiert/85-statement-2011.
- 98 Neonatal hair analysis by liquid chromatography-high resolution mass spectrometry to reveal gestational exposure to venlafaxine. Ther. Drug Monit. 32, 30–39 (2010).
- 99 Quantification of citalopram or escitalopram and their demethylated metabolites in neonatal hair samples by liquid chromatography-tandem mass spectrometry. Ther. Drug Monit. 30, 467–473 (2008).
- 100 Buprenorphine and norbuprenorphine in hair of pregnant women and their infants after controlled buprenorphine administration. Clin. Chem. 53(12), 2136–2143 (2007).
- 101 Perinatal effects of combined use of heroin, methadone, and amphetamine during pregnancy and quantitative measurement of metabolites in hair. Pediatr. Neonatol. 53, 112–117 (2012).
- 102 Simultaneous detection of seventeen drugs of abuse and metabolites in hair using solid phase micro extraction (SPME) with GC/MS. Forensic Sci. Int. 218, 31–36 (2012).
- 103 Nicotine and its metabolites in amniotic fluid at birth – assessment of prenatal tobacco smoke exposure. Hum. Exp. Toxicol. 29(5), 385–391 (2010).
- 104 . Detection of cocaine analytes and opiates in nails from postmortem cases. J. Anal. Toxicol. 26, 489–492 (2002).
- 105 . Nails of newborns in monitoring drug exposure during pregnancy. Forensic Sci. Int. 179, 176–180 (2008).