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Maternal asthma is associated with increased rates of neonatal lung disease, and fetuses from asthmatic ewes have fewer surfactant-producing cells and lower surfactant-protein B gene (SFTPB) expression than controls. Antenatal betamethasone increases lung surfactant production in preterm babies, and we therefore tested this therapy in experimental maternal asthma. Ewes were sensitised to house dust mite allergen, and an asthmatic phenotype induced by fortnightly allergen lung challenges; controls received saline. Pregnant asthmatic ewes were randomised to receive antenatal saline (asthma) or 12 mg intramuscular betamethasone (asthma+beta) at 138 and 139 days of gestation (term = 150 days). Lambs were delivered by Caesarean section at 140 days of gestation and ventilated for 45 min before tissue collection. Lung function and structure were similar in control lambs (n = 16, 11 ewes) and lambs from asthma ewes (n = 14, 9 ewes). Dynamic lung compliance was higher in lambs from asthma+beta ewes (n = 12, 8 ewes) compared to those from controls (P = 0.003) or asthma ewes (P = 0.008). Lung expression of surfactant protein genes SFTPA (P = 0.048) and SFTPB (P < 0.001), but not SFTPC (P = 0.177) or SFTPD (P = 0.285), was higher in lambs from asthma+beta than those from asthma ewes. Female lambs had higher tidal volume (P = 0.007), dynamic lung compliance (P < 0.001), and SFTPA (P = 0.037) and SFTPB gene expression (P = 0.030) than males. These data suggest that betamethasone stimulates lung maturation and function of near-term neonates, even in the absence of impairment by maternal asthma., (© 2024 The Author(s). Experimental Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.)

Introduction: Current clinical management of pregnancies at risk of preterm delivery includes maternal antenatal corticosteroid (ACS) treatment. ACS activate the glucocorticoid receptor (GR) in all fetal tissues, maturing the lungs at the cost of impaired brain development, creating a need for novel treatments. The prodrug ciclesonide (CIC) activates the GR only when converted to des-CIC by specific enzymes, including acetylcholinesterase (ACHE) and carboxylesterase 1 and 2 (CES1, CES2). Importantly, the human placenta expresses ACHE and CES, and could potentially produce des-CIC, resulting in systemic fetal exposure and GR activation in all fetal tissues. We therefore investigated CES gene expression and conversion of CIC to des-CIC in human placentae collected during the second trimester (Tri2), and at preterm and term birth., Methods: Differential expression analysis was performed in Tri2 (n = 27), preterm (n = 34), and term (n = 40) placentae using the DESeq2 R-package. Conversion of CIC to des-CIC was measured in a subset of placenta samples (Tri2 n = 7, preterm n = 26, term n = 20) using functional assays., Results: ACHE mRNA expression was higher in Tri2 male than preterm and term male placentae only, whereas CES1 mRNA expression was higher in Tri2 than preterm or term placentae of both sexes. Conversion of CIC to des-CIC did not differ between gestational ages., Discussion: Conversion of CIC to des-CIC by the human placenta may preclude its use as a novel GR-agonist in threatened preterm birth. In vivo studies are required to confirm the extent to which placental activation occurs after maternal treatment., Competing Interests: Declaration of competing interest There are no conflicts of interest to declare., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Maternal asthma affects up to 17% of pregnancies and is associated with adverse infant, childhood, and adult respiratory outcomes, including increased risks of neonatal respiratory distress syndrome, childhood wheeze and asthma. In addition to genetics, these poor outcomes are likely due to the mediating influence of maternal asthma on the in-utero environment, altering fetal lung and immune development and predisposing the offspring to later lung disease. Maternal asthma may impair glucocorticoid signalling in the fetus, a process critical for lung maturation, and increase fetal exposure to proinflammatory cytokines. Therefore, interventions to control maternal asthma, increase glucocorticoid signalling in the fetal lung, or Vitamin A, C, and D supplementation to improve alveologenesis and surfactant production may be beneficial for later lung function. This review highlights potential mechanisms underlying maternal asthma and offspring respiratory morbidities and describes how pregnancy interventions can promote optimal fetal lung development in babies of asthmatic mothers., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Clinical and preclinical evidence indicate that in utero maternal asthma exposure increases progeny asthma risk. Whether maternal asthma also increases the risks of progeny allergy is unclear., Objectives: To synthesise the available evidence on the relationship between in utero exposure to maternal asthma and postnatal asthma, wheezing and allergic diseases (Prospero: CRD42020201538)., Search Strategy: We systematically searched MEDLINE [PubMed], Embase [Ovid], Web of Science, Informit Health, the Cochrane Library, CINAHL [EBSCOhost], MedNar [Deep Web Technologies], ProQuest Theses and Dissertations, Scopus [Elsevier] and Trove, to the end of 2023., Selection Criteria: Studies reporting asthma, wheeze and/or allergic disease in progeny of women with and without asthma or with asthma classified by control, exacerbation or severity., Data Collection and Analysis: Double screening, selection, data extraction and quality assessment were performed, using Joanna Briggs Institute (JBI) scoring., Main Results: Of 134 non-overlapping studies, 127 were included in ≥1 meta-analysis. Maternal asthma ever was associated with greater risks of asthma (65 studies, risk ratio [95% confidence interval] 1.76 [1.57-1.96]), wheeze (35 studies, 1.59 [1.52-1.66]), food allergy (5 studies, 1.32 [1.23-1.40]), allergic rhinitis (7 studies, 1.18 [1.06-1.31]) and allergic dermatitis (14 studies, 1.17 [1.11-1.23]) ever in progeny. Asthma during the pregnancy, more severe, and uncontrolled maternal asthma were each associated with greater risks of progeny asthma., Conclusions: Children of mothers with asthma are at increased risk for the development of allergic diseases. Whether improved maternal asthma control reduces risks of child allergy as well as asthma requires further investigation., (© 2024 The Author(s). BJOG: An International Journal of Obstetrics and Gynaecology published by John Wiley & Sons Ltd.)

Context: Pregnancy increases nutrient demand, but how nutrient uptake and its determinants adapt to facilitate this is unclear., Objective: This review aimed to identify and characterize evidence and evidence gaps regarding changes in gastrointestinal nutrient absorption and its determinants during pregnancy in monogastric mammals., Data Sources: A scoping review of peer-reviewed sources was conducted across PubMed, Scopus, Web of Science, Embase, and ProQuest (theses and dissertations) databases., Data Extraction: Data extracted included species, pregnancy stages and outcomes. Where sufficient data for a given outcome was available, relative values were summarized graphically or in tables, to allow comparison across pregnancy stages and/or small intestine regions. Searches identified 26 855 sources, of which only 159 were eligible. Mechanistic studies were largely restricted to rodents, and most compared non- and late-pregnant groups, with fewer studies including early- or mid-pregnant groups., Data Analysis: During pregnancy, there is some evidence for greater capacity for glucose uptake but unchanged amino acid uptake, and good evidence for increased uptake of calcium, iron, and zinc, and slower gastrointestinal passage of nutrients. The available evidence indicates that acute glucose uptake, gastric emptying, and the activities of sucrase, maltase, and lactase do not change during pregnancy. Gaps in the knowledge include the effects of pregnancy on uptake of specific amino acids, lipids, and most minerals and vitamins., Conclusion: The results indicate that the gastrointestinal tract adapts during pregnancy to facilitate increased nutrient absorption. Additional data is required in order to assess the underlying mechanisms for and impacts on the absorption of many nutrients, as well as to determine the timing of these adaptations., (© The Author(s) 2024. Published by Oxford University Press on behalf of the International Life Sciences Institute. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Food intake and activity adapt during pregnancy to meet the increased energy demands. In comparison to non-pregnant females, pregnant mice consume more food, eating larger meals during the light phase, and reduce physical activity. How pregnancy changes the circadian timing of behaviour was less clear. We therefore randomised female C57BL/6J mice to mating for study until early (n = 10), mid- (n = 10) or late pregnancy (n = 11) or as age-matched, non-pregnant controls (n = 12). Mice were housed individually in Promethion cages with a 12 h light-12 h dark cycle [lights on at 07.00 h, Zeitgeber (ZT)0] for behavioural analysis. Food intake between ZT10 and ZT11 was greater in pregnant than non-pregnant mice on days 6.5-12.5 and 12.5-17.5. In mice that exhibited a peak in the last 4 h of the light phase (ZT8-ZT12), peaks were delayed by 1.6 h in the pregnant compared with the non-pregnant group. Food intake immediately after dark-phase onset (ZT13-ZT14) was greater in the pregnant than non-pregnant group during days 12.5-17.5. Water intake patterns corresponded to food intake. From days 0.5-6.5 onwards, the pregnant group moved less during the dark phase, with decreased probability of being awake, in comparison to the non-pregnant group. The onset of dark-phase activity, peaks in activity, and wakefulness were all delayed during pregnancy. In conclusion, increased food intake during pregnancy reflects increased amplitude of eating behaviour, without longer duration. Decreases in activity also contribute to positive energy balance in pregnancy, with delays to all measured behaviours evident from mid-pregnancy onwards. KEY POINTS: Circadian rhythms synchronise daily behaviours including eating, drinking and sleep, but how these change in pregnancy is unclear. Food intake increased, with delays in peaks of food intake behaviour late in the light phase from days 6.5 to 12.5 of pregnancy, in comparison to the non-pregnant group. The onset of activity after lights off (dark phase) was delayed in pregnant compared with non-pregnant mice. Activity decreased by ∼70% in the pregnant group, particularly in the dark (active) phase, with delays in peaks of wakefulness evident from days 0.5-6.5 of pregnancy onwards. These behavioural changes contribute to positive energy balance during pregnancy. Delays in circadian behaviours during mouse pregnancy were time period and pregnancy stage specific, implying different regulatory mechanisms., (© 2024 The Authors. The Journal of Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society.)

Livestock heat stress threatens production, particularly in semi-arid, arid and tropical regions. Using established temperature thresholds for sheep, we modelled +1 °C and +3 °C temperature increases over the historical baseline, estimating that 2.1 million potential lambs are lost annually due to heat stress alone, increasing to 2.5 and 3.3 million, respectively, as temperatures rise. Heat stress poses risks at key periods of the reproductive cycle, with consequences across the Australian sheep flock., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

There is an increased risk of adverse perinatal outcomes in the ∼17% of women with asthma during pregnancy. The mechanisms linking maternal asthma and adverse outcomes are largely unknown, but reflect joint effects of genetics and prenatal exposure to maternal asthma. Animal models are essential to understand the underlying mechanisms independent of genetics and comorbidities, and enable safe testing of interventions. This scoping review aimed to explore the methodology, phenotype, characteristics, outcomes and quality of published studies using preclinical maternal asthma models. MEDLINE (PubMed), Embase (Elsevier) and Web of Science were systematically searched using previously validated search strings for maternal asthma and for animal models. Two reviewers independently screened titles and abstracts, full texts, and then extracted and assessed the quality of each study using the Animal Research: Reporting of In Vivo Experiments (ARRIVE) 2.0 guidelines. Out of 3618 studies identified, 39 were eligible for extraction. Most studies were in rodents (86%) and all were models of allergic asthma. Maternal and progeny outcomes included airway hyperresponsiveness, airway resistance, inflammation, lung immune cells, lung structure and serum immunoglobulins and cytokines. Experimental design (100%), procedural details (97%) and rationale (100%) were most often reported. Conversely, data exclusion (21%), blinding (18%) and adverse events (8%) were reported in a minority of studies. Species differences in physiology and timing of development, the use of allergens not relevant to humans and a lack of comparable outcome measures may impede clinical translation. Future studies exploring models of maternal asthma should adhere to the minimum core outcomes set presented in this review., Competing Interests: Conflict of interest: The authors declare no conflicts of interest., (Copyright ©The authors 2024.)

Small intestinal satiation pathways involve nutrient-induced stimulation of chemoreceptors leading to release of satiety hormones from intestinal enteroendocrine cells (ECCs). Whether adaptations in these pathways contribute to increased maternal food intake during pregnancy is unknown. To determine the expression of intestinal nutrient-sensors and satiety hormone transcripts and proteins across pregnancy in mice. Female C57BL/6J mice (10-12 weeks old) were randomized to mating and then tissue collection at early- (6.5 d), mid- (12.5 d) or late-pregnancy (17.5 d), or to an unmated age matched control group. Relative transcript expression of intestinal fatty acid, peptide and amino acid and carbohydrate chemoreceptors, as well as gut hormones was determined across pregnancy. The density of G-protein coupled receptor 93 (GPR93), free fatty acid receptor (FFAR) 4, cholecystokinin (CCK) and glucagon-like peptide1 (GLP-1) immunopositive cells was then compared between non-pregnant and late-pregnant mice. Duodenal GPR93 expression was lower in late pregnant than non-pregnant mice (P < 0.05). Ileal FFAR1 expression was higher at mid- than at early- or late-pregnancy. Ileal FFAR2 expression was higher at mid-pregnancy than in early pregnancy. Although FFAR4 expression was consistently lower in late-pregnant than non-pregnant mice (P < 0.001), the density of FFAR4 immunopositive cells was higher in the jejunum of late-pregnant than non-pregnant mice. A subset of protein and fatty acid chemoreceptor transcripts undergo region-specific change during murine pregnancy, which could augment hormone release and contribute to increased food intake. Further investigations are needed to determine the functional relevance of these changes., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: Sex differences in prenatal growth may contribute to sex-dependent programming effects on postnatal phenotype., Methods: We integrated for the first time phenotypic, histomorphological, clinico-chemical, endocrine and gene expression analyses in a single species, the bovine conceptus at mid-gestation., Results: We demonstrate that by mid-gestation, before the onset of accelerated growth, the female conceptus displays asymmetric lower growth compared to males. Female fetuses were smaller with lower ponderal index and organ weights than males. However, their brain:body weight, brain:liver weight and heart:body weight ratios were higher than in males, indicating brain and heart 'sparing'. The female placenta weighed less and had lower volumes of trophoblast and fetal connective tissue than the male placenta. Female umbilical cord vessel diameters were smaller, and female-specific relationships of body weight and brain:liver weight ratios with cord vessel diameters indicated that the umbilico-placental vascular system creates a growth-limiting environment where blood flow is redistributed to protect brain and heart growth. Clinico-chemical indicators of liver perfusion support this female-specific growth-limiting phenotype, while lower insulin-like growth factor 2 (IGF2) gene expression in brain and heart, and lower circulating IGF2, implicate female-specific modulation of key endocrine mediators by nutrient supply., Conclusion: This mode of female development may increase resilience to environmental perturbations in utero and contribute to sex-bias in programming outcomes including susceptibility to non-communicable diseases., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Estrella, Gatford, Xiang, Javadmanesh, Ghanipoor-Samami, Nattrass, Shuaib, McAllister, Beckman, Thomsen, Clifton, Owens, Roberts, Hiendleder and Kind.)

Objective: Asthma occurs in ∼17% of Australian pregnancies and is associated with adverse perinatal outcomes, which worsen with poor asthma control. Consequently, the South Australian 'Asthma in Pregnancy' perinatal guidelines were revised in 2012 to address management according to severity. This study investigated if these revised guidelines reduced the impact of maternal asthma on risks of adverse perinatal outcomes before (Epoch 1, 2006-2011) and after the revision (Epoch 2, 2013-2018)., Methods: Routinely collected perinatal and neonatal datasets from the Women's and Children's Hospital (Adelaide, Australia) were linked. Maternal asthma (prevalence:7.5%) was defined as asthma medication use or symptoms described to midwives. In imputation ( n  = 59131) and complete case datasets ( n  = 49594), analyses were conducted by inverse proportional weighting and multivariate logistic regression, accounting for confounders., Results: Overall, maternal asthma was associated with increased risks of any antenatal corticosteroid treatment for threatened preterm birth (aOR 1.319, 95% CI 1.078-1.614), any Cesarean section (aOR 1.196, 95% CI 1.059-1.351), Cesarean section without labor (aOR 1.241, 95% CI 1.067-1.444), intrauterine growth restriction (IUGR, aOR 1.285, 95% CI 1.026-1.61), and small for gestational age (aOR 1.324, 95% CI 1.136-1.542). After guideline revision, asthma-associated risks of any Cesarean section ( p  < 0.001), any antenatal corticosteroids ( p  = 0.041), and small for gestational age ( p  = 0.050), but not IUGR and Cesarean section without labor, were reduced., Conclusions: Clinical practice guidelines based on the latest evidence do not guarantee clinical efficacy. Since adverse perinatal outcomes did not all improve, this work highlights the need to evaluate the ongoing impact of guidelines on clinical outcomes.

Objective: This scoping review will describe the methodology, phenotype, and characteristics of maternal asthma models used in preclinical studies and the outcomes that have been measured in the mother and progeny. The review This will identify gaps in knowledge of maternal and progeny outcomes following maternal asthma in pregnancy., Introduction: Maternal asthma affects up to 17% of pregnancies worldwide and is associated with adverse perinatal outcomes in mothers and babies, including pre-eclampsia, gestational diabetes, cesarean section, preterm birth, small for gestational age, nursery admission, and neonatal death. While the associations are well established, the mechanisms linking maternal asthma and adverse perinatal outcomes are largely unknown due to the difficulties of human mechanistic studies. The appropriate selection of animal models is vital to understanding the mechanisms underlying associations between human maternal asthma and adverse perinatal outcomes., Inclusion Criteria: This review will include primary studies published in English where outcomes have been studied in vivo in non-human mammalian species., Methods: This review will follow the JBI methodology for scoping reviews. We will search MEDLINE (PubMed), Embase, and Web of Science to identify papers published before the end of 2022. Initial keywords will include pregnancy, gestation, asthma , and wheeze , as well as validated search strings to identify papers that describe animal models. Extracted data will include information on methods used to induce maternal asthma; asthmatic phenotypes and characteristics; and maternal, pregnancy, placental, and progeny outcomes. The characteristics of each study will be presented in summary tables and a core outcome list to assist researchers in developing, reporting, and comparing future animal studies of maternal asthma., Review Registration: Open Science Framework osf.io/trwk5., Competing Interests: The authors declare no conflict of interest., (Copyright © 2023 JBI.)

New Findings: What is the central question of this study? Body mass and food intake change during the female ovarian cycle: does glucose transport by the small intestine also vary? What is the main finding and its importance? We have optimised Ussing chamber methodology to measure region-specific active glucose transport in the small intestine of adult C57BL/6 mice. Our study provides the first evidence that jejunal active glucose transport changes during the oestrous cycle in mice, and is higher at pro-oestrus than oestrus. These results demonstrate adaptation in active glucose uptake, concurrent with previously reported changes in food intake., Abstract: Food intake changes across the ovarian cycle in rodents and humans, with a nadir during the pre-ovulatory phase and a peak during the luteal phase. However, it is unknown whether the rate of intestinal glucose absorption also changes. We therefore mounted small intestinal sections from C57BL/6 female mice (8-9 weeks old) in Ussing chambers and measured active ex vivo glucose transport via the change in short-circuit current (∆I sc ) induced by glucose. Tissue viability was confirmed by a positive ∆I sc response to 100 µM carbachol following each experiment. Active glucose transport, assessed after addition of 5, 10, 25 or 45 mM d-glucose to the mucosal chamber, was highest at 45 mM glucose in the distal jejunum compared to duodenum and ileum (P < 0.01). Incubation with the sodium-glucose cotransporter 1 (SGLT1) inhibitor phlorizin reduced active glucose transport in a dose-dependent manner in all regions (P < 0.01). Active glucose uptake induced by addition of 45 mM glucose to the mucosal chamber in the absence or presence of phlorizin was assessed in jejunum at each oestrous cycle stage (n = 9-10 mice per stage). Overall, active glucose uptake was lower at oestrus compared to pro-oestrus (P = 0.025). This study establishes an ex vivo method to measure region-specific glucose transport in the mouse small intestine. Our results provide the first direct evidence that SGLT1-mediated glucose transport in the jejunum changes across the ovarian cycle. The mechanisms underlying these adaptations in nutrient absorption remain to be elucidated., (© 2023 The Authors. Experimental Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society.)

Objective: The aim of this review is to characterize the current state of literature and knowledge regarding adaptations of gastrointestinal nutrient absorption, and the determinants of this absorption during pregnancy in monogastric mammals., Introduction: Energy demands increase significantly during pregnancy due to the metabolic demands associated with placental and fetal growth, and the deposition of fat stores that support postnatal lactation. Previous studies have examined anatomical changes within the small intestine, but have focused on specific pregnancy stages or specific regions of the small intestine. Importantly, little is known about changes in nutrient absorption during pregnancy, and the underlying mechanisms that lead to these changes. An understanding of these adaptations will inform research to improve pregnancy outcomes for both mothers and newborns in the future., Inclusion Criteria: This review will include primary literature that describes gastrointestinal nutrient absorption and/or its determinants during pregnancy in monogastric mammals, including humans and rodents. Only data for normal pregnancies will be included, and models of pathology and illness will be excluded. Studies must include comparisons between pregnant animals at known stages of pregnancy, and non-pregnant controls, or compare animals at different stages of pregnancy., Methods: The following databases will be searched for literature on this topic: PubMed, Scopus, Web of Science, Embase, MEDLINE, and ProQuest Dissertations and Theses. Evidence screening and selection will be carried out independently by two reviewers, and conflicts will be resolved through discussion with additional members of the review team. Data will be extracted and presented in tables and/or figures, together with a narrative summary., Competing Interests: The authors declare no conflict of interest., (Copyright © 2021 JBI.)

A sufficient and balanced maternal diet is critical to meet the nutritional demands of the developing fetus and to facilitate deposition of fat reserves for lactation. Multiple adaptations occur to meet these energy requirements, including reductions in energy expenditure and increases in maternal food intake. The central nervous system plays a vital role in the regulation of food intake and energy homeostasis and responds to multiple metabolic and nutrient cues, including those arising from the gastrointestinal tract. This review describes the nutrient requirements of pregnancy and the impact of over- and undernutrition on the risk of pregnancy complications and adult disease in progeny. The central and peripheral regulation of food intake is then discussed, with particular emphasis on the adaptations that occur during pregnancy and the mechanisms that drive these changes, including the possible role of the pregnancy-associated hormones progesterone, estrogen, prolactin, and growth hormone. We identify the need for deeper mechanistic understanding of maternal adaptations, in particular, changes in gut-brain axis satiety signaling. Improved understanding of food intake regulation during pregnancy will provide a basis to inform strategies that prevent maternal under- or overnutrition, improve fetal health, and reduce the long-term health and economic burden for mothers and offspring., (© 2021 The Obesity Society.)

The growth hormone (GH)-insulin-like growth factor (IGF) axis is one of the main drivers of mammalian growth and development. Pituitary secretion of GH is pulsatile and under positive and negative hypothalamic control, as well as stimulation from gastric-secreted acyl-ghrelin. GH has anabolic and metabolic effects both directly via the GH-receptor (GHR) and indirectly via stimulation of IGF1 production at multiple target tissues. In this review, we describe the major changes to this axis during pregnancy, with increasing GH abundance in the maternal circulation across multiple species. This stimulates secretion of IGFs, whose bioavailability is also increased by proteolytic cleavage of their circulating binding proteins during pregnancy. These changes in turn induce maternal metabolic adaptations to pregnancy and promote placental function and fetal growth, as does exogenous GH or IGF treatment in animal models of normal and compromised pregnancy. Finally, we explore alternative approaches to enhance maternal GH abundance during pregnancy to promote maternal adaptations, placental function and hence fetal growth.

Objective: The primary objective of this systematic review is to synthesize the best available evidence on the relationship between in utero exposure to maternal asthma and postnatal allergy. Secondary objectives are to investigate the impact of asthma loss of control, asthma exacerbation, and asthma severity during pregnancy on risks of allergy and asthma in progeny., Introduction: Maternal asthma is a well-known risk factor for childhood asthma, with recent evidence suggesting that children of asthmatic mothers are also at increased risk of allergic diseases. Importantly, these do not appear to be purely genetic associations, since maternal asthma is more strongly associated with childhood asthma than paternal asthma. In addition, experimentally induced allergic asthma during pregnancy increases allergic responses to sensitization in mice. The strength of the relationships between exposure to maternal asthma or severity of maternal asthma, and progeny asthma and allergy are unknown., Inclusion Criteria: This review will include primary studies that report incidence of physician-diagnosed asthma or allergic disease in human progeny who were exposed in utero to maternal asthma, in comparison to progeny not exposed to maternal asthma., Methods: Initial search terms include (pregnan∗ OR gestat∗) AND asthma∗ AND allerg∗. We will search the following electronic databases for published and unpublished evidence: PubMed, Embase, MEDLINE (Ovid), Web of Science, Cochrane Library, CINAHL, Scopus, Informit Health, MedNar, ProQuest, and Trove. There will be no restrictions on publication date. Only studies available as a full-text English publication will be considered for inclusion., Systematic Review Registration Number: PROSPERO CRD42020201538., Competing Interests: The authors declare no conflict of interest., (Copyright © 2021 JBI.)

Heat stress significantly impairs reproduction of sheep, and under current climatic conditions is a significant risk to the efficiency of the meat and wool production, with the impact increasing as global temperatures rise. Evidence from field studies and studies conducted using environmental chambers demonstrate the effects of hot temperatures (≥ 32 °C) on components of ewe fertility (oestrus, fertilisation, embryo survival and lambing) are most destructive when experienced from 5 d before until 5 d after oestrus. Temperature controlled studies also demonstrate that ram fertility, as measured by rates of fertilisation and embryo survival, is reduced when mating occurs during the period 14 to 50 d post-heating. However, the contribution of the ram to heat induced reductions in flock fertility is difficult to determine accurately. Based primarily on temperature controlled studies, it is clear that sustained exposure to high temperatures (≥ 32 °C) during pregnancy reduces lamb birthweight and will, therefore, decrease lamb survival under field conditions. It is concluded that both ewe and ram reproduction is affected by relatively modest levels of heat stress (≥ 32 °C) and this is a concern given that a significant proportion of the global sheep population experiences heat stress of this magnitude around mating and during pregnancy. Despite this, strategies to limit the impacts of the climate on the homeothermy, behaviour, resource use and reproduction of extensively grazed sheep are limited, and there is an urgency to improve knowledge and to develop husbandry practices to limit these impacts.

Animal models are needed to develop interventions to prevent or treat intrauterine growth restriction (IUGR). Foetal growth rates and effects of in utero exposures differ between sexes, but little is known about sex-specific effects of increasing litter size. We established a murine IUGR model using pregnancies generated by multiple embryo transfers, and evaluated sex-specific responses to increasing litter size. CBAF1 embryos were collected at gestation day 0.5 (GD0.5) and 6, 8, 10 or 12 embryos were transferred into each uterine horn of pseudopregnant female CD1 mice (n = 32). Foetal and placental outcomes were measured at GD18.5. In the main experiment, foetuses were genotyped (Sry) for analysis of sex-specific outcomes. The number of implantation sites (P = 0.033) and litter size (number of foetuses, P = 0.008) correlated positively with the number of embryos transferred, while placental weight correlated negatively with litter size (both P < 0.01). The relationship between viable litter size and foetal weight differed between sexes (interaction P = 0.002), such that foetal weights of males (P = 0.002), but not females (P = 0.233), correlated negatively with litter size. Placental weight decreased with increasing litter size (P < 0.001) and was lower in females than males (P = 0.020). Our results suggest that male foetuses grow as fast as permitted by nutrient supply, whereas the female maintains placental reserve capacity. This strategy reflecting sex-specific gene expression is likely to place the male foetus at greater risk of death in the event of a 'second hit'.

Maternal asthma is known to impact intrauterine growth outcomes, which may be mediated, in part, by altered androgen signalling. Our aim was to explore whether the sheep placenta expresses androgen receptor (AR) isoforms and determine if the differential expression of AR protein isoforms is altered by maternal asthma. Four known AR isoforms were detected (AR-FL, AR-v1, AR-v7, and AR-45), and their expression and subcellular distribution was altered in the presence of maternal allergic asthma. These findings underscore the importance for in vivo models of maternal asthma to delineate molecular patterns that may contribute to feto-placental growth and development., (Crown Copyright © 2021. Published by Elsevier Ltd. All rights reserved.)

Gastric vagal afferents (GVAs) sense food-related mechanical stimuli and signal to the central nervous system, to integrate control of meal termination. Pregnancy is characterized by increased maternal food intake, which is essential for normal fetal growth and to maximize progeny survival and health. However, it is unknown whether GVA function is altered during pregnancy to promote food intake. This study aimed to determine the mechanosensitivity of GVAs and food intake during early, mid-, and late stages of pregnancy in mice. Pregnant mice consumed more food compared with nonpregnant mice, notably in the light phase during mid- and late pregnancy. The increased food intake was predominantly due to light-phase increases in meal size across all stages of pregnancy. The sensitivity of GVA tension receptors to gastric distension was significantly attenuated in mid- and late pregnancy, whereas the sensitivity of GVA mucosal receptors to mucosal stroking was unchanged during pregnancy. To determine whether pregnancy-associated hormonal changes drive these adaptations, the effects of estradiol, progesterone, prolactin, and growth hormone on GVA tension receptor mechanosensitivity were determined in nonpregnant female mice. The sensitivity of GVA tension receptors to gastric distension was augmented by estradiol, attenuated by growth hormone, and unaffected by progesterone or prolactin. Together, the data indicate that the sensitivity of GVA tension receptors to tension is reduced during pregnancy, which may attenuate the perception of gastric fullness and explain increased food intake. Further, these adaptations may be driven by increases in maternal circulating growth hormone levels during pregnancy. NEW & NOTEWORTHY This study provides first evidence that gastric vagal afferent signaling is attenuated during pregnancy and inversely associated with meal size. Growth hormone attenuated mechanosensitivity of gastric vagal afferents, adding support that increases in maternal growth hormone may mediate adaptations in gastric vagal afferent signaling during pregnancy. These findings have important implications for the peripheral control of food intake during pregnancy.

Key Points: Maternal shift work increases the risk of pregnancy complications, although its effects on progeny health after birth are not clear. We evaluated the impact of a simulated shift work protocol for one-third, two-thirds or all of pregnancy on the metabolic health of sheep progeny. Simulated shift work had no effect on growth, body size, body composition or glucose tolerance in pre-pubertal or young adult progeny. Glucose-stimulated insulin secretion was reduced in adult female progeny and insulin sensitivity was increased in adult female singleton progeny. The results of the present study do not support the hypothesis that maternal shift work exposure impairs metabolic health of progeny in altricial species., Abstract: Disrupted maternal circadian rhythms, such as those experienced during shift work, are associated with impaired progeny metabolism in rodents. The effects of disrupted maternal circadian rhythms on progeny metabolism have not been assessed in altricial, non-litter bearing species. We therefore assessed postnatal growth from birth to adulthood, as well as body composition, glucose tolerance, insulin secretion and insulin sensitivity, in pre-pubertal and young adult progeny of sheep exposed to control conditions (CON: 10 males, 10 females) or to a simulated shift work (SSW) protocol for the first one-third (SSW0-7: 11 males, 9 females), the first two-thirds (SSW0-14: 8 males, 11 females) or all (SSW0-21: 8 males, 13 females) of pregnancy. Progeny growth did not differ between maternal treatments. In pre-pubertal progeny (12-14 weeks of age), adiposity, glucose tolerance and insulin secretion during an i.v. glucose tolerance test and insulin sensitivity did not differ between maternal treatments. Similarly, in young adult progeny (12-14 months of age), food intake, adiposity and glucose tolerance did not differ between maternal treatments. At this age, however, insulin secretion in response to a glucose bolus was 30% lower in female progeny in the combined SSW groups compared to control females (P = 0.031), and insulin sensitivity of SSW0-21 singleton females was 236% compared to that of CON singleton female progeny (P = 0.025). At least in this model, maternal SSW does not impair progeny metabolic health, with some evidence of greater insulin action in female young adult progeny., (© 2020 The Authors. The Journal of Physiology © 2020 The Physiological Society.)

High preweaning mortality rates continue to limit sheep production globally, constituting a major economic and welfare concern. Greater losses in twin lambs (≥30%) compared with singletons (≥10%) are attributed primarily to lower birth weight and increased risk of intrapartum hypoxia, leading to impairment of thermoregulation, neuromotor activity, and maternal bonding behavior. Previous intensive studies demonstrated that supplementing pregnant ewes with melatonin reduced the adverse effects of fetal growth restriction and perinatal hypoxia on the neonatal brain via increased umbilical blood flow, placental efficiency, and antioxidant actions. The current study examined the effects of supplementing pregnant ewes with melatonin on lamb survival, birth weight, and behavior under intensive conditions. From gestational day (gD) 80 until parturition, pregnant singleton and twin-bearing ewes were supplemented with melatonin via a 2-mg capsule fed daily (Mel-FED, n = 61) or 18 mg subcutaneous implant (Regulin), with one implant administered at gD80 and another at gD125 (Mel-IMP, n = 60). Control ewes received no supplementation (CTL, n = 60). Ewes and lambs were monitored via video throughout parturition. Postpartum measures were taken from lambs at 4 and 24 h (live weight [LW], rectal temperature, serum immunoglobulin G, and latency to stand and suck after birth) and LW at 72 h, 7 d, marking (49.7 ± 0.2 d), and weaning (124.2 ± 0.8 d). Chi-square analysis was used to compare lamb survival between treatment groups. There were no treatment effects on singleton lamb survival. Melatonin supplementation tended to increase the proportion of twin lambs surviving from birth to weaning (Mel-FED = 85.5%; Mel-IMP = 85.9%; CTL = 72.9%; each P < 0.1). Survival of first-born twins did not differ between treatment (each ~90%, P = 0.745) but within second-born twins, survival of Mel-FED was greater than CTL (81.6 vs. 57.1%, P = 0.023), and Mel-IMP (78.1%) tended to be greater than CTL (P = 0.068). Similarly, in second-born twins exposed to prolonged parturition (≥ 90 min), survival of lambs from Mel-FED ewes was greater than CTL (86.7% vs. 42.9%, P = 0.032), while Mel-IMP was intermediate (66.7%). These data suggest that the neuroprotective actions of melatonin may improve twin lamb survival by increasing tolerance of prolonged parturition and provide a sound basis for continued testing in extensively managed sheep flocks., (© The Author(s) 2020. Published by Oxford University Press on behalf of the American Society of Animal Science. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

High incidences of pre-weaning mortality continue to limit global sheep production, constituting a major economic and welfare concern. Despite significant advances in genetics, nutrition, and management, the proportion of lamb deaths has remained stable at 15-20% over the past four decades. There is mounting evidence that melatonin can improve outcomes in compromised ovine pregnancies via enhanced uterine bloodflow and neonatal neuroprotection. This review provides an overview of the major risk factors and underlying mechanisms involved in perinatal lamb mortality and discusses the potential of melatonin treatment as a remedial strategy. Supplementing pregnant ewes with melatonin enhances uterine bloodflow and fetal oxygenation, and potentially birthweight and neonatal thermogenic capacity. Melatonin freely crosses the ovine placenta and blood-brain barrier and provides neuroprotection to the fetal lamb during periods of chronic and acute hypoxia throughout gestation, with improved behavioural outcomes in hypoxic neonates. The current literature provides strong evidence that maternal melatonin treatment improves outcomes for lambs which experience compromised in utero development or prolonged parturition, though to date this has not been investigated in livestock production systems. As such there is a clear basis for continued research into the effects of maternal melatonin supplementation during gestation on pre-weaning survival under extensive production conditions.

High preweaning mortality rates cost the Australian sheep industry an estimated $540 million annually in lost production, with losses significantly greater in twin (≥30%) compared with singleton lambs (≥10%). Previous intensive studies demonstrated that supplementing pregnant ewes with melatonin reduces adverse effects of fetal growth restriction and perinatal hypoxia on the neonatal brain via increased umbilical blood flow, placental efficiency, and antioxidant actions. The current study examined the effects of supplementing ewes with melatonin on the survival of twin Merino lambs under extensive grazing conditions. Pregnant mixed age ewes were implanted with 1 (M1, n = 50) or 2 (M2, n = 53) slow-release melatonin implants (18 mg, Regulin) at gestational days 70 to 90. Control ewes received no supplementation (CTL, n = 54). Ewes were monitored twice daily throughout the lambing period. Lamb survival, weight, and rectal temperature were recorded on the day of birth. Lamb blood samples were taken the following day for serum immunoglobulin G (IgG) analysis. Lamb survival and weight were recorded again at marking (30.6 ± 0.6 d postpartum) and weaning (70.7 ± 0.6 d postpartum). Lamb survival was increased in both melatonin treatments to 3 d postpartum (M1 = 98.0%; M2 = 95.3%; CTL = 83.3%; each P < 0.01), and this improvement was maintained to weaning (M1 = 94.0%; M2 = 92.5%; CTL = 79.6%; each P < 0.01). Melatonin did not affect lamb birthweight, rectal temperature, or growth rate. However, the rates of parturition-related death (dystocia, stillbirth, and birth injury) were greater in CTL lambs than M1 (P = 0.009) and M2 (P = 0.035). This suggests that improved survival is primarily due to melatonin-induced neuroprotection, although further studies are required to clarify the underlying mechanisms. These data provide evidence that supplementing pregnant twin-bearing Merino ewes with melatonin may be a practical strategy to reduce neonatal mortality and improve weaning rates in extensively managed sheep flocks. Although the present data are promising, this study is limited by small sample size and requires further replication., (© The Author(s) 2020. Published by Oxford University Press on behalf of the American Society of Animal Science. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Aims/hypothesis: The aim of this study was to determine whether presence of the metabolic syndrome in pregnancy associates with child telomere length or child anthropometry (weight, BMI) and BP, measured at 10 years of age., Methods: The Screening for Pregnancy Endpoints study (SCOPE) was a multicentre, international prospective cohort of nulliparous pregnant women recruited from Australia, New Zealand, Ireland and the UK (N = 5628). The current analysis is a 10 year follow-up of SCOPE pregnant women and their children, from the Australian cohort. Clinical data collected at 14-16 weeks' gestation during the SCOPE study were used to diagnose the metabolic syndrome using IDF criteria. Telomere length, a biomarker of ageing, was assessed by quantitative PCR from children's saliva collected at 10 years of age., Results: In women who completed follow-up (n = 255), 20% had the metabolic syndrome in pregnancy. After adjusting for a range of confounders, children of mothers who had the metabolic syndrome in pregnancy had 14% shorter telomeres than children of mothers without the metabolic syndrome in pregnancy (mean difference -0.36 [95% CI -0.74, 0.01]). Height- and weight-for-age, and BMI z scores were similar in children of mothers who did and did not have the metabolic syndrome during pregnancy., Conclusions/interpretation: Children of mothers who had the metabolic syndrome in pregnancy have shorter telomeres, a biomarker of accelerated ageing. These findings warrant further studies in larger cohorts of children, as well as investigations into whether telomere length measured in cord blood associates with telomere length in childhood.

Preeclampsia is a common pregnancy complication, affecting 2% to 8% of pregnancies worldwide, and is an important cause of both maternal and fetal morbidity and mortality. Importantly, although aspirin and calcium are able to prevent preeclampsia in some women, there is no cure apart from delivery of the placenta and fetus, often necessitating iatrogenic preterm birth. Preclinical models of preeclampsia are widely used to investigate the causes and consequences of preeclampsia and to evaluate safety and efficacy of potential preventative and therapeutic interventions. In this review, we provide a summary of the published preclinical models of preeclampsia that meet human diagnostic criteria, including the development of maternal hypertension, together with new-onset proteinuria, maternal organ dysfunction, and uteroplacental dysfunction. We then discuss evidence from preclinical models for multiple causal factors of preeclampsia, including those implicated in early-onset and late-onset preeclampsia. Next, we discuss the impact of exposure to a preeclampsia-like environment for later maternal and progeny health. The presence of long-term impairment, particularly cardiovascular outcomes, in mothers and progeny after an experimentally induced preeclampsia-like pregnancy, implies that later onset or reduced severity of preeclampsia will improve later maternal and progeny health. Finally, we summarize published intervention studies in preclinical models and identify gaps in knowledge that we consider should be targets for future research.

Preeclampsia (PE) is now recognised as a cardiovascular risk factor for women. Emerging evidence suggests that children exposed to PE in utero may also be at increased risk of cardiovascular disease (CVD) in later life. Individuals exposed to PE in utero have higher systolic and diastolic blood pressure and higher body mass index (BMI) compared to those not exposed to PE in utero. The aim of this review is to discuss the potential mechanisms driving the relationship between PE and offspring CVD. Exposure to an adverse intrauterine environment as a consequence of the pathophysiological changes that occur during a pregnancy complicated by PE is proposed as one mechanism that programs the fetus for future CVD risk. Consistent with this hypothesis, animal models of PE where progeny have been studied demonstrate causality for programming of offspring cardiovascular health by the preeclamptic environment. Shared alleles between mother and offspring, and shared lifestyle factors between mother and offspring provide alternate pathways explaining associations between PE and offspring CVD risk. In addition, adverse lifestyle habits can also act as second hits for those programmed for increased CVD risk. PE and CVD are both multifactorial diseases and, hence, identifying the relative contribution of PE to offspring risk for CVD is a very complex task. However, considering the emerging strong association between PE and CVD, those exposed to PE in utero may benefit from targeted primary CVD preventive strategies.

Circulating growth hormone (GH) concentrations increase during pregnancy in mice and remain pituitary-derived. Whether abundance or activation of the GH secretagogue ghrelin increase during pregnancy, or in response to dietary octanoic acid supplementation, is unclear. We therefore measured circulating GH profiles in late pregnant C57BL/6J mice and in aged-matched non-pregnant females fed with standard laboratory chow supplemented with 5% octanoic or palmitic (control) acid (n = 4-13/group). Serum total and acyl-ghrelin concentrations, stomach and placenta ghrelin mRNA and protein expression, Pcsk1 (encoding prohormone convertase 1/3) and Mboat4 (membrane bound O-acyl transferase 4) mRNA were determined at zeitgeber (ZT) 13 and ZT23. Total and basal GH secretion were higher in late pregnant than non-pregnant mice (P < 0.001), regardless of diet. At ZT13, serum concentrations of total ghrelin (P = 0.004), but not acyl-ghrelin, and the density of ghrelin-positive cells in the gastric antrum (P = 0.019) were higher, and gastric Mboat4 and Pcsk1 mRNA expression were lower in pregnant than non-pregnant mice at ZT23. In the placenta, ghrelin protein was localised mostly to labyrinthine trophoblast cells. Serum acyl-, but not total, ghrelin was lower at mid-pregnancy than in non-pregnant mice, but not different at early or late pregnancy. In conclusion, dietary supplementation with 5% octanoic acid did not increase activation of ghrelin in female mice. Our results further suggest that increases in maternal GH secretion throughout murine pregnancy are not due to circulating acyl-ghrelin acting at the pituitary. Nevertheless, time-dependent increased circulating total ghrelin could potentially increase ghrelin action in tissues that express the acylating enzyme and receptor.

Background: Individual susceptibility to allergic diseases is developmentally programmed by early-life exposures. Evidence from preclinical studies suggests that intrauterine growth restriction is protective against later inflammatory responses to allergens., Objective: We sought to evaluate whether prenatal growth affects susceptibility to allergy in human subjects., Methods: We systematically searched for relevant studies in 11 databases, including Web of Science, ProQuest, EMBASE, and PubMed. We included only studies that corrected for gestational age or were restricted to full-term infants to separate effects of fetal growth from those of prematurity., Results: The 42 eligible studies included prospective and retrospective cohort, cross-sectional, and case-control studies. Only 2 studies reported allergic asthma. A birth weight increase of 1 kg was associated with a 44% greater risk of food allergy in children (odds ratio [OR], 1.44; 95% CI, 1.04-1.99; P = .001), a 17% greater risk of ever allergic dermatitis in children (OR, 1.17; 95% CI, 1.04-1.32; P = .008), and a 34% greater risk of ever or current allergic dermatitis in infants up to 2 years of age (OR, 1.34; 95% CI, 1.08-1.68; P = .009). Risks of allergic rhinitis were not associated with birth weight., Conclusions: The results of these meta-analyses suggest that intrauterine growth restriction protects against allergic diseases in human subjects consistent with preclinical evidence but that effects might differ between allergic diseases. The strongest evidence is available for infancy and early childhood, and additional studies in older children and adults are needed to determine whether the effects of prenatal growth on each allergic disease persist or differ between those with severe and mild phenotypes., (Copyright © 2019 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Maternal asthma increases the risk of adverse pregnancy outcomes and may affect fetal growth and placental function by differential effects on the expression of glucocorticoid receptor (GR) isoforms, leading to altered glucocorticoid signalling. Our aim was to examine the effect of maternal asthma on placental GR profiles using a pregnant sheep model of asthma. Nine known GR isoforms were detected. There was a significant increase in the expression of placental GR isoforms that are known to have low trans-activational activity in other species including GR A, GR P and GRγ which may result in a pro-inflammatory environment in the presence of allergic asthma., (Crown Copyright © 2019. Published by Elsevier Ltd. All rights reserved.)

Key Points: Experimental maternal allergic asthma in sheep provides an experimental model in which to test impacts on progeny. Fetuses from allergic asthmatic ewes had fewer surfactant-producing cells in lungs. A greater proportion of lymphocytes from thymus were CD44 positive in fetuses from allergic asthmatic ewes than in controls. These changes to fetal development might contribute to poor neonatal lung function and increased risk of allergy seen in offspring of pregnancies complicated by asthma., Abstract: Asthma is prevalent in pregnancy and increases the risk of disease in offspring, including neonatal respiratory distress and childhood asthma and allergy, but the mechanisms are not understood. We hypothesized that fetal lung structure and immune phenotype in late gestation fetal sheep would be impaired in our sheep model of maternal allergic asthma during pregnancy. Singleton-bearing ewes were either sensitized before pregnancy to house dust mite (HDM, allergic, n = 7) or were non-allergic (control, n = 5). The ewes were subsequently subjected to repeated airway challenges with HDM (allergic group) or saline (control group) throughout gestation. Tissues were collected at 140 ± 1 days gestational age (term, ∼147 days). The density of type II alveolar epithelial cells (surfactant protein C-immunostained) in the lungs was 30% lower in fetuses from allergic ewes than in controls (P < 0.001), but tissue-to-air space ratio and numbers of leucocytes and macrophages were not different between groups. The proportion of CD44 + lymphocytes in the fetal thymus was 3.5-fold higher in fetuses from allergic ewes than in control ewes (P = 0.043). Fewer surfactant-producing type II alveolar epithelial cells may contribute to the increased risk of neonatal respiratory distress in infants of asthmatic mothers, suggesting that interventions to promote lung maturation could improve their neonatal outcomes. If the elevated lymphocyte expression of CD44 persists postnatally, this would confer greater susceptibility to allergic diseases in progeny of asthmatic mothers, consistent with observations in humans. Further experiments are needed to evaluate postnatal phenotypes of progeny and investigate potential interventions., (© 2019 The Authors. The Journal of Physiology © 2019 The Physiological Society.)

Key Points: Shift work impairs metabolic health, although its effects during pregnancy are not well understood We evaluated the effects of a simulated shift work protocol for one-third, two-thirds or all of pregnancy on maternal and pregnancy outcomes in sheep. Simulated shift work changed the timing of activity, disrupted hormonal and cellular rhythms, and impaired maternal glucose tolerance during early pregnancy. Gestation length was increased in twin pregnancies, whereas singleton lambs were lighter at a given gestational age if mothers were subjected to shift work conditions in the first one-third of pregnancy. Exposure to rotating night and day shifts, even if only in early pregnancy, may adversely affect maternal metabolic and pregnancy outcomes., Abstract: Shift workers are at increased risk of developing type 2 diabetes and obesity; however, the impact during pregnancy on maternal metabolism is unknown. Using a large animal model, we assessed the impact of simulated shift work (SSW) exposure during pregnancy on maternal circadian rhythms, glucose tolerance and pregnancy outcomes. Following mating, ewes were randomly allocated to a control photoperiod (CON 12 h light, 12 h dark) or to SSW, where the timing of light exposure and food presentation was reversed twice each week for one-third, two-thirds or all of pregnancy. Maternal behaviour followed SSW cycles with increased activity during light exposure and feeding. Melatonin rhythms resynchronized within 2 days of the photoperiod shift, whereas peripheral circadian rhythms were arrhythmic. SSW impaired glucose tolerance (+29%, P = 0.019) and increased glucose-stimulated insulin secretion (+32%, P = 0.018) in ewes with a singleton fetus in early but not late gestation. SSW exposure did not alter rates of miscarriage or stillbirth, although it extended gestation length in twin pregnancies (+2.4 days, P = 0.032). Relative to gestational age, birth weight was lower in singleton progeny of SSW than CON ewes (-476 g, P = 0.016). These results have implications for the large number of women currently engaged in shift work, and further studies are required to determine progeny health impacts., (© 2019 The Authors. The Journal of Physiology © 2019 The Physiological Society.)

Intrauterine growth restriction (IUGR) and subsequent neonatal catch-up growth are implicated in programming of insulin resistance later in life. Spontaneous IUGR in the guinea pig, due to natural variation in litter size, produces offspring with asymmetric IUGR and neonatal catch-up growth. We hypothesized that spontaneous IUGR and/or accelerated neonatal growth would impair insulin sensitivity in adult guinea pigs. Insulin sensitivity of glucose metabolism was determined by hyperinsulinemic-euglycemic clamp (HEC) in 38 (21 male, 17 female) young adult guinea pigs from litters of two-to-four pups. A subset (10 male, 8 female) were infused with d-[3- 3 H]glucose before and during the HEC to determine rates of basal and insulin-stimulated glucose utilization, storage, glycolysis, and endogenous glucose production. n males, the insulin sensitivity of whole body glucose uptake ( r = 0.657, P = 0.002) and glucose utilization ( r = 0.884, P = 0.004) correlated positively and independently with birth weight, but not with neonatal fractional growth rate (FGR 10-28 ). In females, the insulin sensitivity of whole body and partitioned glucose metabolism was not related to birth weight, but that of endogenous glucose production correlated negatively and independently with FGR 10-28 ( r = -0.815, P = 0.025). Thus, perinatal growth programs insulin sensitivity of glucose metabolism in the young adult guinea pig and in a sex-specific manner; impaired insulin sensitivity, including glucose utilization, occurs after IUGR in males and impaired hepatic insulin sensitivity after rapid neonatal growth in females.

Introduction: Proper placental function is essential for optimal fetal growth in utero. Placental transfer of nutrients to the fetus can be measured using radiolabelled tracers, but non-radioactive methods have potential advantages. This study aimed to develop a fluorescence-based method to measure placental glucose transport in mice., Methods: Time course and localisation of the IRDye 800CW 2-deoxyglucose were recorded (Lumina IVIS Live Imaging System) following tail vein injection into anaesthetised late pregnant mice. Fluorescent signals in placental and fetal tissues were assessed after injecting conscious dams with 10 nmol IRDye 800CW 2-deoxyglucose (3, 30, 60, 120 min) or vehicle. Specificity of dye uptake was determined by comparing uptake of IRDye 800CW conjugated to 2-deoxyglucose or carboxylate, at 2 and 24 h. Finally, we assessed relationships of fetal size and umbilical blood flow velocities with relative dye uptake., Results: In late pregnant mice, uterine fluorescent signal localised rapidly over placentas and remained consistent for >1 h. Signal intensity in whole and homogenised tissues increased in fetuses and decreased in placentas after 3 min and stabilised by 30 min post-injection. Relative fetal dye uptake at 2 and 24 h was greater in littermates with the highest compared to lowest placental efficiency; signals were similar for 2-deoxyglucose- or carboxylate-conjugated dyes. Relative fetal dye uptake correlated positively with fetal weight and placental efficiency and negatively with umbilical artery resistance indices., Conclusions: Fetal uptake of IRDye 800CW correlates with markers of placental blood flow and fetal growth, but does not specifically measure placental glucose transport., (Copyright © 2019. Published by Elsevier Ltd.)

Over 30 years ago Professor David Barker first proposed the theory that events in early life could explain an individual's risk of non-communicable disease in later life: the developmental origins of health and disease (DOHaD) hypothesis. During the 1990s the validity of the DOHaD hypothesis was extensively tested in a number of human populations and the mechanisms underpinning it characterised in a range of experimental animal models. Over the past decade, researchers have sought to use this mechanistic understanding of DOHaD to develop therapeutic interventions during pregnancy and early life to improve adult health. A variety of animal models have been used to develop and evaluate interventions, each with strengths and limitations. It is becoming apparent that effective translational research requires that the animal paradigm selected mirrors the tempo of human fetal growth and development as closely as possible so that the effect of a perinatal insult and/or therapeutic intervention can be fully assessed. The guinea pig is one such animal model that over the past two decades has demonstrated itself to be a very useful platform for these important reproductive studies. This review highlights similarities in the in utero development between humans and guinea pigs, the strengths and limitations of the guinea pig as an experimental model of DOHaD and the guinea pig's potential to enhance clinical therapeutic innovation to improve human health., (© 2018 The Authors. The Journal of Physiology © 2018 The Physiological Society.)

Experimental studies that are relevant to human pregnancy rely on the selection of appropriate animal models as an important element in experimental design. Consideration of the strengths and weaknesses of any animal model of human disease is fundamental to effective and meaningful translation of preclinical research. Studies in sheep have made significant contributions to our understanding of the normal and abnormal development of the fetus. As a model of human pregnancy, studies in sheep have enabled scientists and clinicians to answer questions about the etiology and treatment of poor maternal, placental, and fetal health and to provide an evidence base for translation of interventions to the clinic. The aim of this review is to highlight the advances in perinatal human medicine that have been achieved following translation of research using the pregnant sheep and fetus.