Evaluation of three-year neurodevelopmental outcomes in infants prenatally exposed to substance use.

INTRODUCTION: Prenatal exposure to substance use is associated with long-term deficits in the neurodevelopment of children. The objective was to investigate the association between cognitive, motor, and language neurodevelopment at three years of age in infants prenatally exposed to substance use. MATERIAL AND METHODS: A prospective matched case-control study was conducted. Biomarkers of fetal exposure were measured in meconium samples. The Bayley Scales of Infant and Toddler Development (BSID-III) were used to calculate neurodevelopment scores. RESULTS: 32 non-exposed and 32 exposed infants were evaluated, of which 16 were exposed to cannabis, 8 to ethanol, 2 to cocaine and 6 to more than one substance. Normal BSID-III scores ≥85 in all domains, were detected in 23 exposed infants to any substance and 29 infants non-exposed. Neurodevelopmental delay was detected in the language domain, specifically in male infants exposed to cannabis. Two infants exposed to cannabis had a severe developmental delay (score<70). Infants exposed to any substance obtained significantly lower total scores than control infants in all domains. Infants exposed to cannabis obtained significantly lower composite scores in the cognitive and motor domains. Infants exposed to more than one substance had lower scores in motor skills. By gender, only males exposed obtained significantly lower composite scores than non-exposed males in the cognitive domain. CONCLUSIONS: The most common and severe neurodevelopmental delay at 36 months was detected in the domain of language in male infants prenatally exposed to cannabis. Neurodevelopmental disorders detected can enable an early intervention and plan therapeutic strategies.

Características clínicas y factores de riesgo asociados a la exposición prenatal a drogas de abuso / Clinical features and risk factors associated with prenatal exposure to drugs of abuse

Introducción: La identificación temprana de los neonatos expuestos a drogas de abuso permite realizar un manejo clínico más preciso.Objetivos: Describir las características clínicas e identificar factores de riesgo asociados a la detección precoz de neonatos expuestos a drogas de abuso en una Unidad de Cuidados Intensivos e Intermedios Neonatales.Métodos: Estudio observacional prospectivo de neonatos con y sin sospecha clínica de exposición prenatal a drogas de abuso. Se analizó meconio empleando técnicas cromatográficas estandarizadas. Se realizaron análisis estadísticos univariante y multivariante.Resultados: Se incluyeron 372 neonatos. En 49 (13,2%) casos se detectó exposición a alguna droga de abuso; en 41 (83,7%) a una, y en ocho (16,3%) a más de una. La somatometría al nacimiento objetivó: a) menor percentil de longitud en expuestos a alguna droga, a más de una y a cannabis; b) menor percentil de peso en expuestos a cannabis, y de éstos en comparación con los expuestos a alcohol. En mayores de 34 semanas de gestación (SG): a) menor percentil de longitud en expuestos a alguna droga; b) menor percentil de longitud y peso en expuestos a más de una. Los factores de riesgo independientes clínicamente útiles para detectar casos de exposición prenatal a drogas de abuso fueron (odds ratio [IC 95%]): motivo de ingreso distinto a prematuridad (5,52 [2,55-1,93]), percentil de longitud menor a 33 (1,95 [1,05-3,60]) y (2,14 [1,04-3,40]) en mayores de 34 SG y distocia social/embarazo no controlado en mayores a 34SG (4,47 [1,03-19,29]).Conclusiones: Existen alteraciones somatométricas y factores de riesgo que pueden ayudar a detectar precozmente a los neonatos expuestos a drogas de abuso. Las alteraciones somatométricas identificadas pueden servir para ampliar su diagnóstico diferencial y el estudio de sus causas. (AU)

Introduction: Early identification of neonates exposed to drugs of abuse during pregnancy allows a more precise clinical management.Objectives: To describe the clinical characteristics and to identify risk factors associated with the early detection of neonates exposed to drugs of abuse in a Neonatal Intermediate and Intensive Care Unit.Methods: Prospective observational study of neonates with and without clinical suspicion of prenatal exposure to drugs of abuse. Meconium was analyzed using standard chromatographic techniques. Univariate and multivariate statistical analyzes were performed.Results: 372 neonates were included. Exposure to drugs of abuse was detected in 49 (13.2%) cases: in 41 (83.7%) one drug and in 8 (16.3%) more than one. Somatometry at birth revealed: a) lower length percentile in those exposed to some drug, more than one and cannabis; b) lower weight percentile in those exposed to cannabis and of these compared to those exposed to alcohol. In neonates older than 34 pregnancy weeks (PW): a) lower length percentile in those exposed to any substance; b) lower percentile of length and weight in exposed to more than one. The most clinically relevant independent risk factors useful to detect cases of prenatal exposure to drugs of abuse were (Odds ratio (95% CI)): reason for admission other than prematurity (5.52 (2.55-1.93)), length percentile less than 33 (1.95 (1.05-3.60) and 2.14 (1.04-3.40) in older than 34 PW) and social dystocia/uncontrolled pregnancy in older than 34 PW (4.47 (1.03-19.29)).Conclusions: There are somatometric alterations and risk factors that can help in the early detection of neonates exposed to drugs of abuse. The somatometric alterations identified can be useful to extend the differential diagnosis of these alterations and to study their causes.

Clinical features and risk factors associated with prenatal exposure to drugs of abuse.

INTRODUCTION: Early identification of neonates exposed to drugs of abuse during pregnancy allows a more precise clinical management. OBJECTIVES: To describe the clinical characteristics and to identify risk factors associated with the early detection of neonates exposed to drugs of abuse in a Neonatal Intermediate and Intensive Care Unit. METHODS: Prospective observational study of neonates with and without clinical suspicion of prenatal exposure to drugs of abuse. Meconium was analyzed using standard chromatographic techniques. Univariate and multivariate statistical analyzes were performed. RESULTS: 372 neonates were included. Exposure to drugs of abuse was detected in 49 (13.2%) cases: in 41 (83.7%) one drug and in 8 (16.3%) more than one. Somatometry at birth revealed: a) lower length percentile in those exposed to some drug, more than one and cannabis; b) lower weight percentile in those exposed to cannabis and of these compared to those exposed to alcohol. In neonates older than 34 pregnancy weeks (PW): a) lower length percentile in those exposed to any substance; b) lower percentile of length and weight in exposed to more than one. The most clinically relevant independent risk factors useful to detect cases of prenatal exposure to drugs of abuse were (Odds ratio (95% CI)): reason for admission other than prematurity (5.52 (2.55-1.93)), length percentile less than 33 (1.95 (1.05-3.60) and 2.14 (1.04-3.40) in older than 34 PW) and social dystocia/uncontrolled pregnancy in older than 34 PW (4.47 (1.03-19.29)). CONCLUSIONS: There are somatometric alterations and risk factors that can help in the early detection of neonates exposed to drugs of abuse. The somatometric alterations identified can be useful to extend the differential diagnosis of these alterations and to study their causes.

Role of Neonatal Biomarkers of Exposure to Psychoactive Substances to Identify Maternal Socio-Demographic Determinants.

BACKGROUND: The accurate assessment of fetal exposure to psychoactive substances provides the basis for appropriate clinical care of neonates. The objective of this study was to identify maternal socio-demographic profiles and risk factors for prenatal exposure to drugs of abuse by measuring biomarkers in neonatal matrices. METHODS: A prospective, observational cohort study was completed. Biomarkers of fetal exposure were measured in meconium samples. The mothers were interviewed using a questionnaire. Univariate and multivariate logistic regression analyses were performed. RESULTS: A total of 372 mothers were included, 49 (13.2%) testing positive for psychoactive substances use: 24 (49.0%) for cannabis, 11 (22.5%) for ethyl glucuronide, six (12.2%) for cocaine, and in eight (16.3%) more than one psychoactive substance. Mothers who consumed any psychoactive substance (29.7 ± 6.6 years) or cannabis (27.0 ± 5.7 years) were younger than non-users (32.8 ± 6.2 years, p < 0.05). Cocaine (50.0% vs. 96.9%, p < 0.05) and polydrug users (37.5% vs. 96.9%, p < 0.05) showed a lower levels of pregnancy care. Previous abortions were associated with the use of two or more psychoactive substances (87.5% vs. 37.8%, p < 0.05). Single-mother families (14.3% vs. 2.5%, p < 0.05) and mothers with primary level education (75.5% vs. 55.1%, p < 0.05) presented a higher consumption of psychoactive substances. Independent risk factors that are associated with prenatal exposure include: maternal age < 24 years (odds ratio: 2.56; 95% CI: 1.12-5.87), lack of pregnancy care (odds ratio: 7.27; 95%CI: 2.51-21.02), single-mother families (odds ratio: 4.98; 95%CI: 1.37-8.13), and active tobacco smoking (odds ratio: 8.13; 95%CI: 4.03-16.43). CONCLUSIONS: These results will allow us to develop several risk-based drug screening approaches to improve the early detection of exposed neonates.

Diminished Consciousness in a Woman Following an Unsuspected Scopolamine Overdose.

Scopolamine is used clinically, but it is also used as a recreational drug and as an incapacitating drug, in sexual crimes and robberies. In this paper, the authors report the case of a woman with a diminished consciousness following an unsuspected overdose with scopolamine and review published articles on scopolamine poisoning that included concentrations in biological samples. Scopolamine was identified in the patient's serum and urine samples collected 1 h post-admission to intensive care unit at concentrations of 8.4 ng/mL and 62,560 ng/mL (169,539 ng/mg creatinine), respectively. In non-fatal cases, the median [interquartile range] of serum scopolamine levels was 1.9 [2.1] ng/mL. The serum concentration found in our case would explain the abrupt clinical presentation suffered by the patient. Scopolamine in urine could be detected up to 48 h after admission. This report illustrates that broad toxicology screening, including scopolamine, should be considered when patients with diminished consciousness are attended after ruling out infection or cerebrovascular disease. This can play an important role in identifying this potentially life-threatening etiology.

[Clinical features and risk factors associated with prenatal exposure to drugs of abuse]. / Características clínicas y factores de riesgo asociados a la exposición prenatal a drogas de abuso.

INTRODUCTION: Early identification of neonates exposed to drugs of abuse during pregnancy allows a more precise clinical management. OBJECTIVES: To describe the clinical characteristics and to identify risk factors associated with the early detection of neonates exposed to drugs of abuse in a Neonatal Intermediate and Intensive Care Unit. METHODS: Prospective observational study of neonates with and without clinical suspicion of prenatal exposure to drugs of abuse. Meconium was analyzed using standard chromatographic techniques. Univariate and multivariate statistical analyzes were performed. RESULTS: 372 neonates were included. Exposure to drugs of abuse was detected in 49 (13.2%) cases: in 41 (83.7%) one drug and in 8 (16.3%) more than one. Somatometry at birth revealed: a) lower length percentile in those exposed to some drug, more than one and cannabis; b) lower weight percentile in those exposed to cannabis and of these compared to those exposed to alcohol. In neonates older than 34 pregnancy weeks (PW): a) lower length percentile in those exposed to any substance; b) lower percentile of length and weight in exposed to more than one. The most clinically relevant independent risk factors useful to detect cases of prenatal exposure to drugs of abuse were (Odds ratio (95% CI)): reason for admission other than prematurity (5.52 (2.55-1.93)), length percentile less than 33 (1.95 (1.05-3.60) and 2.14 (1.04-3.40) in older than 34 PW) and social dystocia/uncontrolled pregnancy in older than 34 PW (4.47 (1.03-19.29)). CONCLUSIONS: There are somatometric alterations and risk factors that can help in the early detection of neonates exposed to drugs of abuse. The somatometric alterations identified can be useful to extend the differential diagnosis of these alterations and to study their causes.

Detectability of Dissociative Psychoactive Substances in Urine by Five Commercial Phencyclidine Immunoassays.

Methoxetamine (MXE) and the arylcyclohexylamines 3-methoxy-PCP (3-MeO-PCP) and 4-methoxy-PCP (4-MeO-PCP) are substituted analogs of the dissociative psychoactive substances ketamine and phencyclidine (PCP), respectively. They have emerged on the new psychoactive substances (NPS) market as legal alternatives to these classically banned dissociatives. Little data has been published regarding the cross-reactivity of these NPS in PCP immunoassays (IAs). The aim of this work was to explore the possibilities of detecting 3-MeO-PCP, 4-MeO-PCP, MXE and ketamine in commercial IAs for PCP. The cross-reactivity study was performed in five different PCP IAs using urine-free, spiked samples and urine samples obtained from two 3-MeO-PCP overdose cases. 3-MeO-PCP and 4-MeO-PCP showed cross-reactivity (ranging from 1-143%) in all PCP IAs evaluated. MXE only showed very weak cross-reactivity (ranged from 0.04 to 0.25%) and ketamine was not detected in any PCP IA evaluated. Urine samples from the two overdose cases were positive for PCP in all IAs evaluated. The commercial PCP IAs evaluated exhibited utility as rapid, preliminary screening techniques for 3-MeO-PCP and 4-MeO-PCP, but not for ketamine. The low reactivity of MXE limits its detectability in the PCP IAs evaluated.

2,4-Diamino-N10-methylpteroic acid (DAMPA) crystalluria in a patient with osteosarcoma treated with carboxypeptidase-G2 rescue after high-dose methotrexate-induced nephrotoxicity.

BACKGROUND: High-dose methotrexate (HDMTX) therapy is a key component of many chemotherapy protocols. However, some patients develop HDMTX-induced nephrotoxicity. Carboxypeptidase-G2 (CPDG2) hydrolyses MTX into 2,4-diamino-N10-methylpteroic acid (DAMPA) and glutamic acid, and is used as a rescue agent in patients with nephrotoxicity and delayed elimination. Despite the frequency of HDMTX-induced renal injury, crystalluria is uncommon. Furthermore, crystals are rarely identified by conventional chemical methods. OBJECTIVE: To determine the composition of crystalluria in a patient with osteosarcoma who was treated with CPDG2. METHODS: Crystalluria was evaluated by optical microscopy, and chemical identification was performed by Fourier-transform infrared (FT-IR) spectroscopy, scanning electron microscopy (SEM) and Orbitrap™ high-resolution mass spectrometry (HRMS). RESULTS: The HRMS spectra of the patient's urine sediment showed a main peak at m/z 326.13, corresponding to the molecular mass of DAMPA [(C15H15O2N7) + H+]. The FT-IR spectral patterns of the sediment and DAMPA were not identical. SEM was unable to identify the crystal. CONCLUSION: DAMPA crystalluria was identified by Orbitrap™ HRMS in a patient treated with CPDG2 after HDMTX nephrotoxicity. This case reinforces the need to implement adequate measures to prevent nephrotoxicity. In cases of HDMTX-induced nephrotoxicity, urine sediment analysis should be requested.

Value of glycolic acid analysis in ethylene glycol poisoning: A clinical case report and systematic review of the literature.

OBJECTIVE: To evaluate the clinical utility of glycolic acid (GA) determination in the diagnosis and prognosis of ethylene glycol (EG) intoxications. METHOD: Systematic review of serum and/or urine GA concentrations available in the literature in cases of EG poisoning. Present a clinical case in which the determination of the GA was decisive. RESULTS: In total, 137 patients were included. Serum GA concentrations (but not EG) of patients who survive are different from those who die. The optimal cut-off of serum GA to predict mortality was 990.5mg/L (sensitivity 85.2%, specificity 54.3%) with an Odds Ratio of 6.838 (2.868-16.302). In our clinical case, serum EG was negative; however, urine GA was positive (1230.7mg/L). CONCLUSIONS: In all suspected cases of EG poisoning, it is advisable to carry out the simultaneous analysis of EG and GA.

Building Bridges between Clinical and Forensic Toxicology Laboratories.

BACKGROUND: Clinical and forensic toxicology can be defined as two disciplines involving the detection, identification and measurement of xenobiotics in biological and non-biological samples to assist in the diagnosis, treatment, prognosis and prevention of poisonings and to disclose causes and contributory causes of fatal intoxications, respectively. OBJECTIVE: This article explores the close connections between clinical and forensic toxicology in overlapping areas of interest. METHODS: An update has been carried out of the following seven areas of interest in analytical toxicology: doping control, Sudden Cardiac Death (SCD), brain death, Sudden Infant Death Syndrome (SIDS) and Munchausen Syndrome by Proxy (MSBP), prenatal exposure to drugs and Fetal Alcohol Syndrome (FAS), Drug-Facilitated Crimes (DFC) and intoxications by new psychoactive substances (NPS). RESULTS: While issues such as SCD, SIDS or doping control are investigated mainly in forensic laboratories, others such as prenatal exposure to drugs or FAS are mainly treated in clinical laboratories. On the other hand, areas such MSBP, DFC or the intoxications by NPS are of interest in both laboratories. Some of these topics are initially treated in hospital emergency departments, involving clinical laboratories and sometimes lately derived to forensic laboratories. Conversely, cases with initial medicallegal implications and fatalities are directly handled by forensic toxicology, but may trigger further studies in the clinical setting. CONCLUSION: Many areas of common interest between clinical and forensic laboratories are building bridges between them. The increasing relationships are improving the growth, the reliability and the robustness of both kinds of laboratories.

Quantification of Methamphetamine «Shabu¼ in Biological Matrices to Detect Prenatal Exposure: A Case Report and a Literature Review.

BACKGROUND: Methamphetamine misuse represents an increasing global public health problem. Its consumption during pregnancy becomes a relevant issue, since it has clinical consequences for the child's health and the pregnant woman. Despite this, there are only few data in the literature that include analytical results in the matrices used to detect prenatal exposure. OBJECTIVES: 1) Present a case report of prenatal methamphetamine exposure with toxicological analytical confirmation in biological matrices; and 2) Perform a compilation of prenatal methamphetamine exposure studies and case reports which include toxicological analytical results. METHODS: Prenatal methamphetamine exposure was confirmed using a traditional "screen with reflex" approach. Methamphetamine and amphetamine were quantified in urine, meconium and hair samples of the neonate and mother by gas chromatography-mass spectrometry. Also, a detailed revision of the existent literature that provides information on the analytical toxicology results has been included. RESULTS: In the neonatal biological matrices test results of methamphetamine/amphetamine were: urine 2,966.43/1,638.71 ng/mL, meconium 1,450/<0.1 ng/g and hair 36.54/9.66 ng/mg. In the maternal biological matrices, test results were: urine 13,393.89/3,074.95 ng/mL and hair 11.29/3.37 ng/mg (0-3 cm), 4.68/2.58 (3-6 cm), 6.43/3.13 ng/mg (6-9 cm) and 4.72/2.49 ng/mg (9-12 cm). These results confirm a recent and continued regular substance use throughout pregnancy including delivery. CONCLUSION: The data provided will be useful for clinical purposes to improve the diagnostic and follow- up of acute and chronic intoxications. Additionally, results will be used to support interpretations in the field of forensic and legal medicine.

Cross-reactivity of selected benzofurans with commercial amphetamine and ecstasy immunoassays in urine.

AIM: The aim of this study was to perform a cross-reactivity investigation of six benzofurans with immunoassays (IAs) screening tests for amphetamines and ecstasy in urine samples. METHODS: The following benzofuranes were investigated: 5-(2-Methylaminopropyl)Benzofuran (5-MAPB), 5-(2-methylaminopropyl)-2,3-dihydrobenzofuran (5-MAPDB), 5-(2-Aminopropyl)-Benzofuran (5-APB), 5-(2-Aminopropyl)-2,3-dihydrobenzofuran (5-APDB), 5-(2-Ethylaminopropyl)Benzofuran (5-EAPB) and 5-(2-Aminoethyl)-2,3-dihydrobenzofuran (5-AEDB). The study was performed with urine-free spiked samples and authentic urine samples using eight different IAs for amphetamines and ecstasy. Results: All evaluated benzofurans showed cross-reactivity in some of the IAs tested, except for 5-AEDB. Urine samples of an intoxication case involving 5-MAPB, 5-APB and 5-EAPB were also positives in the IAs tested. CONCLUSION: There is an important variability in the cross-reactivity of the IAs for amphetamine and ecstasy caused by benzofurans depending on the immunoassay employed and the tested compounds.

Cross-Reactivity of Pantoprazole with Three Commercial Cannabinoids Immunoassays in Urine.

Pantoprazole is a frequently prescribed proton pump inhibitor (PPI) commonly utilized in the management of gastrointestinal symptoms. Few substances have proved to cause a false-positive cannabinoid urine screen. However, a case of false-positive urine cannabinoid screen in a patient who received a pantoprazole dose has been recently published. The purpose of this study was to determine the potential cross-reactivity of pantoprazole in the cannabinoid immunoassays: Alere Triage® TOX Drug Screen, KIMS® Cannabinoids II and DRI® Cannabinoids Assay. Drug-free urine to which pantoprazole was added up to 12,000 µg/mL produced negative results in the DRI® Cannabinoids and KIMS® Cannabinoids II. Alere Triage® TOX Drug Screen assay gave positive results at pantoprazole concentrations higher than 1,000 µg/mL. Urine samples from 8 pediatric patients were collected at the beginning of their pantoprazole treatment. Alere Triage® TOX Drug Screen assay produced positive test results in all patient samples and KIMS® Cannabinoids II immunoassay produced positive test results in one patient sample. None patient sample gave a false-positive result when analyzed by the DRI® Cannabinoids Assay. Our findings demonstrate that some cannabinoids immunoassays are susceptible to cross-reaction errors resulting from the presence in urine of pantoprazole and the resulting metabolism of the parent drug. Clinicians should be aware of the possibility of false-positive results for cannabinoids after a pantoprazole treatment.

Pharmacology and Literature Review Based on Related Death and Non-Fatal Case Reports of the Benzofurans and Benzodifurans Designer Drugs.

BACKGROUND: Benzofurans and benzodifurans are two groups of psychoactive substances that had originally been synthesized for research purpose. Benzofurans' structure is quite similar to the known recreational drug 3,4-methylenedioxymethamphetamine together with its active metabolite 3,4-methylenedioxyamphetamine. Benzodifurans are closely related to phenethylamines, but have more hallucinogens effects and much longer duration of action. This study aims to review the accessible evidence-based literature on benzofurans and benzodifurans pharmacology and toxicology. METHODS: A literature search on benzofurans and benzodifurans has been conducted using PubMed. We reviewed articles up to February 2017 and also included data from various governmental websites and discussion groups. RESULTS: This review describes the emergent literature that illustrates the chemical composition of these drugs, patterns of use, pharmacology, toxicology, desired and clinical effects, and treatments of patients. It also provides a compilation of case reports. CONCLUSION: The knowledge regarding usage prevalence, pharmacokinetic and pharmacodynamic profiles, acute toxic effects, the effects desired on patients and drug related mortality attributed to these drugs is still limited. Nowadays, there are no specific guidelines available to treat benzofurans or dibenzofurans intoxications. For that reason, clinical effects should be the base of treatment. Backing exposures analytically confirmed in clinical and forensic cases and reported clinical effects need to be combined with these compounds while monitoring its prevalence.

Intoxication caused by new psychostimulants: analytical methods to disclose acute and chronic use of benzofurans and ethylphenidate.

The acute and chronic toxicity of several new psychoactive substances (NPS) is unknown, and only little information is available on the pharmacology and toxicology, toxicokinetics, and detectability in body samples of such new compounds. We here propose analytical methods to disclose acute and chronic use of two types of new psychostimulants: benzofurans and ethylphenidate and we applied them to a real case of a subject attending Emergency Department with signs of acute intoxication due to psychotropic drug(s). After a urinary immunoassay screening which gave a positivity to amphetamines, general unknown gas chromatography-mass spectrometry (GC-MS) urine analysis identified 5-(2-methylaminopropyl)benzofuran (5-MAPB), 5-(2-aminopropyl)benzofuran (5-APB), 5-(2-ethylaminopropyl)benzofuran (5-EAPB), ethylphenidate, and ritalinic acid. All these substances were confirmed and quantified not only in urine but also in serum samples at different times after hospitalization by GC-MS and ultra-high performance liquid chromatography tandem mass spectrometry (UHPLC-MS/MS). Two subsequent 2-cm hair segments were also analyzed and tested positive for the above reported substances, evidencing repeated use. The matching quantitative results in all the analyzed biological matrices demonstrated that both analytical methodologies were suitable to correctly quantify NPS involved in the current intoxication. The objective assessment of acute and chronic intoxication by the above reported compounds demonstrate that the development of analytical methods aiming at the detection of a broad spectrum of compounds in conventional and non-conventional biological matrices is helpful when facing the new challenging threat of intoxications caused by NPS.