Events around conception such as maternal undernutrition and twinning may have effects on offspring physiology and disease risk in adulthood. Periconceptional undernutrition alters offspring physiology and adult pathology without affecting birth size, while twinning affects birth size and physiology but with inconsistent effects on adult pathology. We investigated the effects of these two periconceptional events and their interaction on maternal cardiovascular adaptation to pregnancy and fetal growth, physiology and endocrinology in late gestation in sheep. Pre and/or postconception undernutrition resulted in increased uterine blood flow in late gestation, but no change in maternal blood volume. Preconception undernutrition alone resulted in a relatively large placenta with a small, slow-growing fetus in late gestation. In contrast, postconception undernutrition alone resulted in a fetus with rapid late-gestation growth that was maintained through a maternal fast. Fetuses of ewes undernourished throughout both periods were similar in growth rate and size to controls. Maternal fasting also demonstrated that plasma levels of C-type natriuretic peptide are acutely and independently regulated by nutrient supply in mother and fetus. Fetuses of ewes undernourished both pre- and postconception had increased glucose disposal following a glucose challenge. Hypothalamic-pituitary-adrenal axis tests in these fetuses showed decreased pituitary adrenocorticotropin hormone response to direct stimulation but increased adrenal response to decreased cortisol negative feedback. Twin fetuses grew more slowly in late gestation than singletons. Twins also had a smaller insulin response to arginine and a greater insulin response to glucose, but periconceptional undernutrition abolished this difference. Twins had suppressed baseline hypothalamic-pituitary-adrenal axis function and decreased adrenal sensitivity compared to singletons, but increased fetal pituitary adrenocorticotropin hormone response to direct stimulation and decreased cortisol negative feedback. These studies suggest that firstly, fetal size is a poor reflection of fetal growth trajectory, physiology and endocrinology. Secondly, pre- and postconception undernutrition affect late-gestation fetal growth in different ways, while undernutrition in both periods alters fetal endocrine status in late gestation. Thirdly, the biology of twin fetal development is fundamentally different from that of singletons, which may explain the inconsistency of the relationship between birth weight and adult disease risk in twins. / Auckland Medical Research Foundation, Health Research Council of New Zealand

Events around conception such as maternal undernutrition and twinning may have effects on offspring physiology and disease risk in adulthood. Periconceptional undernutrition alters offspring physiology and adult pathology without affecting birth size, while twinning affects birth size and physiology but with inconsistent effects on adult pathology. We investigated the effects of these two periconceptional events and their interaction on maternal cardiovascular adaptation to pregnancy and fetal growth, physiology and endocrinology in late gestation in sheep. Pre and/or postconception undernutrition resulted in increased uterine blood flow in late gestation, but no change in maternal blood volume. Preconception undernutrition alone resulted in a relatively large placenta with a small, slow-growing fetus in late gestation. In contrast, postconception undernutrition alone resulted in a fetus with rapid late-gestation growth that was maintained through a maternal fast. Fetuses of ewes undernourished throughout both periods were similar in growth rate and size to controls. Maternal fasting also demonstrated that plasma levels of C-type natriuretic peptide are acutely and independently regulated by nutrient supply in mother and fetus. Fetuses of ewes undernourished both pre- and postconception had increased glucose disposal following a glucose challenge. Hypothalamic-pituitary-adrenal axis tests in these fetuses showed decreased pituitary adrenocorticotropin hormone response to direct stimulation but increased adrenal response to decreased cortisol negative feedback. Twin fetuses grew more slowly in late gestation than singletons. Twins also had a smaller insulin response to arginine and a greater insulin response to glucose, but periconceptional undernutrition abolished this difference. Twins had suppressed baseline hypothalamic-pituitary-adrenal axis function and decreased adrenal sensitivity compared to singletons, but increased fetal pituitary adrenocorticotropin hormone response to direct stimulation and decreased cortisol negative feedback. These studies suggest that firstly, fetal size is a poor reflection of fetal growth trajectory, physiology and endocrinology. Secondly, pre- and postconception undernutrition affect late-gestation fetal growth in different ways, while undernutrition in both periods alters fetal endocrine status in late gestation. Thirdly, the biology of twin fetal development is fundamentally different from that of singletons, which may explain the inconsistency of the relationship between birth weight and adult disease risk in twins. / Auckland Medical Research Foundation, Health Research Council of New Zealand

Events around conception such as maternal undernutrition and twinning may have effects on offspring physiology and disease risk in adulthood. Periconceptional undernutrition alters offspring physiology and adult pathology without affecting birth size, while twinning affects birth size and physiology but with inconsistent effects on adult pathology. We investigated the effects of these two periconceptional events and their interaction on maternal cardiovascular adaptation to pregnancy and fetal growth, physiology and endocrinology in late gestation in sheep. Pre and/or postconception undernutrition resulted in increased uterine blood flow in late gestation, but no change in maternal blood volume. Preconception undernutrition alone resulted in a relatively large placenta with a small, slow-growing fetus in late gestation. In contrast, postconception undernutrition alone resulted in a fetus with rapid late-gestation growth that was maintained through a maternal fast. Fetuses of ewes undernourished throughout both periods were similar in growth rate and size to controls. Maternal fasting also demonstrated that plasma levels of C-type natriuretic peptide are acutely and independently regulated by nutrient supply in mother and fetus. Fetuses of ewes undernourished both pre- and postconception had increased glucose disposal following a glucose challenge. Hypothalamic-pituitary-adrenal axis tests in these fetuses showed decreased pituitary adrenocorticotropin hormone response to direct stimulation but increased adrenal response to decreased cortisol negative feedback. Twin fetuses grew more slowly in late gestation than singletons. Twins also had a smaller insulin response to arginine and a greater insulin response to glucose, but periconceptional undernutrition abolished this difference. Twins had suppressed baseline hypothalamic-pituitary-adrenal axis function and decreased adrenal sensitivity compared to singletons, but increased fetal pituitary adrenocorticotropin hormone response to direct stimulation and decreased cortisol negative feedback. These studies suggest that firstly, fetal size is a poor reflection of fetal growth trajectory, physiology and endocrinology. Secondly, pre- and postconception undernutrition affect late-gestation fetal growth in different ways, while undernutrition in both periods alters fetal endocrine status in late gestation. Thirdly, the biology of twin fetal development is fundamentally different from that of singletons, which may explain the inconsistency of the relationship between birth weight and adult disease risk in twins. / Auckland Medical Research Foundation, Health Research Council of New Zealand

Events around conception such as maternal undernutrition and twinning may have effects on offspring physiology and disease risk in adulthood. Periconceptional undernutrition alters offspring physiology and adult pathology without affecting birth size, while twinning affects birth size and physiology but with inconsistent effects on adult pathology. We investigated the effects of these two periconceptional events and their interaction on maternal cardiovascular adaptation to pregnancy and fetal growth, physiology and endocrinology in late gestation in sheep. Pre and/or postconception undernutrition resulted in increased uterine blood flow in late gestation, but no change in maternal blood volume. Preconception undernutrition alone resulted in a relatively large placenta with a small, slow-growing fetus in late gestation. In contrast, postconception undernutrition alone resulted in a fetus with rapid late-gestation growth that was maintained through a maternal fast. Fetuses of ewes undernourished throughout both periods were similar in growth rate and size to controls. Maternal fasting also demonstrated that plasma levels of C-type natriuretic peptide are acutely and independently regulated by nutrient supply in mother and fetus. Fetuses of ewes undernourished both pre- and postconception had increased glucose disposal following a glucose challenge. Hypothalamic-pituitary-adrenal axis tests in these fetuses showed decreased pituitary adrenocorticotropin hormone response to direct stimulation but increased adrenal response to decreased cortisol negative feedback. Twin fetuses grew more slowly in late gestation than singletons. Twins also had a smaller insulin response to arginine and a greater insulin response to glucose, but periconceptional undernutrition abolished this difference. Twins had suppressed baseline hypothalamic-pituitary-adrenal axis function and decreased adrenal sensitivity compared to singletons, but increased fetal pituitary adrenocorticotropin hormone response to direct stimulation and decreased cortisol negative feedback. These studies suggest that firstly, fetal size is a poor reflection of fetal growth trajectory, physiology and endocrinology. Secondly, pre- and postconception undernutrition affect late-gestation fetal growth in different ways, while undernutrition in both periods alters fetal endocrine status in late gestation. Thirdly, the biology of twin fetal development is fundamentally different from that of singletons, which may explain the inconsistency of the relationship between birth weight and adult disease risk in twins. / Auckland Medical Research Foundation, Health Research Council of New Zealand

Sabe-se que algumas alterações nutricionais maternas durante o período perinatal estão associadas com doenças metabólicas na vida adulta das proles, tais como diabetes melito tipo 2, resistência à insulina, obesidade e hipertensão arterial. O período da gestação em que estas alterações nutricionais influenciam a prole na idade adulta ainda não está elucidado. Modificações epigenéticas têm sido propostas como mecanismos responsáveis por estas desordens metabólicas. Ratas Wistar de doze semanas de idade foram alimentadas com dieta com conteúdo baixo (HO - 0,15% NaCl) ou normal (NR - 1,3% NaCl) de sódio desde o primeiro dia de gestação até o nascimento da prole ou HO durante a primeira (HO10) ou segunda (HO20) metade da gestação. O peso corpóreo e a ingestão de água e ração foram avaliados semanalmente durante a gestação. Teste de tolerância à insulina (ITT) e à glicose (GTT) e HOMA-IR foram realizados nas proles adultas. Expressão gênica por qRT-PCR e metilação do DNA na região promotora dos genes foram mapeadas utilizando tratamento com bissulfito de sódio e avaliadas por pirosequenciamento. O ganho de peso materno foi menor no HO e HO20 na terceira semana de gestação em comparação com NR e HO10. O peso ao nascimento da prole foi menor em machos e fêmeas dos grupos HO e HO20 em relação ao NR e HO10. O HOMA-IR foi maior nos machos com 12 semanas de idade do grupo HO em comparação com NR e com 20 semanas de idade do grupo HO10 em comparação com NR e HO20. Nas fêmeas com 12 semanas de idade o HOMA-IR foi maior no HO10 comparado com HO. Os níveis de insulina no soro foram maiores tanto nos machos com 20 semanas de idade do grupo HO10 comparado com NR quanto nas fêmeas com 12 semanas de idade do grupo HO10 comparado com HO. A área sob a curva do GTT indicou intolerância à glicose nos machos do grupo HO. A porcentagem de metilação das ilhas CpG no promotor dos genes de Igf1, Igf1r, Ins1, Ins2 e Insr no fígado de machos e fêmeas neonatais e no fígado, tecido adiposo branco e músculo em machos com 20 semanas de idade foi influenciada pela baixa ingestão de sal durante a gestação. Nenhuma destas alterações foi identificada nas fêmeas com 20 semanas de idade. Em conclusão, a baixa ingestão de sal na segunda metade da gestação é responsável pelo baixo peso ao nascimento em ambos os sexos. A intolerância à glicose observada na prole adulta ocorreu somente se a dieta hipossódica é dada durante a gestação inteira. Por outro lado, a resistência à insulina em resposta ao consumo de dieta hipossódica durante a gestação está relacionada com o momento em que ocorre este insulto e com o envelhecimento da prole. Também foi observado que alterações na metilação do promotor do gene Igf1 está correlacionado com o baixo peso ao nascimento em resposta a ingestão de dieta hipossódica durante a gestação / It is known that some maternal nutritional alterations during pregnancy are associated with metabolic disorders in adult offspring, such as insulin resistance, type 2 diabetes mellitus, obesity and arterial hypertension. The period of pregnancy in which these nutritional alterations influence adult offspring remains uncertain. Epigenetic changes are proposed to underlie these metabolic disorders. Twelve-week-old female Wistar rats were fed a low-salt (LS - 0.15% NaCl) or normal-salt (NS - 1.3% NaCl) diet since the first day of gestation until delivery or LS during the first (LS10) or second (LS20) half of gestation. Body weight, food and water intake were weekly evaluated during gestation. Blood glucose, insulin (ITT) and glucose (GTT) tolerance tests, HOMA-IR were performed in adult offspring. Gene expression and DNA methylation were mapped using bisulfite treatment evaluated by pyrosequencing in the male and female neonates and adult offspring. Weight gain was lower in LS and LS20 dams than in NS and LS10 dams in the third week of pregnancy. Birth weights were lower in male and female LS20 and LS rats compared with NS and LS10 neonates. HOMA-IR was higher in 12-week-old LS males compared with NS and in 20-week-old male LS10 rats compared with NS and LS20 rats. In 12-week-old LS10 females, HOMA-IR was higher than in LS. Serum insulin levels were higher in 20 week-old LS10 male compared with NS rats and in 12-week-old LS10 female compared to LS rats. The area under the curve of GTT indicated glucose intolerance in 12- and 20-week-old LS male. Methylation of CpG islands of the Insr, Igf1, Igf1r, Ins1 and Ins2 genes in liver in neonates male and female offspring and liver, white adipose tissue and muscle in 20-week-old male offspring were influenced by low-salt intake during pregnancy. None of these alterations was identified in 20-week-old females. In conclusion, low-salt diet consumption in the second half of pregnancy can result in low birth weights in the males and females offspring. Glucose intolerance observed in adult offspring occurred only if low salt intake was given throughout pregnancy. However, insulin resistance in response to low salt intake during pregnancy is related to the time at which this insult occurs and to the age of the offspring. Alterations in the DNA methylation of Igf1 were observed to be correlated with low birth weight in response to low salt feeding during pregnancy

A greater understanding of critical periods of body weight regulation, including pregnancy, may aid in efforts to optimize weight management strategies for the mother and her baby. The gestational period has been implicated to play, in the child, a vital role in the developmental origins of obesity and other cardiometabolic diseases later in life. Therefore, we initially examined existing literature on the role of maternal obesity and its link to pediatric obesity and documented the known underlying physiological mechanisms responsible for this relationship while suggesting potential intervention targets that may improve maternal-fetal outcomes. In a second paper, we aimed to quantify maternal predictors of large for gestational age (LGA) neonates in the Ottawa and Kingston (OaK) birth cohort with specific hypotheses verifying the independent contribution of maternal prepregnancy body mass index (BMI) and excessive gestational weight gain (GWG) to fetal overgrowth. This paper also highlights the clinical utility of the revised 2009 Institute of Medicine GWG guidelines and discusses the potential role of physiological factors underlying the observed associations between BMI, excessive GWG and LGA neonates. As a follow-up to our population-level analysis (i.e., OAK cohort), papers three and four highlight how the insulin-like growth factor (IGF) axis, a vital regulator of growth and development, may be compromised at the molecular level in cases of maternal obesity (paper 3) and excessive GWG (paper 4). In paper 3 we show that maternal obesity is associated with attenuated expression of IGF binding protein-4 (IGFBP4) in umbilical cord blood and discuss how this may preferentially promote fetal adipogenesis. The effects of excessive GWG on IGF axis protein expression are addressed in paper four where we show that excessive weight gain during pregnancy is associated with increased expression of IGFBP3 in maternal circulation in normoglycemic term pregnancies. In this paper we discuss the potential inhibitory role of IGFBP3 on adipogenesis and how it relates to glucose intolerance during pregnancy. Recognizing that both obesity and excessive GWG can alter physiological processes in mother and her baby, appropriate evidence-based interventions are warranted to best optimize outcomes. In paper five, we discuss the results of a study which sought to assess patient information channels and knowledge of nutrition and physical activity during pregnancy with the intent that these findings be applied to best design efficacious strategies that cater to the needs of our target group of pregnant women. In our analysis we show that the majority of pregnant women studied would be willing to participate in a lifestyle intervention for their own personal health and that of their child. Of great interest was the observation that most women were not informed of the importance of pregnancy-specific energy intake, or made aware of their own healthy GWG targets. Additionally, many of the respondents reported receiving no information pertaining to appropriate physical activity recommendations; despite the fact that the vast majority of participants consider this lifestyle modality to be safe during their pregnancy. Finally in paper six, we build on the results of our previous work and evaluate the risks and benefits of physical activity during pregnancy on maternal-fetal outcomes through a review of the literature and note that engaging in non-sedentary pursuits during gestation may aid in maternal weight regulation, protect against metabolic disorders and optimize neonatal birth weight and body composition. Overall, the collective nature of the papers presented in this dissertation provides qualitative and quantitative evidence to support not only the complexity of body weight regulation in the mother and her baby, but also highlights potential avenues for intervention that may improve maternal-fetal outcomes during this critical period.