Epidemiology formed the basis of 'the Barker hypothesis', the concept of 'developmental programming' and today's discipline of the Developmental Origins of Health and Disease (DOHaD). Animal experimentation provided proof of the underlying concepts, and continues to generate knowledge of underlying mechanisms. Interventions in humans, based on DOHaD principles, will be informed by experiments in animals. As knowledge in this discipline has accumulated, from studies of humans and other animals, the complexity of interactions between genome, environment and epigenetics, has been revealed. The vast nature of programming stimuli and breadth of effects is becoming known. As a result of our accumulating knowledge we now appreciate the impact of many variables that contribute to programmed outcomes. To guide further animal research in this field, the Australia and New Zealand DOHaD society (ANZ DOHaD) Animals Models of DOHaD Research Working Group convened at the 2nd Annual ANZ DOHaD Congress in Melbourne, Australia in April 2015. This review summarizes the contributions of animal research to the understanding of DOHaD, and makes recommendations for the design and conduct of animal experiments to maximize relevance, reproducibility and translation of knowledge into improving health and well-being.

While the use of creatine in human pregnancy is yet to be fully evaluated, its long-term use in healthy adults appears to be safe, and its well documented neuroprotective properties have recently been extended by demonstrations that creatine improves cognitive function in normal and elderly people, and motor skills in sleep-deprived subjects. Creatine has many actions likely to benefit the fetus and newborn, because pregnancy is a state of heightened metabolic activity, and the placenta is a key source of free radicals of oxygen and nitrogen. The multiple benefits of supplementary creatine arise from the fact that the creatine-phosphocreatine [PCr] system has physiologically important roles that include maintenance of intracellular ATP and acid–base balance, post-ischaemic recovery of protein synthesis, cerebral vasodilation, antioxidant actions, and stabilisation of lipid membranes. In the brain, creatine not only reduces lipid peroxidation and improves cerebral perfusion, its interaction with the benzodiazepine site of the GABAA receptor is likely to counteract the effects of glutamate excitotoxicity – actions that may protect the preterm and term fetal brain from the effects of birth hypoxia. In this review we discuss the development of creatine synthesis during fetal life, the transfer of creatine from mother to fetus, and propose that creatine supplementation during pregnancy may have benefits for the fetus and neonate whenever oxidative stress or feto-placental hypoxia arise, as in cases of fetal growth restriction, premature birth, or when parturition is delayed or complicated by oxygen deprivation of the newborn.

Background: acute kidney injury (aKI) is a major complication for infants following an asphyxic insult at birth. We aimed to determine if kidney structure and function were affected in an animal model of birth asphyxia and if maternal dietary creatine supplementation could provide an energy reserve to the fetal kidney, maintaining cellular respiration during asphyxia and preventing aKI. Methods: Pregnant spiny mice were maintained on normal chow or chow supplemented with creatine from day 20 gestation. On day 38 (term ~39 d), pups were delivered by cesarean section (c-section) or subjected to intrauterine asphyxia. Twenty-four hours after insult, kidneys were collected for histological or molecular analysis. Urine and plasma were also collected for biochemical analysis. results: aKI was evident at 24 h after birth asphyxia, with a higher incidence of shrunken glomeruli (P < 0.02), disturbance to tubular arrangement, tubular dilatation, a twofold increase (P < 0.02) in expression of Ngal (early marker of kidney injury), and decreased expression of the podocyte differentiation marker nephrin. Maternal creatine supplementation prevented the glomerular and tubular abnormalities observed in the kidney at 24 h and the increased expression of Ngal. conclusion: Maternal creatine supplementation may prove useful in ameliorating kidney injury associated with birth asphyxia.

Objectives: Placental insufficiency contributes to altered maternal-fetal amino acid transfer, and thereby to poor fetal growth. An important placental function is the uptake of tryptophan and its metabolism to serotonin (5-HT) and kynurenine metabolites, which are essential for fetal development. We hypothesised that placental 5-HT content will be increased in pregnancies affected with fetal growth restriction (FGR). Methods: The components of the 5-HT synthetic pathway were determined in chorionic villus samples (CVS) from small-for gestation (SGA) and matched control collected at 10–12 weeks of human pregnancy; and in placentae from third trimester FGR and gestation-matched control pregnancies using the Fluidigm Biomarker array for mRNA expression, the activity of the enzyme TPH and 5-HT concentrations using an ELISA. Results: Gene expression for the rate limiting enzymes, TPH1 and TPH2; 5-HT transporter, SLC6A4; and 5-HT receptors HTR5A, HTR5B, HTR1D and HTR1E were detected in all CVS and third trimester placentae. No significant difference in mRNA was observed in SGA compared with control. Although there was no significant change in TPH1 mRNA, the mRNA of TPH2 and SLC6A4 was significantly decreased in FGR placentae (p < 0.05), while 5-HT receptor mRNA was significantly increased in FGR compared with control (p < 0.01). Placental TPH enzyme activity was significantly increased with a concomitant increase in the total placental 5-HT concentrations in FGR compared with control. Conclusion: This study reports differential expression and activity of the key components of the 5-HT synthetic pathway associated with the pathogenesis of FGR. Further studies are required to elucidate the functional consequences of increased placental 5-HT in FGR pregnancies.

The spiny mouse undergoes spontaneous decidualization, demonstrating for the first time menstruation in a rodent. The spiny mouse provides a readily accessible nonprimate model to study the mechanisms of menstrual shedding and repair, and may therefore be useful in furthering studies of human menstrual and pregnancy-associated disorders.

Birth asphyxia is a significant global health problem, responsible for ~1.2 million neonatal deaths each year worldwide. Those who survive often suffer from a range of health issues including brain damage—manifesting as cerebral palsy (CP)—respiratory insufficiency, cardiovascular collapse, and renal dysfunction, to name a few. Although the majority of research is directed toward reducing the brain injury that results from intrapartum birth asphyxia, the multi-organ injury observed in surviving neonates is of equal importance. Despite the advent of hypothermia therapy for the treatment of hypoxic–ischemic encephalopathy (HIE), treatment options following asphyxia at birth remain limited, particularly in low-resource settings where the incidence of birth asphyxia is highest. Furthermore, although cooling of the neonate results in improved neurological outcomes for a small proportion of treated infants, it does not provide any benefit to the other organ systems affected by asphyxia at birth. The aim of this review is to summarize the current knowledge of the multi-organ effects of intrapartum asphyxia, with particular reference to the findings from our laboratory using the precocial spiny mouse to model birth asphyxia. Furthermore, we reviewed the current treatments available for neonates who have undergone intrapartum asphyxia, and highlight the emergence of maternal dietary creatine supplementation as a preventative therapy, which has been shown to provide multi-organ protection from birth asphyxia-induced injury in our preclinical studies. This cheap and effective nutritional supplement may be the key to reducing birth asphyxia-induced death and disability, particularly in low-resource settings where current treatments are unavailable.

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IntroductionThe creatine kinase circuit is central to the regulation of high-energy phosphate metabolism and the maintenance of cellular energy turnover. This circuit is fuelled by creatine, an amino acid derivative that can be obtained from a diet containing animal products, and by synthesis in the body de novo. A recent retrospective study conducted in a cohort of 287 pregnant women determined that maternal excreted levels of creatine may be associated with fetal growth. This prospective study aims to overcome some of the limitations associated with the previous study and thoroughly characterise creatine homeostasis throughout gestation in a low-risk pregnant population.Methods and analysisThis study is recruiting women with a singleton low-risk pregnancy who are attending Monash Health, in Melbourne, Australia. Maternal blood and urine samples, along with dietary surveys, are collected at five time points during pregnancy and then at delivery. Cord blood and placenta (including membranes and cord) are collected at birth. A biobank of tissue samples for future research is being established. Primary outcome measures will include creatine, creatine kinase and associated metabolites in antenatal bloods and urine, cord bloods and placenta, along with molecular analysis of the creatine transporter (SLC6A8) and synthesising enzymes L - arginine:glycine amidinotransferase (AGAT) and guanidinoacetate methyltransferase (GAMT) in placental tissues. Secondary outcome measures include dietary protein intake over pregnancy and any associations with maternal creatine, pregnancy events and birth outcomes.Ethics and disseminationEthical approval was granted in August 2015 from Monash Health (Ref: 14140B) and Monash University (Ref: 7785). Study outcomes will be disseminated at international conferences and published in peer-reviewed scientific journals.Trial registration numberACTRN12618001558213; Pre-results.