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In the first days of life, the newborns' intestinal microbiota develops simultaneously with the intestinal gut barrier and follows intestinal immunity. The mode of delivery shows significant impact on microbial development and, thus, the initiation of the tryptophan catabolism pathway. Further antibiotics (ATB) treatment of mothers before or during delivery affects the microbial and tryptophan metabolite composition of stool of the caesarean- and vaginal-delivered newborns. The determination of microbiome and levels of tryptophan microbial metabolites in meconium and stool can characterize intestinal colonization of a newborn. From 134 samples from the Central European Longitudinal Studies of Parents and Children: The Next Generation (CELSPAC: TNG) cohort study, 16S rRNA gene sequencing was performed, and microbial tryptophan metabolites were quantified using ultra-high-performance liquid chromatography with triple-quadrupole mass spectrometry. Microbial diversity and concentrations of tryptophan metabolites were significantly higher in stool compared to meconium. Treatment of mothers with ATB before or during delivery affects metabolite composition and microbial diversity in stool of vaginal- and caesarean-delivered newborns. Correlation of microbial and metabolite composition shows significant positive correlations of indol-3-lactic acid, N-acetyl-tryptophan and indol-3-acetic acid with Bifidobacterium, Bacteroides and Peptoclostridium. The positive effect of vaginal delivery on newborns' microbiome development is degraded when mother is treated with ATB before or during delivery. KEY POINTS: • Antibiotic treatment diminishes the positive effects of vaginal delivery. • Antibiotic treatment affects metabolite and microbial composition in newborns. • Bifidobacterium and Peptoclostridium could be the producer of indole-lactic acid., (© 2024. The Author(s).)

Neonatal birth weight is a crucial indicator of intrauterine growth and development with important implications for child development and adult health. The birth weight of a newborn is closely linked to the nutrition and health of the mother during pregnancy as well as genetic factors. Therefore, assessing the metabolic status of the fetus in utero is greatly significant for understanding the mechanisms responsible for abnormal birth weight. While previous studies often analyzed the impact of maternal metabolism on fetal development using umbilical cord blood from pregnant women, such blood may not accurately reflect the actual intrauterine environment owing to the barrier function of the placenta; moreover, obtaining biological samples during the fetal period is challenging. Meconium, the first feces excreted by a newborn, provides ideal biological material for studying maternal and infant health. Metabolomics can reveal metabolic changes in living organisms by analyzing small molecules in biological samples; hence studying meconium samples using metabolomics technology is expected to reveal fetal metabolic changes during pregnancy, thereby providing new insights into fetal nutritional intake, growth, and development, as well as metabolic pathways related to birth weight. To gain a deeper understanding of the metabolic changes associated with birth weight, this study collected metabolomic data from the meconium of 484 newborns in the established Xiaogan birth cohort using an untargeted metabolomics technique based on liquid chromatography-high resolution mass spectrometry (LC-HRMS) and analyzed the association between meconium metabolites and birth weight. This cohort exhibited incidence rates of low birth weight (<2500 g) and macrosomia (>4000 g) of 3.3% and 7.2%, respectively, which were roughly equivalent to the national average. Orthogonal partial least squares discriminant analysis revealed significant differences between the meconium metabolomes of the low birth weight and macrosomic groups when compared to the normal weight group. We discovered significant distinctions between the differential metabolites of newborns of low birth weight and those of normal weight, as well as between macrosomic and normal weight newborns that point to disparate biological pathways. Newborns with low birth weight exhibited significantly lower levels of critical amino acids, such as glutamate and proline, compared to the normal weight group, which may be associated with placental dysfunction and maternal nutritional deficiencies. Conversely, the meconium of macrosomic newborns contained significantly elevated levels of hormone metabolites such as estrone that reflected the pathophysiological state associated with maternal metabolic diseases or excessive placental hormone levels. Our study suggests that the metabolomic profile of the meconium reflects the metabolic pathways and regulatory mechanisms at play during fetal growth and development, and offers potential metabolic biomarkers and directions for future in-depth research into diseases related to fetal development. However, this study was based solely on the Xiaogan birth cohort, which was limited to specific regions and populations. A multicenter, multiethnic, and multiregional study is expected to help validate the universality of our research findings.

Meconium, the first stool produced by neonates, has been used as an analyte for exogenous fetal exposures. However, few studies have investigated the relationship between meconium and androgen exposure in utero. Here, we examine the associations of testosterone and dehydroepiandrosterone (DHEA) across maternal antenatal salivary testosterone, cord blood, meconium, and infant salivary testosterone. A total of 47 women with singleton, uncomplicated pregnancies, and their infants were included in this study. Participants were recruited from an academic obstetric clinic. Maternal saliva was collected at 36-weeks' gestation. Cord blood and meconium were collected at birth. Infant salivary testosterone was collected at 1 and 4 weeks of age. Multivariate model results showed that meconium testosterone was associated with neonatal testosterone at 1 (F = 5.62, p = 0.029) and 4 weeks (F = 4.28, p = 0.048) postnatal age; no sex differences were detected. This study suggests meconium is a valuable tool for evaluating endogenous androgen exposure and should be used in future studies to investigate the fetal hormonal milieu., (© 2024 Wiley Periodicals LLC.)

Surfactant replacement therapy is crucial in managing neonatal respiratory distress syndrome (RDS). Currently licensed clinical surfactants in the United States and Europe, including Survanta, Infasurf, Curosurf, and Alveofact, are all derived from bovine or porcine sources. We conducted a comprehensive examination of the biophysical properties of these four clinical surfactant preparations under physiologically relevant conditions, using constrained drop surfactometry (CDS). The assessed biophysical properties included the adsorption rate, quasi-static and dynamic surface activity, resistance to surfactant inhibition by meconium, and the morphology of the adsorbed surfactant films. This comparative study unveiled distinct in vitro biophysical properties of these clinical surfactants and revealed correlations between their chemical composition, lateral film structure, and biophysical functionality. Notably, at 1 mg/mL, Survanta exhibited a significantly lower adsorption rate compared with the other preparations at the same surfactant concentration. At 10 mg/mL, Infasurf, Curosurf, and Survanta all demonstrated excellent dynamic surface activity, whereas Alveofact exhibited the poorest quasi-static and dynamic surface activity. The suboptimal surface activity of Alveofact is found to be correlated with its unique monolayer-predominant morphology, in contrast to other surfactants forming multilayers. Curosurf, in particular, showcased superior resistance to biophysical inhibition by meconium compared with other preparations. Understanding the diverse biophysical behaviors of clinical surfactants provides crucial insights for precision and personalized design in treating RDS and other respiratory conditions. The findings from this study contribute valuable perspectives for the development of more efficacious and fully synthetic surfactant preparations. NEW & NOTEWORTHY A thorough investigation into the biophysical properties of four animal-derived clinical surfactant preparations was conducted through constrained drop surfactometry under physiologically relevant conditions. This comparative study unveiled unique in vitro biophysical characteristics among these clinical surfactants, establishing correlations between their chemical composition, lateral film structure, and biophysical functionality. The acquired knowledge offers essential insights for the precise and personalized design of clinical surfactant for the treatment of respiratory distress syndrome and other respiratory conditions.

Fetal Alcohol Spectrum Disorders (FASD) is an encompassing term used to describe a range of afflictions brought about by the consumption of alcohol during gestation. The detrimental effects primarily manifest in the central nervous system, growth, and distinctive facial features. Given that there are no known treatments for FASD, the meticulous screening for this condition in the earliest stages of pregnancy bears immense significance, ensuring the avoidance of the grievous consequences stemming from exposure to alcohol in utero. Screening measures for FASD encompass the assessment of alcohol biomarkers such as Phosphatidylethanol (PEth) in the maternal bloodstream, Fatty Acid Ethyl Esters (FAEEs) in the meconium, and Ethyl Glucuronide (EtG) in the meconium, maternal urine and hair. In particular, urinary EtG is highly sensitive and could be routinely used in pregnant women for detecting also occasional drinking. Questionnaire evaluations including AUDIT-C, T-ACE, and TWEAK, alongside a detailed Food Diary method to identify alcohol misuse and high-risk pregnancies, are also available. However, these questionnaires might provide an inadequate reflection of alcohol consumption in women due to their inclination to dissemble to comply with prevailing sociocultural expectations. Hence, this comprehensive review advocates for the indispensable integration of alcohol biomarkers detection in the course of pregnancy monitoring, as it constitutes a valuable tool for facilitating FASD screening.

Background: Substance use during pregnancy is common, as is biological testing that is intended to help identify prenatal exposures. However, there is no standardized requirement for biological testing with either maternal or newborn specimens, nor is there standardization related to when testing occurs, how frequently testing occurs, what specimen(s) to test, what substances to test for, or how to perform testing., Content: We review common specimen types tested to detect maternal and newborn substance exposure with a focus on urine, meconium, and umbilical cord tissue. We also review common analytical methods used to perform testing, including immunoassay, and mass spectrometry platforms. Considerations regarding the utilization of testing relative to the purpose of testing, the drug analyte(s) of interest, the specific testing employed, and the interpretation of results are emphasized to help guide decisions about clinical utilization of testing. We also highlight specific examples of unexpected results that can be used to guide interpretation and appropriate next steps., Summary: There are strengths and limitations associated with all approaches to detecting substance exposure in pregnant persons as well as biological testing to evaluate a newborn with possible substance exposure. Standardization is needed to better inform decisions surrounding evaluation of substance exposures in pregnant people and newborns. If biological sampling is pursued, testing options and results must be reviewed in clinical context, acknowledging that false-positive and -negative results can and do occur., (© Association for Diagnostics & Laboratory Medicine 2024.)

Exposure to fine particulate matter (PM 2.5 ) during pregnancy has been inversely associated with neonatal neurological development. However, the associations of exposure to specific PM 2.5 constituents with neonatal neurological development remain unclear. We investigated these associations and examined the mediating role of meconium metabolites in a Chinese birth cohort consisting of 294 mother-infant pairs. Our results revealed that exposure to PM 2.5 and its specific constituents (i.e., organic matter, black carbon, sulfate, nitrate, and ammonium) in the second trimester, but not in the first or third trimester, was inversely associated with the total neonatal behavioral neurological assessment (NBNA) scores. The PM 2.5 constituent mixture in the second trimester was also inversely associated with NBNA scores, and sulfate was identified as the largest contributor. Furthermore, meconium metabolome analysis identified four metabolites, namely, threonine, lysine, leucine, and saccharopine, that were associated with both PM 2.5 constituents and NBNA scores. Threonine was identified as an important mediator, accounting for a considerable proportion (14.53-15.33%) of the observed inverse associations. Our findings suggest that maternal exposure to PM 2.5 and specific constituents may adversely affect neonatal behavioral development, in which meconium metabolites may play a mediating role.

Objective: The U.S. opioid epidemic has been characterized by increases in opioid misuse, overdose deaths, and neonatal opioid withdrawal syndrome. Research suggests that marijuana legalization has contributed to decreased use of opiates, although many studies had methodological weaknesses and failed to address the pregnant population. Implementation of medical cannabis laws has the potential to reduce maternal opioid use and, therefore, neonatal exposure to the drugs. This study aimed to examine the association between Oklahoma's implementation of state medical marijuana laws and the neonatal exposure to opioids., Study Design: Electronic medical records at two sites (Oklahoma City and Lawton) were searched for results of cord, urine, and meconium screens to detect amphetamines, barbiturates, benzodiazepines, cocaine, ethanol, opiates, phencyclidine, and tetrahydrocannabinol (THC). Two study periods were compared: 19 months before Oklahoma's medical marijuana law took effect and 19 months after legalization began., Results: A total of 16,804 babies were born alive at the two sites during the study period. The rate of positive THC tests per 1,000 liveborn infants significantly increased from 16.2 per 1,000 during the prelaw period to 22.2 per 1,000 during the postlaw period ( p  = 0.004). Neonatal opioid exposure incidence showed a nonsignificant decrease from 7.6 positive tests per 1,000 liveborn infants to 6.8 per 1,000 from prelaw to postlaw period ( p  = 0.542). The number of positive tests for THC and concomitant use of opioids doubled from the prelaw period ( n  = 4) to postlaw ( n  = 9), but there were too few cases for statistical significance. Infants at the more rural site had significantly higher rates for amphetamines, benzodiazepines, and THC, with a trend toward higher rates for opiates., Conclusion: Marijuana legalization was related to significant increases in positive test rates for THC, but no significant change/association was noted for neonatal exposure to opioids., Key Points: · Prior studies have not examined neonatal exposure to opioids following marijuana legalization.. · Oklahoma's new law led to higher neonatal marijuana exposure.. · Legalization of medical marijuana did not change Oklahoma's neonatal opioid positivity rate.., Competing Interests: None declared., (Thieme. All rights reserved.)

Background: Hypospadias is a male genital tract defect for which an increase in prevalence has been documented over the last few decades. A role for environmental risk factors is suspected, including prenatal exposure to pesticides., Objectives: To study the risk of hypospadias in association with multiple pesticide measurements in meconium samples., Methods: The Brittany Registry of Congenital Anomalies (France) conducted a case-control study between 2012 and 2018. Cases were hypospadias, ascertained by a pediatrician and a pediatric surgeon, excluding genetic conditions, following European Surveillance of Congenital Anomalies guidelines (N = 69). Controls (N = 135) were two male infants without congenital anomaly born after each case in the same maternity unit. Mothers in the maternity units completed a self-administered questionnaire, we collected medical data from hospital records, and medical staff collected meconium samples. We performed chemical analysis of 38 pesticides (parent compound and/or metabolite) by UHPLC/MS/MS following strict quality assurance/quality control criteria and blind to case-control status. We carried out logistic regression accounting for frequency-matching variables and major risk factors., Results: Among the 38 pesticides measured, 16 (42%) were never detected in the meconium samples, 18 (47%) were in <5% of samples, and 4 (11%) in ≥5% of the samples. We observed an association between the detection of fenitrothion in meconium and the risk of hypospadias (OR = 2.6 [1.0-6.3] with n cases = 13, n controls = 21), but not the other pesticides., Conclusions: Our small study provides a robust assessment of fetal exposure. Fenitrothion's established antiandrogenic activities provide biologic plausibility for our observations. Further studies are needed to confirm this hypothesis., Competing Interests: The authors report no conflicts of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Introduction: Prenatal alcohol exposure causes a variety of impairments to the fetus called Fetal Alcohol Spectrum Disorders (FASD). Since it is very difficult to identify women that consume alcohol during pregnancy, different methods have been studied to evaluate alcohol exposure. Ethyl Glucuronide (EtG) and Fatty Acid Ethyl Esters (FAEEs) are commonly used to measure alcohol consumption in individuals at-risk for alcohol abuse, including pregnant women., Materials and Methods: We conducted a study of two cohorts of 1.5 year-old infants (of mothers without a history of alcohol abuse) with or without meconium samples positive to both EtG and FAEEs and we evaluated their cognitive-behavioral development by the Griffiths Mental Developmental Scale (GMDS) method. Our protocol included 8 infants with meconium positive to alcohol metabolites (EtG and FAEEs) and 7 with meconium negative to alcohol metabolites., Results: None of the 8 alcohol metabolites positive meconium infants exhibited distinctive facial features and growth retardation of severe FASD, showing that other factors may contribute to the FASD onset but elevations in EtG and FAEEs in the meconium were significantly associated with disrupted neurodevelopment and adaptive functions within the first year and a half of life. Indeed, we found out that infants with meconium positive for both EtG and FAEEs, although without displaying any FASD morphological features, had a delay in the fine regulation of their own locomotory capabilities., Conclusions: Further analyses and larger studies are needed to estimate the right link between prenatal alcohol exposure and the different range of disorders connected but this study provides an additional step in the field of FASD in order to suggest early treatments for at-risk newborns and infants.

Alterations in the diversity and relative abundances of the gut microbiome have been associated with a broad spectrum of medical conditions. Maternal psychological symptoms during pregnancy may impact on offspring development by altering the maternal and the foetal gut microbiome. We aimed to investigate whether self-reported maternal anxiety, depressive symptoms, and distress as well as saliva cortisol levels in late pregnancy alter the bacterial composition of the infant's meconium., Methods: A total of N = 100 mother-infant pairs were included. Maternal psychological symptoms were measured using psychological questionnaires (EPDS, PSS-10, STAI) at 34-36 weeks gestation and salivary cortisol was measured at 34-36 and 38 weeks gestation. Infant meconium samples were collected in the first five days postpartum and analysed using 16S rRNA amplicon sequencing., Results: Correlations showed that lower alpha diversity of the meconium microbiome was significantly associated with increased maternal prenatal depressive symptoms in late gestation (τ = -0.15, p = .04). Increased saliva cortisol AUCg at T2 was significantly related to higher beta diversity of the meconium samples (Pr(>F) = 0.003*). Pseudomonas was the most abundant phylum and was associated with maternal saliva cortisol total decline. No other associations were found., Conclusions: Maternal prenatal depressive symptoms are associated with infant faecal microbiome alpha diversity, whereas maternal saliva cortisol AUCg is linked to increased beta diversity and total decline related to increased Psuedomonas. Future studies are warranted to understand how these microbiota community alterations are linked to child health outcomes., Competing Interests: Declaration of Competing Interest The authors have no conflict of interest to declare., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

This review aims to bring together the works on pesticide analysis in alternative biological matrices, such as hair, breast milk, meconium, and placenta. Much is known about the harmful effects of the use and indirect consumption of pesticides; however, the assessment of long-term contamination is still unclear. In this sense, the use of hair as an alternative biological matrix has some advantages, such as segmentation, which makes it possible to assess the presence of xenobiotics to which individuals have been exposed over the years, and possibly relate this exposure to symptoms or diseases that may affect them. Complementarily, the other matrices discussed are able to provide information about the exposure of mothers and newborn children, who may have been indistinctly exposed to pesticides while in the womb. Through the analysis of studies already performed, it can be observed that organochlorine pesticides (OCPs) are the most likely to be found within the biological matrices discussed here, due to the lipophilic characteristics of these compounds. For the other classes, biotransformation products are more easily detected.

Maternal drug use during pregnancy has significant health and socio-legal implications. The Substance Abuse and Mental Health Services Administration publishes self-reported rates of drug use during pregnancy; however, comprehensive long-term laboratory data on neonatal drug exposure are lacking. Over 175,000 meconium specimens originating from 46 US states were analyzed at ARUP Laboratories between the years 2015 and 2020. A retrospective investigation of drug positivity rates, multidrug detection and median drug concentrations was conducted for 28 compounds in six drug classes. The overall meconium drug positivity rate was lowest in 2015 (47.3%), which increased over 6 years, reaching a peak in 2020 (53.4%). 11-Nor-9-carboxy-tetrahydrocannabinol (THC-COOH) was the most frequently detected compound across all 6 years. The second most frequently detected analyte was morphine in 2015-2016 and amphetamines in 2017-2020. The THC-COOH positivity rate rose from 29.7% in 2015 to 38.2% in 2020. The positivity rates for stimulants also increased in the range of 0.4-2.9% in 2020 compared to 2015. Conversely, opioid positivity rates declined in the range of 1.6-2.3% in 2020 as compared to 2015. The most common two-drug combination was THC-COOH-opioids (2.4%) in 2015-2016, which was replaced by THC-COOH-amphetamines (2.6%) in 2017-2020. The most common three-drug combination was THC-COOH-opioids-amphetamines throughout all 6 years. Neonatal drug exposure positivity rates have increased over the past 6 years based on retrospective data analysis from the patient population submitted for testing at ARUP Laboratories., (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Previous studies investigated prenatal exposure to neurotoxic metals in relation to birth anthropometrics. However, limited information has been developed on associations with birth outcomes of fetal exposure to metal mixtures using the meconium as a biomarker. The purpose of this study was to evaluate relationships of the combined effects of mercury (Hg), lead (Pb), cadmium (Cd), and arsenic (As) concentrations in the meconium on birth outcomes (i.e., birth weight, birth length, and head circumference). This cross-sectional study was conducted in northern Taiwan between January 2007 and December 2009. We collected 526 meconium samples within the first 24 h after birth to measure the in utero mixed-metal exposure determined using inductively coupled plasma/mass spectrometry (ICP-MS). We used a multivariable regression and Bayesian kernel machine regression (BKMR) to estimate associations of the combined effects and identify important mixture components with growth impairments. Our results revealed Hg, Pb, Cd, and As concentrations in the meconium and enhanced the quantity of research on meconium analyses. The overall effects of Hg, Pb, Cd, and As concentrations in the meconium as prenatal exposure biomarkers were negatively associated with birth growth. Fetal exposure to Hg and Pb was correlated with decreased birth weights. Hg and Pb concentrations in the meconium were linearly inversely related to the birth weight, birth length, and head circumference. Effects of fetal exposure to As and Cd on birth outcomes were not obvious. A significant increasing relationship was detected between Hg concentrations in the meconium and maternal fish consumption during pregnancy. Higher Pb concentrations in the meconium were observed among infants of mothers who consumed Chinese herbal medicines. Reducing maternal fish consumption and Chinese herbal medicine consumption during pregnancy could limit infant exposure to metals., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest., (Copyright © 2022 Elsevier GmbH. All rights reserved.)

Maternal drug use during pregnancy is a significant concern. Drug-exposed newborns are often born premature and may suffer from birth defects, neonatal abstinence syndrome and cognitive and developmental delays. Because of this, testing of neonatal specimens is carried out to assess fetal drug exposure during pregnancy. Umbilical cord tissue (UC) and meconium are commonly used specimens for this purpose. However, comprehensive studies comparing drug positivity rates and concentration in the two specimen types are lacking. To this end, 4,036 paired UC and meconium specimens originating from 13 states within the USA were identified, and retrospective analysis of drug positivity rates and drug concentration was performed for 31 analytes in 5 drug classes. Testing for 11-Nor-9-carboxy-tetrahydrocannabinol (THC-COOH) is a separate orderable for UC specimen at our laboratory, so a second data set was created for evaluation of this drug analyte with 2,112 paired UC and meconium specimens originating from 11 states. Testing of UC was performed by semi-quantitative liquid chromatography-tandem mass spectrometry (LC-MS-MS) assays, whereas, for meconium, an immunoassay-based screening preceded LC-MS-MS confirmation tests. Results generated for UC and meconium specimens were therefore compared for a total of 32 drug analytes from 6 drug classes. Drug concentrations for analytes were higher in meconium compared to UC, with the exception of phencyclidine. Despite this, the positivity rates for individual analytes were higher in UC, with the exception of THC-COOH and cocaine. Furthermore, analysis for multidrug positivity revealed that THC-COOH and opioids were the most common multidrug combination detected in both matrices. In conclusion, this study suggests that for most drug compounds, UC was more analytically sensitive to assess neonatal drug exposure by current methodologies. Additionally, by demonstrating that meconium has higher drug concentrations for most compounds, this study sets the stage for developing more sensitive assays in meconium., (© The Author(s) 2022. Published by Oxford University Press.)

Background/aims: Alpha-1 antitrypsin (AAT), vitamin-D binding protein (VDBP) and neutrophil granule proteins are specifically related to the neutrophil function and may be considered candidate biomarkers detected and measured in meconium (the first feces of newborn infants) as signals indicating abnormal processes in the fetal stage. Individual proteins found in meconium can be a source of information pertaining to the intrauterine metabolic processes., Methods: Concentrations of AAT, VDBP, calprotectin, myeloperoxidase, lactoferrin and elastase were measured using ELISA tests in 80 meconium samples collected from 19 healthy, full-term neonates., Results: The meconium concentrations of VDBP and AAT (mean±SD, [mg/g meconium]: 3.74±6.93, 3.72±1.79, respectively) were approximately 1000 times higher than those of the protein granule proteins calprotectin, myeloperoxidase, elastase and lactoferrin (mean ± SD, [µg/g meconium]: 285.7±215.8, 1.83±1.73, 1.72±2.70, 45.58±78.89, respectively). The correlation between VDBP and AAT was negative (r= - 0.40. p=0.000) and those between VDBP and calprotectin (r=0.38, p=0.000) and VDBP and myeloperoxidase (r=0.45, p=0.000) were positive. AAT was found to correlate positively with lactoferrin (r=0.38, p=0.000)., Conclusion: The correlations between the concentrations of VDBP and AAT, and with neutrophil granule proteins observed in meconium indicate their functional relationship in the intrauterine environment of the developing fetus. Meconium can be seen as an apparently underutilized source of biomarkers for evaluation of metabolic processes specific to fetal development., Competing Interests: The authors have no conflicts of interest to declare., (© Copyright by the Author(s). Published by Cell Physiol Biochem Press.)

Paclitaxel is often excluded during pregnancy for women with breast cancer due to limited neonatal follow-up. We confirmed in utero fetal Paclitaxel exposure for 8 newborns. Birth details and follow-up to 36 months of age is reported. Meconium samples from newborns exposed to chemotherapy were screened by liquid chromatography-high resolution mass spectrometry while blinded to maternal treatment during pregnancy. Newborn information at birth and annually was obtained. Mean gestational age (GA) at cancer diagnosis and start of chemotherapy was 8.7 + 6.2 weeks and 17.1 ± 3.5 weeks. Paclitaxel was started at a mean GA of 27.0 ± 5.8 weeks. Paclitaxel followed Doxorubicin/Cyclophosphamide in 6 cases, 5-Fluouracil/Doxorubicin/Cyclophosphamide in 1, and was used alone in 1. Mean number of days between Paclitaxel and birth was 23 ± 15. Identification of Paclitaxel and/or metabolites was made in all meconium from paclitaxel-exposed fetuses. Birthweight was < 10% for GA in 3 infants. Three anomalies occurred: mild hip dysplasia without further treatment and mitral valve stenosis. The third child was diagnosed with Cleidocranial Dysostosis, a familial anomaly. Mean age at pediatric follow-up is 18.7 + 9.3 months. Pediatricians report eczema and recurrent otitis media in 1 child, iron deficiency anemia and upper respiratory infection in 2. One child is < 10% for height and weight at 15 months. All are meeting developmental milestones at median age of 18.7 months, range: 6-36 months., Conclusion: Up to 3 years of age, follow-up of neonates exposed to Paclitaxel in utero is reassuring. Continued observation of neonatal development is essential., What Is Known: • Chemotherapy during the second and third trimester of pregnancy does not result in an increase in congenital malformations or developmental delay. • In non-human primate studies by Van Calsteren et al., variable plasma and/or tissue concentrations of taxanes, carboplatin, and trastuzumab were encountered in the fetal compartment. • Pilot data reported by the current investigators proved that paclitaxel crosses the human placenta., What Is New: • This current article provides medical and developmental follow up on the newborns from this exposure for 3 years after birth., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

In this study, we aimed to analyse the clinical features of the third-trimester pregnant women, with echogenic amniotic fluid and to compare their obstetric and neonatal outcomes with pregnant women with normal amniotic fluid echogenicity. This case-control study was conducted in a tertiary antenatal care centre. A total of 560 term (37-42 weeks of gestation) singleton women; 280 with echogenic particles in amniotic fluid and 280 with clear amniotic fluid, who delivered within 24 h after the ultrasound scan were evaluated. The women in the two groups were similar in terms of age, parity, body mass index, foetal birth weight, and gestational age. More patients in the particulate amnion group had lower Apgar scores (<7) in 1st and 5th minutes than controls ( p  = .006, p  = .031 respectively) however the rate of admission to neonatal intensive care was similar. Vernix stained amniotic fluid was more common in the study group (48.8%, p  = .031), the rate of meconium-stained amniotic fluid was similar in the study and control groups (9.6-9.2%, p  = .881). The primary caesarean section rate was higher in women with particulate amnion (18.4%, p  = .037). Echogenic particles in the amniotic fluid in the third trimester could not be attributed to meconium, however, higher rates of primary caesarean section may require further attention.IMPACT STATEMENT What is already known on this subject? Previous studies showed that high-density intra-amniotic particles were possibly related to vernix caseosa, intra-amniotic bleeding, and meconium. The number of study groups in these studies was also limited. What do the results of this study add? Additional to other previous studies, we found an increased rate of intra-amniotic echogenic particles in male foetuses. What are the implications of these findings for clinical practice and/or further research? The presence of echogenic particles on ultrasound was not related to increased risk for the presence of meconium. Significantly more neonates born to mothers with intra-amniotic echogenic particles tended to have lower Apgar scores (<7), however, this significant difference did not affect the need for NICU admission. The presence of echogenic particles in the amniotic fluid of the third-trimester pregnant women could not be attributed to meconium and adverse perinatal outcomes, however, the higher rates of primary caesarean section may require further attention.

New psychoactive substances (NPS) have been introduced into the market in recent years, with new analytes reported every year. The use of these substances in women can occur at any stage of life, even in the childbearing age. Drug use during pregnancy presents significant risks for the mother and the fetus, so it is important to have tools that allow to detect prenatal exposure to these substances of abuse. Therefore, an analytical method for the determination of 137 NPS and other drugs of abuse in meconium by UHPLC-QTOF was developed and validated for semi-quantitative purpose. Linearity range, limit of detection (LOD), precision, matrix effect, selectivity, and specificity were evaluated. For all analytes, the calibration curves were studied in the ranges between 2, 10, or 50 ng/g and 750 or 1000 ng/g, (depending on the analyte) and the LOD ranged between 0.04 and 2.4 ng/g. The method was applied to 30 meconium specimens from cases in which fentanyl had been administered as epidural anesthesia at the time of delivery or cases in which the maternal hair was positive to other drug of abuse. Four meconium samples tested positive for fentanyl (range concentration = 440-750 ng/g) and two samples tested positive to acetylfentanyl (range concentration = 190-1400 ng/g)., (© 2021. The Author(s).)

Cannabis consumption has been increasing worldwide among pregnant women. Due to the negative effects of prenatal cannabis exposure, it is necessary to develop an objective, sensitive, and specific method to determine cannabinoids use during pregnancy. In this study, we compared four different biological samples, maternal hair, meconium, umbilical cord, and placenta, for the detection of in utero cannabis exposure. The biological samples were collected from 627 mother-newborn dyads. All hair and meconium samples were analyzed, and umbilical cord and placenta if hair and/or meconium were positive for cannabinoids. Meconium and hair showed to complement each other, with an agreement between hair and meconium results of 96.7% but only 34.3% if just positive results were considered. Umbilical cord and placenta results showed a better agreement with meconium (91.3% and 92.6%, respectively) than with hair (39.1% and 34.6%, respectively). The predominant metabolites in meconium were 11-nor-carboxy-THC (THCCOOH) and 8,11-dihydroxy-THC (diOHTHC), and in umbilical cord and placenta was THCCOOH-glucuronide. Cannabidiol (CBD) and cannabinol (CBN) were detected in meconium but not in any umbilical cord or placenta. For the first time, prenatal marijuana exposure was analyzed and compared in paired hair, meconium, umbilical cord, and placental samples. Hair and meconium positivity rate was similar, but a more sensitive and specific analytical method for the hair may resolve discrepancies between the matrices. Umbilical cord and placenta may be considered suitable alternative matrices to meconium through the determination of THCCOOH-glucuronide as a biomarker of cannabis exposure., (© 2021 John Wiley & Sons, Ltd.)

Alcohol consumption during pregnancy constitutes one of the leading preventable causes of birth defects and neurodevelopmental disorders in the exposed children. Fatty acid ethyl esters (FAEEs), ethyl glucuronide (EtG) and ethyl sulfate (EtS) have been studied as potential biomarkers of alcohol consumption. However, most analytical approaches proposed for their analysis in meconium samples consist of separated extraction procedures requiring the use of two meconium aliquots, which is costly in terms of both time and materials. Therefore, the aim of this study was to develop and validate a method for the simultaneous extraction of 9 FAEEs, EtG and EtS from one meconium aliquot. The sample was homogenized using methanol, and then FAEEs were extracted with hexane while EtG and EtS were isolated using acetonitrile. Then, extracts were applied to solid-phase extraction columns and analysed by gas chromatography mass spectrometry (FAEEs) and liquid chromatography tandem mass spectrometry (EtG and EtS). Calibration curves were linear with r values greater than 0.99. The LODs ranged from 0.8 to 7.5 ng/g for FAEEs and were 0.2 ng/g and 0.8 ng/g for EtS and EtG, respectively. LOQs ranged from 5 to 25 ng/g for FAEEs and were 1 ng/g and 2.5 ng/g for EtS and EtG, respectively. Accuracies and precisions were between 93.8 and 107% and between 3.5 and 9.7%, respectively. The recovery values ranged from 89.1 to 109%. The method proved to be sensitive, specific, simple and fast and allowed for the reduction of the amount of organic solvent used for extraction compared to other published data while higher recoveries were obtained. The method was used for analysis of meconium samples in two cases of mothers who were consuming alcohol during pregnancy.

Objectives: Antenatal exposure to organic pollutants is a leading public health problem. Meconium is a unique matrix to perform prenatal studies because it enables us to retrospectively evaluate fetal exposure accumulated during the second and third trimester. The aim of the present study was to evaluate associations between organic pollutant levels in meconium and birth weight in NW Spain., Methods: In this study, we quantify the concentrations of 50 organic pollutants together with the total values of the most important chemical groups in meconium using gas chromatography coupled to tandem mass spectrometry., Results: Organochlorine pesticides, polychlorinated biphenyls and polybrominated diphenyl ethers were detected with the highest levels in meconium from small for gestational age newborns. It was estimated that several congeners were statistically significant (p<0.05). However, organophosphorus pesticides attained higher concentrations in newborns with an appropriate weight., Conclusions: The occurrence of transplacental transfer can be confirmed. Prenatal exposure to organic pollutants was associated with a decrease in birth weight and, therefore, organic pollutants could have an impact on fetal growth. Nevertheless, these results need validation in larger sample sized studies., (© 2021 Walter de Gruyter GmbH, Berlin/Boston.)

Background: Early diagnosis of nicotine, ethanol and drug use during pregnancy is critical in order to provide adequate care. Current screening procedures show limitations in terms of reliability and short windows of detection., Objectives: To investigate the prevalence and identify biomarkers of substance use and changes in substance use during pregnancy. To compare drug testing results in different types of biological samples (maternal hair, meconium, placenta, umbilical-cord) with self-reported data., Participants and Setting: Prospective cohort study using data from pregnant women and their newborns., Methods: Biological matrices were collected at birth and analyzed by liquid chromatography tandem mass spectrometry. A paper survey was provided to determine substance use habits., Results: 867 mother-newborn pairs were included. According to the analysis of biological samples, 29.1% cases were positive for one or more substances (13.6% nicotine, 8.4% ethanol, 8.3% cocaine, 6.4% cannabis, 5.7% opioids). The profile of the substance-using mother was a single woman, <28 years-old, with no higher education and unemployed. Segmental maternal hair analysis showed a decrease in tobacco, cannabis and cocaine use throughout pregnancy (p < 0.001). The level of concordance between results from interviews and from biological analyses was weak for opioids, cocaine, and cannabis (kappa coefficient < 0.40). Maternal hair detected the highest number of cases, followed by meconium and by placenta and/or umbilical-cord., Conclusions: Maternal survey was not a reliable screening technique. Analysis of maternal hair detected the highest number of cases with the broadest detection window (whole pregnancy).

Prenatal exposure to total mercury (T-Hg) comes from both natural and anthropogenic sources. T-Hg can cross the blood-brain and placental barriers, and may be associated with future neurological and physiological dysfunctions. Scalp hair is an optimal and non-invasive indicator of chronic T-Hg exposure. As part of the Maternal-Infant Research on Environmental Chemicals (MIREC) Study, hair samples from 350 women were collected within weeks after giving birth, to determine temporal variations in T-Hg levels from preconception to delivery, and to compare these levels to corresponding levels measured in other matrices (maternal and umbilical cord blood, and infant's meconium). A maximum of 12 one-cm hair segments were cut starting at the scalp; segments closer to the scalp reflected recent exposure (within the last month). For proper comparison, the hair segments were matched with the collection dates for other matrices. GM hair T-Hg levels greatly decreased during pregnancy, from 0.26 μg g -1 (preconception or full-length hair) to 0.18 μg g -1 (at delivery or segments closer to the scalp). A similar decreasing trend was found for T-Hg in maternal blood: 1st trimester (0.60 μg L -1 ) to 3rd trimester (0.47 μg L -1 ). The median hair-to-blood ratios of T-Hg levels varied from 364 (1st trimester), to 408 (3rd trimester), to 229 (cord blood). Very low T-Hg levels were detected in meconium. Mercury levels in blood and hair correlated with consumption of large predatory fish., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Crown Copyright © 2020. Published by Elsevier Ltd. All rights reserved.)

Objective: To examine associations between amounts of fatty acid ethyl esters (FAEEs) in meconium and behavior in school aged children exposed to alcohol and drugs in utero., Methods: A secondary analysis of a prospective cohort of cocaine, polydrug exposed children, primarily African-American, low socioeconomic status, recruited at birth into a longitudinal study. FAEEs were quantified with gas chromatography via a flame ionization detector. Meconium was analyzed for FAEEs for 216 newborns of whom 194 were assessed with the Child Behavior Checklist (CBCL) at ages 4, 6, 9, 10, 11, and 12. Generalized estimating equation analyses were used to assess the relationship of quantity of FAEEs to outcomes, controlling for maternal psychological distress., Results: Higher concentrations of FAEEs (ethyl myristate, ethyl palmitate, ethyl oleate, ethyl linoleate, and ethyl linolenate) were associated with caregiver reported aggressive and/or delinquent behavior at ages 10 and 12. After control for caregiver psychological distress, and age, significant (p < 0.05) FAEE by age interactions were found for ethyl myristate for aggression and for ethyl oleate, ethyl linoleate and ethyl linolenate for delinquency. Thus, higher concentrations of FAEE were related to more caregiver reported aggressive and delinquent behaviors of clinical significance at ages 10 and 12., Conclusion: Higher concentrations of FAEEs in meconium are potential markers for children at risk for aggressive and delinquent behaviors related to the effects of prenatal alcohol exposure., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Importance: Despite evidence of an association between prenatal acetaminophen exposure and attention-deficit/hyperactivity disorder (ADHD) in offspring, the drug is not contraindicated during pregnancy, possibly because prior studies have relied on maternal self-report, failed to quantify acetaminophen dose, and lacked mechanistic insight., Objective: To examine the association between prenatal acetaminophen exposure measured in meconium (hereinafter referred to as meconium acetaminophen) and ADHD in children aged 6 to 7 years, along with the potential for mediation by functional brain connectivity., Design, Setting, and Participants: This prospective birth cohort study from the Centre Hospitalier Université de Sherbrooke in Sherbrooke, Québec, Canada, included 394 eligible children, of whom 345 had meconium samples collected at delivery and information on ADHD diagnosis. Mothers were enrolled from September 25, 2007, to September 10, 2009, at their first prenatal care visit or delivery and were followed up when children were aged 6 to 7 years. When children were aged 9 to 11 years, resting-state brain connectivity was assessed with magnetic resonance imaging. Data for the present study were collected from September 25, 2007, to January 18, 2020, and analyzed from January 7, 2019, to January 22, 2020., Exposures: Acetaminophen levels measured in meconium., Main Outcomes and Measures: Physician diagnosis of ADHD was determined at follow-up when children were aged 6 to 7 years or from medical records. Resting-state brain connectivity was assessed with magnetic resonance imaging; attention problems and hyperactivity were assessed with the Behavioral Assessment System for Children Parent Report Scale. Associations between meconium acetaminophen levels and outcomes were estimated with linear and logistic regressions weighted on the inverse probability of treatment to account for potential confounders. Causal mediation analysis was used to test for mediation of the association between prenatal acetaminophen exposure and hyperactivity by resting-state brain connectivity., Results: Among the 345 children included in the analysis (177 boys [51.3%]; mean [SD] age, 6.58 [0.54] years), acetaminophen was detected in 199 meconium samples (57.7%), and ADHD was diagnosed in 33 children (9.6%). Compared with no acetaminophen, detection of acetaminophen in meconium was associated with increased odds of ADHD (odds ratio [OR], 2.43; 95% CI, 1.41-4.21). A dose-response association was detected; each doubling of exposure increased the odds of ADHD by 10% (OR, 1.10; 95% CI, 1.02-1.19). Children with acetaminophen detected in meconium showed increased negative connectivity between frontoparietal and default mode network nodes to clusters in the sensorimotor cortices, which mediated an indirect effect on increased child hyperactivity (14%; 95% CI, 1%-26%)., Conclusions and Relevance: Together with the multitude of other cohort studies showing adverse neurodevelopment associated with prenatal acetaminophen exposure, this work suggests caution should be used in administering acetaminophen during pregnancy. Research into alternative pain management strategies for pregnant women could be beneficial.

Phthalates are hormonally active pollutants. In-utero exposure to phthalates has been reported to be associated with birth size parameters and pregnancy outcomes. However, previous reports were inconsistent. We examined the associations between meconium exposure to phthalates and the effects on birth size parameters, pregnancy outcomes and sex and thyroid hormones in 251 mother-infant pairs from a Shanghai hospital. We measured 10 metabolites of phthalates in meconium samples collected during the first 24h after delivery. Information on seven birth size parameters (birth weight, birth length, abdominal circumference, head circumference, femur length, biparietal diameter and anogenital distance) and three pregnancy outcomes (gestational diabetes, premature rupture of membrane, and premature birth) was available from the birth record. Concentrations of free testosterone, estradiol (E2), thyroid stimulating hormone, concentrations of total and free thyroxine and triiodothyronine were measured from cord blood. Multivariate linear regression and logistic regression were used to estimate associations between phthalate exposure and health outcomes. mono-iso-butylphthalate (MiBP), mono-n-butylphthalate (MnBP) and mono-2-ethyl-5-oxohexyl phthalate (MEOHP) were positively associated with birth length and femur length which seemed more obvious in female newborn; MiBP, MnBP and mono-2-ethylhexylphthalate (MEHP) were positively associated with gestational diabetes mellitus (GDM) only in mothers with male newborns; monomethyl phthalate (MMP), MiBP and MEOHP were positively associated with E2 in male newborns. This study indicates that meconium exposure to phthalates may adversely affect some fetal growth parameters and GDM with a potential gender effect.

Background: Titanium dioxide (TiO 2 ) is broadly used in common consumer goods, including as a food additive (E171 in Europe) for colouring and opacifying properties. The E171 additive contains TiO 2 nanoparticles (NPs), part of them being absorbed in the intestine and accumulated in several systemic organs. Exposure to TiO 2 -NPs in rodents during pregnancy resulted in alteration of placental functions and a materno-foetal transfer of NPs, both with toxic effects on the foetus. However, no human data are available for pregnant women exposed to food-grade TiO 2 -NPs and their potential transfer to the foetus. In this study, human placentae collected at term from normal pregnancies and meconium (the first stool of newborns) from unpaired mothers/children were analysed using inductively coupled plasma mass spectrometry (ICP-MS) and scanning transmission electron microscopy (STEM) coupled to energy-dispersive X-ray (EDX) spectroscopy for their titanium (Ti) contents and for analysis of TiO 2 particle deposition, respectively. Using an ex vivo placenta perfusion model, we also assessed the transplacental passage of food-grade TiO 2 particles., Results: By ICP-MS analysis, we evidenced the presence of Ti in all placentae (basal level ranging from 0.01 to 0.48 mg/kg of tissue) and in 50% of the meconium samples (0.02-1.50 mg/kg), suggesting a materno-foetal passage of Ti. STEM-EDX observation of the placental tissues confirmed the presence of TiO 2 -NPs in addition to iron (Fe), tin (Sn), aluminium (Al) and silicon (Si) as mixed or isolated particle deposits. TiO 2 particles, as well as Si, Al, Fe and zinc (Zn) particles were also recovered in the meconium. In placenta perfusion experiments, confocal imaging and SEM-EDX analysis of foetal exudate confirmed a low transfer of food-grade TiO 2 particles to the foetal side, which was barely quantifiable by ICP-MS. Diameter measurements showed that 70 to 100% of the TiO 2 particles recovered in the foetal exudate were nanosized., Conclusions: Altogether, these results show a materno-foetal transfer of TiO 2 particles during pregnancy, with food-grade TiO 2 as a potential source for foetal exposure to NPs. These data emphasize the need for risk assessment of chronic exposure to TiO 2 -NPs during pregnancy.

Human exposure to environmental organic pollutants (OPs) begins in the uterine life period by trans-placental transfer. Epidemiological studies have consistently demonstrated the vulnerability of human fetuses and infants to the effects of OPs because of their rapid growth and organ development, cell differentiation, and immaturity of metabolism. The aim of the present study was to evaluate the prenatal exposure to OPs characterized by different physicochemical properties using non-invasive biological samples (meconium and placenta). A total of 88 placenta and 53 meconium samples were collected in Ourense, a city located in northwestern Spain, at the delivery and after birth from mothers and their infants from the University Hospital of Ourense, respectively. Selective pressurized liquid extraction (SPLE) methodologies were used to determine the targeted OPs in the selected biological samples. Cleanup of extracts was performed by solid-phase extraction (SPE) using EZ-POP cartridges and detection by gas chromatography (GC) coupled to tandem mass spectrometry (QqQ-MS/MS). The targeted OPs were detected with the following mean level total concentration order polycyclic aromatic hydrocarbons (PAHs) > organophosphorus pesticides (OPPs) > non-dioxin like polychlorinated biphenyls (NDLPCBs) > pyrethroids (PYRs) > polybrominated diphenyl ethers (PBDEs) > dioxin like polychlorinated biphenyls (DLPCBs) > organochlorine pesticides (OCPs) for placenta and ΣNDLPCBs > ΣPAHs > ΣOCPs > ΣPYRs > ΣOPPs > ΣDLPCBs > ΣPBDEs for meconium, respectively. Significant correlations (p < .050) between the socio-demographic characteristics of the selected population (mother's parity, age, weight increase during pregnancy, place of living and smoking habits) and log transformed concentration of some of the targeted OPs (OCPs, PBDEs, PYRs, OPPs and PAHs) were detected. The results obtained shown the complementary information given by both biological samples selected. Nevertheless, additional research will be needed to gain an understanding of the trans-placental transfer of OPs, to choose the best biological matrix to evaluate the prenatal exposure to OPs in a correct way and to know their health implications., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)

An LC-MS-MS method for the determination of 14 benzodiazepines (BZDs) (alprazolam, α-hydroxyalprazolam, clonazepam, bromazepam, diazepam, nordiazepam, lorazepam, lormetazepam, oxazepam, flunitrazepam, 7-aminoflunitrazepam, triazolam, midazolam and zolpidem) and 15 antidepressants (ADs) (amitriptyline, nortriptyline, imipramine, desipramine, clomipramine, norclomipramine, fluoxetine, norfluoxetine, sertraline, norsertraline, paroxetine, venlafaxine, desmethylvenlafaxine, citalopram and desmethylcitalopram) in meconium was developed and validated. Meconium samples (0.25 ± 0.02 g) were homogenized in methanol and subjected to mixed-mode cation exchange solid-phase extraction. Chromatographic separation was performed in reversed phase, with a gradient of 0.1% formic acid in 2 mM ammonium formate and acetonitrile. Two different chromatographic gradient methods were employed, one for the separation of ADs and another for BZDs. Analytes were monitored by tandem mass spectrometry employing electrospray positive mode in MRM mode (2 transitions per compound). Method validation included: linearity [n = 5, limit of quantification (LOQ) to 400 ng/g], limits of detection (n = 6, 1-20 ng/g), LOQ (n = 9, 5-20 ng/g), selectivity (no endogenous or exogenous interferences), accuracy (n = 15, 90.6-111.5%), imprecision (n = 15, 0-14.6%), matrix effect (n = 10, -73 to 194.9%), extraction efficiency (n = 6, 35.9-91.2%), process efficiency (n = 6, 20.1-188.2%), stability 72 h in the autosampler (n = 3, -8.5 to 9%) and freeze/thaw stability (n = 3, -1.2 to -47%). The method was applied to four meconium specimens, which were analyzed with and without hydrolysis (enzymatic and alkaline). The authentic meconium samples tested positive for alprazolam, α-hydroxyalprazolam, clonazepam, diazepam, nordiazepam, fluoxetine, norfluoxetine, clomipramine and norclomipramine. Therefore, the present LC-MS-MS method allows a high throughput determination of the most common BZDs and ADs in meconium, which could be useful in clinical and forensic settings., (© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background/objective: As a developing country, Brazil presents a wide range of environmental risks that can constitute hazards to child health. The country also presents different socio-economic-cultural conditions that could be responsible for determining different vulnerability and susceptibility levels for the population, which can potentiate the effects of the environmental pollutants. The Rio Birth Cohort Study (PIPA project) is a prospective maternal-infant health study, hosted in the city of Rio de Janeiro (Southeastern Brazil), designed to investigate separate and combined effects of environmental chemical pollutants, as well as the interactions between these exposures and sociocultural environment and epigenetic patterns. This paper presents the learned lessons and strategies to address the shortcomings detected from this pilot study., Methods: The study population will be all children born at the Federal University of Rio de Janeiro Maternity Hospital from July 1st, 2020 to June 30th, 2021. The estimated population is of 2,500 children. The study will collect social, demographic, and health information from pregnant women and their children up to four years of age. Biological samples from both mothers and newborns will be collected to assess metal, pesticide and plasticizer exposure. All newborns will have their landmarks of physical, neurological, psychological, and cognitive development recorded at specific ages., Findings: A pilot study was carried out between September 2017 and August 2018, totaling 142 enrolled pregnant women, leading to 135 (95%) births and the collection of umbilical cord (126-93%,) and mother (139-98%) blood samples, as well as both mother (142-100%) and newborn (54-40%) urine samples and newborn meconium samples (117-86.7%)., Conclusions: The study proposes a comprehensive assessment of pre- and postnatal exposure to environmental chemicals at multiple time points in a population living in a highly urbanized developing country. As far as we know, this is the only birth cohort in Brazil specifically designed for this purpose., Competing Interests: The authors have no competing interests to declare., (Copyright: © 2020 The Author(s).)

Purpose: Buprenorphine and methadone are international gold standards for managing opioid use disorders. Although they are efficacious in treating opioid dependence, buprenorphine and methadone present risks, especially during pregnancy, causing neonatal abstinence syndrome and adverse obstetrical outcomes. Buprenorphine and methadone are also abused during pregnancy, and identifying their use is important to limit unprescribed prenatal exposure. Previous studies have suggested that concentrations of buprenorphine, but not methadone markers in unconventional matrices may predict child outcomes, although currently only limited data exist. We reviewed the literature on concentrations of buprenorphine, methadone, and their metabolites in unconventional matrices to improve data interpretation., Methods: A literature search was conducted using scientific databases (PubMed, Scopus, Web of Science, and reports from international institutions) to review published articles on buprenorphine and methadone monitoring during pregnancy., Results: Buprenorphine and methadone and their metabolites were quantified in the meconium, umbilical cord, placenta, and maternal and neonatal hair. Methadone concentrations in the meconium and hair were typically higher than those in other matrices, although the concentrations in the placenta and umbilical cord were more suitable for predicting neonatal outcomes. Buprenorphine concentrations were lower and required sensitive instrumentation, as measuring buprenorphine glucuronidated metabolites is critical to predict neonatal outcomes., Conclusions: Unconventional matrices are good alternatives to conventional ones for monitoring drug exposure during pregnancy. However, data are currently scarce on buprenorphine and methadone during pregnancy to accurately interpret their concentrations. Clinical studies should be conducted with larger cohorts, considering confounding factors such as illicit drug co-exposure.

The number of newborns exposed to therapeutic drugs during pregnancy is growing because of the increased use of drugs during pregnancy. In recent years, advances in our understanding of drug placental transfer have augmented the likelihood of a healthy baby in mothers with chronic diseases needing drug therapy. Globally, for example, more than 1.4 million pregnancies in 2015 have been burdened with antiretroviral drugs due to an increasing number of HIV-positive women treated with these drugs, particularly in low- and middle-income countries. In most cases, the fetus is exposed to much higher drug doses in utero than the newborn nursed by the mother. Drug transfer through the placenta takes place by passive diffusion, active transport, or facilitated transport, and drug concentrations in the fetal circulation may be comparable to that in the mother's blood concentration. The excretion of drugs into breastmilk predominantly occurs by passive diffusion, allowing only the non-protein-bound fraction of the blood drug concentration to penetrate. Drug agencies in the United States and Europe highly recommend performing clinical trials in pregnant or breastfeeding women. However, only a few drugs have reported statistically sound data in these patient groups. Most available results concerning pregnancy are obtained from observational studies after birth, assessing outcomes in the newborn or by measuring drug concentrations in the mother and umbilical cord blood. In the case of the lactation period, some studies have evaluated drug concentrations in breastmilk and blood of the mother and/or infant. In this review, exposure to antiretrovirals, immunosuppressants used after solid organ transplantation, and antiepileptics during pregnancy and lactation has been discussed in detail.

Background: The prevalence of drug use during pregnancy continues to increase despite the associated serious adverse obstetrical outcomes, including increased risk of miscarriage, fetal growth restriction, brain development impairment, neonatal abstinence syndrome, preterm delivery, and stillbirths. Monitoring drug use during pregnancy is crucial to limit prenatal exposure and provide suitable obstetrical health care. The authors reviewed published literature reporting the concentrations of common drugs of abuse and new psychoactive substances (NPS), such as synthetic cathinones and synthetic opioids, NPS, and their metabolites using unconventional matrices to identify drug use during pregnancy and improve data interpretation., Methods: A literature search was performed from 2010 to July 2019 using PubMed, Scopus, Web of Science scientific databases, and reports from international institutions to review recently published articles on heroin, cocaine, amphetamine, methamphetamine, synthetic cathinone, and synthetic opioid monitoring during pregnancy., Results: Meconium has been tested for decades to document prenatal exposure to drugs, but data regarding drug concentrations in amniotic fluid, the placenta, the umbilical cord, and neonatal hair are still lacking. Data on prenatal exposure to NPS are limited., Conclusions: Maternal hair testing is the most sensitive alternative matrix for identifying drug use during pregnancy, while drug concentrations in the meconium, placenta, and umbilical cord offer the identification of prenatal drug exposure at birth. Adverse developmental outcomes for the infant make it critical to promptly identify maternal drug use to limit fetal exposure or, if determined at birth, to provide resources to the exposed child and family. Alternative matrices offer choices for monitoring and challenge laboratories to deliver highly sensitive and specific analytical methods for detection.

Purpose: Drug use during pregnancy is a critical global challenge, capable of severe impacts on neonatal development. However, the consumption of cannabis and synthetic cannabinoids is on the rise in pregnant women. Obstetric complications with increased risks of miscarriage, fetal growth restriction, and brain development impairment have been associated with perinatal cannabis exposure, but data on synthetic cannabinoid use during pregnancy are limited., Methods: We reviewed studies that investigated the risks associated with cannabis and synthetic cannabinoid use and those that reported the concentrations of cannabinoids and synthetic cannabinoids in maternal (breast milk) and neonatal (placenta, umbilical cord, meconium, and hair) matrices during human pregnancy. A MEDLINE and EMBASE literature search to identify all relevant articles published in English from January 1998 to April 2019 was performed., Results: Cannabis use during pregnancy is associated with increased risks of adverse obstetrical outcomes, although neurobehavioral effects are still unclear. Analyses of cannabinoids in meconium are well documented, but further research on other unconventional matrices is needed. Adverse effects due to perinatal synthetic cannabinoid exposure are still unknown, and analytical data are scarce., Conclusions: Awareness of the hazards of drug use during pregnancy should be improved to encourage health care providers to urge pregnant women to abstain from cannabis and, if cannabis-dependent, seek treatment. Moreover, substances used throughout pregnancy should be monitored as a deterrent to cannabis use, and potential cannabis-dependent women should be identified, so as to limit cannabis-fetal exposure during gestation, and provided appropriate treatment.

Meconium is formed early in gestation and it is normally not excreted until after birth. Thus it may provide a longer and cumulative record of exposure to mercury (Hg). The present study aims to speciate Hg in meconium samples (N = 488) from Slovenian and Croatian new-borns prenatally exposed to low levels of methyl-Hg (MeHg) from maternal seafood intake and to Hg 0 from maternal dental amalgam fillings. We had complete data of total Hg (THg) and MeHg in meconium and THg in maternal hair (MH), while THg and MeHg in maternal blood (MB) were available only for Croatian mothers. Personal data namely maternal seafood intake, age, pre-pregnancy BMI, parity, smoking, estimated gestational age at birth, sex, and birth weight were available for the majority of participants, except the number of dental amalgams which was in most cases missing for Croatian mothers. The median THg concentration in meconium was 11.1 (range: 0.41-375.2) ng/g and inorganic Hg (Hg(II)) presented 98.8% (range: 82%-100%, CV: 2%) of THg. We observed significant correlation between meconium and MH Hg levels, with the highest correlation between hair THg and meconium MeHg. Correlation analysis including MB (available only for Croatian population) showed a significant positive correlation between THg in meconium and THg in MB (R s  = 0.642). Additionally, MeHg from MB was correlated with MeHg in meconium (R s  = 0.898), while the correlation between Hg(II) in MB and meconium was positive, but not significant. Maternal seafood intake was significantly correlated with meconium MeHg (R s  = 0.498) and Hg(II) (R s  = 0.201). Multiple linear regression (performed on the Slovenian population, N = 143) confirmed a positive association between meconium MeHg and seafood intake. Furthermore, meconium Hg(II) was positively associated with the number of maternal dental amalgam fillings, but linear regression models did not confirm correlation between seafood intake and meconium Hg(II) levels. We assume that Hg 0 released from maternal dental amalgam fillings and MeHg from seafood intake were both transported through the placental barrier and portioned between different foetal compartments including meconium. Weak correlation between maternal seafood intake and Hg(II) levels in meconium suggests that there is certain evidence of MeHg demethylation. However, because this correlation was not confirmed by the multiple regression, MeHg demethylation during prenatal life cannot be neither confirmed nor excluded. Further investigations at higher level of exposure are needed to confirm this observations. We can conclude that meconium is a suitable biomarker for MeHg and Hg 0 exposure during pregnancy. However, comparability of the results reported in meconium in different studies is hindered by a lack of standardized sampling protocols, storage, and analysis., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Fetal Alcohol Spectrum Disorder (FASD) describes the wide range of adverse physical, behavioral and cognitive effects resulting from ethanol exposure during embryonic and fetal development. Identification of children suffering from FASD is often difficult, as abuse of ethanol during pregnancy is a heavily stigmatized behavior that receives little prenatal screening attention in routine care. Over the last 3 decades, measurement of the ethanol metabolites fatty acid ethyl esters (FAEE) has emerged as a useful tool to detect in the neonatal period fetal alcohol exposure starting from mid gestation. This review aims at updating clinicians and researchers on the validity and utility of this biological marker in two aspects: The association with adverse fetal outcomes and in generating population estimates of fetal alcohol exposure.

Prenatal exposure to maternal ethanol leads to serious physical and mental irreversible disabilities. Ethyl glucuronide (EtG) is a direct metabolite of alcohol and its measurement in neonatal meconium has been established as the best biomarker to assess prenatal exposure to social and excessive gestational ethanol. We developed and validated the first gas chromatography tandem mass spectrometry method to quantify EtG extracted from meconium by a simple solid phase extraction pretreatment. The method was linear from limit of quantification (2 ng/g) to 200 ng/g matrix with good determination coefficient (r 2  = 0.99). Recovery of EtG from meconium was always higher than 70% and intra-assay and inter-assay precision and accuracy were always better than 10%. Robustness of the developed GC-MS/MS method was tested by analysing 150 real samples coming from a previous national epidemiological project pre-screened through an ultra-chromatography tandem mass spectrometry assay obtaining a good comparability of results obtained by the two methods., (Copyright © 2019 Elsevier B.V. All rights reserved.)

New psychoactive substances have been introduced into the market in the last years due to their unregulated status. Synthetic cathinones are one of their main representatives, and they have shown to produce neonatal complications. It is important to have objective tools to identify in utero exposure to drugs that have shown to produce neonatal complications. An analytical method was developed and fully validated for the determination of common synthetic cathinones, including methylone, methedrone, mephedrone, 3,4-methylenedioxypyrovalerone (MDPV), (±)-4-fluoromethamphetamine and 4-fluoromethcathinone in meconium. Meconium (0.25 ± 0.02 g) was homogenized with methanol by sonication for 30 min. After centrifugation, the sample was extracted with Oasis MCX columns. The analysis was performed by LC-MS/MS using an Atlantis T3 column (3 μm, 2.1 × 50 mm) and a gradient with acetonitrile and 0.1% formic acid in water. Method validation included the following parameters: selectivity (no endogenous or exogenous interferences), limits of detection (n = 3, 0.5-1 ng/g) and quantification (n = 3, 1-2 ng/g), linearity (n = 5, LOQ-200 ng/g), imprecision (n = 15, 0% to 10%), accuracy (n = 15, 87.3% to 97.8%), matrix effect (n = 10, -76% to -28.1%), extraction efficiency (n = 6, 63.7% to 91.3%), total process efficiency (n = 6, 16% to 60.2%) and stability for 72 h in the autosampler (n = 3, %loss = -6.7% to 5.1%). The method was applied to 28 meconium specimens., (Copyright © 2018. Published by Elsevier B.V.)

In the last decade there has been a dramatic increase in the availability and abuse of synthetic cathinones - new amphetamine-like stimulants. Even though their abuse during pregnancy could have serious adverse effects on the fetus, cathinones are not readily included in neonatal toxicological screenings. Meconium (first neonatal stool) is the specimen of choice to reveal long term drug exposure, however as it is a highly complex matrix, the sample preparation is a critical step before the instrumental analysis. The aim of this work was to develop a suitable meconium sample extraction technique using the advantages of salting-out assisted liquid-liquid extraction (SALLE) and using only MS-friendly organic ammonium salts. We further developed and validated liquid chromatography tandem-mass spectrometry method for the determination of 'traditional' stimulants (methamphetamine, amphetamine, MDMA) and cathinones (mephedrone, methylenedioxypyrovalerone (MDPV), α-pyrrolidinopentiophenone (α-PVP), methylone, butylone, flephedrone, and naphyrone). Matrix-matched calibration was prepared in the concentration range 10-2000 ng/g. The limits of quantification were determined as 10 ng/g, recoveries ranged from 48.2% to 94.3% and the matrix effect was between 60.2% and 101.4%. Accuracy (86.1-114.5%) and precision (4.9-14.9%) were determined and all validation criteria were met for all analytes except for naphyrone. Finally, our analytical method was tested on a set of real meconium samples, which were found positive for amphetamine, methamphetamine and methylone, thus demonstrating the validity of the method., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Neonates who swallow a considerable amount of maternal blood may exhibit vomiting and suckling disorder during the first few days of the postnatal period. Some clinicians treat these neonates with gastric lavage (GL) to prevent vomiting and the establishment of enteral feeding empirically, but there was no study assessing the effect of GL for neonates with coffee-ground emesis. We designed a multicenter randomized controlled trial to evaluate the efficacy and safety of GL in neonates with coffee-ground emesis. Vigorous neonates with birth weight ranging from 2500 g to 3999 g and gestational age between 37w0d and 41w6d who presented with coffee-ground emesis on more than twice and diagnosed as false melena, were divided into two groups using computerized randomization. We defined feeding intolerance (FI) as (1) ≥2 vomiting episodes in 4h or ≥3 episodes in 24h and/or (2) feeding failure on at least two occasions because of retching or poor sucking. Primary outcome is percentage of infants who present FI within 24 hours from admission. We also assessed the residual volumes, number of vomiting episodes, percentage of weight reduction at postnatal day 4, rates of body weight gain at 1 month of age, and peak serum total bilirubin value before discharge. To our knowledge, this is the first study to evaluate the safety and efficacy of GL for neonates with coffee-ground emesis. This trial is registered at UMIN Clinical Trials Registry as UMIN000026483., Competing Interests: The authors have no conflicts of interest to disclose.

Tobacco and/or alcohol use during pregnancy is a major public health concern. The aim of our study was to identify risk factors associated to maternal alcohol and tobacco use assessed by maternal self-reports combined with biological measurements in meconium samples of cotinine and ethylglucuronide which reflect fetal exposure to tobacco and alcohol, respectively, during the 3rd trimester of pregnancy. We conducted a prospective study in three maternity hospitals in a large urban area during consecutive weeks (2010 and 2011). Maternal sociodemographic and clinical characteristics were assessed after delivery, using the French version of the Addiction Severity Index. Cotinine and ethylglucuronide were measured in meconium samples. Seven hundred and twenty-four women were included, and 645 meconium samples collected. Using multivariate analyses, we found that not being married or having a smoking partner predicts maternal tobacco use. In contrast, a decreased risk was associated with higher education level and wanted pregnancy. The risk for alcohol use increased when the mother had been in conflict with any relative or her partner for a long time throughout her life, as well as in case of previous treatment for any mental or emotional disorder. Using multivariate analyses and cotinine presence in meconium samples, the risks were similar except for marital status, which was not associated to cotinine presence. Community education and prevention programs should urgently be improved for all women of childbearing age with a special focus on those with past histories of mental or emotional disorders and addictive disorders. Smoking cessation should be recommended to both parents.

Our study aimed to estimate the prevalence of heavy fetal alcohol exposure through the analysis of meconium FAEEs as an objective biomarker of fetal exposure. We conducted a study on meconium samples collected nationwide through the Maternal-Infant Research on Environmental Chemicals (MIREC) Study Group. FAEE in meconium was quantified by an established headspace solid-phase microextraction coupled with gas chromatography-mass spectrometry (SPME GC-MS). Out of 1315 samples collected in 10 Canadian obstetric units coast to coast between 2008-2011, the estimated prevalence of positive meconium FAEE ranged between 1.16% and 2.40%, translating into at least 1800 new cases of FASD in Canada each year. Positive maternal self- reports of heavy alcohol use were tenfold lower (0.24%). Use of meconium FAEE revealed tenfold more cases of heavy exposure to maternal drinking than did maternal reports. The use of objective measures of maternal alcohol exposure is critical in accurately estimating risks and in monitoring effective prevention of FASD.

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., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: The association between antibiotic use during pregnancy and neonatal birth outcomes has received considerable attention. Most of the previous assessment of antibiotic exposure during pregnancy relied on questionnaires and clinical prescriptions, and very few studies examined pregnancy exposure to antibiotics using human biomonitoring data., Objective: To explore the association between the cumulative exposure of antibiotics during the whole pregnancy and neonatal birth measurements using biomonitoring data of antibiotics in meconium., Methods: Three hundred and sixty nine pregnant women within the Maternal Psychological and Environmental Assessments of Kids Cohort Study were randomly selected into this study. Eighteen common antibiotics of six categories (six β‑lactams, three tetracyclines, four sulfonamides, one phenicols, one lincosamides and three fluoroquinolones) were selected as the target antibiotics in meconium. The measurement was conducted by ultraperformance liquid chromatography coupled to quadrupole time-of-flight mass spectrometry platform. Neonatal birth measurements were obtained from the medical records. Multiple linear regression models were used to examine the associations of antibiotic exposure with neonatal birth outcome (birth weight, birth length) and placental growth indicators (placental surface area, placental weight). Logistic regressions were used to evaluate associations with small for gestational age (SGA) and large for gestational age (LGA)., Results: Twelve of the eighteen antibiotics were found in 62.1% of the meconium, with detection rates ranging from 0.3% to 43.9%. The three antibiotics with the highest detection rates were chlortetracycline (43.9%), penicillin (16.5%) and chloramphenicol (10.8%), respectively. The highest antibiotic concentration among detected antibiotics was penicillin (24,243.15 μg/kg). The concentration of penicillin was positively associated with the birth weight (β: 0.025; 95% CIs: 0.003-0.047). A significant positive association was also observed between the concentration of chlortetracycline and the placental surface area (β: 2.559; 95% CIs: 0.296-4.822). These associations were sex related and mainly observed in female newborns. Exposure to penicillin was also found to be associated with increased risk of LGA, which was consistent with changes in birth weight., Conclusions: Pregnancy exposure to certain antibiotics was associated with altered fetal growth and development, which may affect the normal growth trajectory of infants and children in later life., (Copyright © 2018 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Drug testing commonly involves serum, blood, or urine. More recently, alternative specimens for drug testing have been increasingly used for clinical and forensic toxicology. Examples include oral fluid (saliva), hair, meconium, and umbilical cord tissue. Each of these matrices has unique properties that provide advantages for certain applications. Oral fluid has easier and less invasive collection requirements than urine, the most common specimen for drug screening. Oral fluid drug testing is common in Europe and steadily gaining popularity in the United States. Hair accumulates drugs and drug metabolites and provides a much longer window of detection than blood or urine. Meconium and umbilical cord tissue each allow for assessment of prenatal drug exposure over the course of months. Limitations of these alternative matrices include need for laboratory-developed tests (exception being some oral fluid immunoassays), challenges with the specimen matrix, and incomplete understanding of drug incorporation and kinetics. This chapter briefly describes each of the above alternative specimens in terms of their utility, advantages, and limitations.

Meconium, the first stool of a newborn, can be analyzed to identify prenatal exposure to drugs of abuse. Meconium accumulates in a fetus during the second and third trimesters of pregnancy providing a wide window of exposure. Identification of in utero drug exposure is essential for the diagnosis and treatment of infants for dependency/withdrawal caused from the exposure. However, testing of meconium samples is often cumbersome and time-consuming. Unlike liquid samples, meconium is a viscous, semisolid, tar-like substance that needs to be individually weighed prior to extraction. Additionally, the meconium matrix is not homogeneous and not easily mixed or extracted. A method for analyzing cocaine and metabolites as well as amphetamines in meconium utilizing ceramic homogenizers prior to salt-assisted liquid-liquid extraction and liquid chromatography tandem-mass spectrometry (LC-MS/MS) is presented.

Acetaminophen is the only over-the-counter pain reliever that is not contraindicated during pregnancy, but recent studies have questioned whether acetaminophen is safe for the fetus, particularly the developing brain. This prospective birth cohort study probed the previously observed association between in utero exposure to acetaminophen and neurodevelopment by using concentrations of acetaminophen measured in meconium, which more objectively captures exposure of the fetus than maternal report. Exposure, measured by liquid chromatography coupled with tandem mass spectrometry, was categorized into nondetection, low detection, and high detection levels. At age 6-8 years, children completed a set of subtests from the Wechsler Intelligence Scale for Children, 4th edition. Additionally, this study examined potential effect modification by child sex on the association between acetaminophen exposure and neurodevelopment. In fully adjusted models, in utero exposure to acetaminophen was not statistically significantly associated with decreased scores on any of the examined subtests in all children combined (n = 118). The effect of in utero acetaminophen exposure on the Coding subtest was marginally significantly different among boys and girls, with girls performing significantly better on the task with higher levels of acetaminophen compared with girls with undetectable levels of exposure (βgirls, low = 2.83 [0.97, 4.70], βgirls, high = 1.95 [-0.03, 3.93], βboys, low = .02 [-1.78, 1.81], βboys, high = -.39 [-2.09, 1.31], pinteraction = .06). Effect modification by child sex was not observed on other subtests. These results do not support prior reports of adverse neurodevelopmental effects of in utero exposure to acetaminophen.

Background: Gestational diabetes mellitus (GDM) is a typical fetus development niches dysfunction and many toxic/nutrient elements have been associated with its onset and progression. However, the classic epidemiologic approach is regarded as "black-box epidemiology" and fails to elucidate these elements' biological roles on the damaged fetus developmental microenvironment., Objective: We aimed to characterize the associations between meconium of multiple elements with GDM for illustrating their interruption effects on in-uterus microenvironment., Methods: In this case-control study (n = 137 cases; n = 197 controls), the participants were nested from a cross-sectional retrospection of 1359 recruitments in Xiamen, China. Twenty-one meconium elements were characterized using inductively coupled plasma mass spectrometry (ICP-MS) or inductively coupled plasma optical emission spectrometry (ICP-OES). For shifting the present paradigm from a black-box approach to a molecular approach, GDM-related metabolic markers were identified in our previous metabolome report. Based on the meet-in-middle strategy, the associations among the elements, metabolic markers and GDM incidence were assessed by using redundancy analysis and correlation-adjusted correlation; mediation analysis was further used to test the hypothesis that metabolic markers mediate the associations of the elements with GDM incidence., Results: Eight elements were related with the GDM occurrence in dose-dependent manners, which positively (Al, As, Ba, Cd, Hg, and Sn) or negatively (Ca and V) associated with GDM. Among them, As, Cd, Ba, and Ca significantly contributed to the variation of GDM-related metabolic markers. Additionally, the associations of Cd, Ba, Ca and As with GDM were mediated by the metabolic markers which majorly involved in the lipid metabolism and the Adenosine/l-Arginine/Nitric Oxide (ALANO) pathways., Conclusions: The two-side mediations of meconium metabolic markers between the multiple elements and GDM occurrence indicated that maternal exposure to As, Ba, Cd, and Ca may be associated with the dysfunction of fetus development niche through disrupting lipid metabolism and ALANO pathways., (Copyright © 2018 The Authors. Published by Elsevier Ltd.. All rights reserved.)