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Table 2 Maternal, placental and fetal mechanistic hypotheses

From: Perspectives on the design and methodology of periconceptional nutrient supplementation trials

Maternal (biochemical, endocrine factors, and plasma volume)

- Glucocorticoid effects on the fetal hypothalamic-adrenal axis (see fetal effects) [54, 82]

- Glucose homeostasis on metabolic responses leading to greater fetal fat deposition, insulin secretion, DNA methylation, and differential development of fetal endocrine systems [51, 55]

- Specific mineral deficiencies and impaired metabolic pathways [82]

- Limited macronutrients required for fetal growth [82]

- Adiposity [83]

- Oxidative stress associated with deficiencies of specific micronutrient antioxidant activities [84]

- Infection with transcriptional inflammatory response through IL-6 receptor alpha and prostaglandin response leads to cervical ripening and uterine contractions [85]

- Homocysteine metabolic effects on obstetrical vascular disease or placental spiral artery function [86]

- Interferon tau and progesterone effects on selective nutrient transport to the uterine lumen, with cell signalling pathways effecting, migration, and protein synthesis in trophectoderm [64]

- Urinary metabolites measured at the end of the first trimester and increased risk of negative birth outcomes [87]

- Biochemical markers of early placentation and downstream resistance to uterine arterial flow [77]

- Sex-specific effects of first trimester progesterone levels [52]

Placental (growth, morphology, vascularisation and function)

- Placental oxygen consumption is greater than fetal, and anaemia and placental hypoxia lead to free radical production, alteration in placental size, and vascularisation [15, 88–90]

- Alterations of number and surface area of arterioles in tertiary villi, and factors controlling endothelial re-modelling and trophoblast cell turnover from immature villi to conductance villi and gas exchanging terminal villi [16]

- Impaired molecular signalling networks [91]

- Reduced transfer capacity due to impaired utero-placental flow and fetal nutrient uptake [92]

- Impairment of fetal trophoblast and angiogenesis due to oxidative stress and inflammation [15, 93, 94]

- Long-chain polyunsaturated fatty effects on placental weight and surface area of gas exchanging placental capillaries [89, 95]

- Iron associated with markers of vasculopathy and placental growth factor excess [96]

- Alterations in placental phenotype and availability of placental hormone receptors and effects of hormones on the morphology, transport capacity and endocrine function of the placenta [56]

- Decreased nitric oxide bioavailability through low dietary arginine substrate and antioxidant supply [82]

- Interference with folate homeostasis in malaria infected placentae [97]

Fetal (embryonic, fetal growth factors and endocrine axes)

- Periconceptional undernutrition accelerating fetal hypothalamic-pituitary-adrenal (HPA) axis activation [54], mediated by different influences of maternal glucocorticoid on maturation of the fetal HPA axis, via placental 11-beta-hydroxysteroid dehydrogenase isozymes. Fetal exposure to glucose, fatty acids, and micronutrients, with resultant increased fetal insulin secretion, could influence development of the HPA axis controlling infant appetite [57]

- Placental metabolic alterations associated with the growth restricted fetus [89]

- Pre-term birth frequency in the growth restricted fetus [98]

- Altered fragility of chorioamniotic membrane [99]

- Inadequate micronutrient supply [48]

- One-carbon metabolic effects on methyl groups and DNA methylation [100]

- Fetal epigenomic effects during early stages of embryogenesis leading to stable and inheritable alterations in genes through covalent modifications of DNA and gatekeeper genes leading to nutritional programming [53, 101]

- Transport effects on methionine from the mother to the coelomic cavity and amniotic fluid [64]

- Vitamin independent effect of homocysteine in the fetal metabolic cycle [64]

- Thyroid hormone effects of mild/moderate iodine deficiency on cognitive ability and growth [102]

- Fetal angiogenic and placental growth factors affecting newborn thyroid function [103]

- Association of rapidly growing fetus with increased vulnerability to impaired nutrient supply [104, 105]

- Influence on development and activation of regulatory T cells in the human fetus [106]