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Environmental exposure to heavy metals is a potentially modifiable risk factor for preeclampsia (PE). Toxicologically, there are known interactions between the toxic metal cadmium (Cd) and essential metals such as selenium (Se) and zinc (Zn), as these metals can protect against the toxicity of Cd. As they relate to preeclampsia, the interaction between Cd and these essential metals is unknown. The aims of the present study were to measure placental levels of Cd, Se, and Zn in a cohort of 172 pregnant women from across the southeast US and to examine associations of metals levels with the odds of PE in a nested case-control design. Logistic regressions were performed to assess odds ratios (OR) for PE with exposure to Cd controlling for confounders, as well as interactive models with Se or Zn. The mean placental Cd level was 3.6 ng/g, ranging from 0.52 to 14.5 ng/g. There was an increased odds ratio for PE in relationship to placental levels of Cd (OR = 1.5; 95% CI: 1.1-2.2). The Cd-associated OR for PE increased when analyzed in relationship to lower placental Se levels (OR = 2.0; 95% CI: 1.1-3.5) and decreased with higher placental Se levels (OR = 0.98; 95% CI: 0.5-1.9). Similarly, under conditions of lower placental Zn, the Cd-associated OR for PE was elevated (OR = 1.8; 95% CI: 0.8-3.9), whereas with higher placental Zn it was reduced (OR = 1.3; 95% CI: 0.8-2.0). Data from this pilot study suggest that essential metals may play an important role in reducing the odds of Cd-associated preeclampsia and that replication in a larger cohort is warranted.

PurposeSertraline, a selective serotonin reuptake inhibitor (SSRI), is one of the most commonly used antidepressant during pregnancy. Plasma sertraline concentrations vary markedly between individuals, partly explained by variability in hepatic drug metabolizing cytochrome P450-enzyme activity. Our purpose was to study the variability in the plasma concentrations in pregnant women and the passage to their infants.MethodPregnant women with moderate untreated depression were recruited in 2016–2019 in Stockholm Region and randomized to treatment with sertraline or placebo. All received Internet-based cognitive behavior therapy as non-medical treatment. Sertraline plasma concentrations were measured around pregnancy weeks 21 and 30, at delivery, 1-month postpartum, in cord blood and at 48 h of age in the infant. The clinical course of the infants was followed.ResultsNine mothers and 7 infants were included in the analysis. Median dose-adjusted sertraline concentration in second trimester was 0.15(ng/mL) /(mg/day), in third trimester and at delivery 0.19 and 1-month postpartum 0.25, with a 67% relative difference between second trimester and postpartum. The interindividual variation was 10-fold. Median concentrations in the infants were 33% and 25% of their mothers’, measured in cord blood, and infant plasma, respectively. Only mild and transient adverse effects were seen on the infants.ConclusionPlacental passage of sertraline to the infant is low. However, the interindividual variation in maternal concentrations during pregnancy is huge, why therapeutic drug monitoring might assist in finding the poor metabolizers at risk for adversity and increase the safety of the treatment.Trial registrationThe trial was registered at clinicaltrials.gov July 9, 2014 with TRN: NCT02185547.

Maternal cigarette smoking during pregnancy (MSDP) is associated with numerous adverse health outcomes in infants and children with potential lifelong consequences. Negative effects of MSDP on placental DNA methylation (DNAm), placental structure, and function are well established. Our aim was to develop biomarkers of MSDP using DNAm measured in placentas ( ), collected as part of the Vitamin C to Decrease the Effects of Smoking in Pregnancy on Infant Lung Function double-blind, placebo-controlled randomized clinical trial conducted between 2012 and 2016. We also aimed to develop a digital polymerase chain reaction (PCR) assay for the top ranking cytosine-guanine dinucleotide (CpG) so that large numbers of samples can be screened for exposure at low cost. We compared the ability of four machine learning methods [logistic least absolute shrinkage and selection operator (LASSO) regression, logistic elastic net regression, random forest, and gradient boosting machine] to classify MSDP based on placental DNAm signatures. We developed separate models using the complete EPIC array dataset and on the subset of probes also found on the 450K array so that models exist for both platforms. For comparison, we developed a model using CpGs previously associated with MSDP in placenta. For each final model, we used model coefficients and normalized beta values to calculate placental smoking index (PSI) scores for each sample. Final models were validated in two external datasets: the Extremely Low Gestational Age Newborn observational study, ; and the Rhode Island Children's Health Study, . Logistic LASSO regression demonstrated the highest performance in cross-validation testing with the lowest number of input CpGs. Accuracy was greatest in external datasets when using models developed for the same platform. PSI scores in smokers only ( ) were moderately correlated with maternal plasma cotinine levels. One CpG (cg27402634), with the largest coefficient in two models, was measured accurately by digital PCR compared with measurement by EPIC array ( ). To our knowledge, we have developed the first placental DNAm-based biomarkers of MSDP with broad utility to studies of prenatal disease origins. https://doi.org/10.1289/EHP13838.

BackgroundMaternal exposure to fine particulate matter (PM2.5) was associated with pregnancy complications. However, we still lack comprehensive evidence regarding which specific chemical components of PM2.5 are more harmful for maternal and foetal health.ObjectiveWe focused on exposure over the first trimester (0–13 weeks of gestation), which includes the early placentation period, and investigated whether PM2.5 and its components were associated with placenta-mediated pregnancy complications (combined outcome of small for gestational age, preeclampsia, placental abruption, and stillbirth).MethodsFrom 2013 to 2015, we obtained information, from the Japan Perinatal Registry Network database, on 83,454 women who delivered singleton infants within 23 Tokyo wards (≈627 km2). Using daily filter sampling of PM2.5 at one monitoring location, we analysed carbon and ion components, and assigned the first trimester average of the respective pollutant concentrations to each woman.ResultsThe ORs of placenta-mediated pregnancy complications were 1.14 (95% CI = 1.08–1.22) per 0.51 μg/m3 (interquartile range) increase of organic carbon and 1.11 (1.03–1.18) per 0.06 μg/m3 increase of sodium. Organic carbon was also associated with four individual complications. There was no association between ozone and outcome.SignificanceThere were specific components of PM2.5 that have adverse effects on maternal and foetal health.

To determine the effects of combined aerobic and resistance exercise training during the second half of pregnancy on endothelial NOS expression (eNOS), nitric oxide (NO) production and oxygen metabolism in human placenta. The study included 20 nulliparous in gestational week 16-20, attending prenatal care at three tertiary hospitals in Colombia who were randomly assigned into one of two groups: The exercise group (n = 10) took part in an exercise session three times a week for 12 weeks which consisted of: aerobic exercise at an intensity of 55-75% of their maximum heart rate for 60 min and 25 mins. Resistance exercise included 5 exercise groups circuit training (50 repetitions of each) using barbells (1-3 kg/exercise) and low-to-medium resistance bands. The control group (n = 10) undertook their usual physical activity. Mitochondrial and cytosol fractions were isolated from human placental tissue by differential centrifugation. A spectrophotometric assay was used to measure NO production in cytosolic samples from placental tissue and Western Blot technique to determine eNOS expression. Mitochondrial superoxide levels and hydrogen peroxide were measured to determine oxygen metabolism. Combined aerobic and resistance exercise training during pregnancy leads to a 2-fold increase in eNOS expression and 4-fold increase in NO production in placental cytosol (p = 0.05). Mitochondrial superoxide levels and hydrogen peroxide production rate were decreased by 8% and 37% respectively in the placental mitochondria of exercising women (p = 0.05). Regular exercise training during the second half of pregnancy increases eNOS expression and NO production and decreases reactive oxygen species generation in human placenta. Collectively, these data demonstrate that chronic exercise increases eNOS/NO production, presumably by increasing endothelial shear stress. This adaptation may contribute to the beneficial effects of exercise on the vascular and antioxidant system and in turn reduce the risk of preeclampsia, diabetes or hypertension during pregnancy.

Imprinted genes in mammals are expressed from only one of the parental chromosomes, and are crucial for placental development and fetal growth 1 , 2 , 3 , 4 . The insulin-like growth factor II gene ( Igf2 ) is paternally expressed in the fetus and placenta 5 . Here we show that deletion from the Igf2 gene of a transcript (P0) 6 , 7 specifically expressed in the labyrinthine trophoblast of the placenta leads to reduced growth of the placenta, followed several days later by fetal growth restriction. The fetal to placental weight ratio is thus increased in the absence of the P0 transcript. We show that passive permeability for nutrients of the mutant placenta is decreased, but that secondary active placental amino acid transport is initially upregulated, compensating for the decrease in passive permeability. Later the compensation fails and fetal growth restriction ensues. Our study provides experimental evidence for imprinted gene action in the placenta that directly controls the supply of maternal nutrients to the fetus, and supports the genetic conflict theory of imprinting 8 . We propose that the Igf2 gene, and perhaps other imprinted genes, control both the placental supply of, and the genetic demand for, maternal nutrients to the mammalian fetus.

Multiple epidemiological studies have shown that exposure to pesticides is associated with adverse health outcomes. However, the literature on pesticide-related health effects in the Latin American and the Caribbean (LAC) region, an area of intensive agricultural and residential pesticide use, is sparse. We conducted a scoping review to describe the current state of research on the health effects of pesticide exposure in LAC populations with the goal of identifying knowledge gaps and research capacity building needs. We searched PubMed and SciELO for epidemiological studies on pesticide exposure and human health in LAC populations published between January 2007 and December 2021. We identified 233 publications from 16 countries that met our inclusion criteria and grouped them by health outcome (genotoxicity, neurobehavioral outcomes, placental outcomes and teratogenicity, cancer, thyroid function, reproductive outcomes, birth outcomes and child growth, and others). Most published studies were conducted in Brazil (37%, ) and Mexico (20%, ), were cross-sectional in design (72%, ), and focused on farmworkers (45%, ) or children (21%, ). The most frequently studied health effects included genotoxicity (24%, ) and neurobehavioral outcomes (21%, ), and organophosphate (OP) pesticides were the most frequently examined (26%, ). Forty-seven percent ( ) of the studies relied only on indirect pesticide exposure assessment methods. Exposure to OP pesticides, carbamates, or to multiple pesticide classes was consistently associated with markers of genotoxicity and adverse neurobehavioral outcomes, particularly among children and farmworkers. Our scoping review provides some evidence that exposure to pesticides may adversely impact the health of LAC populations, but methodological limitations and inconsistencies undermine the strength of the conclusions. It is critical to increase capacity building, integrate research initiatives, and conduct more rigorous epidemiological studies in the region to address these limitations, better inform public health surveillance systems, and maximize the impact of research on public policies. https://doi.org/10.1289/EHP9934.

Background Data on efficacy of artemisinin-based combination therapy (ACT) to treat Plasmodium falciparum during pregnancy in sub-Saharan Africa is scarce. A recent open label, randomized controlled trial in Mbarara, Uganda demonstrated that artemether-lumefantrine (AL) is not inferior to quinine to treat uncomplicated malaria in pregnancy. Haemozoin can persist in the placenta following clearance of parasites, however there is no data whether ACT can influence the amount of haemozoin or the dynamics of haemozoin clearance. Methods Women attending antenatal clinics with weekly screening and positive blood smears by microscopy were eligible to participate in the trial and were followed to delivery. Placental haemozoin deposition and inflammation were assessed by histology. To determine whether AL was associated with increased haemozoin clearance, population haemozoin clearance curves were calculated based on the longitudinal data. Results Of 152 women enrolled in each arm, there were 97 and 98 placental biopsies obtained in the AL and quinine arms, respectively. AL was associated with decreased rates of moderate to high grade haemozoin deposition (13.3% versus 25.8%), which remained significant after correcting for gravidity, time of infection, re-infection, and parasitaemia. The amount of haemozoin proportionately decreased with the duration of time between treatment and delivery and this decline was greater in the AL arm. Haemozoin was not detected in one third of biopsies and the prevalence of inflammation was low, reflecting the efficacy of antenatal care with early detection and prompt treatment of malaria. Conclusions Placental haemozoin deposition was decreased in the AL arm demonstrating a relationship between pharmacological properties of drug to treat antenatal malaria and placental pathology at delivery. Histology may be considered an informative outcome for clinical trials to evaluate malaria control in pregnancy. Trial registration REGISTRY: http://clinicaltrials.gov/ct2/show/NCT00495508

Human placental-derived allografts are biomaterials categorized as cellular, acellular, matrix-like products (CAMPs) that can serve as wound coverings due to placenta tissue’s innate barrier function. The placental membrane consists of three layers, the amnion, the intermediate layer (IL), and the chorion, each contributing distinct functional and biological properties. This study investigates how variations in layer composition influence the Extracellular Matrix (ECM) and growth factor profiles of placental allografts. We compared Dual Layer (amnion–amnion), Full Thickness (amnion–intermediate–chorion, FT), and a novel four-layer allograft configuration (amnion–intermediate–chorion–amnion, ACA). Histological analyses using hematoxylin and eosin (H&E) and Masson’s trichrome staining revealed distinct structural architecture among the three allografts, with FT and ACA exhibiting 4.9 times and 5.7 times greater thickness as compared with the Dual Layer, respectively. Compositional studies revealed different concentrations of key ECM components (collagen, elastin, proteoglycans, hyaluronic acid) and growth factors (ANG-2, EGF, PDGF-AA, VEGF) across allografts. The collagen concentration was two times higher in ACA as compared with the Dual Layer and FT. Additionally, FT and ACA demonstrated higher levels of growth factors and other ECM components, underscoring their biochemical diversity. These findings highlight the fact that the structural and biochemical properties of placental-derived allografts depend on their layer composition. This study underscores the importance of tailoring layer configurations that are optimized for clinical applications of CAMPs, enabling clinicians to select the most suitable grafts for clinical use, such as for wound management.

The placenta, a temporary organ that connects mother and child for nutrient and metabolite exchange, becomes medical waste after birth but can provide valuable metabolic insights. Thirty-three placenta samples were analyzed using ICP-OES to determine concentrations of ten elements, including macro-, micro-, trace, and heavy metals. Results were compared with maternal and neonatal data, including Apgar scores, maternal age, and blood parameters. Correlations were found between elements (e.g., Ca–Mg, Fe–Zn, and Mn–Cu) and between mineral levels and maternal or infant parameters (e.g., Ca–RBC, Mn–Hb, Cu–PLT, and Cu–UA Pi). No quantifiable heavy metals were detected, nor associations with smoking, gestational diabetes, preterm birth, birth weight, or Apgar scores. Findings suggest that maintaining proper blood morphology and preventing anemia in pregnancy requires attention not only to iron but also to Ca2+, Mg2+, and Mn2+ levels. Manganese and copper assessment may be beneficial for diagnostic purposes in pregnant women. Further large-scale tissue studies are recommended, including comprehensive maternal–fetal health data such as Doppler velocimetry of placental vessels.