Investigating maternal and neonatal health outcomes associated with continuing or ceasing dexamphetamine treatment for women with attention-deficit hyperactivity disorder during pregnancy: a retrospective cohort study.

PURPOSE: Attention-deficit hyperactivity disorder (ADHD) is becoming more commonly diagnosed in women, consequently, more women of reproductive age are taking ADHD medication, such as dexamphetamine. However, the safety associated with continuing or ceasing dexamphetamine during pregnancy is unclear. This study investigates outcomes associated with the continuation of dexamphetamine during pregnancy compared to those who ceased or were unexposed. METHODS: A population-based retrospective cohort of women from Western Australia who had been dispensed dexamphetamine during pregnancy and gave birth between 2003 and 2018. Women had either continued to take dexamphetamine throughout pregnancy (continuers, n = 547) or ceased dexamphetamine before the end of the second trimester (ceasers, n = 297). Additionally, a matched (1:1) comparison group of women who were dispensed an ADHD medication prior to pregnancy but not during pregnancy (unexposed) was included in the study (n = 844). Multivariable generalised linear models were used to compare maternal and neonatal health outcomes. RESULTS: Compared to continuers, ceasers had greater odds of threatened abortion (OR: 2.28; 95%CI: 1.00, 5.15; p = 0.049). The unexposed had some benefits compared to the continuers, which included lower risk of preeclampsia (OR: 0.58; 95%CI: 0.35, 0.97; p = 0.037), hypertension (OR: 0.32; 95%CI: 0.11, 0.93; p = 0.036), postpartum haemorrhage (OR: 0.57; 95%CI: 0.41, 0.80; p = 0.001), neonatal special care unit admittance (OR: 0.16; 95%CI: 0.12, 0.20; p < 0.001) and fetal distress (OR: 0.73; 95%CI: 0.54, 0.99; p = 0.042). CONCLUSION: Continuing dexamphetamine throughout pregnancy was not associated with an increase in adverse neonatal and maternal health outcomes compared to ceasing. Ceasing dexamphetamine during pregnancy was associated with increased odds of threatened abortion compared with continuing dexamphetamine. However, this is something that requires further investigation due to the small sample size, difficulties examining timing, and the inability to examine spontaneous abortions. The unexposed showed some benefits compared to the continuers, suggesting that where possible the cessation of dexamphetamine prior to pregnancy may be advisable.

Prenatal Opioid Exposure and Immune-Related Conditions in Children.

Importance: Prenatal opioid exposure (POE) may alter with fetal development of the immune system, which may influence long-term health and susceptibility to immune-related conditions. Objective: To compare the risk of hospitalization and emergency department presentation for immune-related conditions in children with and without POE. Design, Setting, and Participants: This retrospective, population-based cohort study used linked administrative health records of all children born in Western Australia between January 1, 2003, and December 31, 2018 (N = 401 462). Exposure: Prenatal exposure to prescription opioids (overall and by trimester), neonatal abstinence syndrome diagnosis, and opioid indication (pain or opioid use disorder [OUD]). Main Outcomes and Measures: The main outcome was hospital admissions and emergency department presentations during which a child was diagnosed with an immune-related condition, including infections, conditions associated with an overactive immune system (eg, asthma, eczema, and allergy and anaphylaxis), and autoimmune diseases diagnosed before age 5 years or June 30, 2020. Data were analyzed between August 30, 2022, and February 27, 2023. Results: Neonates with POE (1656 [0.4%]; mean [SD] gestational age, 37.7 [2.1] weeks; 836 females [50.5%]; 820 males [49.5%]) were more likely to be born preterm, have low birth weight for gestational age, and be coexposed to cigarette smoke compared with nonexposed neonates. Perinatal opioid exposure was associated with an increased risk of perinatal infection (adjusted odds ratio [AOR], 1.62; 95% CI, 1.38-1.90) and eczema and dermatitis (AOR, 11.91; 95% CI, 9.84-14.41) compared with nonexposure. Neonatal abstinence syndrome was also associated with both conditions (AOR, 2.91 [95% CI, 2.36-3.57] and 31.11 [95% CI, 24.64-39.28], respectively). Prenatal opioid exposure was also associated with an increased risk of childhood asthma (adjusted hazard ratio [AHR], 1.44; 95% CI, 1.16-1.79), but not allergies and anaphylaxis. It was also associated with an increased risk of childhood eczema and dermatitis, but only in children with POE from opioids used to treat OUD (AHR, 1.47; 95% CI, 1.08-1.99) rather than pain. In contrast, POE from opioids used for pain was associated with an increased risk of infection (AHR, 1.44; 95% CI, 1.32-1.58), but POE to opioids used to treat OUD was not. Autoimmune conditions were rare and were not observed to be associated with POE. Conclusions and Relevance: In this cohort study, POE was associated with an increased risk of infection, eczema and dermatitis, and asthma, but not allergies and anaphylaxis or autoimmune conditions. These findings highlight the importance of further study of opioid-induced immune changes during pregnancy, the potential impact on long-term health in exposed children, and the mechanisms of opioid-induced immune dysregulation.

RISING STARS: The heat is on: how does heat exposure cause pregnancy complications?

The incidence and severity of heatwaves are increasing globally with concomitant health complications. Pregnancy is a critical time in the life course at risk of adverse health outcomes due to heat exposure. Dynamic physiological adaptations, which include altered thermoregulatory pathways, occur in pregnancy. If heat dissipation is ineffective, maternal and neonate health outcomes can be compromised. Indeed, epidemiological studies and animal models reveal that exposure to heat in pregnancy likely elicits an array of health complications including miscarriage, congenital anomalies, low birth weight, stillbirth, and preterm birth. Despite these associations, the reasons for why these complications occur are unclear. An array of physiological and endocrine changes in response to heat exposure in pregnancy likely underpin the adverse health outcomes, but currently, conclusive evidence is sparse. Accompanying these fundamental gaps in knowledge is a poor understanding of what exact climatic conditions challenge pregnant physiology. Moreover, the overlay of thermoregulatory-associated behaviours such as physical activity needs to be taken into consideration when assessing the risks to human health and identifying critical populations at risk. While the health impacts from heat are largely preventable through strategic interventions, for the related clinical practice, public health, and policy approaches to be effective, the gaps in basic science understanding urgently need to be addressed.

"Well, what can I do?": An examination of the role supervisors, peers and scientific societies can play in the multicultural student experience.

International graduate students are a multi-cultural and diverse demographic of researchers that are integral to higher education globally. Although their contributions to research and innovation are acknowledged, the experiences of international students overseas are influenced by structural inequalities and challenges, some similar, and some unique to their domestic colleagues, that are often compounded by a "deficit narrative". This paper was defined by the inaugural 'Pressure Cooker' workshop held at the Australian and New Zealand Placental Association (ANZPRA) conference in 2022, and discusses some of the major institutional and social structures that can define an international student's graduate degree trajectory. Further, we provide examples of collaborative programs and methods for academics, scientific societies and domestic graduate peer groups to promote an equitable and accessible environment for all researchers.

Switching from tobacco cigarettes in very early pregnancy: The effects of in utero e-cigarette exposure on mouse offspring neurodevelopment and behaviour.

INTRODUCTION: Electronic cigarettes (e-cigarettes) are often perceived to be safer than smoking, which has led to some women switching to e-cigarettes during pregnancy. However, the effects of switching from smoking to e-cigarettes on both pregnancy outcomes and the foetus are largely unknown. This study aimed to investigate the effects of switching from tobacco smoking to e-cigarette use in very early pregnancy on birth outcomes, neurodevelopment and behaviour of the offspring. METHODS: Female BALB/c mice were exposed to cigarette smoke for up to two weeks before being mated. Mated dams were then allocated to one of four treatment groups: (i) continued exposure to cigarette smoke (ii) exposure to e-cigarette aerosol with nicotine, (iii) or without nicotine, or (iv) medical air. Pregnant mice were exposed for 2 h per day for the duration of pregnancy. Gestational outcomes including litter size and sex ratio were assessed, in addition to early-life markers of physical- and neuro- development. At 8 weeks of age, motor coordination, anxiety, locomotion, memory and learning of the adult offspring were assessed. RESULTS: Gestational outcomes and early markers of physical- and neuro- development were unaffected by in utero exposure, as well as locomotion, anxiety-like behaviour, and object recognition memory during adulthood. However, both e-cigarette groups displayed increased spatial recognition memory compared to air exposed controls. Maternal exposure to nicotine containing e-cigarette aerosol was found to increase offspring bodyweight and impair motor skill learning. CONCLUSIONS: These results suggest there may be some benefits as well as negative effects of switching to e-cigarettes in early pregnancy.

The effects of acamprosate on maternal and neonatal outcomes in a mouse model of alcohol use disorders.

BACKGROUND: Despite the teratogenic effects of alcohol, little is known about the safety of pharmacotherapies such as acamprosate for the treatment of alcohol use disorders in pregnancy. The aims of this study were to investigate, in a mouse model, the effects of maternally administered acamprosate on maternal and neonatal health, offspring neurodevelopment and behaviour, as well as examine whether acamprosate reduces the neurological harm associated with alcohol consumption in pregnancy. METHODS: Dams were randomly allocated to one of four treatment groups: (i) control (water), (ii) acamprosate (1.6 g/L), (iii) alcohol (5% v/v) or (iv) acamprosate and alcohol (1.6 g/L; 5% v/v ethanol) and exposed from 2-weeks pre-pregnancy until postpartum day 7. Gestational outcomes including litter size and sex ratio were assessed, in addition to early-life markers of neurodevelopment. At 8 weeks of age, motor coordination, anxiety, locomotion, and memory of the adult offspring were also examined. RESULTS: Exposure to acamprosate did not affect maternal and birth outcomes (mating success, gestational weight gain, litter size, sex ratio), neonatal outcomes (head and body length, postnatal weight) or neurodevelopmental markers (righting reflex and negative geotaxis). Acamprosate exposure did not affect offspring motor control, locomotion or anxiety, however the effects on short-term memory remain uncertain. Prenatal alcohol exposed offspring exhibited various alterations, such as lower postnatal weight, smaller head (p = 0.04) and body lengths (p = 0.046) at postnatal day 70 (males only), increased negative geotaxis speed (p = 0.03), an increased time spent in the inner zone of the open field (p = 0.02). Acamprosate mitigated the effects of alcohol for negative geotaxis at postnatal day 7 (p = 0.01) and female offspring weight at postnatal day 70 (p = 0.03). CONCLUSIONS: Overall, we show that prenatal acamprosate exposure was not associated with poor maternal or neonatal health outcomes or impaired neurodevelopment and behaviour. However, acamprosate's effects on short-term memory remain uncertain. We present preliminary evidence to suggest acamprosate displayed some neuroprotective effects against damage caused by in utero alcohol exposure.

Exploring sex differences in fetal programming for childhood emotional disorders.

In examining maternal depression, placental 11ß-HSD2 mRNA expression and offspring cortisol regulation as a potential fetal programming pathway in relation to later child emotional disorders, it has become clear that sex differences may be important to consider. This study reports on data obtained from 209 participants in the Mercy Pregnancy and Emotional Wellbeing Study (MPEWS) recruited before 20 weeks of pregnancy. Maternal depressive disorders were diagnosed using the SCID-IV and maternal childhood trauma using the Childhood Trauma Questionnaire. Placental 11ß-HSD2 mRNA was measured using qRT-PCR. For assessment of stress-induced cortisol reactivity, salivary cortisol samples were taken at 12 months of age. At 4 years of age, measurement of Childhood Emotional Disorders (depression and anxiety) was based on maternal report using the Preschool Age Psychiatric Assessment (PAPA) and internalizing symptoms using the Child Behavior Checklist (CBCL). Maternal depression in pregnancy and postpartum, and infant cortisol reactivity, was associated with internalizing symptoms for females only. For female offspring only, increased 12-month cortisol reactivity was also associated with increased emotional disorders at 4 years of age; however, there was no association with placental 11ß-HSD2 mRNA expression. In females only, the combination of lower placental 11ß-HSD2 mRNA expression and higher cortisol reactivity at 12 months of age predicted increased internalising problems. These findings suggest there may be sex differences in prenatal predictors and pathways for early childhood depression and anxiety symptoms and disorder.

Long-term exposure of mice to 890 ppm atmospheric CO2 alters growth trajectories and elicits hyperactive behaviours in young adulthood.

Atmospheric carbon dioxide (CO2 ) levels are currently at 418 parts per million (ppm), and by 2100 may exceed 900 ppm. The biological effects of lifetime exposure to CO2 at these levels is unknown. Previously we have shown that mouse lung function is altered by long-term exposure to 890 ppm CO2 . Here, we assess the broader systemic physiological responses to this exposure. Mice were exposed to either 460 or 890 ppm from preconception to 3 months of age, and assessed for effects on developmental, renal and osteological parameters. Locomotor, memory, learning and anxiety-like behaviours of the mice were also assessed. Exposure to 890 ppm CO2 increased birthweight, decreased female body weight after weaning, and, as young adults, resulted in reduced engagement in memory/learning tasks, and hyperactivity in both sexes in comparison to controls. There were no clear anxiety, learning or memory changes. Renal and osteological parameters were minimally affected. Overall, this study shows that exposure of mice to 890 ppm CO2 from preconception to young adulthood alters growth and some behaviours, with limited evidence of compensatory changes in acid-base balance. These findings highlight the potential for a direct effect of increased atmospheric CO2 on mammalian health outcomes. KEY POINTS: Long-term exposure to elevated levels of atmospheric CO2 is an uncontrolled experiment already underway. This is the first known study to assess non-respiratory physiological impacts of long-term (conception to young adulthood) exposure of mice to CO2 at levels that may arise in the atmosphere due to global emissions. Exposure to elevated CO2 , in comparison to control mice, altered growth patterns in early life and resulted in hyperactive behaviours in young adulthood. Renal and bone parameters, which are important to balance acid-base levels to compensate for increased CO2 exposure, remained relatively unaffected. This work adds to the body of evidence regarding the effects of carbon emissions on mammalian health and highlights a potential future burden of disease.

Glucocorticoids regulate mitochondrial fatty acid oxidation in fetal cardiomyocytes.

The late gestational rise in glucocorticoids contributes to the structural and functional maturation of the perinatal heart. Here, we hypothesized that glucocorticoid action contributes to the metabolic switch in perinatal cardiomyocytes from carbohydrate to fatty acid oxidation. In primary mouse fetal cardiomyocytes, dexamethasone treatment induced expression of genes involved in fatty acid oxidation and increased mitochondrial oxidation of palmitate, dependent upon a glucocorticoid receptor (GR). Dexamethasone did not, however, induce mitophagy or alter the morphology of the mitochondrial network. In vivo, in neonatal mice, dexamethasone treatment induced cardiac expression of fatty acid oxidation genes. However, dexamethasone treatment of pregnant C57Bl/6 mice at embryonic day (E)13.5 or E16.5 failed to induce fatty acid oxidation genes in fetal hearts assessed 24 h later. Instead, at E17.5, fatty acid oxidation genes were downregulated by dexamethasone, as was GR itself. PGC-1α, required for glucocorticoid-induced maturation of primary mouse fetal cardiomyocytes in vitro, was also downregulated in fetal hearts at E17.5, 24 h after dexamethasone administration. Similarly, following a course of antenatal corticosteroids in a translational sheep model of preterm birth, both GR and PGC-1α were downregulated in heart. These data suggest that endogenous glucocorticoids support the perinatal switch to fatty acid oxidation in cardiomyocytes through changes in gene expression rather than gross changes in mitochondrial volume or mitochondrial turnover. Moreover, our data suggest that treatment with exogenous glucocorticoids may interfere with normal fetal heart maturation, possibly by downregulating GR. This has implications for clinical use of antenatal corticosteroids when preterm birth is considered a possibility. KEY POINTS: Glucocorticoids are steroid hormones that play a vital role in late pregnancy in maturing fetal organs, including the heart. In fetal cardiomyocytes in culture, glucocorticoids promote mitochondrial fatty acid oxidation, suggesting they facilitate the perinatal switch from carbohydrates to fatty acids as the predominant energy substrate. Administration of a synthetic glucocorticoid in late pregnancy in mice downregulates the glucocorticoid receptor and interferes with the normal increase in genes involved in fatty acid metabolism in the heart. In a sheep model of preterm birth, antenatal corticosteroids (synthetic glucocorticoid) downregulates the glucocorticoid receptor and the gene encoding PGC-1α, a master regulator of energy metabolism. These experiments suggest that administration of antenatal corticosteroids in anticipation of preterm delivery may interfere with fetal heart maturation by downregulating the ability to respond to glucocorticoids.

Investigating the Upstream and Downstream Hemodynamic Boundary Conditions of Healthy and Growth-Restricted Rat Feto-Placental Arterial Networks.

The placenta uniquely develops to orchestrate maternal adaptations and support fetal growth and development. The expansion of the feto-placental vascular network, in part, underpins function. However it is unclear how vascular development is synergistically influenced by hemodynamics and how impairment may lead to fetal growth restriction (FGR). Here, we present a robust framework consisting of ex vivo placental casting, imaging and computational fluid dynamics of rat feto-placental networks where we investigate inlet (steady and transient) and outlet (zero-pressure, Murray's Law, asymmetric fractal trees and porous blocks) boundary conditions in a model of growth-restriction. We show that the Murray's Law flow-split boundary condition is not always appropriate and that mean steady-state inlet conditions produce comparable results to transient flow. However, we conclude that transient simulations should be adopted as they provide a larger amount of valuable data, a necessity to bridge the current knowledge gap in placental biomechanics. We also show preliminary data on changes in flow, shear stress, and flow deceleration between control and growth-restricted feto-placental networks. Our proposed framework provides a standardized approach for structural and hemodynamic analysis of feto-placental vasculature and has the potential to enhance our understanding of placental function.

Fetal programming pathway from maternal mental health to infant cortisol functioning: The role of placental 11ß-HSD2 mRNA expression.

Placental 11ß-HSD2 has been a focus of research for understanding potential fetal programming associated with maternal emotional disorders. This study examined the pathway from antenatal mental health via placental 11ß-HSD2 mRNA to cortisol regulation in the infant offspring. This study reports on data obtained from 236 participants in the Mercy Pregnancy and Emotional Wellbeing Study (MPEWS). At term, placental tissue was collected within 30 min of birth from 52 participants meeting current criteria for a depressive disorder, and 184 control participants. Depressive disorders were diagnosed using the SCID-IV. In addition, antidepressant use, depressive and anxiety symptoms were measured in early and late pregnancy. Placental 11ß-HSD2 mRNA expression was measured using qRT-PCR. Infant salivary cortisol samples were taken at 12 months of age. Women on antidepressant medication and with higher trait anxiety had higher placental 11ß-HSD2 expression compared to women not taking medication. Furthermore, the offspring of women taking an antidepressant and who also had a current depressive disorder and high trait anxiety had high cortisol reactivity at 12 months of age and this was mediated through 11ß-HSD2 mRNA expression. In contrast, offspring of women not taking antidepressant medication with depressive disorder and high anxiety there was low cortisol reactivity observed. Our findings suggest that the relationship between maternal antenatal depression and anxiety and infant cortisol reactivity is mediated through placental 11ß-HSD2 mRNA expression. Furthermore, the direction differed for women taking antidepressants, where infant cortisol reactivity was high whereas when compared to those with unmedicated depression and anxiety, where infant cortisol reactivity was low.

Mouse Lung Structure and Function after Long-Term Exposure to an Atmospheric Carbon Dioxide Level Predicted by Climate Change Modeling.

BACKGROUND: Climate change models predict that atmospheric carbon dioxide [CO2] levels will be between 700 and 900 ppm within the next 80 y. Despite this, the direct physiological effects of exposure to slightly elevated atmospheric CO2 (as compared with ∼410 ppm experienced today), especially when exposures extend from preconception to adulthood, have not been thoroughly studied. OBJECTIVES: In this study we aimed to assess the respiratory structure and function effects of long-term exposure to 890 ppm CO2 from preconception to adulthood using a mouse model. METHODS: We exposed mice to CO2 (∼890 ppm) from prepregnancy, through the in utero and early life periods, until 3 months of age, at which point we assessed respiratory function using the forced oscillation technique, and lung structure. RESULTS: CO2 exposure resulted in a range of respiratory impairments, particularly in female mice, including higher tissue elastance, longer chord length, and lower lung compliance. Importantly, we also assessed the lung function of the dams that gave birth to our experimental subjects. Even though these mice had been exposed to the same level of increased CO2 for a similar amount of time (∼8wk), we measured no impairments in lung function. This suggests that the early life period, when lungs are undergoing rapid growth and development, is particularly sensitive to CO2. DISCUSSION: To the best of our knowledge, this study, for the first time, shows that long-term exposure to environmentally relevant levels of CO2 can impact respiratory function in the mouse. https://doi.org/10.1289/EHP7305.

Maternal, Placental, and Fetal Responses to Intermittent Heat Exposure During Late Gestation in Mice.

Physiological adaptations during heat exposure are critical in pregnancy. Maternal thermoregulation has to accommodate the increased metabolic load of the developing fetus. Here, we assess the consequences of intermittent heat exposure, as occurs in heat waves, for maternal adaptations during pregnancy, and chronic feto-placental outcomes. Following timed mating, C57BL/6J mice were allocated to either standard animal housing temperature conditions (SH) or housing at a temperature within the thermoneutral zone (TNZ). A subset of the TNZ group was exposed to 37 °C for 8 h a day from E15.5 to E17.5 to simulate a heat wave (HW). Maternal weight gain, food intake, rectal temperature, and nesting behaviors were measured across gestation. Fetal and placental tissues were collected at E18.5. With heat exposure, maternal rectal temperature increased while food intake and nest complexity decreased. Maternal daily weight gain initially decreased due to heat exposure, but on the last day of exposure, it was comparable to the other experimental groups. These maternal responses during heat exposure impacted on the fetus, with restrictions in placental and fetal development evident just before birth. Thus, the vascular portion of the placenta, and the relative fetal head size, was smaller. Furthermore, SH and TNZ animals demonstrated distinct differences in food intake and nesting behavior during pregnancy, reinforcing the need for caution in extrapolating from animal models to humans when housing occurs outside of thermoneutral zone conditions. This study highlights the direct effects of temperature conditions on health in pregnancy and provides a foundation for future studies to investigate fetal health consequences that are associated with intermittent heat exposure.

Advances in imaging feto-placental vasculature: new tools to elucidate the early life origins of health and disease.

Optimal placental function is critical for fetal development, and therefore a crucial consideration for understanding the developmental origins of health and disease (DOHaD). The structure of the fetal side of the placental vasculature is an important determinant of fetal growth and cardiovascular development. There are several imaging modalities for assessing feto-placental structure including stereology, electron microscopy, confocal microscopy, micro-computed tomography, light-sheet microscopy, ultrasonography and magnetic resonance imaging. In this review, we present current methodologies for imaging feto-placental vasculature morphology ex vivo and in vivo in human and experimental models, their advantages and limitations and how these provide insight into placental function and fetal outcomes. These imaging approaches add important perspective to our understanding of placental biology and have potential to be new tools to elucidate a deeper understanding of DOHaD.

Maternal vitamin D deficiency during rat gestation elicits a milder phenotype compared to the mouse model: Implications for the placental glucocorticoid barrier.

Maternal vitamin D deficiency disturbs fetal development and programmes neurodevelopmental complications in offspring, possibly through increased fetal glucocorticoid exposure. We aimed to determine whether prenatal exposure to excess glucocorticoids underlies our rat model of early-life vitamin D deficiency, leading to altered adult behaviours. Vitamin D deficiency reduced the expression of the glucocorticoid-inactivating enzyme Hsd11b2 in the female placenta, but did not alter maternal glucocorticoid levels, feto-placental weights, or placental expression of other glucocorticoid-related genes at mid-gestation. This differs to the phenotype previously observed in vitamin D deficient mice, and highlights important modelling considerations.

Quantitative characterization of rodent feto-placental vasculature morphology in micro-computed tomography images.

BACKGROUND AND OBJECTIVE: Optimal development of placental vasculature is critical for fetal growth and health outcomes. Many studies characterizing the vascular structure of the fetal side of the placenta have utilized a range of two-dimensional and three-dimensional (3D) imaging techniques including X-ray micro-computed tomography (micro-CT) following perfusion of the vasculature with a radio-opaque compound. The CT approach has been used to study feto-placental vasculature in rodents and humans. Its inherent advantage is that it reveals the 3D structure in high resolution without destroying the sample. This permits both multiple scanning of the sample and follow-up histological investigations in the same sample. Nevertheless, the applicability of the approach is hampered both by the challenging segmentation of the vasculature and a lack of straightforward methodology to quantitate the feto-placental vascular network. This paper addresses these challenges. METHODS: An end-to-end methodology is presented for automatically segmenting the vasculature; obtaining a Strahler-ordered rooted-tree representation and extracting quantitative features from its nodes, segments and branches (including volume, length, tortuosity and branching angles). The methodology is demonstrated for rat and mouse placentas at the end of gestation (day 22 and day 18, respectively), perfused with Microfil® and imaged using two different micro-CT scanners. RESULTS: The 3D visualizations of the resulting vascular trees clearly demonstrate differences between the branching complexity, tree span and tree depth of the mouse and rat placentas. The quantitative characterizations of these trees include not only the fundamental features that have been utilized in other studies of feto-placental vasculature but also several additional features. Boxplots of several of these-tortuosity, number of side branches, number of offspring per branch and branch volume-computed at each Strahler order are presented and interpreted. Differences and similarities between the mouse and rat casts are readily detected. CONCLUSION: The proposed end-to-end methodology, and the implementation presented using a combination of Amira and Matlab, offers researchers in the field of placental vasculature characterization a straightforward and objective approach for quantifying micro-CT vascular datasets.

The Role of 11ß-Hydroxy Steroid Dehydrogenase Type 2 in Glucocorticoid Programming of Affective and Cognitive Behaviours.

Developmental exposure to stress hormones, i.e. glucocorticoids, is central to the process of prenatal programming of later-life health. Glucocorticoid overexposure, through stress or exogenous glucocorticoids, results in a reduced birthweight, as well as affective and neuropsychiatric outcomes in adults, combined with altered hypothalamus-pituitary-adrenal (HPA) axis activity. As such, glucocorticoids are tightly regulated during development through the presence of the metabolizing enzyme 11ß-hydroxysteroid dehydrogenase type 2 (HSD2). HSD2 is highly expressed in 2 hubs during development, i.e. the placenta and the fetus itself, protecting the fetus from inappropriate glucocorticoid exposure early in gestation. Through manipulation of HSD2 expression in the mouse placenta and fetal tissues, we are able to determine the relative contribution of glucocorticoid exposure in each compartment. Feto-placental HSD2 deletion resulted in a reduced birthweight and the development of anxiety- and depression-like behaviours in adult mice. The placenta itself is altered by glucocorticoid overexposure, which causes reduced placental weight and vascular arborisation. Furthermore, altered flow and resistance in the umbilical vessels and modification of fetal heart function and development are observed. However, brain-specific HSD2 removal (HSD2BKO) also generated adult phenotypes of depressive-like behaviour and memory deficits, demonstrating the importance of fetal brain HSD2 expression in development. In this review we will discuss potential mechanisms underpinning early-life programming of adult neuropsychiatric disorders and the novel therapeutic potential of statins.

Vitamin D is crucial for maternal care and offspring social behaviour in rats.

Early life vitamin D plays a prominent role in neurodevelopment and subsequent brain function, including schizophrenic-like outcomes and increasing evidence for an association with autism spectrum disorder (ASD). Here, we investigate how early life vitamin D deficiency during rat pregnancy and lactation alters maternal care and influences neurodevelopment and affective, cognitive and social behaviours in male adult offspring. Sprague-Dawley rats were placed on either a vitamin D control (2195 IU/kg) or deficient diet (0 IU/kg) for five weeks before timed mating, and diet exposure was maintained until weaning of offspring on postnatal day (PND) 23. MRI scans were conducted to assess brain morphology, and plasma corticosterone levels and neural expression of genes associated with language, dopamine and glucocorticoid exposure were characterised at PND1, PND12 and 4 months of age. Compared to controls, vitamin D-deficient dams exhibited decreased licking and grooming of their pups but no differences in pup retrieval. Offspring neurodevelopmental markers were unaltered, but vitamin D-deficient pup ultrasonic vocalisations were atypical. As adults, males that had been exposed to vitamin D deficiency in early life exhibited decreased social behaviour, impaired learning and memory outcomes and increased grooming behaviour, but unaltered affective behaviours. Accompanying these behavioural changes was an increase in lateral ventricle volume, decreased cortical FOXP2 (a protein implicated in language and communication) and altered neural expression of genes involved in dopamine and glucocorticoid-related pathways. These data highlight that early life levels of vitamin D are an important consideration for maternal behavioural adaptations as well as offspring neuropsychiatry.

Viscosity and haemodynamics in a late gestation rat feto-placental arterial network.

The placenta is a transient organ which develops during pregnancy to provide haemotrophic support for healthy fetal growth and development. Fundamental to its function is the healthy development of vascular trees in the feto-placental arterial network. Despite the strong association of haemodynamics with vascular remodelling mechanisms, there is a lack of computational haemodynamic data that may improve our understanding of feto-placental physiology. The aim of this work was to create a comprehensive 3D computational fluid dynamics model of a substructure of the rat feto-placental arterial network and investigate the influence of viscosity on wall shear stress (WSS). Late gestation rat feto-placental arteries were perfused with radiopaque Microfil and scanned via micro-computed tomography to capture the feto-placental arterial geometry in 3D. A detailed description of rat fetal blood viscosity parameters was developed, and three different approaches to feto-placental haemodynamics were simulated in 3D using the finite volume method: Newtonian model, non-Newtonian Carreau-Yasuda model and Fåhræus-Lindqvist effect model. Significant variability in WSS was observed between different viscosity models. The physiologically-realistic simulations using the Fåhræus-Lindqvist effect and rat fetal blood estimates of viscosity revealed detailed patterns of WSS throughout the arterial network. We found WSS gradients at bifurcation regions, which may contribute to vessel enlargement, and sprouting and pruning during angiogenesis. This simulation of feto-placental haemodynamics shows the heterogeneous WSS distribution throughout the network and demonstrates the ability to determine physiologically-relevant WSS magnitudes, patterns and gradients. This model will help advance our understanding of vascular physiology and remodelling in the feto-placental network.