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Since 2006, iPLEDGE, a risk evaluation and mitigation strategy (REMS), has attempted to prevent fetal exposures in people taking isotretinoin through contraceptive requirements and regular pregnancy testing. There has been criticism of iPLEDGE’s requirements, results, and accessibility. iPLEDGE has placed significant burdens on physicians, patients, and administrative staff. Some level of burden is acceptable to prevent fetal exposures, but iPLEDGE burdens are so strenuous that physicians may choose not to prescribe isotretinoin because of them. There are several evidence-based adaptations that iPLEDGE and physicians can enact to improve the isotretinoin experience. First, physicians can practice shared-decision making in contraceptive counseling and educate patients on long-acting reversible contraceptives (LARCs) to improve the counseling process and outcomes. Second, physicians can take advantage of the reimbursed iPLEDGE contraceptive counseling sessions and refer patients accordingly. Finally, iPLEDGE should recognize the variation in efficacy among contraceptives. Specifically, LARCs and permanent surgical sterilization should be exempt from certain iPLEDGE requirements such as monthly pregnancy testing and attestations. iPLEDGE should work with dermatologists for the continual improvement of iPLEDGE. Communication, repetitive reassessment, and subsequent adaptations will result in better care for patients requiring isotretinoin. [ABSTRACT FROM AUTHOR]

In human pregnancy, metformin administered to the mother crosses the placenta resulting in metformin exposure to the fetus. However, the effects of metformin exposure on the fetus are poorly understood and difficult to study in humans. Pregnant sheep are a powerful large animal model for studying fetal physiology. The objective of this study was to determine if maternally administered metformin at human dose-equivalent concentrations crosses the ovine placenta and equilibrates in the fetal circulation. To test this, metformin was administered to the pregnant ewe via continuous intravenous infusion or supplementation in the drinking water. Both administration routes increased maternal metformin concentrations to human dose-equivalent concentrations of ~ 10 µM, yet metformin was negligible in the fetus even after 3–4 days of maternal administration. In cotyledon and caruncle tissue, expression levels of the major metformin uptake transporter organic cation transporter 1 (OCT1) were < 1% of expression levels in the fetal liver, a tissue with abundant expression. Expression of other putative uptake transporters OCT2 and OCT3, and efflux transporters multidrug and toxin extrusion (MATE)1 and MATE2were more abundant. These results demonstrate that the ovine placenta is impermeable to maternal metformin administration. This is likely due to anatomical differences and increased interhaemal distance between the maternal and umbilical circulations in the ovine versus human placenta limiting placental metformin transport. [ABSTRACT FROM AUTHOR]

Abstract Background Per-/polyfluoroalkyl substances (PFASs) are persistent organic pollutants and suspected endocrine disruptors. Objective The aim of this work was to conduct a systematic review with meta-analysis to summarise the associations between prenatal or childhood exposure to PFASs and childhood overweight/obesity. Methods The search was performed on the bibliographic databases PubMed and Embase with text strings containing terms related to prenatal, breastfeeding, childhood, overweight, obesity, and PFASs. Only papers describing a biomonitoring study in pregnant women or in children up to 18 years that assessed body mass index (BMI), waist circumference (WC), or fat mass in children were included. When the estimates of the association between a PFAS and an outcome were reported from at least 3 studies, a meta-analysis was conducted; moreover, to correctly compare the studies, we developed a method to convert the different effect estimates and made them comparable each other. Meta-analyses were performed also stratifying by sex and age, and sensitivity analyses were also performed. Results In total, 484 and 779 articles were retrieved from PubMed and Embase, respectively, resulting in a total of 826 articles after merging duplicates. The papers included in this systematic review were 49: 26 evaluating prenatal exposure to PFASs, 17 childhood exposure, and 6 both. Considering a qualitative evaluation, results were conflicting, with positive, negative, and null associations. 30 papers were included in meta-analyses (19 prenatal, 7 children, and 4 both). Positive associations were evidenced between prenatal PFNA and BMI, between PFOA and BMI in children who were more than 3 years, and between prenatal PFNA and WC. Negative associations were found between prenatal PFOS and BMI in children who were 3 or less years, and between PFHxS and risk of overweight. Relatively more consistent negative associations were evidenced between childhood exposure to three PFASs (PFOA, PFOS, and PFNA) and BMI, in particular PFOS in boys. However, heterogeneity among studies was high. Conclusion Even though heterogeneous across studies, the pooled evidence suggests possible associations, mostly positive, between prenatal exposure to some PFASs and childhood BMI/WC; and relatively stronger evidence for negative associations between childhood exposure to PFASs and childhood BMI.

ABC transporters are ubiquitous in the human body and are responsible for the efflux of drugs. They are present in the placenta, intestine, liver and kidney, which are the major organs that can affect the pharmacokinetic and pharmacologic properties of drugs. P-gp and BCRP transporters are the best-characterized transporters in the ABC superfamily, and they have a pivotal role in the barrier tissues due to their efflux mechanism. Moreover, during pregnancy, drug efflux is even more important because of the developing fetus. Recent studies have shown that placental and intestinal ABC transporters have great importance in drug absorption and distribution. Placental and intestinal P-gp and BCRP show gestational-age-dependent expression changes, which determine the drug concentration both in the mother and the fetus during pregnancy. They may have an impact on the efficacy of antibiotic, antiviral, antihistamine, antiemetic and oral antidiabetic therapies. In this review, we would like to provide an overview of the pharmacokinetically relevant expression alterations of placental and intestinal ABC transporters during pregnancy. [ABSTRACT FROM AUTHOR]

Background: Per-/polyfluoroalkyl substances (PFASs) are persistent organic pollutants and suspected endocrine disruptors. Objective: The aim of this work was to conduct a systematic review with meta-analysis to summarise the associations between prenatal or childhood exposure to PFASs and childhood overweight/obesity. Methods: The search was performed on the bibliographic databases PubMed and Embase with text strings containing terms related to prenatal, breastfeeding, childhood, overweight, obesity, and PFASs. Only papers describing a biomonitoring study in pregnant women or in children up to 18 years that assessed body mass index (BMI), waist circumference (WC), or fat mass in children were included. When the estimates of the association between a PFAS and an outcome were reported from at least 3 studies, a meta-analysis was conducted; moreover, to correctly compare the studies, we developed a method to convert the different effect estimates and made them comparable each other. Meta-analyses were performed also stratifying by sex and age, and sensitivity analyses were also performed. Results: In total, 484 and 779 articles were retrieved from PubMed and Embase, respectively, resulting in a total of 826 articles after merging duplicates. The papers included in this systematic review were 49: 26 evaluating prenatal exposure to PFASs, 17 childhood exposure, and 6 both. Considering a qualitative evaluation, results were conflicting, with positive, negative, and null associations. 30 papers were included in meta-analyses (19 prenatal, 7 children, and 4 both). Positive associations were evidenced between prenatal PFNA and BMI, between PFOA and BMI in children who were more than 3 years, and between prenatal PFNA and WC. Negative associations were found between prenatal PFOS and BMI in children who were 3 or less years, and between PFHxS and risk of overweight. Relatively more consistent negative associations were evidenced between childhood exposure to three PFASs (PFOA, PFOS, and PFNA) and BMI, in particular PFOS in boys. However, heterogeneity among studies was high. Conclusion: Even though heterogeneous across studies, the pooled evidence suggests possible associations, mostly positive, between prenatal exposure to some PFASs and childhood BMI/WC; and relatively stronger evidence for negative associations between childhood exposure to PFASs and childhood BMI. [ABSTRACT FROM AUTHOR]

Depression is common in pregnant women. However, the rate of antidepressant treatment in pregnancy is significantly lower than in nonpregnant women. Although some antidepressants may cause potential risks to the fetus, not treating or withdrawing the treatment is associated with relapsing and adverse pregnancy outcomes such as preterm birth. Pregnancy‐associated physiologic changes can alter pharmacokinetics (PK) and may impact dosing requirements during pregnancy. However, pregnant women are largely excluded from PK studies. Dose extrapolation from the nonpregnant population could lead to ineffective doses or increased risk of adverse events. To better understand PK changes during pregnancy and guide dosing decisions, we conducted a literature review to catalog PK studies of antidepressants in pregnancy, with a focus on maternal PK differences from the nonpregnant population and fetal exposure. We identified 40 studies on 15 drugs, with most data from patients taking selective serotonin reuptake inhibitors and venlafaxine. Most of the studies have relatively poor quality, with small sample sizes, reporting concentrations at delivery only, a large amount of missing data, and not including times and adequate dose information. Only four studies collected multiple samples following a dose and reported PK parameters. In general, there are limited data available regarding PK of antidepressants in pregnancy and deficiencies in data reporting. Future studies should provide accurate information on drug dosing and timing of dose, PK sample collection, and individual‐level PK data. [ABSTRACT FROM AUTHOR]

Abstract Background Patients with metabolic syndrome (MS) have a higher incidence of cardiovascular disease (CVD), but the possible mechanisms are not fully understood and further exploration of the possible factors influencing the high incidence of CVD in patients with MS is still needed. Objectives This study aims to examine the association between fetal famine exposure and the risk of CVD in adulthood with MS. Methods Of 13,744 MS patients free of CVD selected from the Kailuan Study in 2006 (referred as the baseline survey) were included in the study. China suffered a severe famine from 1959 to 1962, so the participants born during this period were classified as the uterine famine exposed group. All patients were born between January 1, 1949, and December 31, 1974. Based on the date of birth, all patients were divided into the no-exposed group (born between January 1, 1963, and December 31, 1974), uterine famine exposed group (born between January 1, 1959 and December 31, 1962), and childhood famine exposed group (born between January 1, 1949 and December 31, 1958). After following up to December 31, 2019, the weighted Cox regression analysis model was used to calculate the effect of early life famine exposure in MS individuals on the risk of CVD in adulthood. Results During the 12.12 years of follow-up, the incidence of CVD was 5.87%, 10.13%, and 10.90% in the no-exposed group, uterine famine exposed group, and childhood famine exposed group, respectively. Compared with participants in the no-exposed group, the CVD risk and stroke risk increased in participants in the uterine famine exposed group (for CVD, HR: 1.32, 95% CI 1.04–1.67; for stroke, HR:1.37, 95% CI 1.05–1.79), but not in childhood famine exposed group. However, the increased CVD risks were only observed in females or smokers. No increased MI risks were observed for participants in the uterine famine exposed group or childhood famine exposed group. Conclusions Our findings suggested that exposure to famine during uterine life might increase the risk of CVD in adulthood in participants with MS.

BackgroundAlthough the incidence of gastroschisis is increasing, risk factors are not clearly identified.MethodsUsing the Linked Birth Database from the California Office of Statewide Health Planning and Development from 1995 to 2012, patients with gastroschisis were identified by ICD-9 diagnosis/procedure code or birth certificate designation. Logistic regressions examined demographics, birth factors, and maternal exposures on risk of gastroschisis.ResultsThe prevalence of gastroschisis was 2.7 cases per 10,000 live births. Patients with gastroschisis had no difference in fetal exposure to alcohol (p = 0.609), narcotics (p = 0.072), hallucinogenics (p = 0.239), or cocaine (p = 0.777), but had higher exposure to unspecified/other noxious substances (OR 3.27, p = 0.040; OR 2.02, p = 0.002). Gastroschisis was associated with low/very low birthweight (OR 5.08-16.21, p

Background and purpose: Data on pregnancy outcomes following fetal exposure to disease‐modifying drugs (DMDs) in women with multiple sclerosis (MS) are sparse although growing. Methods: Data from the Danish Multiple Sclerosis Registry were linked with nationwide registries enabling an investigation of adverse pregnancy outcomes in newborns of women with MS following fetal exposure to injectable first‐line treatments, dimethyl fumarate, glatiramer acetate, or natalizumab. Logistic regression models accounting for clustered data were used to estimate odds ratios (ORs) with 95% confidence intervals (CIs) for individual and composite adverse outcomes after adjusting for relevant covariates. Results: A total of 1009 DMD‐exposed pregnancies were compared with 1073 DMD‐unexposed pregnancies as well as 91,112 pregnancies from the general population. No association of an increased risk of any perinatal outcome was found when comparing newborns with fetal exposure with the general population, including preterm birth (OR = 1.19, 95% CI = 0.86–1.64), small for gestational age (OR = 1.38, 95% CI = 0.92–2.07), spontaneous abortion (OR = 1.04, 95% CI = 0.84–1.27), congenital malformation (OR = 0.99, 95% CI = 0.68–1.45), low Apgar score (OR = 0.62, 95% CI = 0.23–1.65), stillbirth (OR = 1.05, 95% CI = 0.33–3.31), placenta complication (OR = 0.53, 95% CI = 0.22–1.27), and any adverse event (OR = 1.10, 95% CI = 0.93–1.30). Similar results were found when comparing DMD‐exposed pregnancies with DMD‐unexposed pregnancies. Conclusions: We found no increased association of adverse pregnancy outcomes in newborns with fetal exposure to DMDs when compared with either DMD‐unexposed pregnancies or the general population. [ABSTRACT FROM AUTHOR]

Preliminary research suggests that maternal prenatal stress may alter the development of the fetal microbiome and resulting microbial composition after birth. However, the findings of existing studies are mixed and inconclusive. The purpose of this exploratory study was to assess whether maternal stress during pregnancy is associated with the overall number and diversity of various microbial species in the infant gut microbiome or the abundance of specific bacterial taxa. Fifty-one women were recruited during their third trimester of pregnancy. The women completed a demographic questionnaire and Cohen's Perceived Stress Scale at recruitment. A stool sample was collected from their neonate at one month of age. Data on potential confounders, such as gestational age and mode of delivery, were extracted from medical records to control for their effects. 16s rRNA gene sequencing was used to identify the diversity and abundance of microbial species, along with multiple linear regression models to examine the effects of prenatal stress on microbial diversity. We employed negative binomial generalized linear models to test for differential expression of various microbial taxa among infants exposed to prenatal stress and those not exposed to prenatal stress. More severe symptoms of prenatal stress were associated with a greater diversity of microbial species in the gut microbiome of neonates (β =.30, p =.025). Certain microbial taxa, such as Lactobacillus and Bifidobacterium, were enriched among infants exposed to greater maternal stress in utero, while others, such as Bacteroides and Enterobacteriaceae, were depleted in contrast to infants exposed to less stress. Findings suggest that mild to moderate stress exposure in utero could be associated with a microbial environment in early life that is more optimally prepared to thrive in a stressful postnatal environment. Adaptation of gut microbiota under conditions of stress may involve upregulation of bacterial species, including certain protective microorganisms (e.g. Bifidobacterium), as well as downregulation of potential pathogens (e.g. Bacteroides) via epigenetic or other processes within the fetal/neonatal gut-brain axis. However, further research is needed to understand the trajectory of microbial diversity and composition as infant development proceeds and the ways in which both the structure and function of the neonatal microbiome may mediate the relationship between prenatal stress and health outcomes over time. These studies may eventually yield microbial markers and gene pathways that are biosignatures of risk or resilience and inform targets for probiotics or other therapies in utero or during the postnatal period. [ABSTRACT FROM AUTHOR]

The renin–angiotensin–aldosterone system (RAAS) plays a key role in development of fetal kidney. Angiotensin‐converting enzyme (ACE) inhibitors or angiotensin II receptor type 1 (AT1) antagonists alter RAAS‐signaling compromising metanephrogenesis, and vascular and tubular development. The result is a fetal "RAS blockage syndrome" that may occur not only following exposure during the second and third trimester, but also after the use of these drugs at the beginning of pregnancy. The in‐utero exposure to AT1 antagonists is not confined exclusively to the risk of neonatal renal failure, but also to skull ossification defect that worsens the neonatal prognosis. We report the case of early arterial hypertension development, marked increase of plasma renin and aldosterone, severe hypocalvaria, and low bone mineralization in a female preterm infant in‐utero exposed to AT1 antagonists. [ABSTRACT FROM AUTHOR]

Background: Patients with metabolic syndrome (MS) have a higher incidence of cardiovascular disease (CVD), but the possible mechanisms are not fully understood and further exploration of the possible factors influencing the high incidence of CVD in patients with MS is still needed. Objectives: This study aims to examine the association between fetal famine exposure and the risk of CVD in adulthood with MS. Methods: Of 13,744 MS patients free of CVD selected from the Kailuan Study in 2006 (referred as the baseline survey) were included in the study. China suffered a severe famine from 1959 to 1962, so the participants born during this period were classified as the uterine famine exposed group. All patients were born between January 1, 1949, and December 31, 1974. Based on the date of birth, all patients were divided into the no-exposed group (born between January 1, 1963, and December 31, 1974), uterine famine exposed group (born between January 1, 1959 and December 31, 1962), and childhood famine exposed group (born between January 1, 1949 and December 31, 1958). After following up to December 31, 2019, the weighted Cox regression analysis model was used to calculate the effect of early life famine exposure in MS individuals on the risk of CVD in adulthood. Results: During the 12.12 years of follow-up, the incidence of CVD was 5.87%, 10.13%, and 10.90% in the no-exposed group, uterine famine exposed group, and childhood famine exposed group, respectively. Compared with participants in the no-exposed group, the CVD risk and stroke risk increased in participants in the uterine famine exposed group (for CVD, HR: 1.32, 95% CI 1.04–1.67; for stroke, HR:1.37, 95% CI 1.05–1.79), but not in childhood famine exposed group. However, the increased CVD risks were only observed in females or smokers. No increased MI risks were observed for participants in the uterine famine exposed group or childhood famine exposed group. Conclusions: Our findings suggested that exposure to famine during uterine life might increase the risk of CVD in adulthood in participants with MS. [ABSTRACT FROM AUTHOR]

ABC transporters are ubiquitous in the human body and are responsible for the efflux of drugs. They are present in the placenta, intestine, liver and kidney, which are the major organs that can affect the pharmacokinetic and pharmacologic properties of drugs. P-gp and BCRP transporters are the best-characterized transporters in the ABC superfamily, and they have a pivotal role in the barrier tissues due to their efflux mechanism. Moreover, during pregnancy, drug efflux is even more important because of the developing fetus. Recent studies have shown that placental and intestinal ABC transporters have great importance in drug absorption and distribution. Placental and intestinal P-gp and BCRP show gestational-age-dependent expression changes, which determine the drug concentration both in the mother and the fetus during pregnancy. They may have an impact on the efficacy of antibiotic, antiviral, antihistamine, antiemetic and oral antidiabetic therapies. In this review, we would like to provide an overview of the pharmacokinetically relevant expression alterations of placental and intestinal ABC transporters during pregnancy.

Purpose: To investigate the occupational and environmental factors in the etiology of infantile hypertrophic pyloric stenosis (IHPS). Methods: Protocol was drafted according to the PRISMA guidelines and registered on PROSPERO (CRD42020152460). A search for a combination of terms related to IHPS, fetus and neonates, and environmental exposure was performed for studies published between 2000 and 2020 in the EMBASE, Pubmed, and MEDLINE databases. Results: Overall, 2203 abstracts were identified and 829 were screened. The full text of the selected articles (N = 98) was assessed for eligibility. Fifteen studies were included in quantitative synthesis. IHPS risk was significantly lower in black and Hispanic mothers than in white mothers [OR 0.47 (95% CI 0.44–0.51, p < 0.001), OR 0.85 (95% CI 0.77–0.94, p = 0.002), respectively]. Lower maternal education level and maternal smoking were risk factor for IHPS. We further observed a non-significant association between maternal folic acid usage and IHPS risk. Data were insufficient to evaluate occupational exposure. Conclusion: This review provides an understanding of the role of environmental exposures in IHPS etiology. Lower maternal educational level, maternal smoking, and white ethnicity are associated with a significantly increased risk of IHPS, while folic acid use seems non-significantly associated with IHPS risk. Level of evidence: III. [ABSTRACT FROM AUTHOR]

Objectives: Lithium is an effective treatment for bipolar disorder, also during pregnancy to prevent the recurrence of episodes in the perinatal period. Little is known about the neuropsychological development of lithium‐exposed offspring. The current study was designed to investigate neuropsychological functioning in lithium‐exposed children with the aim to provide further knowledge on the long‐term effects of lithium use during pregnancy. Methods: Participants were offspring of women with a diagnosis of bipolar spectrum disorder, aged 6–14 years. In total, 99 children participated in the study, 56 were exposed to lithium in utero and 43 were not exposed to lithium. Neuropsychological tests were administered, including the Snijders‐Oomen Nonverbal Intelligence Test and the NEPSY‐II‐NL assessment. Linear and negative binomial regression models were used to investigate the association between prenatal lithium exposure and neuropsychological functioning. In secondary analyses, the association between lithium blood level during pregnancy and neuropsychological functioning was assessed. Additionally, norm scores and percentiles for task outcomes were calculated. Results: Lithium use during pregnancy was associated with the total number of mistakes made on the Auditory Attention task, but not statistically significant after full adjustment for potential confounding factors. No association between prenatal lithium exposure and IQ was found. Also, no relationship between lithium blood level during pregnancy and neuropsychological functioning was found after adjustment for potential confounders. Task outcomes in both groups were comparable to the general population. Conclusion: In this study, we found no evidence for significantly altered neuropsychological functioning of lithium‐exposed children at the age of 6–14 years, when compared to non‐lithium‐exposed controls. [ABSTRACT FROM AUTHOR]

Abstract: Fetal brain development depends on maternofetal thyroid function. In rodents and sheep, perinatal BPA exposure is associated with maternal and/or fetal thyroid disruption and alterations in central nervous system development as demonstrated by metabolic modulations in the encephala of mice. We hypothesized that a gestational exposure to a low dose of BPA affects maternofetal thyroid function and fetal brain development in a region-specific manner. Pregnant ewes, a relevant model for human thyroid and brain development, were exposed to BPA (5 µg/kg bw/d, sc). The thyroid status of ewes during gestation and term fetuses at delivery was monitored. Fetal brain development was assessed by metabolic fingerprints at birth in 10 areas followed by metabolic network-based analysis. BPA treatment was associated with a significant time-dependent decrease in maternal TT4 serum concentrations. For 8 fetal brain regions, statistical models allowed discriminating BPA-treated from control lambs. Metabolic network computational analysis revealed that prenatal exposure to BPA modulated several metabolic pathways, in particular excitatory and inhibitory amino-acid, cholinergic, energy and lipid homeostasis pathways. These pathways might contribute to BPA-related neurobehavioral and cognitive disorders. Discrimination was particularly clear for the dorsal hippocampus, the cerebellar vermis, the dorsal hypothalamus, the caudate nucleus and the lateral part of the frontal cortex. Compared with previous results in rodents, the use of a larger animal model allowed to examine specific brain areas, and generate evidence of the distinct region-specific effects of fetal BPA exposure on the brain metabolome. These modifications occur concomitantly to subtle maternal thyroid function alteration. The functional link between such moderate thyroid changes and fetal brain metabolomic fingerprints remains to be determined as well as the potential implication of other modes of action triggered by BPA such as estrogenic ones. Our results pave the ways for new scientific strategies aiming at linking environmental endocrine disruption and altered neurodevelopment.

Paracetamol (acetaminophen) is the preferred antipyretic/analgesic for pregnant women as it is believed there are no adverse fetal effects at the recommended dose. However, emerging evidence suggests that intrauterine paracetamol exposure may be associated with certain urogenital/reproductive disorders in the offspring. In this mini-review, we describe human fetal sex development and possible pharmacological mechanisms by which paracetamol may disrupt this process, including reduced testicular production of testosterone and/or insulin-like peptide 3. We then review the available epidemiological literature on associations between maternal paracetamol exposure and offspring sexual development. Three epidemiological studies have reported associations between maternal paracetamol intake and increased risk of cryptorchidism, although five others have not. None have found associations with hypospadias or penile length. Two out of three studies have reported a shorter anogenital distance (a marker of androgen action during the masculinisation programming window, ∼8–14 weeks of gestation) in male infants antenatally exposed to paracetamol. One study has described a dose-dependent relationship between maternal paracetamol consumption and earlier female (but not male) attainment of puberty. Such epidemiological analyses are complicated by various factors, including method of paracetamol exposure assessment (usually retrospective self-report), variation in diagnostic accuracy, selection bias, confounding by clinical indication, and demographic/genetic differences between geographically separated populations. There is an urgent need for stronger evidence in this area, from both relevant experimental studies and large, carefully-designed prospective studies. In the meantime, a precautionary attitude to gestational paracetamol usage should be considered as the evidence for clinically significant reproductive effects in humans is limited.

This study investigated whether and how fetal malnutrition would influence endogenous melatonin synthesis, and whether such effect of fetal malnutrition would transmit to the next generation. We enrolled 2466 participants and 1313 of their offspring. The urine 6‐hydroxymelatonin sulfate and serum melatonin rhythm were measured. Methylation microarray detection and bioinformatics analysis were performed to identify hub methylated sites. Additionally, rat experiment was performed to elucidate mechanisms. The participants with fetal malnutrition had lower 6‐hydroxymelatonin sulfate (16.59 ± 10.12 μg/24 hours vs 24.29 ± 11.99 μg/24 hours, P <.001) and arear under curve of melatonin rhythm (67.11 ± 8.16 pg/mL vs 77.11 ± 8.04 pg/mL, P <.001). We identified 961 differentially methylated sites, in which the hub methylated sites were locating on protein kinase C alpha (PRKCA) and cAMP response element‐binding protein (CREB1) promoters, mediating the association of fetal malnutrition with impaired melatonin secretion. However, such effects were not observed in the offspring (all P >.05). Impaired histomorphology of pineal, decreased melatonin in serum, pineal, and pinealocyte were also found in the in vivo and in vitro experiments (P <.05 for the differences of the indicators). Hypermethylation of 10 CpG sites on the PRKCA promoter and 8 CpG sites on the CREB1 promoter were identified (all P <.05), which down‐regulated PRKCA and CREB1 expressions, leading to decreased expression of AANAT, and then resulting in the impaired melatonin synthesis. Collectively, fetal malnutrition can impair melatonin synthesis through hypermethylation of PRKCA and CREB1 promoters, and such effects cannot be transmitted to the next generation. [ABSTRACT FROM AUTHOR]

Introduction: Parabens are a group of chemicals widely used as preservatives in daily consumer products such as cosmetics, food items, pharmaceuticals and household commodities. They have been broadly detected in human samples indicating a general human exposure, and concerns arose from their potential endocrine disrupting effect. Especially the exposure to parabens during pregnancy is concerning, as the time of fetal development is a particularly vulnerable period. The aim of this study was to investigate the transport and metabolism of four commonly used parabens: methyl-, ethyl-, propyl- and butylparaben (MeP, EtP, PrP and BuP) and the metabolite para-hydroxybenzoic acid (PHBA) across the human placenta.Methods: An ex-vivo human placental perfusion model was used. The test compounds were added in the maternal compartment (with initial concentrations of 1 mM or 0.1 mM). Placental transport was evaluated by fetal-maternal concentration ratios (FM-ratio), transport index (TI) and indicative permeability (IP).Results: Information about parabens kinetics was taken from 10 perfusions and PHBA from 7 perfusions. Paraben metabolism was not detected. The placental transport of MeP, EtP, PrP, BuP and PHBA revealed a transfer from maternal to fetal circulations with FM120 of 0.86 ± 0.27 (MeP), 0.98 ± 0.28 (EtP), 1.00 ± 0.28 (PrP), 1.12 ± 0.59 (BuP) and 0.82 ± 0.37 (PHBA). The test substances accumulated in the perfused tissue in some degree. The average kinetic parameters FM-ratio, TI and IP were not different between chemicals.Discussion: The present study shows that the placenta barrier is permeable to all four parabens and the metabolite, which implies potential fetal exposure. [ABSTRACT FROM AUTHOR]

Katia Keglberg Hærvig,1,2 Jens Peter Bonde,1,2 Cecilia Høst Ramlau-Hansen,3 Gunnar Toft,4 Karin Sørig Hougaard,2,5 Ina Olmer Specht,6 Aleksander Giwercman,7 Anne-Marie Nybo Andersen,2 Jørn Olsen,3 Christian Lindh,8 Birgit Bjerre Høyer,1,* Sandra Søgaard Tøttenborg1,* 1Department of Occupational and Environmental Medicine, Bispebjerg & Frederiksberg Hospital, Copenhagen, Denmark; 2Department of Public Health, The Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark; 3Department of Public Health, Research Unit for Epidemiology, Aarhus University, Aarhus, Denmark; 4Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus, Denmark; 5National Research Centre for the Working Environment, Copenhagen, Denmark; 6The Parker Institute, Research Unit for Dietary Studies, Bispebjerg & Frederiksberg Hospital, Copenhagen, Denmark; 7Molecular Reproductive Medicine, Department of Translational Medicine, Lund University, Lund, Sweden; 8Division of Occupational and Environmental Medicine, Department of Laboratory Medicine, Lund University, Lund, Sweden*These authors contributed equally to this workCorrespondence: Sandra Søgaard TøttenborgDepartment of Occupational and Environmental Medicine, Bispebjerg & Frederiksberg Hospital, Bispebjerg Bakke 23F, Entrance 20F, 1st Floor, Copenhagen 2400, NV, DenmarkTel +45 23 35 58 85Email sandra.soegaard.toettenborg@regionh.dkBackground: Prenatal exposures may contribute to male infertility in adult life, but large-scale epidemiological evidence is still lacking. The Fetal Programming of Semen quality (FEPOS) cohort was founded to provide means to examine if fetal exposures can interfere with fetal reproductive development and ultimately lead to reduced semen quality and reproductive hormone imbalances in young adult men.Methods: Young adult men at least 18 years and 9 months of age born to women in the Danish National Birth Cohort living in relative proximity to Copenhagen or Aarhus and for whom a maternal blood sample and two maternal interviews during pregnancy were available were invited to FEPOS. Recruitment began in March 2017 and ended in December 2019. The participants answered a comprehensive questionnaire and underwent a physical examination where they delivered a semen, urine, and hair sample, measured their own testicular volume, and had blood drawn.Results: In total 21,623 sons fulfilled eligibility criteria of whom 5697 were invited and 1058 participated making the response rate 19%. Semen characteristics did not differ between sons from the Copenhagen and Aarhus clinics. When comparing the FEPOS semen parameters to similar cohorts, the median across all semen characteristics was slightly lower for FEPOS participants, although with smaller variation.Conclusion: With its 1058 young adult men, the FEPOS cohort is the largest population-based male-offspring cohort worldwide specifically designed to investigate prenatal determinants of semen quality. Wide-ranging information on maternal health, lifestyle, socioeconomic status, occupation, and serum concentrations of potential reproductive toxicants during pregnancy combined with biological markers of fertility in their sons collected after puberty allow for in-depth investigations of the ‘fetal origins of adult disease hypothesis’.Keywords: male infertility, prenatal exposure, fetal exposure, maternal-fetal exchange, semen quality, semen analysis

Objective: To examine whether selected endocrine disrupting chemicals were present in pregnant women and passed through the placental barrier to amniotic fluid, potentially exposing the developing fetus. Methods: Paired samples of maternal serum, urine and amniotic fluid were concurrently collected (18 years) with a singleton pregnancy and undergoing amniocentesis between gestational weeks 12 – 36. The concentration of six different parabens, seven phenols, 31 metabolites from 15 phthalate diesters and the polychlorinated substance triclocarban were analyzed by isotope diluted TurboFlow-liquid chromatography-tandem mass spectrometry. Results: Concentrations of all included compounds were highest in maternal urine followed by serum, and lowest in amniotic fluid. Of the six parabens measured in amniotic fluid, methylparaben (MeP) and ethylparaben (EtP) were detectable most often (87% and 33% of the samples, respectively). Of the seven phenols measured, three (2,4-dichlorphenol, 2,5-dichlorphenol, 2-propylphenol) were detectable in the range of 14–21% of the amniotic fluid samples, at low concentrations (

[Display omitted] • Fetal methylphenidate exposure increases spontaneous locomotor activity in adolescents mice. • Fetal methylphenidate exposure decreases anxiety-like behavior in adolescent mice. • Fetal methylphenidate exposure decreases Drd2 and Slc6a3 gene expressions in the striatum. Methylphenidate (MPD) is used as a first-line treatment for attention-deficit/hyperactivity disorder (ADHD). The number of prescriptions for ADHD patients is increasing, suggesting that the number of fertile women using such medication might be also increasing. The purpose of this study was to clarify the effects of MPD exposure during the fetal period on infant development, behavior, learning, and memory in mice. Expression levels of candidate genes associated with ADHD were also determined in the brain of pups born to MDP-treated dams who were administered MPD orally at a dose of 2.5, 7.5, or 15 mg/kg daily from gestational day 1 to the day before delivery. Offspring aged 6–8 weeks were subjected to the spontaneous locomotor activity, elevated plus-maze, and passive avoidance tests and therapeutic treatments with MPD or atomoxetine. Fetal MPD exposure induced ADHD-like phenotypes, such as hyperactivity and impulsivity, in mouse offspring, which were suppressed by treatment with MPD and atomoxetine. These mice showed decreased Drd2 and Slc6a3 expression levels in the brain, which are often observed in ADHD model animals. Our results suggest that continuous use of MPD during pregnancy induces ADHD phenotypes in the offspring. [ABSTRACT FROM AUTHOR]

Hepatitis B e antigen (HBeAg) has been considered to cause immunotolerance to hepatitis B virus (HBV) in newborn infants after fetal HBeAg exposure. This study compared anti-HBs responses to hepatitis B vaccination in infants who were born to HBeAg-positive and -negative mothers respectively, to investigate whether fetal HBeAg exposure may induce immunotolerance to HBV. Totally 265 infants who received recommended neonatal immunoprophylaxis against hepatitis B and had no HBV infection were included. Anti-HBs levels were compared between 124 infants with cord blood positive HBeAg and 141 infants with cord blood negative HBeAg at 7–12 months of age. The infants in two groups had similar age at the follow-up (10.0 ± 2.3 vs 10.1 ± 2.3 months, P = 0.590). Overall, 259 (97.7%) of 265 infants achieved anti-HBs levels (mIU/ml) ≥10 and 6 (2.3%) others had anti-HBs 0.05). Additionally, the distribution of anti-HBs response levels were also comparable in infants with high and low HBeAg levels (P = 0.818). In conclusions, the fetal HBeAg exposure does not inhibit the antibody response to neonatal hepatitis B vaccination. The data suggest that HBeAg appears not inducing immunotolerance to HBV.

Predictions from physiologically based toxicokinetic (PBTK) models can help inform human health risk assessment for potentially toxic chemicals in the environment. Bisphenol S (BPS) is the second most abundant bisphenol detected in humans in the United States, after bisphenol A (BPA). We have recently demonstrated that BPS, much like BPA, can cross the placental barrier and disrupt placental function. Differences in physicochemical properties, toxicokinetics, and exposure outcomes between BPA and other bisphenols prevent direct extrapolation of existing BPA PBTK models to BPS. The current study aimed to develop pregnancy-specific PBTK (p-PBTK) models for BPA and BPS, using a common p-PBTK model structure. Novel paired maternal and fetal pregnancy data sets for total, unconjugated, and conjugated BPA and BPS plasma concentrations from three independent studies in pregnant sheep were used for model calibration. The nine-compartment (maternal blood, liver, kidney, fat, placenta and rest of body, and fetal liver, blood and rest of body) models simulated maternal and fetal experimental data for both BPA and BPS within one standard deviation for the majority of the experimental data points, highlighting the robustness of both models. Simulations were run to examine fetal exposure following daily maternal exposure to BPA or BPS at their tolerable daily intake dose over a two-week period. These predictive simulations show fetal accumulation of both bisphenols over time. Interestingly, the steady-state approximation following this dosing strategy achieved a fetal concentration of unconjugated BPA to levels observed in cord blood from human biomonitoring studies. These models advance our understanding of bisphenolic compound toxicokinetics during pregnancy and may be used as a quantitative comparison tool in future p-PBTK models for related chemicals.

Introduction: The burden of environmental chemicals in the human population is ubiquitous and especially problematic in pregnancy due to potential exposure of the vulnerable fetus. According to the Developmental Origins of Health and Disease hypothesis, the fetal period is highly sensitive to exposure to environmental factors that will determine the development of diseases later in life. A range of environmental chemicals has been studied in the ex vivo placental perfusion model, which is a human model using the intact placenta directly after birth to study the placental transfer and metabolism of selected compounds.Methods: Here, we reviewed the existing knowledge on human placental perfusion of environmental chemicals in order to identify potential correlations between placental transfer and properties of chemicals and areas of future research needs.Results: We found 32 studies of the following groups of environmental chemicals: pesticides, persistent organic pollutants (POPs), plastics and byproducts, phyto/myco-estrogens and fungal toxins, byproducts from heating/curing food, combustion in traffic and industry, and metals. The studies showed highly distinct transfer rates from very fast transport to the fetal side to negligible transfer.Discussion: In general, a low molecular weight favors placental translocation, but placental translocation is dependent on other physicochemical properties of the substances, claiming the need for more standardized studies and proper quantitative structure-activity relationship (QSAR) analysis. Overall, we recommend using placental perfusion studies in the risk assessment of environmental toxicants, to determine the transfer, metabolism and toxic effects of this diverse class of substances, on the human term placenta. [ABSTRACT FROM AUTHOR]

The G protein-coupled estrogen receptor (GPER), also known as GPR30, is a widely conserved 7-transmembrane-domain protein which has been identified as a novel 17β-estradiol-binding protein that is structurally distinct from the classic oestrogen receptors (ERα and ERβ). There are still conflicting data regarding the exact role and the natural ligand of GPER/GPR30 in reproductive tracts as both male and female knock-out mice are fertile and have no abnormalities of reproductive organs. Testicular germ cell cancers (TGCCs) are the most common malignancy in young males and the most frequent cause of death from solid tumors in this age group. Clinical and experimental studies suggested that estrogens participate in the physiological and pathological control of male germ cell proliferation. In human seminoma cell line, while 17β-estradiol (E2) inhibits in vitro cell proliferation through an ERβ-dependent mechanism, an impermeable E2 conjugate (E2 coupled to BSA), in vitro cell proliferation is stimulated by activating ERK1/2 and protein kinase A through a membrane GPCR that we further identified as GPER/GPR30. The same effect was observed with low but environmentally relevant doses of BPA, an estrogenic endocrine disrupting compound. Furthermore, GPER/GPR30 is specifically overexpressed in seminomas but not in non-seminomas and this overexpression is correlated with an ERβ-downregulation. This GPER/GPR30 overexpression could be linked to some genetic variations, as single nucleotide polymorphisms, which was also reported in other hormone-dependent cancers. We will review here the implication of GPER/GPR30 in TGCCs pathophysiology and the arguments to consider GPER/GPR30 as a potential therapeutic target in humans.

The G protein-coupled estrogen receptor (GPER), also known as GPR30, is a widely conserved 7-transmembrane-domain protein which has been identified as a novel 17β-estradiol-binding protein that is structurally distinct from the classic oestrogen receptors (ERα and ERβ). There are still conflicting data regarding the exact role and the natural ligand of GPER/GPR30 in reproductive tracts as both male and female knock-out mice are fertile and have no abnormalities of reproductive organs. Testicular germ cell cancers (TGCCs) are the most common malignancy in young males and the most frequent cause of death from solid tumors in this age group. Clinical and experimental studies suggested that estrogens participate in the physiological and pathological control of male germ cell proliferation. In human seminoma cell line, while 17β-estradiol (E2) inhibits in vitro cell proliferation through an ERβ-dependent mechanism, an impermeable E2 conjugate (E2 coupled to BSA), in vitro cell proliferation is stimulated by activating ERK1/2 and protein kinase A through a membrane GPCR that we further identified as GPER/GPR30. The same effect was observed with low but environmentally relevant doses of BPA, an estrogenic endocrine disrupting compound. Furthermore, GPER/GPR30 is specifically overexpressed in seminomas but not in non-seminomas and this overexpression is correlated with an ERβ-downregulation. This GPER/GPR30 overexpression could be linked to some genetic variations, as single nucleotide polymorphisms, which was also reported in other hormone-dependent cancers. We will review here the implication of GPER/GPR30 in TGCCs pathophysiology and the arguments to consider GPER/GPR30 as a potential therapeutic target in humans. [ABSTRACT FROM AUTHOR]

This study investigates the long-term effect of fetal exposure to the 1974 Tornado Super Outbreak. Using the 2008–2017 American Community Survey and a difference-in-differences framework, we estimate the adverse effects of this stressful in-utero shock on health and socioeconomic outcomes in adulthood. The effects explain 7% of the average probability of having at least one physical/cognitive difficulty and are robust to selection and migration issues. We find weaker effects on adulthood socioeconomic status and birth outcomes. The weaker effects on adulthood socioeconomic outcomes are because of complementing parental behaviours. We suggest maternal stress and fear as a key mechanism. Our estimate implies that the annual earned income loss from disaster-driven health problems was $72 million in 2017. Our findings suggest that the adverse impacts on late outcomes might be largely caused by maternal stress due to the unpredictability of the Tornado Super Outbreak. (JEL I15, O10, Q54) [ABSTRACT FROM AUTHOR]

Recently, we showed that infants with or without fetal hepatitis B e antigen (HBeAg) exposure had comparable antibody response to hepatitis B vaccination and proposed that fetal HBeAg exposure appears to not induce immunotolerance to HBV. Here, we summarized the different results on the topic of fetal HBeAg exposure in inducing immunotolerance to HBV nucleocapsid protein, and the evidence to back up that the tendency of high infection rate in infants of HBeAg-positive mothers is more likely associated with higher maternal viral loads and is less likely associated with the fetal HBeAg exposure. We consider that whether fetal HBeAg exposure plays an important role in the pathogenesis of chronic HBV infection remains to be an open question.

Drugs can have harmful effects on the embryo or the fetus at any point during pregnancy. Not all the damaging effects of intrauterine exposure to drugs are obvious at birth, some may only manifest later in life. Thus, drugs should be prescribed in pregnancy only if the expected benefit to the mother is thought to be greater than the risk to the fetus. Dosing of drugs during pregnancy is often empirically determined and based upon evidence from studies of non-pregnant subjects, which may lead to suboptimal dosing, particularly during the third trimester. This review collates examples of drugs with known recommendations for dose adjustment during pregnancy, in addition to providing an example of the potential use of PBPK models in dose adjustment recommendation during pregnancy within the context of drug-drug interactions. For many drugs, such as antidepressants and antiretroviral drugs, dose adjustment has been recommended based on pharmacokinetic studies demonstrating a reduction in drug concentrations. However, there is relatively limited (and sometimes inconsistent) information regarding the clinical impact of these pharmacokinetic changes during pregnancy and the effect of subsequent dose adjustments. Examples of using pregnancy PBPK models to predict feto-maternal drug exposures and their applications to facilitate and guide dose assessment throughout gestation are discussed. [ABSTRACT FROM AUTHOR]

Background: Prenatal exposures may contribute to male infertility in adult life, but large-scale epidemiological evidence is still lacking. The Fetal Programming of Semen quality (FEPOS) cohort was founded to provide means to examine if fetal exposures can interfere with fetal reproductive development and ultimately lead to reduced semen quality and reproductive hormone imbalances in young adult men. Methods: Young adult men at least 18 years and 9 months of age born to women in the Danish National Birth Cohort living in relative proximity to Copenhagen or Aarhus and for whom a maternal blood sample and two maternal interviews during pregnancy were available were invited to FEPOS. Recruitment began in March 2017 and ended in December 2019. The participants answered a comprehensive questionnaire and underwent a physical examination where they delivered a semen, urine, and hair sample, measured their own testicular volume, and had blood drawn. Results: In total 21,623 sons fulfilled eligibility criteria of whom 5697 were invited and 1058 participated making the response rate 19%. Semen characteristics did not differ between sons from the Copenhagen and Aarhus clinics. When comparing the FEPOS semen parameters to similar cohorts, the median across all semen characteristics was slightly lower for FEPOS participants, although with smaller variation. Conclusion: With its 1058 young adult men, the FEPOS cohort is the largest population-based male-offspring cohort worldwide specifically designed to investigate prenatal determinants of semen quality. Wide-ranging information on maternal health, lifestyle, socioeconomic status, occupation, and serum concentrations of potential reproductive toxicants during pregnancy combined with biological markers of fertility in their sons collected after puberty allow for in-depth investigations of the 'fetal origins of adult disease hypothesis'. [ABSTRACT FROM AUTHOR]

Background: Exposure to heavy metals such as lead, cadmium and mercury during pregnancy carries a great risk to the mother as well as the fetus. Methods: Lead, cadmium and mercury were measured in umbilical cord blood samples of 3 groups women (30 women's for lead, 30 cadmium and 10 from mercury) in maternity of Sidi Bel Abbes region in Algeria between 2016 and 2017.The objective of this study was to measure in the blood of the umbilical cord the concentration of lead (Pb), mercury (Hg) and cadmium (Cd), and to evaluate the relationship between these levels and prematurity. The lead, cadmium and mercury levels were measured by atomic absorption. Results: The study showed obvious variations in, maternal characteristics. The results revealed several factors predisposing to prematurity. The mean concentrations of cord blood lead, cadmium and mercury were; 18.97 μg/L, 0.26 μg/L, and6.20 nmol/L, respectively. There was a highly significant direct correlation between cord lead concentrations and gestational age(r=0.43; P = 0.017), and we found that gestational age and birth weight inversely correlated with cord mercury concentration (r=0.44 and r=0.57 respectively).No correlation was observed between cord cadmium concentrations and gestational age. Conclusion: This study has shown that pregnant women in this region were exposed to high levels for heavy metalswhich need an intervention. [ABSTRACT FROM AUTHOR]

Arsenic is a relatively abundant metalloid that impacts DNA methylation and has been implicated in various adverse health outcomes including several cancers and diabetes. However, uncertainty remains about the identity of genomic CpGs that are sensitive to arsenic exposure, in utero or otherwise. Here we identified a high confidence set of CpG sites whose methylation is sensitive to in utero arsenic exposure. To do so, we analyzed methylation of infant CpGs as a function of maternal urinary arsenic in cord blood and placenta from geographically and ancestrally distinct human populations. Independent analyses of these distinct populations were followed by combination of results across sexes and populations/tissue types. Following these analyses, we concluded that both sex and tissue type are important drivers of heterogeneity in methylation response at several CpGs. We also identified 17 high confidence CpGs that were hypermethylated across sex, tissue type and population; 11 of these were located within protein coding genes. This pattern is consistent with hypotheses that arsenic increases cancer risk by inducing the hypermethylation of genic regions. This study represents an opportunity to understand consistent, reproducible patterns of epigenomic responses after in utero arsenic exposure and may aid towards novel biomarkers or signatures of arsenic exposure. Identifying arsenic-responsive sites can also contribute to our understanding of the biological mechanisms by which arsenic exposure can affect biological function and increase risk of cancer and other age-related diseases. • Identification of CpG sites that are sensitive to in utero arsenic exposure with high confidence • High confidence CpG sites display reproducible responses across tissue-types, sexes, and populations • Tissue-type and infant sex contribute to differences in response to arsenic exposure • CpGs hypermethylation in protein coding genes is most salient in infants with higher in utero arsenic exposure [ABSTRACT FROM AUTHOR]

Abstract Background Animal models show that prenatal bisphenol A (BPA) exposure leads to sexually dimorphic disruption of the neuroendocrine system in offspring, including the hypothalamic-pituitary-adrenal (HPA) neuroendocrine system, but human data are lacking. In humans, prenatal BPA exposure is associated with sex-specific behavioural problems in children, and HPA axis dysregulation may be a biological mechanism. The objective of the current study was to examine sex differences in associations between prenatal maternal urinary BPA concentration and HPA axis function in 3 month old infants. Methods Mother-infant pairs (n = 132) were part of the Alberta Pregnancy Outcomes and Nutrition study, a longitudinal birth cohort recruited (2010–2012) during pregnancy. Maternal spot urine samples collected during the 2nd trimester were analyzed for total BPA and creatinine. Infant saliva samples collected prior to and after a blood draw were analyzed for cortisol. Linear growth curve models were used to characterize changes in infant cortisol as a function of prenatal BPA exposure. Results Higher maternal BPA was associated with increases in baseline cortisol among females (β = 0.13 log μg/dL; 95% CI: 0.01, 0.26), but decreases among males (β = −0.22 log μg/dL; 95% CI: -0.39, −0.05). In contrast, higher BPA was associated with increased reactivity in males (β = .30 log μg/dL; 95% CI: 0.04, 0.56) but decreased reactivity in females (β = −0.15 log μg/dL; 95% CI: -0.35, 0.05). Models adjusting for creatinine yielded similar results. Conclusions Prenatal BPA exposure is associated with sex-specific changes in infant HPA axis function. The biological plausibility of these findings is supported by their consistency with evidence in rodent models. Furthermore, these data support the hypotheses that sexually dimorphic changes in children’s behaviour following prenatal BPA exposure are mediated by sexually dimorphic changes in HPA axis function.

Background: Exposure to heavy metals such as lead, cadmium and mercury during pregnancy carries a great risk to the mother as well as the fetus. Method: Lead, cadmium and mercury were measured in umbilical cord blood samples of 3 groups women (30 women's for lead, 30 cadmium and 10 from mercury) in maternity of Sidi Bel Abbes region in Algeria between 2016 and 2017.The objective of this study was to measure in the blood of the umbilical cord the concentration of lead (Pb), mercury (Hg) and cadmium (Cd), and to evaluate the relationship between these levels and prematurity. The lead, cadmium and mercury levels were measured by atomic absorption. Results: The study showed obvious variations in, maternal characteristics. The results revealed several factors predisposing to prematurity. The mean concentrations of cord blood lead, cadmium and mercury were; 18.97 µg/L, 0.26 µg/L, and6.20 nmol/L, respectively. There was a highly significant direct correlation between cord lead concentrations and gestational age(r=0.43; P = 0.017), and we found that gestational age and birth weight inversely correlated with cord mercury concentration (r=0.44 and r=0.57 respectively).No correlation was observed between cord cadmium concentrations and gestational age. Conclusion: This study has shown that pregnant women in this region were exposed to high levels for heavy metalswhich need an intervention. [ABSTRACT FROM AUTHOR]

Background: Selective serotonin reuptake inhibitors (SSRIs) are antidepressants prescribed in 10% of pregnancies in the USA. We have previously shown in preclinical studies that sertraline exposure impacts cardiomyocyte development, leading to reductions in left ventricular size and cardiac function. Objectives: We hypothesized that in utero SSRI exposure will lead to reduced left ventricular dimensions and cardiac function on echocardiography immediately after birth. Methods: Twenty term infants with and 21 term infants without in utero exposure to SSRIs underwent echocardiograms to assess cardiac size and function. The exclusion criteria for infants were prematurity, small or large for gestational age, any respiratory or cardiovascular support needed after birth, and any major congenital malformation. Results: Infants exposed to in utero SSRIs had significantly reduced right ventricular dimensions in the diastole (controls 1.0 cm [0.86, 1.20], SSRI 0.89 cm [0.730, 1.05], p = 0.03), and left ventricular lengths in the diastole and systole (diastole: controls 3.4 cm [3.25, 3.65], SSRI 3.25 cm [3.10, 3.45], p = 0.03; systole: controls 2.9 cm [2.65, 3.05], SSRI 2.6 cm [2.50, 2.85], p = 0.01). No differences were observed in cardiac function. Importantly, there were no differences in maternal conditions or infant birth weight, body surface area, or gestational age. Conclusions: Our findings suggest an association between in utero exposure to SSRIs and ventricular size in infants. Given the increasing use of SSRIs during pregnancy and the importance of early life programming on future cardiovascular health, larger studies need to be completed to determine if in utero SSRI exposure impacts ventricular size. [ABSTRACT FROM AUTHOR]

Abstract Bisphenol A (BPA), S (BPS), and F (BPF) are among the most abundant bisphenols detected in humans, yet pregnancy toxicokinetics for BPS or BPF remain unknown. Because gestational BPS can disrupt placental function and result in reproductive and metabolic disorders in the progeny, the aim of the study was to investigate BPS and BPF toxicokinetics during pregnancy using an in vivo approach. Fetal catheterizations were conducted in pregnant sheep (n = 6) at mid-pregnancy and injected with either a single dose of BPS (n = 3, 0.5 mg/kg, s.c.), or a combination of BPS, BPF, and BPA (n = 3, 0.5 mg/kg for each chemical, s.c.). Maternal and fetal blood and urine and amniotic fluid were collected over 72 h and analyzed for bisphenols by HPLC-MS/MS. We observed significant differences in half-life, maximum concentration, and total body clearance in maternal circulation among bisphenols. Longer half-lives were observed in fetal vs. maternal circulation for all bisphenols. Fetal toxicokinetics differed among bisphenols with BPS having the longest fetal half-life. All bisphenols reached basal levels at 48 h in maternal plasma, but were still detectable in amniotic fluid, fetal urine, and fetal plasma at 72 h. In this first pregnancy toxicokinetic study of BPS and BPF we have demonstrated maternal and fetal toxicokinetic differences among all three bisphenols. Higher BPS persistence in the fetal compartment warrants studies into progeny adverse outcomes following gestational exposure. Additionally, toxicokinetic differences among bisphenols call for a more careful approach when extrapolating kinetic information from one bisphenol chemical to another. Highlights • Maternal and fetal pharmacokinetics were different among all three bisphenols. • Half-lives were longer in fetal vs. maternal circulation for all three bisphenols. • Bisphenol S had the longest fetal half-life compared to bisphenol A or bisphenol F. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the effects of ionizing radiation exposure during the first trimester of pregnancy in usual clinical situations.Study Design: We conducted a prospective observational cohort study using data collected between 1987 and 2014. This database was authorized by the French "Commission Nationale de l'Informatique et des Libertés". The exposed group consisted of 319 pregnant women exposed to sub diaphragmatic ionizing radiations for diagnostic purposes, during the first trimester of pregnancy, and the control group consisted of 319 pregnant women without any exposure or exposed to non-teratogenic agents. Data on maternal history and radiations exposure were collected on first contact, and pregnancy outcomes were documented at follow-up. An univariate analysis was performed to compare both groups for the main outcomes.Results: Exposure to sub diaphragmatic ionizing radiation for diagnosis purpose (median fetal dose of 3.1 mGy [0.2-130.0]) during the first trimester of pregnancy was not significantly associated with an increased risk of malformations (1.5% vs 1.8%, p = 1.00), miscarriage (7.8% vs 7.2%, p = 0.88), in utero fetal death (0.3% vs 0%, p = 1.00) or fetal growth restriction (5.4% vs 3.5%, p = 0.62).Conclusion: Pregnant women exposed to irradiant diagnostic procedures do not present a higher risk of malformations, miscarriage, in utero fetal death or fetal growth restriction and should be reassured, even if the examination focused on the pelvis. [ABSTRACT FROM AUTHOR]

Abstract Domoic acid (DA) is a neuroexcitotoxic amino acid that is naturally produced by some species of marine diatoms during harmful algal blooms (HABs). The toxin is transferred through the food web from plantivorous fish and shellfish to marine mammals resulting in significant morbidity and mortality. Due to the timing and location of DA producing HABs, it is well documented that pregnant female California sea lions (CSL) are regularly exposed to DA through their diet thereby posing exposure risks to a neuroteratogen in developing fetuses. In the present study, fluids from 36 fetuses sampled from naturally exposed pregnant CSLs were examined for DA. Domoic acid was detected in 79% of amniotic fluid (n = 24), 67% of allantoic fluid (n = 9), 75% of urine (n = 4), 41% of meconium (n = 17) and 29% of stomach content (n = 21) samples opportunistically collected from CSL fetuses. The distribution of DA in fetal samples indicates an increased prenatal exposure risk due to recirculation of DA in fetal fluids and continuous exposure to the developing brain. [ABSTRACT FROM AUTHOR]

Abstract Bisphenol S (BPS) is widely used as a substitute for Bisphenol A in consumer products. Despite its potential endocrine-disrupting effects and widespread exposure, toxicokinetic data, particularly during the critical period of pregnancy, are not available for BPS. The objectives of our study were to evaluate the mechanisms determining fetal exposure to BPS and to BPS glucuronide (BPSG) and to compare them with those prevailing for BPA. The disposition of BPS and BPSG was evaluated in the materno-fetal unit of the catheterized pregnant ewe model, following intravenous administrations of BPS and BPSG to mothers and their fetuses. In a second experiment, the rate of BPS accumulation in the fetal compartment was determined under steady-state conditions after repeated intravenous BPS administrations to the mother. In the maternal compartment, BPS was mainly metabolized into BPSG and totally eliminated in urine. Only 0.40% of the maternal dose was transferred to the fetus. However, once in the fetal compartment, 26% of the fetal dose was rapidly eliminated through placental transfer, while 46% of BPS was metabolized into BPSG which remained trapped in the fetal compartment. Thus, the elimination of BPSG from the fetal compartment required its back-conversion into bioactive BPS, leading to an 87% enhancement of the fetal BPS exposure. Our findings demonstrate that, despite the low materno-fetal placental transfer of BPS, this substitute for BPA is able to accumulate in the fetal compartment after repeated maternal exposure, leading to chronic fetal exposure to BPS in a range of concentrations similar to those of BPA. Graphical abstract Unlabelled Image Highlights • Fetal sheep was used to evaluate BPS and BPSG toxicokinetic parameters. • The materno-fetal placental transfer of BPS is limited, ten times lower than for BPA. • BPS is able to accumulate in the fetal compartment after repeated maternal exposure. • The chronic fetal internal exposure to BPS is similar to that of BPA. [ABSTRACT FROM AUTHOR]