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Objective Methods Results Significance The human brain undergoes an activity‐dependent organization during late gestation, making it very sensitive to all effects on the spontaneous neuronal activity. Pregnant mothers with epilepsy are treated with antiepileptic drugs (AEDs) that may reach the fetus and cause altered cortical network activity after birth. However, it is not known whether these functional effects of intrauterine AED exposure persist later in childhood.We studied cortical activity networks computed from electroencephalographic recordings during sleep of 25, 6‐year‐old children with in utero exposure to AEDs and 21 without exposure. The frequency‐specific networks were determined for N1 and N2 sleep states, and the study groups were compared for sleep‐state–specific changes and dynamic differences between sleep states. Finally, we correlated these difference networks with the children's neurophysiological performance at 6 years.We found brain‐wide changes in the cortical activity networks and their sleep‐state dynamics in the children with intrauterine AED exposure. Moreover, the strength of cortical network connectivity was significantly associated with multiple domains of neurocognitive performance, in particular, verbal comprehension, processing speed, and IQ. Our findings together suggest that fetal AED exposure causes very long‐lasting changes in the cortical networks with significant links to early school‐age cognitive performance.AED treatment of pregnant mothers is indicated for maternal health reasons; however, the long‐term neurodevelopmental effects on the offspring are poorly understood. Our present study shows that in utero exposure to AEDs causes persisting changes in the cortical activity networks, which can be measured with electroencephalography at 6 years of age. Moreover, these network changes correlate to the child's neurocognitive performance at the same age. These findings together suggest a pathway for how fetal drug exposures may cause persisting and neurocognitively meaningful changes in cortical connectivity patterns. [ABSTRACT FROM AUTHOR]

The article discusses the challenges of drug exposure to fetuses and infants during pregnancy and lactation, leading to the exclusion of pregnant and lactating women from clinical trials. Regulatory initiatives like the Diversity Action Plan and E21 Efficacy Guidelines aim to increase inclusion in clinical studies. Pharmacometrics and systems pharmacology play a crucial role in making studies more inclusive and optimizing drug therapy for pregnant and lactating women. The article highlights the importance of robust data on drug exposure, non-clinical safety data, and quantitative applications to inform drug therapy decisions for pregnant and lactating women. [Extracted from the article]

The article discusses the underutilization of pharmacometrics in obstetrics and maternal-fetal medicine research, despite the widespread use of medications during pregnancy. It highlights the importance of leveraging mathematical models like PBPK and PopPK approaches to predict maternal and fetal drug exposure, optimize therapeutic regimens, and address drug safety concerns. The text also emphasizes the need for advanced modeling approaches to improve drug dosing, efficacy, and safety profiles during pregnancy, as well as the challenges and barriers hindering the implementation of pharmacometrics in obstetrics. Overall, the article underscores the potential of pharmacometrics to enhance personalized drug therapy for pregnant women and improve outcomes for both mother and baby. [Extracted from the article]

The article discusses the challenges of using medicines during pregnancy due to limited clinical data and the need for a clinical pharmacology extrapolation framework to support pregnancy drug development strategies. It highlights the regulatory landscape, the impact of pregnancy-related physiological changes on drug exposure, and the importance of including pregnant women in clinical trials. The article emphasizes the need for an extrapolation approach to generate data in pregnancy, focusing on mother and fetal safety management, study design, and labeling updates. Additionally, it suggests using model-informed drug development (MIDD) approaches, such as physiologically-based pharmacokinetic (PBPK) modeling, to predict drug exposure and inform dosing decisions during pregnancy. [Extracted from the article]

The article discusses the underrepresentation of pregnant individuals in clinical trials and drug development programs, leading to a lack of safety and efficacy data for this population. It highlights the importance of model‐informed drug development (MIDD) tools and early engagement between pharmaceutical companies and regulatory agencies. The use of physiologically-based pharmacokinetic (PBPK) modeling, toxicology modeling, quantitative systems pharmacology, real-world data, and machine learning are proposed as methods to enhance drug development for pregnant individuals. Efforts to improve inclusivity in clinical trials for pregnant individuals are ongoing, with regulatory agencies emphasizing the need for postmarketing required (PMR) studies to gather essential information. [Extracted from the article]

It is critical to understand the impact of significant physiological changes during pregnancy on the extent of maternal and fetal drug exposure. Fostemsavir (FTR) is a prodrug of temsavir (TMR) and is approved in combination with other antiretrovirals for multi‐drug‐resistant human immunodeficiency virus (HIV) infections. This physiologically based pharmacokinetic model (PBPK) study was used to estimate TMR PK in pregnant populations during each trimester of pregnancy to inform FTR dosing. A PBPK model was developed and validated for TMR using PK data collected following intravenous TMR and oral FTR dosing (immediate‐release and extended‐release tablets) in healthy volunteers. Predicted TMR concentration–time profiles accurately predicted the reported clinical data and variability in healthy (dense data) and pregnant (sparse data) populations. Predicted versus observed TMR geometric mean (CV%) clearance following intravenous administration was 18.01 (29) versus 17 (21) (L/h). Predicted versus observed TMR AUC0–inf (ng.h/mL) in healthy volunteers following FTR administration of the extended‐release tablet were 9542 (66) versus 7339 (33). The validated TMR PBPK model was then applied to predict TMR PK in a population of pregnant individuals during each trimester. Simulations showed TMR AUC in pregnant individuals receiving FTR 600 mg twice daily was decreased by 25% and 38% in the second and third trimesters, respectively. However, TMR exposure remained within the range observed in nonpregnant adults with no need for dose adjustment. The current PBPK model can also be applied for the prediction of local tissue concentrations and drug–drug interactions in pregnancy. [ABSTRACT FROM AUTHOR]

Fetal exposures to many drugs of abuse, e.g., opioids and alcohol (EtOH), are associated with adverse neurodevelopmental problems in early childhood, including abnormalities in activity of the serotonin (5HT) transporter (SERT), which transports 5HT across the placenta. Little is known about the effects of these drugs on SERT expression. Pregnant women who used EtOH or opioids were compared to gestational age-matched controls using a structured questionnaire to determine prenatal substance exposure. Following elective pregnancy termination, placental membranous vesicles and exosomes were prepared from first and second trimester human placentas. Changes in EtOH- or opioid-exposed placental SERT expression and modifications were assessed by quantitative western blot. Novel SERT isoforms were sequenced and analyzed. Opioid-exposed but not EtOH-exposed maternal placentas showed SERT cleavage and formation of new SERT fragments (isoforms). Alcohol-exposed cases showed reduced SERT levels. Antibodies to the N-terminal SERT region did not recognize either of the two cleavage products, while antibodies to the central and C-terminal regions recognized both bands. The secondary band seen in the opioid group may represent a hypophosphorylated SERT fragment. These changes in SERT modifications and expression may result in altered fetal brain serotonergic neurotransmission, which could have neurodevelopmental implications. [ABSTRACT FROM AUTHOR]

This document explores the relationship between antiepileptic drugs (AEDs), folate, one-carbon metabolism, genetics, and epigenetics. It highlights the potential complications that can arise from AEDs interfering with folate metabolism, such as cognitive, mood, and psychiatric issues. The document also discusses the risks associated with the use of valproate, a commonly used AED, and emphasizes the importance of folic acid supplementation during pregnancy, especially for women taking AEDs. Further research is needed to fully understand the mechanisms involved and develop preventive measures. The document does not provide any specific recommendations or conclusions. [Extracted from the article]

Background: Prenatal and postnatal exposure to drugs such as cocaine is a public health problem that causes deficits in brain development and function in humans and animals. One of the main effects of prenatal and postnatal cocaine exposure is increased vulnerability to developing the substance use disorder at an early age. Furthermore, the negative emotional states associated with cocaine withdrawal increase the fragility of patients to relapse into drug abuse. In this sense, prenatal and postnatal cocaine exposure enhanced the cocaine‐ and nicotine‐induced locomotor activity and locomotor sensitization, and rats exposed prenatally to cocaine displayed an increase in anxiety‐ and depressive‐like behaviors in adulthood (PND 60–70). Objective: Therefore, the objective of this study was to determine the effect of prenatal and postnatal cocaine exposure on anxiety‐ and depressive‐like behaviors at different ages (30, 60, 90, and 120 days of age) in rats. Methods: The study was divided into two stages: prenatal and postnatal. In the prenatal stage, a group of pregnant female Wistar rats was administered daily from GD0 to GD21 cocaine (cocaine pre‐exposure group), and another group of pregnant female rats was administered daily saline (saline pre‐exposure group). In the postnatal stage, during lactation (PND0 to PND21), pregnant rats received administration of cocaine or saline, respectively. Of the litters resulting from the cocaine pre‐exposed and saline pre‐exposed pregnant female groups, only the male rats were used for the recording of the anxiety‐ and depressive‐like behaviors at different postnatal ages (30, 60, 90, and 120 days), representative of adolescence, adult, adulthood, and old age. Results: The study found that prenatal and postnatal cocaine exposure generated age‐dependent enhancement in anxiety‐ and depressive‐like behaviors, being greater in older adult (PND 120) rats than in adolescent (PND 30) or adults (PND 60–90) rats. Conclusions: This suggests that prenatal and postnatal cocaine exposure increases anxiety‐ and depressive‐like behaviors, which may increase the vulnerability of subjects to different types of drugs in young and adult age. [ABSTRACT FROM AUTHOR]

This article discusses the characteristics of newborns and birthing parents affected by Neonatal Abstinence Syndrome (NAS) in Rhode Island from 2020 to 2023. NAS occurs when newborns experience withdrawal symptoms from prenatal drug exposure, primarily opioids. The study found that the incidence of NAS in Rhode Island decreased during the study period. Newborns with NAS were more likely to have low birthweight, be preterm, and require admission to the neonatal intensive care unit. The study also provides demographic information about the birthing parents of NAS cases. The findings suggest that reducing stigma, improving access to prenatal care, and expanding medication for opioid use disorder (MOUD) use could improve outcomes for newborns with NAS and their parents. [Extracted from the article]

Summary: Often, causal mediation analysis is of interest when both the mediator and the final outcome are repeatedly measured, but limited work has been done for this situation (as opposed to where only the mediator is repeatedly measured). Available methods are primarily based on parametric models and tend to be sensitive to model assumptions. This article presents semiparametric, continuous‐time models to provide a flexible and robust approach to causal mediation analysis for longitudinal data, which allows these data to be unbalanced or irregular. Specifically, the method uses spline linear mixed‐effects models for the mediator and for the final outcome, with a two‐step approach to model‐fitting in which a predicted mediator is used as a covariate in the final outcome model. The models allow flexible functions for both the mean and individual response functions for each outcome. We derive estimated natural direct and indirect effects as a function of time using an extended mediation formula and sequential ignorability assumption. In simulation studies, we compare properties of estimated direct and indirect effects, and a delta method estimate of the standard error of the latter, under alternative approaches for predicting the mediator. The approach is illustrated using harmonised data from two cohort studies to examine attention as a mediator of the effect of prenatal tobacco exposure on externalising behaviour in children. [ABSTRACT FROM AUTHOR]

Clinical studies demonstrate that the risk of developing neurological disorders is increased by overconsumption of the commonly used drugs, alcohol, nicotine and cannabis. These drug-induced neurological disorders, which include substance use disorder (SUD) and its co-occurring emotional conditions such as anxiety and depression, are observed not only in adults but also with drug use during adolescence and after prenatal exposure to these drugs, and they are accompanied by long-lasting disturbances in brain development. This report provides overviews of clinical and preclinical studies, which confirm these adverse effects in adolescents and the offspring prenatally exposed to the drugs and include a more in-depth description of specific neuronal systems, their neurocircuitry and molecular mechanisms, affected by drug exposure and of specific techniques used to determine if these effects in the brain are causally related to the behavioral disturbances. With analysis of further studies, this review then addresses four specific questions that are important for fully understanding the impact that drug use in young individuals can have on future pregnancies and their offspring. Evidence demonstrates that the adverse effects on their brain and behavior can occur: (1) at low doses with short periods of drug exposure during pregnancy; (2) after pre-conception drug use by both females and males; (3) in subsequent generations following the initial drug exposure; and (4) in a sex-dependent manner, with drug use producing a greater risk in females than males of developing SUDs with emotional conditions and female offspring after prenatal drug exposure responding more adversely than male offspring. With the recent rise in drug use by adolescents and pregnant women that has occurred in association with the legalization of cannabis and increased availability of vaping tools, these conclusions from the clinical and preclinical literature are particularly alarming and underscore the urgent need to educate young women and men about the possible harmful effects of early drug use and to seek novel therapeutic strategies that might help to limit drug use in young individuals. [ABSTRACT FROM AUTHOR]

In 2018, a significant neural tube defects (NTD) signal was reported after pre‐conceptional exposure to dolutegravir, but was not confirmed in further analysis. Since 2019, dolutegravir‐based regimen, an integrase inhibitor (INI), is recommended by WHO as the most‐effective first‐line therapy in all patients living with HIV. To explore the potential INI‐related teratogenic effect, we searched disproportionate signals between exposure to INI‐class drugs and congenital anomalies, compared to non‐INI drugs, using the international pharmacovigilance database, VigiBase®. We selected all the reports registered in VigiBase® between 01/01/2007 and 30/03/2021 on any antiretroviral drug‐related fetal or neonatal adverse drug reactions, declared either in children (<2 years) exposed in utero or in pregnant women (12–50 years). A case/non‐case study was conducted to detected signals between congenital anomalies and prenatal exposure to any INI‐class drug, compared to non‐INI drugs, by estimating adjusted reporting odds ratios (aROR) with 95% confidence intervals (95%CI). We identified 2521 unique reports, among which 664 (26.3%) were related to INI‐class use. Overall, 520 congenital anomalies were cited from 327 unique reports, of whom 31.0% were INI‐related. Compared to non‐INI drugs, no significant disproportionate reporting signal between prenatal exposure to INI‐class drugs and congenital anomalies was found (aROR 1.13; 95% CI:0.85–1.51). However, specific significant signals were reported for raltegravir/elvitegravir/dolutegravir drug exposure and urinary malformations (aROR 2.43; 95%CI:1.08–5.43), digestive malformations (aROR 3.09; 95%CI:1.22–7.84), and NTDs (aROR 3.02; 95%CI:1.09–8.37). Although specific congenital anomalies signals associated with raltegravir/elvitegravir/dolutegravir exposure were notified, causal relationship needs to be further investigated in prospective studies. [ABSTRACT FROM AUTHOR]

El Niño Southern Oscillation (ENSO) has been shown to relate to the epidemiology of childhood infectious diseases, but evidence for whether they increase child deaths is limited. Here, we investigate the impact of mothers' ENSO exposure during and prior to delivery on child mortality by constructing a retrospective cohort study in 38 low- and middle-income countries. We find that high levels of ENSO indices cumulated over 0–12 lagged months before delivery are associated with significant increases in risks of under-five mortality; with the hazard ratio ranging from 1.33 (95% confidence interval [CI], 1.26, 1.40) to 1.89 (95% CI, 1.78, 2.00). Child mortality risks are particularly related to maternal exposure to El Niño-like conditions in the 0th–1st and 6th–12th lagged months. The El Niño effects are larger in rural populations and those with unsafe sources of drinking water and less education. Thus, preventive interventions are particularly warranted for the socio-economically disadvantaged. El Niño Southern Oscillation (ENSO) has been shown to relate to the epidemiology of child infectious diseases, but evidence for child deaths is limited. Here, the authors show that maternal exposure to high levels of ENSO before conception and giving birth may increase under-five mortality. [ABSTRACT FROM AUTHOR]

Expression of the breast cancer resistance protein (BCRP/ABCG2) transporter is downregulated in placentas from women with preeclampsia (PE) and in an immunological rat model of PE. While many drugs are substrates of this important efflux transporter, the impact of PE associated BCRP downregulation on maternal and fetal drug exposure has not been investigated. Using the PE rat model, we performed a pharmacokinetic study with rosuvastatin (RSV), a BCRP substrate, to investigate this impact. PE was induced in rats during gestational days (GD) 13 to 16 with daily low-dose endotoxin. On GD18, RSV (3 mg/kg) was administrated intravenously, and rats were sacrificed at time intervals between 0.5 and 6 h. As compared to controls, placental expression of Bcrp and Oatp2b1 significantly decreased in PE rats. A corresponding increase in RSV levels was seen in fetal tissues and amniotic fluid of the PE group (p < 0.05), while maternal plasma concentrations remained unchanged from the controls. An increase in Bcrp expression and decreased RSV concentration were seen in the livers of PE dams. This suggests that PE-mediated transporter dysregulation leads to significant changes in the maternal and fetal RSV disposition. Overall, our findings demonstrate that altered placental expression of transporters in PE can increase fetal accumulation of their substrates. [ABSTRACT FROM AUTHOR]

Prenatal and infant exposure to drugs of abuse is an emerging social and public health problem affecting children health and which may relate to child abuse and neglect. Exposure to drugs of abuse may occur through different routes, including intrauterine, breastfeeding, accidental intake, passive inhalation, and intentional administration. Currently, cases of suspected exposure can be investigated by hair toxicological analysis, the interpretation of which is, however, often difficult, leading to consequent difficulties in the management of such cases. In order to provide a contribution in terms of interpretation of the analytical results, this study aimed to search for the possible existence of elements, from a toxicological point of view, indicative towards the route of exposure. A retrospective study was performed on cases of suspected exposure to drugs of abuse in children aged 0–1 year, evaluated at a University Hospital between 2018 and 2022. Data of children hair toxicological analysis were analyzed and then compared with those of their mothers, when available; 41.6% children tested positive for cocaine. The study found a significant correlation between cocaine and benzoylecgonine concentrations, and a benzoylecgonine/cocaine ratio that tends to decrease as the age of children increases. From the comparison with mothers, a child/mother cocaine concentration ratio lower than 1 was found in all cases of hair sampled within the first week of life, and a ratio greater than or equal to 1 in all cases in which the sampling was performed later. These results, if confirmed in a larger cohort, could represent a contribution in the interpretation of cases of infant exposure to drugs of abuse and be integrated in the context of their multidisciplinary evaluation. [ABSTRACT FROM AUTHOR]

Abstract Background Children exposed prenatally to alcohol or cannabinoids individually can exhibit growth deficits and increased risk for adverse birth outcomes. However, these drugs are often co-consumed and their combined effects on early brain development are virtually unknown. The blood vessels of the fetal brain emerge and mature during the neurogenic period to support nutritional needs of the rapidly growing brain, and teratogenic exposure during this gestational window may therefore impair fetal cerebrovascular development. Study Design To determine whether prenatal polysubstance exposure confers additional risk for impaired fetal-directed blood flow, we performed high resolution in vivo ultrasound imaging in C57Bl/6J pregnant mice. After pregnancy confirmation, dams were randomly assigned to one of four groups: drug-free control, alcohol-exposed, cannabinoid-exposed or alcohol-and-cannabinoid-exposed. Drug exposure occurred daily between Gestational Days 12–15, equivalent to the transition between the first and second trimesters in humans. Dams first received an intraperitoneal injection of either cannabinoid agonist CP-55,940 (750 µg/kg) or volume-equivalent vehicle. Then, dams were placed in vapor chambers for 30 min of inhalation of either ethanol or room air. Dams underwent ultrasound imaging on three days of pregnancy: Gestational Day 11 (pre-exposure), Gestational Day 13.5 (peri-exposure) and Gestational Day 16 (post-exposure). Results All drug exposures decreased fetal cranial blood flow 24-hours after the final exposure episode, though combined alcohol and cannabinoid co-exposure reduced internal carotid artery blood flow relative to all other exposures. Umbilical artery metrics were not affected by drug exposure, indicating a specific vulnerability of fetal cranial circulation. Cannabinoid exposure significantly reduced cerebroplacental ratios, mirroring prior findings in cannabis-exposed human fetuses. Post-exposure cerebroplacental ratios significantly predicted subsequent perinatal mortality (p = 0.019, area under the curve, 0.772; sensitivity, 81%; specificity, 85.70%) and retroactively diagnosed prior drug exposure (p = 0.005; AUC, 0.861; sensitivity, 86.40%; specificity, 66.7%). Conclusions Fetal cerebrovasculature is significantly impaired by exposure to alcohol or cannabinoids, and co-exposure confers additional risk for adverse birth outcomes. Considering the rising potency and global availability of cannabis products, there is an imperative for research to explore translational models of prenatal drug exposure, including polysubstance models, to inform appropriate strategies for treatment and care in pregnancies affected by drug exposure.

Introduction: Drug trials in neonates are scarce, and the neonates may consequently be at risk of adverse drug reactions (ADRs). Spontaneous ADR reporting is an important tool for expanding the knowledge on drug safety in neonates. This study explores the quality of current neonatal ADR reports and the ADR reports of the most common drugs used in neonatal departments. Methods: An observational cross-sectional study focused on neonates was conducted using data on spontaneous reports extracted from the U.S. Food and Drug Administration Adverse Events Reporting System (FAERS) from the third quarter of 2014 up to December 2022. Only the primary suspect drugs given to neonates or subjects aged <30 days were included in the analysis. Results: Spontaneous reports from 13 million patients of all ages, totaling 50 million ADRs, were evaluated. Information regarding the age was missing in 40% of the reports, and data on 43,737 neonates with 948 different suspected drugs were identified and included in the analysis. We report the frequency of spontaneous ADR reports in the FAERS database for the ten most frequently administered drugs in neonatal intensive care units in the USA. Conclusion: Overall, neonatal ADRs are still underreported. The FAERS database in its current form discriminates insufficiently between prenatal and postnatal drug exposures. Hence, improved neonatal pharmacovigilance systems are urgently needed. [ABSTRACT FROM AUTHOR]

Fetal Alcohol Spectrum Disorders affect up to 5% of the population, with additional children affected by prenatal drug exposures. The majority of these children display symptoms of ADHD and poor emotional dysregulation, a common reason for seeking psychiatric care. However, high prevalence of comorbid look-alike symptoms and limited availability of evidence-based treatments complicates psychiatric decision making in this population. The goal of the current study is to report on the effectiveness of psychotropic medications in a case series of 16 individuals with prenatal alcohol/drug exposure and propose a model for psychiatric care for this population. In addition to traditional subjective reports, an objective continuous performance test (T.O.V.A.®) was used to aid with guiding treatment. We found that T.O.V.A.®-scores improved on average from − 6.5 to − 2.9 with our psychiatric approach (p = 0.03). T.O.V.A.®-measurements were helpful in differentiating ADHD symptoms from comorbid symptoms and to guide decision-making on starting and changing medications. [ABSTRACT FROM AUTHOR]

Children and youths diagnosed with FASD may experience a range of adverse health and social outcomes. This cross-sectional study investigated the characteristics and outcomes of children and youths diagnosed with FASD between 2015 and 2018 at the Sunny Hill Centre in British Columbia, Canada and examined the relationships between prenatal substance exposures, FASD diagnostic categories, and adverse health and social outcomes. Patient chart data were obtained for 1187 children and youths diagnosed with FASD and analyzed. The patients (mean age: 9.7 years; range: 2–19) had up to 6 physical and 11 mental health disorders. Prenatal exposure to other substances (in addition to alcohol) significantly increased the severity of FASD diagnosis (OR: 1.18): the odds of FASD with sentinel facial features (SFF) were 41% higher with prenatal cigarette/nicotine/tobacco exposure; 75% higher with exposure to cocaine/crack; and two times higher with exposure to opioids. Maternal mental health issues and poor nutrition also increase the severity of FASD diagnosis (60% and 6%, respectively). Prenatal exposure to other substances in addition to alcohol significantly predicts involvement in the child welfare system (OR: 1.52) and current substance use when adjusted for age (aOR: 1.51). Diagnosis of FASD with SFF is associated with an increased number of physical (R2 = 0.071, F (3,1183) = 30.51, p = 0.000) and mental health comorbidities (R2 = 0.023, F (3,1185) = 9.51, p = 0.000) as compared to FASD without SFF adjusted for age and the number of prenatal substances. Screening of pregnant women for alcohol and other substance use, mental health status, and nutrition is extremely important. [ABSTRACT FROM AUTHOR]

Over the past two decades, Opioid Use Disorder (OUD) among pregnant women has become a major global public health concern. OUD has been characterized as a problematic pattern of opioid use despite adverse physical, psychological, behavioral, and or social consequences. Due to the relapsing-remitting nature of this disorder, pregnant mothers are chronically exposed to exogenous opioids, resulting in adverse neurological and neuropsychiatric outcomes. Collateral fetal exposure to opioids also precipitates severe neurodevelopmental and neurocognitive sequelae. At present, much of what is known regarding the neurobiological consequences of OUD and prenatal opioid exposure (POE) has been derived from preclinical studies in animal models and postnatal or postmortem investigations in humans. However, species-specific differences in brain development, variations in subject age/health/background, and disparities in sample collection or storage have complicated the interpretation of findings produced by these explorations. The ethical or logistical inaccessibility of human fetal brain tissue has also limited direct examinations of prenatal drug effects. To circumvent these confounding factors, recent groups have begun employing induced pluripotent stem cell (iPSC)-derived brain organoid technology, which provides access to key aspects of cellular and molecular brain development, structure, and function in vitro. In this review, we endeavor to encapsulate the advancements in brain organoid culture that have enabled scientists to model and dissect the neural underpinnings and effects of OUD and POE. We hope not only to emphasize the utility of brain organoids for investigating these conditions, but also to highlight opportunities for further technical and conceptual progress. Although the application of brain organoids to this critical field of research is still in its nascent stages, understanding the neurobiology of OUD and POE via this modality will provide critical insights for improving maternal and fetal outcomes. [ABSTRACT FROM AUTHOR]

Background: Evaluating drug transplacental clearance is vital for forecasting fetal drug exposure. Ex vivo human placenta perfusion experiments are the most suitable approach for this assessment. Various in silico methods are also proposed. This study aims to compare these prediction methods for drug transplacental clearance, focusing on the large molecular weight drug vancomycin (1449.3 g/mol), using maternal–fetal physiologically based pharmacokinetic (m-f PBPK) modeling. Methods: Ex vivo human placenta perfusion experiments, in silico approaches using intestinal permeability as a substitute (quantitative structure property relationship (QSPR) model and Caco-2 permeability in vitro-in vivo correlation model) and midazolam calibration model with Caco-2 scaling were assessed for determining the transplacental clearance (CLPD) of vancomycin. The m-f PBPK model was developed stepwise using Simcyp, incorporating the determined CLPD values as a crucial input parameter for transplacental kinetics. Results: The developed PBPK model of vancomycin for non-pregnant adults demonstrated excellent predictive performance. By incorporating the CLPD parameterization derived from ex vivo human placenta perfusion experiments, the extrapolated m-f PBPK model consistently predicted maternal and fetal concentrations of vancomycin across diverse doses and distinct gestational ages. However, when the CLPD parameter was derived from alternative prediction methods, none of the extrapolated maternal–fetal PBPK models produced fetal predictions in line with the observed data. Conclusion: Our study showcased that combination of ex vivo human placenta perfusion experiments and m-f PBPK model has the capability to predict fetal exposure for the large molecular weight drug vancomycin, whereas other in silico approaches failed to achieve the same level of accuracy. [ABSTRACT FROM AUTHOR]

Child protection system removal within the first 30 days of life in the setting of prenatal substance exposure was associated with short interpregnancy intervals and repeat substance-exposed birth for the mother. Child protection systems often intervene after substance-exposed births but are not designed to address the postpartum needs of the delivering parent. In this retrospective cohort study, we aimed to estimate the association between early child protection system removal and high-risk subsequent birth trajectories among a cohort of mothers with substance-exposed births in California. Of 6,893 births in 2015 with documented prenatal drug and alcohol exposure, 20.4% of mothers experienced child protection system removal within 30 days after birth. First-month child protection system removal was associated with short-interval birth (adjusted hazard ratio [HR] 1.61, 95% CI, 1.09–2.36) and short-interval birth with documentation of substance exposure (adjusted HR 3.17, 95% CI, 1.65–6.08). We found that child separation was associated with an increase, not a reduction, in subsequent substance-exposed births. These findings indicate the need for focused public health and supportive services to address the treatment, health care, family-building, and psychological needs of parents with substance use during pregnancy. [ABSTRACT FROM AUTHOR]

Prenatal drug exposure is a public health problem, which results in profound behavioral problems during childhood and adolescence, mainly represented by an increase in the risk of cocaine abuse at an early age. In rodents, prenatal and postnatal cocaine exposure enhanced locomotor activity and cocaine‐ or nicotine‐induced locomotor sensitization. Various authors consider that the adverse emotional states (anxiety and depression) that occur during cocaine withdrawal are the main factors that precipitate, relapse, and increase chronic cocaine abuse, which could increase the risk of relapse of cocaine abuse. Therefore, the objective of this study was to characterize anxiety‐ and depression‐like behaviors at different times (30, 60, 90, and 120 days) of cocaine withdrawal in rats born to females exposed prenatally and postnatally to cocaine. A group of pregnant female Wistar rats were administered daily from day GD0 to GD21 with cocaine (cocaine preexposure group), and another group of pregnant female rats was administered daily with saline (saline preexposure group). Of the litters resulting from the cocaine‐pre‐exposed and saline‐pre‐exposed pregnant female groups, only the male rats were used for the recording of the anxiety‐ and depression‐like behaviors at different times (30, 60, 90, and 120 days) of cocaine withdrawal The study found that prenatal and postnatal cocaine exposure dose‐dependent enhanced anxiety‐ and depression‐like behaviors. This suggests that prenatal and postnatal cocaine exposure can result in enhanced vulnerability to cocaine abuse in young and adult humans. [ABSTRACT FROM AUTHOR]

To inform fetal drug safety, it is important to determine or predict fetal drug exposure throughout pregnancy. The former is not possible in the first or second trimester. In contrast, at the time of birth, fetal drug exposure, relative to maternal exposure, can be estimated as Kp,uu (unbound fetal umbilical venous (UV) plasma area under the curve (AUC)/unbound maternal plasma (MP) AUC), provided the observed UV/MP values, spanning the dosing interval, are available from multiple maternal‐fetal dyads. However, this fetal Kp,uu cannot be extrapolated to other drugs. To overcome the above limitations, we have used an efflux ratio‐relative expression factor (ER‐REF) approach to successfully predict the fetal Kp,uu of P‐gp substrates. Because many drugs taken by pregnant people are also BCRP substrates, here, we extend this approach to drugs that are effluxed by both placental BCRP and P‐gp or P‐gp alone. To verify our predictions, we chose drugs for which UV/MP data were available at term: glyburide and imatinib (both BCRP and P‐gp substrates) and nelfinavir (only P‐gp substrate). First, the ER of the drugs was determined using Transwells and MDCKII cells expressing either BCRP or P‐gp. Then, the ER was scaled using the proteomics‐informed REF value to predict the fetal Kp,uu of the drug at term. The ER‐REF predicted fetal Kp,uu of glyburide (0.43), imatinib (0.42), and nelfinavir (0.40) fell within two‐fold of the corresponding in vivo fetal Kp,uu (0.44, 0.37, and 0.46, respectively). These data confirm that the ER‐REF approach can successfully predict fetal drug exposure to BCRP/P‐gp and P‐gp substrates, at term. [ABSTRACT FROM AUTHOR]

Background: Children exposed prenatally to alcohol or cannabinoids individually can exhibit growth deficits and increased risk for adverse birth outcomes. However, these drugs are often co-consumed and their combined effects on early brain development are virtually unknown. The blood vessels of the fetal brain emerge and mature during the neurogenic period to support nutritional needs of the rapidly growing brain, and teratogenic exposure during this gestational window may therefore impair fetal cerebrovascular development. Study Design: To determine whether prenatal polysubstance exposure confers additional risk for impaired fetal-directed blood flow, we performed high resolution in vivo ultrasound imaging in C57Bl/6J pregnant mice. After pregnancy confirmation, dams were randomly assigned to one of four groups: drug-free control, alcohol-exposed, cannabinoid-exposed or alcohol-and-cannabinoid-exposed. Drug exposure occurred daily between Gestational Days 12–15, equivalent to the transition between the first and second trimesters in humans. Dams first received an intraperitoneal injection of either cannabinoid agonist CP-55,940 (750 µg/kg) or volume-equivalent vehicle. Then, dams were placed in vapor chambers for 30 min of inhalation of either ethanol or room air. Dams underwent ultrasound imaging on three days of pregnancy: Gestational Day 11 (pre-exposure), Gestational Day 13.5 (peri-exposure) and Gestational Day 16 (post-exposure). Results: All drug exposures decreased fetal cranial blood flow 24-hours after the final exposure episode, though combined alcohol and cannabinoid co-exposure reduced internal carotid artery blood flow relative to all other exposures. Umbilical artery metrics were not affected by drug exposure, indicating a specific vulnerability of fetal cranial circulation. Cannabinoid exposure significantly reduced cerebroplacental ratios, mirroring prior findings in cannabis-exposed human fetuses. Post-exposure cerebroplacental ratios significantly predicted subsequent perinatal mortality (p = 0.019, area under the curve, 0.772; sensitivity, 81%; specificity, 85.70%) and retroactively diagnosed prior drug exposure (p = 0.005; AUC, 0.861; sensitivity, 86.40%; specificity, 66.7%). Conclusions: Fetal cerebrovasculature is significantly impaired by exposure to alcohol or cannabinoids, and co-exposure confers additional risk for adverse birth outcomes. Considering the rising potency and global availability of cannabis products, there is an imperative for research to explore translational models of prenatal drug exposure, including polysubstance models, to inform appropriate strategies for treatment and care in pregnancies affected by drug exposure. [ABSTRACT FROM AUTHOR]

This study examined the relationship between perceived stigma in healthcare settings during pregnancy and psychological distress and well-being in the postpartum period among individuals who took opioids while pregnant. Analyses included 134 birth mothers of opioid-exposed infants. At 0–1 months postpartum, perceived stigma and psychological distress were measured using the Prenatal Opioid use Perceived Stigma scale and measures from the Patient-Reported Outcome Measurement Information System (PROMIS). Food insecurity, housing instability, and Adverse Childhood Experiences (ACEs) were also assessed. Linear and generalized linear mixed-effect models were conducted to compare PROMIS scale scores and unmet needs by stigma, adjusting for site/location, age, race/ethnicity, marital status, education, public insurance, and parity. More than half of participants (54%) perceived stigma in healthcare settings. Individuals reporting stigma had higher depression, anxiety, and anger scores (p < 0.001) indicating greater psychological distress in the postpartum period compared to those reporting no stigma, after controlling for demographic characteristics. In addition, they scored significantly lower on the PROMIS meaning and purpose scale, an indicator of well-being (p = 0.002). Those reporting stigma were more likely to have food insecurity (p = 0.003), three or more ACEs (p = 0.040), verbal or physical abuse during pregnancy (p < 0.001), and less emotional support (p = 0.006) than those who did not. An association was observed between perceived stigma in the prenatal period and psychological distress in the postpartum period, providing support for stigma reduction interventions and education for healthcare providers on trauma-informed care. [ABSTRACT FROM AUTHOR]

This document explores the use of physiologically based pharmacokinetic (PBPK) modeling to study the effects of drugs on pregnant women, lactating women, and neonates. It discusses the limitations of traditional dosing methods and the potential risks of inadequate or harmful drug effects. The document provides examples of successful applications of PBPK modeling, such as predicting drug concentrations in human milk. It emphasizes the need for further research and data to improve these models and better understand the unique physiological characteristics of these populations. The authors stress the importance of systematic searches, data integration, and clinical data in refining these models and promoting evidence-based pharmacotherapy for vulnerable populations. [Extracted from the article]

Physiological changes during pregnancy can alter maternal and fetal drug exposure. The objective of this work was to predict maternal and umbilical ceftazidime pharmacokinetics during pregnancy. Ceftazidime transplacental permeability was predicted from its physicochemical properties and incorporated into the model. Predicted concentrations and parameters from the PBPK model were compared to the observed data. PBPK predicted ceftazidime concentrations in non-pregnant and pregnant subjects of different gestational weeks were within 2-fold of the observations, and the observed concentrations fell within the 5th–95th prediction interval from the PBPK simulations. The calculated transplacental clearance (0.00137 L/h/mL of placenta volume) predicted an average umbilical cord-to-maternal plasma ratio of 0.7 after the first dose, increasing to about 1.0 at a steady state, which also agrees well with clinical observations. The developed maternal PBPK model adequately predicted the observed exposure and kinetics of ceftazidime in the pregnant population. Using a verified population-based PBPK model provides valuable insights into the disposition of drug concentrations in special individuals that are otherwise difficult to study and, in addition, offers the possibility of supplementing sparse samples obtained in vulnerable populations with additional knowledge, informing the dosing adjustment and study design, and improving the efficacy and safety of drugs in target populations. [ABSTRACT FROM AUTHOR]

Introduction: Major Depressive Disorder (MDD) is a chronic, recurrent, and highly prevalent disease that is associated with significant functional disability. During pregnancy, the prevalence of the disease is approximately 20%, with 12% of these, requiring treatment to avoid important negative consequences for the mother-baby binomial. Risk-benefit assessment of the use of antidepressants during pregnancy is mandatory, in addition to knowledge of the long-term effects of prenatal exposure to these drugs in the offspring. In this study, we will perform an updated systematic review and meta-analysis to explore the treatment of depression during pregnancy, along with its effectiveness, safety, and possible harm to women and children. Materials and methods: We will search for publications in the following databases: Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, Web of Science, Scopus, Lilacs, and PsycINFO. The reference lists of the included studies will be manually reviewed to identify potentially relevant studies. There will be no restrictions on language or date of publication. Quality assessment of the included studies will be performed independently according to the Cochrane Risk of Bias (RoB2) instrument. To assess the certainty of the findings' body of evidence, we will use the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology. This study aimed to ascertain the efficacy and safety of antidepressants in pregnant women and children. Ethics and dissemination: Ethical approval was not required as individual patient data were not collected. Dissemination: Plan to publish a systematic review in an open-access medical journal at the end of the process. [ABSTRACT FROM AUTHOR]

Background and Objective: Physiologically based pharmacokinetic (PBPK) models for pregnant women have recently been successfully used to predict maternal and umbilical cord pharmacokinetics (PK). Because there is very limited opportunity for conducting clinical and PK investigations for fetal drug exposure, PBPK models may provide further insights. The objectives of this study were to extend a whole-body pregnancy PBPK model by multiple compartments representing fetal organs, and to predict the PK of cefuroxime in the maternal and fetal plasma, the amniotic fluid, and several fetal organs. Methods: To this end, a previously developed pregnancy PBPK model for cefuroxime was updated using the open-source software Open Systems Pharmacology (PK-Sim®/MoBi®). Multiple compartments were implemented to represent fetal organs including brain, heart, liver, lungs, kidneys, the gastrointestinal tract (GI), muscles, and fat tissue, as well as another compartment lumping organs and tissues not explicitly represented. Results: This novel PBPK model successfully predicted cefuroxime concentrations in maternal blood, umbilical cord, amniotic fluid, and several fetal organs including heart, liver, and lungs. Further model validation with additional clinical PK data is needed to build confidence in the model. Conclusions: Being developed with an open-source software, the presented generic model can be freely re-used and tailored to address specific questions at hand, e.g., to assist the design of clinical studies in the context of drug research or to predict fetal organ concentrations of chemicals in the context of fetal health risk assessment. [ABSTRACT FROM AUTHOR]

This article examines the impact of conservatorships on women's reproductive rights, using Britney Spears' case as an example. It argues that conservatorships can limit a person's autonomy, including their ability to use birth control or have children, which infringes upon their constitutional right to procreate. The article also discusses the historical context of eugenics and forced sterilization in the United States, highlighting the discriminatory practices that targeted women based on race, socioeconomic status, and mental ability. It emphasizes the need for a more supportive and empowering approach to reproductive decision-making for individuals under conservatorships, and explores the concept of supportive decision-making as an alternative to conservatorships. The article also addresses the issue of forced birth control under conservatorships in California, highlighting the lack of oversight and potential for abuse within these arrangements. It advocates for recognizing the constitutional right to reproductive autonomy for individuals with disabilities and the intersection between the reproductive justice and disability rights movements. [Extracted from the article]

The World Health Organization has recommended dolutegravir (DTG) as a preferred first-line treatment for treatment naive and experienced people living with human immunodeficiency virus type one (PLWHIV). Based on these recommendations 15 million PLWHIV worldwide are expected to be treated with DTG regimens on or before 2025. This includes pregnant women. Current widespread use of DTG is linked to the drug’s high potency, barrier to resistance, and cost-effectiveness. Despite such benefits, potential risks of DTGlinked fetal neurodevelopmental toxicity remain a concern. To this end, novel formulation strategies are urgently needed in order to maximize DTG’s therapeutic potentials while limiting adverse events. In regard to potential maternal fetal toxicities, we hypothesized that injectable long-acting nanoformulated DTG (NDTG) could provide improved safety by reducing drug fetal exposures compared to orally administered native drug. To test this notion, we treated pregnant C3H/HeJ mice with daily oral native DTG at a human equivalent dosage (5 mg/kg; n = 6) or vehicle (control; n = 8). These were compared against pregnant mice injected with intramuscular (IM) NDTG formulations given at 45 (n = 3) or 25 (n = 4) mg/kg at one or two doses, respectively. Treatment began at gestation day (GD) 0.5. Magnetic resonance imaging scanning of live dams at GD 17.5 was performed to obtain T1 maps of the embryo brain to assess T1 relaxation times of drug-induced oxidative stress. Significantly lower T1 values were noted in daily oral native DTG-treated mice, whereas comparative T1 values were noted between control and NDTG-treated mice. This data reflected prevention of DTG-induced oxidative stress when delivered as NDTG. Proteomic profiling of embryo brain tissues harvested at GD 17.5 demonstrated reductions in oxidative stress, mitochondrial impairments, and amelioration of impaired neurogenesis and synaptogenesis in NDTG-treated mice. Pharmacokinetic (PK) tests determined that both daily oral native DTG and parenteral NDTG achieved clinically equivalent therapeutic plasma DTG levels in dams (4,000–6,500 ng/mL). Importantly, NDTG led to five-fold lower DTG concentrations in embryo brain tissues compared to daily oral administration. Altogether, our preliminary work suggests that long-acting drug delivery can limit DTG-linked neurodevelopmental deficits. [ABSTRACT FROM AUTHOR]

Early adversities, including prenatal drug exposure (PDE) and a negative postnatal emotional caregiving environment, impact children's long-term development. The protracted developmental course of memory and its underlying neural systems offer a valuable framework for understanding the longitudinal associations of pre- and postnatal factors on children with PDE. This study longitudinally examines memory and hippocampal development in 69 parent-child dyads to investigate how the early caregiving emotional environment affects children with PDE's neural and cognitive systems. Measures of physical health, drug exposure, caregiver stress, depression, and distress were collected between 0 and 24 months At age 14 years, adolescents completed multiple measures of episodic memory, and at ages 14 and 18 years, adolescents underwent magnetic resonance imaging (MRI) scans. Latent constructs of episodic memory and the caregiving environment were created using Confirmatory Factor Analysis. Multiple regressions revealed a negative emotional caregiving environment during infancy was associated with poor memory performance and smaller left hippocampal volumes at 14 years. Better memory performance at 14 years predicted larger right hippocampal volume at 18 years. At 18 years, the association between the emotional caregiving environment and hippocampal volume was moderated by sex, such that a negative emotional caregiving environment was associated with larger left hippocampal volumes in males but not females. Findings suggest that the postnatal caregiving environment may modulate the effects of PDE across development, influencing neurocognitive development. [ABSTRACT FROM AUTHOR]

Methadone is used as a substitute for illicit opioids during pregnancy. However, the real effect of this molecule on visual and neurodevelopmental outcomes of the children exposed is not fully understood, since studies considered subjects born to polydrug-dependent mothers and followed for few months/years. We report the long-term outcomes of two infants with congenital nystagmus solely exposed to methadone in utero. Neurological and neurovisual evaluations were performed every year from the first year of life to 11 years of age. One child was diagnosed with developmental coordination disorder. Both cases presented with ophthalmologic (refractive errors), oculomotor (nystagmus and fixation, smooth pursuit, and saccades dysfunctions), and perceptive problems (reduced visual acuity and contrast sensitivity). While nystagmus and other oculomotor dysfunctions remained stable over time, visual acuity and contrast sensitivity improved; refractive errors worsened and required corrective lenses. Both children showed normal neurodevelopmental and cognitive profile. This report highlights the long-term visual and developmental outcomes of two children exclusively exposed to methadone underlining the possibility of a visual dysfunction and motor coordination disorder. These observations prompt the need to investigate prenatal drug exposure as a cause of congenital nystagmus. [ABSTRACT FROM AUTHOR]

Data on the real long-term influences of in utero drug exposure in pregnant women on childhood development are scarce and remain not well determined and depend on the duration of in utero drug exposure and maternal drug levels. Therapeutic drug monitoring (TDM) during pregnancy may help limit fetal drug exposure while maintaining an effective dose for the treatment of the underlying inflammatory bowel disease (IBD) in women. Most antibody therapies used in patients with IBD are IgG molecules which are actively transported across the placenta, especially during the third trimester of the pregnancy. Here, we propose an up-to-date clinical review to summarize the available findings of serum drug levels in maternal blood during pregnancy, in the cord blood, infants at delivery and in breast milk of patients with IBD treated with biologics. Conversely, in comparison to adalimumab (ADA) levels, which are relatively stable during pregnancy, infliximab (IFX) drug clearance decreased significantly during the last two trimesters of the pregnancy, leading to increasing drug concentrations in the blood of the pregnant women. As most guidelines recommend using live vaccines in infants at the age of one or earlier in case of negative serum drug levels in newborns, statistical models could help clinicians in making a decision to adjust the last dose of the biologic during pregnancy and to determine the optimal date to vaccinate. Altogether, data from the literature offers strong reassurance in terms of safety for anti-TNFα therapies during pregnancy not only for IBD patients who intend to conceive, but also for pregnant women and for the physicians taking care of these patients. ADA and IFX levels in breast milk are detectable, but at very low levels, and therefore, it is recommended to pursue breast feeding under anti-TNFα therapy. Our knowledge on ustekinumab or vedolizumab levels in pregnant women remains unclear and scarce. These drugs are currently not recommended for patients with IBD in clinical practice. Therefore, TDM and proactive dose adjustment are not necessary during pregnancy since its impact on making a clinical decision have not yet been clearly demonstrated in routine practice. Overall, drug concentrations in the cord blood, an infant at birth and postpartum serum concentrations in infants, due to active placental drug transfer, may have a greater impact than the limited drug transfer in breast milk during lactation on the risk of infection and developmental outcomes. Ustekinumab and vedolizumab exposure during pregnancy and lactation are both considered low risk by the recent ECCO guidelines despite the limited data that are currently available. [ABSTRACT FROM AUTHOR]

In the therapy of placenta-originated diseases during pregnancy, the main challenges are fetal exposure to drugs, which can pass through the placenta and cause safety concerns for fetal development. The design of placenta-resident drug delivery system is an advantageous method to minimize fetal exposure as well as reduce adverse maternal off-target effects. By utilizing the placenta as a biological barrier, the placenta-resident nanodrugs could be trapped in the local placenta to concentrate on the treatment of this abnormal originated tissue. Therefore, the success of such systems largely depends on the placental retention capacity. This paper expounds on the transport mechanism of nanodrugs in the placenta, analyzes the factors that affect the placental retention of nanodrugs, and summarizes the advantages and concerns of current nanoplatforms in the treatment of placenta-originated diseases. In general, this review aims to provide a theoretical basis for the construction of placenta-resident drug delivery systems, which will potentially enable safe and efficient clinical treatment for placenta-originated diseases in the future. [ABSTRACT FROM AUTHOR]

Introduction: There is growing interest in health, developmental and survival outcomes of children who are born HIV‐free to women living with HIV (children born HIV‐free). To date, the research agenda has been largely determined by researchers, funders and policy makers, with limited involvement of parents, who are key stakeholders. Researchers at UCL Great Ormond Street Institute of Child Health in partnership with community‐based organisation 4M Network of Mentor Mothers conducted two workshops with parents in March 2022 to establish research priorities for children born HIV‐free, and key considerations for methodological approaches both to research and engagement with the affected communities. Discussion: When exploring research on children born HIV‐free, we consider the following: what aspects of current research are aligned with women and parents' priorities, what is missing and what approaches would be preferred. A holistic approach to research on children born HIV‐free should be prioritised, focussing on a breadth of outcomes and how they intersect. Secondary use of existing data sources should be maximised to facilitate this, with a view of monitoring the long‐term effects of fetal antiretroviral drug exposure alongside other key health and developmental outcomes. Involving and engaging with parents, and children where possible, must be at the heart of research design to maximise relevance and impact of findings for the affected communities. Potential barriers to engaging with individuals who were children born HIV‐free include parental disclosure and individuals not identifying as a child born HIV‐free to a mother living with HIV. Stigma‐free language must be incorporated into the vocabulary of researchers and other stakeholders, avoiding reference to exposure; we propose the term "children born HIV‐free." Conclusions: Mothers and parents living with HIV should be involved in research about their children born HIV‐free and are key in identifying research priorities so that findings may translate into an impact on their children's health and wellbeing. Meaningful involvement of women living with HIV through trusted community partners is an effective mechanism by which to elicit views on research about their children. [ABSTRACT FROM AUTHOR]

The article discusses the perspectives of two male patients who were concerned about the effects of their medication on reproductive health while planning to conceive. It highlights the importance of preconception counseling for men and the need for further research in this area. Despite theoretical concerns, studies have not shown any association between paternal drug exposure and adverse fetal outcomes, leading to updated guidelines reassuring men about the safety of conceiving while on certain medications. The patients in the cases discussed were able to proceed with their family plans without experiencing any negative effects on their conditions. [Extracted from the article]

Early adversities, including prenatal drug exposure (PDE) and a negative postnatal emotional caregiving environment, impact children’s long-term development. The protracted developmental course of memory and its underlying neural systems offer a valuable framework for understanding the longitudinal associations of pre- and postnatal factors on children with PDE. This study longitudinally examines memory and hippocampal development in 69 parent–child dyads to investigate how the early caregiving emotional environment affects children with PDE’s neural and cognitive systems. Measures of physical health, drug exposure, caregiver stress, depression, and distress were collected between 0 and 24 months At age 14 years, adolescents completed multiple measures of episodic memory, and at ages 14 and 18 years, adolescents underwent magnetic resonance imaging (MRI) scans. Latent constructs of episodic memory and the caregiving environment were created using Confirmatory Factor Analysis. Multiple regressions revealed a negative emotional caregiving environment during infancy was associated with poor memory performance and smaller left hippocampal volumes at 14 years. Better memory performance at 14 years predicted larger right hippocampal volume at 18 years. At 18 years, the association between the emotional caregiving environment and hippocampal volume was moderated by sex, such that a negative emotional caregiving environment was associated with larger left hippocampal volumes in males but not females. Findings suggest that the postnatal caregiving environment may modulate the effects of PDE across development, influencing neurocognitive development.

Pregnant people are unable to take many prescription and over-the-counter medications because of suspected or known risk to the fetus. This undermedication contributes to the high maternal mortality rate in the United States and detracts from the quality of life of pregnant people. As such, there is an urgent need to develop safe pharmaceutical formulations for use during pregnancy. Most drugs are small molecules that easily cross the placenta, which is the biological barrier that separates the maternal and fetal bloodstreams. One potential approach to preventing fetal drug accumulation is to design drug compounds that are excluded by the placenta; however, there is little understanding of how macromolecular drug properties affect transplacental transport. To address this knowledge gap, we examined the transport behavior of fluorescently-labeled polymers with varying size, conformation, and chemistry. We compared these polymers to unconjugated fluorescein, a small molecule model drug that readily crosses biological barriers. We found that molecular size affected transplacental transport in an in vitro model, BeWo b30 monolayers, as well as in pregnant mice, with larger polymers having lower permeability. In addition to size, polymer chemistry altered behavior, with polyethylene glycol (PEG) molecules permeating the placental barrier to a greater extent than dextrans of equivalent molecular weight. PEG molecules were also more readily taken up into placental cells in vivo. These findings will inform the future development of drug conjugates or other macromolecular medicines that can safely be used during pregnancy. [Display omitted] [ABSTRACT FROM AUTHOR]

Exposure to substances of abuse during pregnancy can have long-lasting effects on offspring. Alcohol is one of the most widely used substances of abuse that leads to the most severe consequences. Recent studies in the United States, Canada, and the United Kingdom showed that between 1% and 7% of all children exhibit signs and symptoms of fetal alcohol spectrum disorder (FASD). Despite preventive campaigns, the rate of children with FASD has not decreased during recent decades. Alcohol consumption often accompanies exposure to such drugs as tobacco, cocaine, opioids, and cannabis. These interactions can be synergistic and exacerbate the deleterious consequences of developmental alcohol exposure. The present review focuses on interactions between alcohol and cannabis exposure and the potential consequences of these interactions. • Cannabis is the most frequently used illicit drug among pregnant women. • Half of pregnant women who report cannabis use, also report the consumption of alcoholic beverages. • Early alcohol and cannabis exposure is linked to worse developmental outcomes than exposure to either drug alone. • Alcohol and cannabinoids exert a synergistic effect during early development through the endocannabinoid system. [ABSTRACT FROM AUTHOR]

Studies suggest prenatal cannabis exposure is associated with mood/behavioral problems in children. However, it is unclear if targeting modifiable domains like sleep behaviors would improve outcomes in exposed youth. Using a causal inference framework, the effect of changing sleep‐hours on changing internalizing/externalizing problems in children was examined using the Adolescent Brain Cognitive Development™ study baseline (ages 9–10; collected during 2016–2018) and year‐1 follow‐up data (N = 9825; 4663 female; 5196 white). Average treatment effects (ATE) indicated that more sleep predicted less internalizing (ATE = −.34, SE =.08, p <.001) and externalizing (ATE = −.29, SE =.07, p <.001) problems over time. However, prenatal cannabis exposure moderated the ATE on internalizing (conditional‐ATE =.91, SE =.39, p =.019), whereby participants with exposure (n = 605) did not show any effect of changing sleep‐hours on mood (B =.09, SE =.24). [ABSTRACT FROM AUTHOR]

Quantification of fetal drug exposure remains challenging since sampling from the placenta or fetus during pregnancy is too invasive. Currently existing in vivo (e.g., cord blood sampling) and ex vivo (e.g., placenta perfusion) models have inherent limitations. A placenta-on-a-chip model is a promising alternative. A systematic search was performed in PubMed on 2 February 2023, and Embase on 14 March 2023. Studies were included where placenta-on-a-chip was used to investigate placental physiology, placenta in different obstetric conditions, and/or fetal exposure to maternally administered drugs. Seventeen articles were included that used comparable approaches but different microfluidic devices and/or different cultured maternal and fetal cell lines. Of these studies, four quantified glucose transfer, four studies evaluated drug transport, three studies investigated nanoparticles, one study analyzed bacterial infection and five studies investigated preeclampsia. It was demonstrated that placenta-on-a-chip has the capacity to recapitulate the key characteristics of the human placental barrier. We aimed to identify knowledge gaps and provide the first steps towards an overview of current protocols for developing a placenta-on-a-chip, that facilitates comparison of results from different studies. Although models differ, they offer a promising approach for in vitro human placental and fetal drug studies under healthy and pathological conditions. [ABSTRACT FROM AUTHOR]

Objective The objective of this study is to investigate the effects of maternal perinatal depression symptoms and infant treatment status for neonatal abstinence syndrome (NAS) on maternal perceptions of infant regulatory behavior at 6 weeks of age. Methods Mothers and their infants (N  = 106; 53 dyads) were recruited from a rural, White cohort in Northeast Maine. Mothers in medication-assisted treatment (methadone) and their infants (n  = 35 dyads) were divided based on the infant's NAS pharmacological treatment (n  = 20, NAS+ group; n  = 15, NAS− group) and compared with a demographically similar, nonexposed comparison group (n  = 18 dyads; COMP group). At 6 weeks postpartum, mothers reported their depression symptoms Beck Depression Inventory—2nd Edition) and infant regulatory behaviors [Mother and Baby Scales (MABS)]. Infant neurobehavior was assessed during the same visit using the Neonatal Network Neurobehavioral Scale (NNNS). Results Mothers in the NAS+ group showed significantly higher depression scores than the COMP group (p <.05) while the NAS− group did not. Across the sample, mothers with higher depression scores reported higher infant "unsettled-irregularity" MABS scores, regardless of group status. Agreement between maternal reports of infant regulatory behaviors and observer-assessed NNNS summary scares was poor in both the NAS+ and COMP groups. Conclusions Postpartum women in opioid recovery with infants requiring pharmacological intervention for NAS are more at risk for depression which may adversely influence their perceptions of their infants' regulatory profiles. Unique, targeted attachment interventions may be needed for this population. [ABSTRACT FROM AUTHOR]

Introduction: An active metabolite of buprenorphine (BUP), called norbuprenorphine (NorBUP), is implicated in neonatal opioid withdrawal syndrome when BUP is taken during pregnancy. Therefore, reducing or eliminating metabolism of BUP to NorBUP is a novel strategy that will likely lower total fetal exposure to opioids and thus improve offspring outcomes. Precision deuteration alters pharmacokinetics of drugs without altering pharmacodynamics. Here, we report the synthesis and testing of deuterated buprenorphine (BUP-D2). Methods: We determined opioid receptor affinities of BUP-D2 relative to BUP with radioligand competition receptor binding assays, and the potency and efficacy of BUP-D2 relative to BUP to activate G-proteins via opioid receptors with [35S]GTP-S binding assays in homogenates containing the human mu, delta, or kappa opioid receptors. The antinociceptive effects of BUP-D2 and BUP were compared using the warm-water tail withdrawal assay in rats. Blood concentration versus time profiles of BUP, BUP-D2, and NorBUP were measured in rats following intravenous BUP-D2 or BUP injection. Results: The synthesis provided a 48% yield and the product was =99% deuterated. Like BUP, BUP-D2 had sub-nanomolar affinity for opioid receptors. BUP-D2 alsoactivated opioid receptors and induced antinociception with equal potency and efficacy as BUP. The maximum concentration and the area under the curve of NorBUP in the blood of rats that received BUP-D2 were over 19- and 10-fold lower, respectively, than in rats that received BUP. Discussion: These results indicate that BUP-D2 retains key pharmacodynamic properties of BUP and resists metabolism to NorBUP and therefore holds promise as an alternative to BUP. [ABSTRACT FROM AUTHOR]

The "developmental origins of health and disease" (DOHaD) hypothesis posits that early-life environmental exposures have a lasting impact on individual's health and permanently shape growth, structure, and metabolism. This reprogramming, which results from fetal stress, is believed to contribute to the development of adulthood cardiovascular diseases such as hypertension, coronary artery disease, heart failure, and increased susceptibility to ischemic injuries. Recent studies have shown that prenatal exposure to drugs, such as glucocorticoids, antibiotics, antidepressants, antiepileptics, and other toxins, increases the risk of adult-onset cardiovascular diseases. In addition, observational and animal experimental studies have demonstrated the association between prenatal drug exposure and the programming of cardiovascular disease in the offspring. The molecular mechanisms underlying these effects are still being explored but are thought to involve metabolism dysregulation. This review summarizes the current evidence on the relationship between prenatal drug exposure and the risk of adult cardiovascular disorders. Additionally, we present the latest insights into the molecular mechanisms that lead to programmed cardiovascular phenotypes after prenatal drug exposure. [ABSTRACT FROM AUTHOR]