The Identification of Prenatal Exposure to Mitragynine Using Umbilical Cord Tissue

Objective: Kratom is widely available and literature exploring the effects of prenatal kratom exposure is lacking. This study aims to report a validated method for the detection of mitragynine in the umbilical cord and report our observations for specimens received at a national commercial reference laboratory. Study Design: Assays were validated according to the recommendations of ANSI/ASB. A retrospective evaluation of records at a national reference laboratory was conducted to determine prevalence and co-exposure to other substances of abuse. Result: Mitragynine was detected in 19 of 4456 specimens (0.43%) with concentrations ranging from 4 to >50 ng/g. Thirteen (13) of these specimens were positive for only mitragynine while the other 6 were also positive for either marijuana or opiates. Conclusion: Umbilical cord is a suitable specimen type for the surveillance of maternal kratom use and can be used to identify exposed neonates for further investigations into short- or long- term health consequences.

Using Umbilical Cord Tissue to Identify Prenatal Exposure to Fentanyl and Other Commonly Abused Drugs

Background: Prenatal exposure to fentanyl may lead to Neonatal Abstinence Syndrome (NAS), a constellation of symptoms observed when newborns begin withdrawing from addictive substances such as opioids. The use of umbilical cord tissue segments (UC) for newborn toxicology has been increasing due to its apparent long detection window, sensitivity, and ease of collection. However, very little has been reported in the literature concerning the prevalence of in utero exposure to fentanyl and co-exposure with other commonly abused substances. Specific aim: The specific aims of this retrospective study are twofold. We will report prevalence of neonatal exposure to fentanyl for a nationwide high-risk population using UC submitted to a national reference laboratory for routine forensic toxicology analysis and the co-exposure patterns observed for these fentanyl-exposed neonates. Methods: A secondary analysis was performed using historical data for UC received between January 1, 2020 and December 31, 2020 for routine forensic toxicology analysis. Results: During the study period, our laboratory received 23,104 UC for analysis and 9667 (41.8%) of those UC were positive for at least one drug. The prevalence of fentanyl detection was 1.9% (n = 429). Of these 429 specimens there were 407 UC where both fentanyl and norfentanyl were detected. There were 14 UC where only fentanyl was detected and 8 UC where only norfentanyl was detected. When detected, the median concentrations of fentanyl and norfentanyl were 4029 pg/g (IQR: 1696, 9230 pg/g) and 10,756 pg/mg (IQR: 3925, 25,288 pg/g), respectively. Of the 429 positive fentanyl and/or norfentanyl UC, 33 (7.7%) were only positive for fentanyl and/or norfentanyl. Of the 396 polypositive UC, morphine was the highest co-exposure with 243 UC (56.6%) being positive for both fentanyls and morphine. The second most prevalent co-exposure observed was methamphetamine/amphetamine (n = 173;40.3%) followed by cannabinoids (n = 113;26.3%) and benzoylecgonine (cocaine metabolite;n = 106;24.7%). Conclusions: Nonmedical use of fentanyl is an alarming trend in this country including this maternal demographic reported here. Fentanyl was typically found with other commonly abused substances.

Neurotoxicity of prenatal alcohol exposure on medullary pre-B?tzinger complex neurons in neonatal rats

Prenatal alcohol exposure disrupts the development of normal fetal respiratory function, but whether it perturbs respiratory rhythmical discharge activity is unclear. Furthermore, it is unknown whether the 5-hydroxytryptamine 2A receptor(5-HT2AR) is involved in the effects of prenatal alcohol exposure. In the present study, pregnant female rats received drinking water containing alcohol at concentrations of 0%, 1%, 2%, 4%, 8% or 10%(v/v) throughout the gestation period. Slices of the medulla from 2-day-old neonatal rats were obtained to record respiratory rhythmical discharge activity. 5-HT2 AR protein and m RNA levels in the pre-B?tzinger complex of the respiratory center were measured by western blot analysis and quantitative RT-PCR, respectively. Compared with the 0% alcohol group, respiratory rhythmical discharge activity in medullary slices in the 4%, 8% and 10% alcohol groups was decreased, and the reduction was greatest in the 8% alcohol group. Respiratory rhythmical discharge activity in the 10% alcohol group was irregular. Thus, 8% was the most effective alcohol concentration at attenuating respiratory rhythmical discharge activity. These findings suggest that prenatal alcohol exposure attenuates respiratory rhythmical discharge activity in neonatal rats by downregulating 5-HT2 AR protein and m RNA levels.

Prenatal amoxicillin exposure induces developmental toxicity in fetal mice and its characteristics

Amoxicillin,a widely used antibiotic in human and veterinary pharmaceuticals,is now considered as an“emerging contaminant”because it exists widespreadly in the environment and brings a series of adverse outcomes.Currently,systematic studies about the developmental toxicity of amoxicillin are still lacking.We explored the potential effects of amoxicillin exposure on pregnancy outcomes,maternal/fetal serum phenotypes,and fetal multiple organ development in mice,at different doses(75,150,300 mg/(kg·day))during late-pregnancy,or at a dose of 300 mg/(kg·day)during different stages(mid-/latepregnancy)and courses(single-/multi-course).Results showed that prenatal amoxicillin exposure(PAmE)had no significant infuence on the body weights of dams,but it could inhibit the physical development and reduce the survival rate of fetuses,especially during the midpregnancy.Meanwhile,PAmE altered multiple maternal/fetal serum phenotypes,especially in fetuses.Fetal multi-organ function results showed that PAmE inhibited testicular/adrenal steroid synthesis,long bone/cartilage and hippocampal development,and enhanced ovarian steroid synthesis and hepatic glycogenesis/lipogenesis,and the order of severity might be gonad(testis,ovary)>liver>others.Further analysis found that PAmE-induced multiorgan developmental and functional alterations had differences in stages,courses and fetal gender,and the most obvious changes might be in high-dose,late-pregnancy and multicourse,but there was no typical rule of a dose-response relationship.In conclusion,this study confirmed that PAmE could cause abnormal development and multi-organ function alterations,which deepens our understanding of the risk of PAmE and provides an experimental basis for further exploration of the long-term harm.

Prenatal nicotine alters development of the laterodorsal tegmentum:Possible role for attention-deficit/hyperactivity disorder and drug dependence

As we cycle between the states of wakefulness and sleep,a bilateral cholinergic nucleus in the pontine brain stem,the laterodorsal tegmentum(LDT),plays a critical role in controlling salience processing,attention,behavioral arousal,and electrophysiological signatures of the sub-and microstates of sleep.Disorders involving abnormal alterations in behavioral and motivated states,such as drug dependence,likely involve dysfunctions in LDT signaling.In addition,as the LDT exhibits connectivity with the thalamus and mesocortical circuits,as well as receives direct,excitatory input from the prefrontal cortex,a role for the LDT in cognitive symptoms characterizing attention-deficit/hyperactivity disorder(ADHD)including impulsivity,inflexibility,and dysfunctions of attention is suggested.Prenatal nicotine exposure(PNE)is associated with a higher risk for later life development of drug dependence and ADHD,suggesting alteration in development of brain regions involved in these behaviors.PNE has been shown to alter glutamate and cholinergic signaling within the LDT.As glutamate and acetylcholine are major excitatory mediators,these alterations would likely alter excitatory output to target regions in limbic motivational circuits and to thalamic and cortical networks mediating executive control.Further,PNE alters neuronal development and transmission within prefrontal cortex and limbic areas that send input to the LDT,which would compound effects of differential processing within the PNE LDT.When taken together,alterations in signaling in the LDT are likely to play a role in negative behavioral outcomes seen in PNE individuals,including a heightened risk of drug dependence and ADHD behaviors.

Neonatal Cord Tox Panel and Maternal Perinatal Fentanyl Exposure: A Retrospective Chart Review

Objective: The specific aim of this study was to determine if the currently available cutoff for fentanyl in umbilical cord (UC) was appropriate to distinguish illicit fentanyl exposure from therapeutic in-hospital administration of fentanyl. Study Design: Medical record review was conducted for perinatal administration of fentanyl and the detection of fentanyl in the corresponding routine UC toxicology. Specimens were initially tested with immunoassay followed by mass spectrometry (n = 62). Result: Excluding a single specimen that was confirmed positive, specimens were below the assays’ limit of quantification. The immunoassay’s mean b/b0 for the cases that received and did not receive fentanyl prior to delivery was 91.3% ± 10.6% and 98.2% ± 6.5%, respectively (p = 0.003). Conclusion: We demonstrated that UC is a suitable specimen type for the detection of fentanyl and that the cutoff selected adequately identifies illicit fentanyl use while not flagging cases where fentanyl was administered by the hospital prior to birth.

Pyridoxal 5'-phosphate alleviates prenatal pyridaben exposureinduced anxiety-like behaviors in offspring

Pyridaben(PY)is a widely used organochlorine acaricide,which can be detected in the peripheral blood of pregnant women.Available evidence suggests that PY has reproductive toxicity.However,it remains uncertain whether prenatal PY exposure impacts neurobehavioral development in offspring.Here,we administered PY to pregnant mice at a dose of 0.5 and 5 mg kg^(-1)day^(-1)via gavage and observed anxietylike behaviors in PY offspring aged five weeks.We then integrated the metabolome and transcriptome of the offspring's brain to explore the underlying mechanism.Metabolome data indicated that the vitamin B6 metabolism pathway was significantly affected,and the pyridoxal 50-phosphate(PLP)concentration and the active form of vitamin B6 was significantly reduced.Moreover,the transcriptome data showed that both PLP generation-related Pdxk and anxiety-related Gad1 were significantly down-regulated.Meanwhile,there was a decreasing trend in the concentration of GABA in the hippocampal DG region.Next,we supplemented PLP at a dose of 20 mg kg^(-1)day^(-1)to the PY offspring via intraperitoneal injection at three weeks.We found up-regulated expression of Pdxk and Gad1 and restored anxiety-like behaviors.This study suggests that prenatal exposure to PY can disrupt vitamin B6 metabolism,reduce the concentration of PLP,down-regulate the expression levels of Pdxk and Gad1,inhibit the production of GABA,and ultimately lead to anxiety-like behaviors in offspring.

Association between antibiotic exposure and adverse outcomes of children and pregnant women: evidence from an umbrella review

Background Antibiotics are widely prescribed among children and pregnant women,but their safety profile is controversial.This study aimed to summarize and appraise current evidence for the potential impact of antibiotic exposure on pregnancy outcomes and children’s health.Methods PubMed,Embase,Web of Science and the Cochrane Database of Systematic Reviews were searched from inception to June 2022.Meta-analyses of any study design comparing the impact of antibiotic exposure with nonexposure among children,pregnant women and prepregnant women on adverse health outcomes of children and pregnancy were retrieved.The quality of evidence was assessed by a Measurement Tool to Assess Systematic Reviews 2(AMSTAR2)and the Grading of Recommendations,Assessment,Development and Evaluation(GRADE).Data were reanalyzed,and the credibility of the evidence was determined.Results Out of 2956 studies identified,19 articles with 39 associations were included.Totally 19 of the associations(48.72%)were statistically significant with a P value≤0.05,while only six were supported by highly suggestive evidence.Children with postnatal antibiotic exposure had a higher risk of developing asthma odds ratio(OR):1.95,95%confidence interval(CI):1.76–2.17,wheezing(OR:1.81,95%CI 1.65–1.97)and allergic rhinoconjunctivitis(OR:1.66,95%CI 1.51–1.83),with prediction intervals excluding the nulls.Quality assessed by both AMSTAR2 and GRADE of included meta-analyses were very low in general.Conclusions Antibiotic exposure in early life was associated with children’s long-term health,especially in cases of allergic diseases.Prenatal exposure might also influence children’s health in some aspects but requires more high-quality evidence.Potential adverse effects of antibiotics on pregnancy outcomes were not observed in our study.Studies with higher quality and better quantification of antibiotic exposure are needed in the future.

Prenatal metal mixture exposure and birth weight: A two-stage analysis in two prospective cohort studies

The understanding of the impact of prenatal exposure to metal mixtures on birth weight is limited.We aimed to identify metal mixture components associated with birth weight and to determine additional pairwise interactions between metals showing such associations.Concentrations of 18 metals were measured using inductively coupled plasma mass spectrometry in urine samples collected in the 3rd trimester from a prenatal cohort(discovery;n=1849)and the Healthy Baby Cohort(replication;n=7255)in Wuhan,China.In the discovery set,we used two penalized regression models,i.e.,elastic net regression for main effects and a lasso for hierarchical interactions,to identify important mixture components associated with birth weight,which were then replicated.We observed that 8 of the 18 measured metals were retained by elastic net regression,with five metals(vanadium,manganese,iron,cesium,and barium)showing negative associations with Z-scores for birth weight and three metals(cobalt,zinc,and strontium)showing positive associations.In replication set,associations remained significant for vanadium(β=-0.035;95%confidence interval[CI],-0.059 to0.010),cobalt(β=-0.073;95%CI,0.049 to 0.097),and zinc(β=-0.040;95%CI,0.016 to 0.065)after Bonferroni correction.We additionally identified and replicated a single pairwise interaction between iron and copper exposure on birth weight(P<0.001).Using a two-stage analysis,we identified and replicated individual metals and additional pairwise interactions-associated birth weight.The approach could be used in other studies estimating the effect of complex mixtures on human health.

Psychotropic drug abuse in pregnancy and its impact on child neurodevelopment:A review

Substance abuse by women of child-bearing age and fetal in utero drug exposure has increased in the number of infants born with health issues.Prenatal exposure to psychoactive substances can lead to neurological and neurodevelopmental deficits later in life.Useful data concerning the effects of psychoactive drugs on fetal neurodevelopmental status are sparse.Understanding the neurodevelopmental consequences of prenatally drug-exposed children has become a pressing global concern.The aim of this review is to gather current evidence and information on neurodevelopmental outcomes of in utero drug exposure.A literature search was performed on the PubMed,Scopus,and Google Scholar databases using the terms“psychotropic drugs”,“neurodevelopmental consequences”,“prenatal drug exposure”,and“pregnancy”.Available studies on in utero drug exposure were reviewed and found to support the idea that some degree of health issues are present in fetuses and children.Different psychoactive substances have profound neurodevelopmental consequences,such as structural brain changes,poor attention span,Down syndrome,attention deficit hyperactivity disorder,autism spectrum disorder,imbalances in neurotransmitter levels,and many structural deficits.The pervasive use of psychoactive drugs in women of child-bearing age is an important health concern.Further scientific efforts are needed to investigate the effect of prenatal exposure to psychoactive drugs on children.

Postnatal renin-angiotensin system inhibition prevents renal damage from prenatal inflammation in rats

OBJECTIVE:To assess the protective role of benazepril,an angiotensin-converting enzyme inhibitor,in renal damage caused by prenatal inflammation.METHODS:Saline or lipopolysaccharide were administered intraperitoneally to pregnant Sprague-Dawley rats on gestation days 8,10,and 12.After birth,offspring received either tap water or benazepril in water between 7 and 68 weeks.Blood pressure,blood urea nitrogen,creatinine,and 24-h urine volume were measured as indices of renal function.Hematoxylin,eosin,periodic acid-Schiff,and Sirius Red staining were used to evaluate renal damage.RESULTS:Postnatal benazepril treatment ameliorated hypertension and restored normal 24-h urine volume and blood urea nitrogen and serum creatinine levels.Benazepril treatment also reduced glycoprotein accumulation and fibrosis in the glomerulus and in tubular epithelial cells and inhibited nuclear factor-kappa B activation.CONCLUSION:Together with our previous findings that postnatal inhibition of nuclear factor-kappa B activation blocks intra-renal renin-angiotensin system activation,our current data demonstrate that intra-renal activation of the renin-angiotensin system interacts with nuclear factor-kappa B activation to cause renal damage in adulthood following prenatal inflammation.

Pulmonary hypertension in extremely low birth weight infants:characteristics and outcomes

Background:To determine the characteristics and outcomes of pulmonary arterial hypertension(PAH)in extremely low birth weight(ELBW)infants.Methods:A retrospective case-control study of all ELBW infants admitted to a level III neonatal intensive care unit(NICU)between January 1,2003 and December 31,2010.Results:During the study period,450 ELBW infants were admitted.6.4%(29/450)were diagnosed with PAH and were matched to 26 controls.The mean gestational age of infants with PAH and their controls were similar[24.5±1.3 vs.24.9±1.8 weeks(P=0.26)];however the cases were smaller at birth than were controls[640.7±119.5 vs.727.0±184.5 g(P=0.04)].The diagnosis of PAH was made at a mean postnatal age of 131.8±53.7 days.Infants with PAH had a higher rate of intrauterine exposure to illicit maternal drug use[12/29(41%)vs.1/25(4%);P=0.001],a longer duration of initial mechanical ventilation[74.9±28.3 vs.59.1±27.8 days;(P=0.04)],a higher incidence of severe BPD[23/29(79%)vs.13/26(50%);P=0.02],and a greater NICU mortality rate[12/29(41%)vs.4/26(15%);P=0.04].Conclusion:PAH in ELBW infants is associated with maternal illicit drug use in pregnancy,longer exposure to mechanical ventilation,severe bronchopulmonary dysplasia and a significant increase in early mortality.