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Bernadette C Baker, Dexter JL Hayes and Rebecca L Jones

Micronutrient deficiencies are common in pregnant women due to low dietary intake and increased requirements for fetal development. Low maternal micronutrient status is associated with a range of pregnancy pathologies involving placental dysfunction, including fetal growth restriction (FGR), small-for-gestational age (SGA), pre-eclampsia and preterm birth. However, clinical trials commonly fail to convincingly demonstrate beneficial effects of supplementation of individual micronutrients, attributed to heterogeneity and insufficient power, potential interactions and lack of mechanistic knowledge of effects on the placenta. We aimed to provide current evidence of relationships between selected micronutrients (vitamin D, vitamin A, iron, folate, vitamin B12) and adverse pregnancy outcomes, combined with understanding of actions on the placenta. Following a systematic literature search, we reviewed data from clinical, in vitro and in vivo studies of micronutrient deficiency and supplementation. Key findings are potential effects of micronutrient deficiencies on placental development and function, leading to impaired fetal growth. Studies in human trophoblast cells and rodent models provide insights into underpinning mechanisms. Interestingly, there is emerging evidence that deficiencies in all micronutrients examined induce a pro-inflammatory state in the placenta, drawing parallels with the inflammation detected in FGR, pre-eclampsia, stillbirth and preterm birth. Beneficial effects of supplementation are apparent in vitro and in animal models and for combined micronutrients in clinical studies. However, greater understanding of the roles of these micronutrients, and insight into their involvement in placental dysfunction, combined with more robust clinical studies, is needed to fully ascertain the potential benefits of supplementation in pregnancy.

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Rebecca L Jones, Chelsea Stoikos, Jock K Findlay and Lois A Salamonsen

Transforming growth factor β (TGFβ) superfamily members are closely associated with tissue remodelling events and reproductive processes. This review summarises the current state of knowledge regarding the expression and actions of TGFβ superfamily members in the uterus, during the menstrual cycle and establishment of pregnancy. TGFβs and activin β subunits are abundantly expressed in the endometrium, where roles in preparation events for implantation have been delineated, particularly in promoting decidualisation of endometrial stroma. These growth factors are also expressed by epithelial glands and secreted into uterine fluid, where interactions with preimplantation embryos are anticipated. Knockout models and embryo culture experiments implicate activins, TGFβs, nodal and bone morphogenetic proteins (BMPs) in promoting pre- and post-implantation embryo development. TGFβ superfamily members may therefore be important in the maternal support of embryo development. Following implantation, invasion of the decidua by fetal trophoblasts is tightly modulated. Activin promotes, whilst TGFβ and macrophage inhibitory cytokine-1 (MIC-1) inhibit, trophoblast migration in vitro, suggesting the relative balance of TGFβ superfamily members participate in modulating the extent of decidual invasion. Activins and TGFβs have similar opposing actions in regulating placental hormone production. Inhibins and activins are produced by the placenta throughout pregnancy, and have explored as a potential markers in maternal serum for pregnancy and placental pathologies, including miscarriage, Down’s syndrome and pre-eclampsia. Finally, additional roles in immunomodulation at the materno-fetal interface, and in endometrial inflammatory events associated with menstruation and repair, are discussed.

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Rebecca L Jones, Tu’uhevaha J Kaitu’u-Lino, Guiying Nie, L Gabriel Sanchez-Partida, Jock K Findlay and Lois A Salamonsen

Maternal–fetal communications are critical for the establishment of pregnancy. Embryonic growth and differentiation factors produced by the oviduct and uterus play essential roles during the pre- and early post-implantation phases. Although several studies indicate roles for activin in embryonic development, gene-knockout studies have failed to identify a critical role in mammalian embryogenesis. We hypothesized that activin is produced by maternal tissues during the establishment of pregnancy, and thus maternally derived activin could compensate for the absence of embryonic activin in null homozygotes during critical developmental stages. We investigated the expression of inhibin α, activin βA, and βB subunits in the mouse oviduct and uterus during the estrous cycle and early pregnancy, and in the early conceptus. Inhibin α subunit was weakly expressed, while activin βA and βB subunits were strongly expressed in oviduct and uterus at estrous, and dramatically upregulated in the uterus on each day of pregnancy between days 3.5 and 8.5 post coitum. Prior to implantation, activin βA and βB subunits were immunolocalized to oviductal and uterine epithelial cells; following implantation they were expressed in the stroma, in a wave preceding decidualization. Later in pregnancy, activin βA and βB subunits were present in decidua basalis, trophoblast giant cells, and labyrinth zone of the developing placenta. Expression of activin βA subunit was also detected in blastocysts and early post-implantation embryos. These data are consistent with a role for maternally derived activins in the support of the pre-implantation embryo, and during gastrulation and embryogenesis.