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Cited by 717Birth, Development, and HealthPregnancy and preeclampsia studiesGestational Diabetes Research and Management

Placental Origins of Chronic Disease

Open access
Burton, Graham J., Fowden, Abigail L., Thornburg, Kent L.·2016·Physiological Reviews
DOI 10.1152/physrev.00029.2015PMC PMC5504455
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Abstract

Epidemiological evidence links an individual's susceptibility to chronic disease in adult life to events during their intrauterine phase of development. Biologically this should not be unexpected, for organ systems are at their most plastic when progenitor cells are proliferating and differentiating. Influences operating at this time can permanently affect their structure and functional capacity, and the activity of enzyme systems and endocrine axes. It is now appreciated that such effects lay the foundations for a diverse array of diseases that become manifest many years later, often in response to secondary environmental stressors. Fetal development is underpinned by the placenta, the organ that forms the interface between the fetus and its mother. All nutrients and oxygen reaching the fetus must pass through this organ. The placenta also has major endocrine functions, orchestrating maternal adaptations to pregnancy and mobilizing resources for fetal use. In addition, it acts as a selective barrier, creating a protective milieu by minimizing exposure of the fetus to maternal hormones, such as glucocorticoids, xenobiotics, pathogens, and parasites. The placenta shows a remarkable capacity to adapt to adverse environmental cues and lessen their impact on the fetus. However, if placental function is impaired, or its capacity to adapt is exceeded, then fetal development may be compromised. Here, we explore the complex relationships between the placental phenotype and developmental programming of chronic disease in the offspring. Ensuring optimal placentation offers a new approach to the prevention of disorders such as cardiovascular disease, diabetes, and obesity, which are reaching epidemic proportions.

AI snapshot

Written from the paper’s full text.

TL;DR

This review argues that the placenta is a central mediator of developmental programming, linking placental phenotype and function to offspring risk of chronic disease. It synthesizes epidemiological associations, comparative placental biology, and mechanisms of oxygen/nutrient sensing to propose how placental adaptations or impairments shape lifelong health.

Key findings

  • In ~15,000 Hertfordshire records, death from ischemic heart disease was ordered across birth weight: babies at 5 lb (2.3 kg) had the highest adult mortality, while those at 9 lb (4.0 kg) had rates two-thirds lower.
  • Placental efficiency shows a “U”-shaped relationship with adult cardiovascular death: heart-related death rates were lowest when placental weight was ~19% of birth weight. In 17,000 Saudi birth weight–placental weight pairs, placental efficiency decreased over a decade because placental weight rose by >100 g without a concomitant birth weight increase.
  • In the Helsinki Birth Cohort (13,345 men and women born 1934–1944), among 644 hypertensive subjects, low placental weight and surface area were associated with hypertension; among shorter women, hypertension prevalence fell from 38% with placental area ≤200 cm² to 21% with area >320 cm² (p=0.0007). Chronic heart failure had an odds ratio of 1.7 (1.1–2.5) for placental area <225 cm² versus >295 cm².
  • Mechanistically, the placenta accounts for ~40% of oxygen consumption of the fetal-placental unit, with ~33% used for active transport and ~33% for protein synthesis. At high altitude, birth weight decreases on average by ~100 g per 1,000 m elevation, with placental vascular and metabolic adaptations.

Methods

  • Narrative review, not a primary study. It synthesizes epidemiological cohorts (e.g., Hertfordshire, Helsinki Birth Cohort, Saudi Arabia, Dutch famine, ALSPAC), comparative placental anatomy in human, mouse, and sheep, and mechanistic literature on placental transport, endocrine function, oxygen sensing, nutrient sensing, epigenetics, and inflammation.
  • No new data are collected; analyses are literature synthesis and interpretation of cited studies, including reported effect sizes, odds ratios, hazard ratios, and p-values from prior cohorts.

Limitations

  • The paper states that epidemiological studies cannot separate cause from effect, and that attributing causation to placental changes is problematic because the same environmental insult may affect multiple systems; placental changes may be secondary to fetal programming or a parallel response.
  • The paper notes that many proposed mechanisms remain speculative or lack confirmatory data, that human placental development is poorly understood, and that sample collection can introduce artifacts.
  • Evident from the text: this is a narrative review rather than a systematic review or meta-analysis, and it relies on heterogeneous cohorts and animal models; species differences in placental structure and function limit extrapolation to humans.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1152/physrev.00029.2015

Cites

623 of 623 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 651 cited sources checked · 0 supported · 0 flagged

  • Interpretationreasoning

    These developmental programming changes predispose the offspring to a variety of disorders that may become manifest in later life, often following exposure to a second precipitating challenge.

    “These changes predispose the offspring to a variety of disorders that may become manifest in later life, often following exposure to a second precipitating challenge.”
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  • Premisecitation

    The relationship between poor growth in the womb and the risk of adult disease has been confirmed in many other countries, including Finland, Sweden, China, India, and the USA.

    “This relationship between poor growth in the womb and the risk of adult disease has since been confirmed in many other countries, including Finland (26), Sweden (332), China (183), India (517), and the USA (464).”
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  • Interpretationnone given

    There is now compelling evidence that the placenta plays a central role in orchestrating the allocation of maternal resources to meet her own needs and those of her offspring.

    “There is now compelling evidence that the placenta plays a central role in orchestrating this process.”
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    • The authors state this as an assumption: Little research has addressed developmental plasticity within the placenta.
  • Premisecitation

    Dual-perfusion of the delivered placenta has validated transfer for approximately 50 drugs.

    “Comparison of the data with maternal-fetal in vivo measurements has validated transfer for approximately 50 drugs (266).”
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    Levels of dioxins in the fetal circulation were found to be approximately half those in the mother.

    “Other studies have compared maternal and fetal blood levels at the time of delivery; for example, levels of dioxins in the fetal circulation were found to be approximately half those in the mother (536).”
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    Premisecitation

    Barker and colleagues reported on approximately 15,000 records from men and women in Hertfordshire, UK, and showed that rates of death from ischemic heart disease were ordered across the birth weight scale.

    “In the late 1980s, they reported on ~15,000 records from men and women in Hertfordshire, UK, and showed that rates of death from ischemic heart disease were ordered across the birth weight scale (40).”
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    Premisecitation

    Perturbation of gene expression or cell proliferation and differentiation during vulnerable periods by nutritional and other environmental influences can alter the structure and functional capacity of major organ systems for life, a process known as developmental programming.

    “Perturbation of gene expression or cell proliferation and differentiation during vulnerable periods by nutritional and other environmental influences can alter the structure and functional capacity of major organ systems for life, a process known as developmental programming.”
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    Premisecitation

    The Barker team reasoned that both the neonates and adults died for the same reason, namely that their development had been compromised before birth.

    “The Barker team reasoned that both the neonates and adults died for the same reason, namely that their development had been compromised before birth.”
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    Interpretationreasoning

    If normal placental function is impaired, or the organ's capacity for adaptation exceeded, then the fetal milieu may be perturbed with major consequences for the lifelong health of the offspring.

    “However, if normal placental function is impaired, or the organ's capacity for adaptation exceeded, then the fetal milieu may be perturbed with major consequences for the lifelong health of the offspring (Figure 1).”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The placenta evolved to transfer nutrients to the fetus and to create a stable milieu in which the fetus can develop, isolated as far as possible from maternal and environmental stressors.
    • Rests on an assumption: The placenta is a remarkably plastic organ, capable of considerable structural and functional adaptations that help to mitigate adverse maternal insults such as nutrient deprivation, and exposure to drugs, toxins or hypoxia.

  • May combine two claims. The quote only partly states this claim.

    Premisecitation

    Babies born at the lower end of the birth weight scale (5 lb or 2.3 kg) had the highest adult mortality rates, while those at the opposite end (9 lb or 4.0 kg) were two-thirds lower.

    “Babies born at the lower end of the scale (5 lb or 2.3 kg) had the highest mortality rates as adults, while those at the opposite end (9 lb or 4.0 kg) were two-thirds lower.”
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    Premisecitation

    An adverse intrauterine environment renders offspring vulnerable to death as neonates and more likely to acquire heart disease later if they survive childhood.

    “Thus, they suggested that an adverse intrauterine environment rendered them vulnerable to death as neonates, and more likely to acquire heart disease later if they survived childhood (33).”
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    A growth-restricted fetus has fewer insulin-producing beta cells and reduced vascularization in the pancreas, and compromised structure and maturation of the brain, lungs, and liver.

    “In addition, the pancreas has fewer insulin-producing beta cells and reduced vascularization (159, 340, 473), and the structure and maturation of the brain (142), lungs (358, 359, 424, 460) and liver (209, 474) are compromised.”
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    A growth-restricted fetus has smaller coronary arteries, fewer but more immature cardiomyocytes, less elastin in the arteries, and fewer nephrons in the kidney.

    “For example, a growth-restricted fetus has smaller coronary arteries (288), fewer but more immature cardiomyocytes (55,348,394), less elastin in the arteries (152, 362, 526), and fewer nephrons in the kidney (22,352).”
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    Expression of the mRNAs encoding the VLDL-R and LDL-R increases across gestation, but is suppressed at term in pregnancies complicated by pre-eclampsia and severe growth restriction.

    “Expression of the mRNAs encoding the VLDL-R and LDL-R increases across gestation (402, 580), but is suppressed at term in pregnancies complicated by pre-eclampsia and severe growth restriction (402, 552).”
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    Interpretationcitation

    Infection of the fetus can lead to growth restriction, and hence developmental programming.

    “Infection of the fetus can lead to growth restriction (3), and hence developmental programming.”
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    Premisereasoning

    These biological links revolve around permanent structural changes in organ systems, premature aging of tissues, and epigenetic changes.

    “These links revolve around permanent structural changes in organ systems, premature aging of tissues and epigenetic changes.”
    Quote in the paperSubstantial claim

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    Premisecitation

    Progesterone and human placental lactogen stimulate maternal appetite during early pregnancy, enabling deposition of maternal adipose energy reserves that can be used later in pregnancy and during lactation.

    “Progesterone also stimulates maternal appetite during early pregnancy, as does human placental lactogen (hPL), enabling the deposition of maternal adipose energy reserves that can be utilized later in pregnancy and during lactation (414).”
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    Premisecitation

    The mRNA and protein levels of P-glycoprotein reduce across gestation, suggesting the fetus may be more exposed to toxic insults later in pregnancy.

    “The mRNA and protein levels of P-glycoprotein reduce across gestation, suggesting the fetus may be more exposed to toxic insults later in pregnancy (519).”
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    Premisecitation

    Erythropoietin is synthesized by the placenta at rates far higher than the fetal kidney and may mediate both classical hematopoietic responses to hypoxia and non-classical changes including increased placental vascularity and defense against oxidative stress.

    “Erythropoietin, in particular, is synthesized at rates far higher than the fetal kidney, and may mediate both classical hematopoietic responses to hypoxia and non-classical changes, including increased placental vascularity and defense against oxidative stress (534).”
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    Targeted disruption of megalin and cubilin leads to failure of somite formation, indicating their key role in supporting early embryogenesis.

    “Targeted disruption of these receptors leads to failure of somite formation, indicating their key role in supporting early embryogenesis (506).”
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    There are three main mechanisms by which exchange across the interhemal membrane can take place: diffusion, transporter-mediated mechanisms, and endocytosis/exocytosis.

    “There are three main mechanisms by which exchange across the interhemal membrane can take place; diffusion, transporter-mediated mechanisms and endocytosis/exocytosis (Figure 2).”
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    Premisecitation

    Exchange of respiratory gases and lipophilic drugs across the placenta is flow-limited, and changes in maternal or fetal blood flow have a profound impact on net flux.

    “Hence, exchange of molecules such as the respiratory gases and lipophilic drugs is considered to be 'flow-limited', and changes in maternal or fetal blood flow have a profound impact on the net flux (573).”
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    Premisecitation

    The links between impaired placental function and fetal outcomes go beyond abnormal maternal nutrient supply and include intrauterine hypoxia, maternal social stress leading to hypercortisolemia, and environmental toxins.

    “These links go beyond an abnormal maternal nutrient supply, and include, for example, intrauterine hypoxia (213), maternal social stress of the severity that leads to hypercortisolemia (128) and, increasingly, environmental toxins.”
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    Unlike the human, the murine syncytiotrophoblast has no endocrine function.

    “Unlike the human, the murine syncytiotrophoblast has no endocrine function (355).”
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    Internally, the mouse placenta has significant differences from the human, the most major being division into a labyrinth zone responsible primarily for exchange and a junctional zone serving an endocrine function.

    “Internally, however, there are significant differences (210), the most major being that the placenta is divided into two morphologically and functionally distinct zones; the labyrinth zone that is responsible primarily for exchange and the junctional zone that serves an endocrine function (Figure 3C).”
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    Interpretationnone given

    There is no perfect model of human placentation, except for the great apes in which experimentation is ethically unacceptable.

    “There is no perfect model of human placentation, except for the great apes in which experimentation is ethically unacceptable.”
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  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

    Premisenone given

    The number of cotyledons in sheep is fixed by about 5-6 weeks of pregnancy and does not increase thereafter.

    “The number of cotyledons is fixed by about 5-6 weeks of pregnancy and does not increase thereafter.”
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    Premisenone given

    The sheep offers opportunities for extended experimentation in conscious, ambulant animals through chronic catheterization of the maternal and fetal circulations.

    “By contrast, the sheep offers opportunities for extended experimentation in conscious, ambulant animals through chronic catheterization of the maternal and fetal circulations.”
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    Premisecitation

    The first trimester is a critical period for placental development, because expression of markers of trophoblast stemness declines rapidly after 12 weeks of gestation, suggesting loss of proliferative potential.

    “The first trimester is a critical period for placental development, for expression of markers of trophoblast stemness decline rapidly after 12 weeks of gestation (252), suggesting loss of proliferative potential.”
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    Premisecitation

    On the maternal side, placental vascular changes are predominantly in capillary diameter rather than number, whereas on the fetal side there is more branching angiogenesis.

    “On the maternal side the changes are predominantly in capillary diameter rather than number, whereas on the fetal side there is more branching angiogenesis.”
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    Premisecitation

    During the first trimester the conceptus is supported by histotrophic secretions from the endometrial glands, the 'uterine milk'.

    “However, it is now accepted that during the first trimester the conceptus is supported by histotrophic secretions from the endometrial glands, the 'uterine milk' (80,83).”
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    Premisecitation

    Villous vascularization increases continuously throughout pregnancy, with the fetal-side rate twice the maternal-side rate.

    “Vascularization of the villi appears to increase continuously throughout pregnancy, although it occurs at twice the rate on the fetal as on the maternal side (54).”
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    Premisereasoning

    The syncytiotrophoblast is vulnerable to oxidative and endoplasmic reticulum stress, which if unresolved leads to activation of the unfolded protein response.

    “Hence the tissue is vulnerable to oxidative and endoplasmic reticulum stress, which if not resolved leads to activation of the unfolded protein response.”
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    Premisecitation

    Placentas associated with female fetuses tend to have higher expression of genes involved in immune regulation, endocrine functions, and placental growth, while those from males have more inflammatory profiles.

    “Placentas associated with female fetuses tend to have higher expression of genes involved in immune regulation, endocrine functions and placental growth (71, 512), whilst those from males have more inflammatory profiles (136).”
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    • Rests on an assumption: The placenta is of the same genotype as the fetus.

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    Premisecitation

    The increase in placental vascularization is matched by exponential rises in uterine and umbilical blood flows throughout pregnancy, which are critical for fetal growth.

    “The increase in vascularization is matched by exponential rises in uterine and umbilical blood flows throughout pregnancy, which are of critical importance for fetal growth (461).”
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    Species with a labyrinthine placenta have gestation lengths less than half those associated with a villous or folded placenta, although there are no relationships with birth weight or brain size.

    “Comparative studies have demonstrated that species with a labyrinthine placenta have gestation lengths less than half those associated with a villous or folded placenta, although there are no relationships with birth weight or brain size (91,92).”
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    Premisenone given

    Implantation is relatively later in the sheep than in the other species, and there is no invasion of the maternal tissues.

    “Implantation is relatively later in the sheep than in the other species, and there is no invasion of the maternal tissues.”
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    Premisenone given

    The maternal arterial circulation to the placenta is established towards the end of the first trimester and is associated with transformation of the early placenta to its definitive form.

    “The maternal arterial circulation to the placenta is established towards the end of the first trimester, and is associated with transformation of the early placenta to its definitive form.”
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    Premisereasoning

    The human placenta is of the hemochorial type.

    “Hence the human placenta is described as being of the hemochorial type (49).”
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    Maintenance on a low protein diet throughout pregnancy results in reduced placental and pup weights, indicating that growth of the conceptus is ultimately constrained by the impoverished nutrient supply.

    “However, maintenance on such a diet throughout pregnancy results in reduced placental and pup weights, indicating that growth of the conceptus is ultimately constrained by the impoverished nutrient supply (120).”
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    Interpretationreasoning

    The labyrinthine placenta is capable of delivering nutrients at a faster rate, which may be traded off against gestational length to prevent maternal depletion.

    “Hence, the labyrinthine placenta is capable of delivering nutrients at a faster rate, which may be traded-off against gestational length in order to prevent maternal depletion.”
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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisenone given

    The labyrinthine trophoblast comprises three layers.

    “The labyrinthine trophoblast comprises three layers.”
    Quote in the paperNot a substantial claim

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    Interpretationreasoning

    Total fetal capillary surface area increases, favoring exchange, although mean capillary diameter is reduced.

    “Consequently, total fetal capillary surface area increases, favoring exchange, although mean diameter is reduced, as in the mouse (54,116).”
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    Premisecitation

    Complete endocrine ablation of gland development in newborn lambs results in cessation of growth of the conceptus and loss of the pregnancy in the adult animal, whereas partial ablation leads to a small, non-expanded conceptus that fails to attach.

    “Complete ablation results in a cessation of growth of the conceptus and loss of the pregnancy in the adult animal, whereas partial ablation leads to a small, non-expanded conceptus that fails to attach.”
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    • cites [515] Spencer TE, 2004, J Anim Sci

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  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    The ovine placenta is of the cotyledonary type, comprising approximately 70 placentomes of 0.5-4.0 cm diameter in a singleton pregnancy.

    “The ovine placenta is of the cotyledonary type, comprising approximately 70 placentomes of 0.5 -4.0 cm diameter in a singleton pregnancy (516).”
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    • cites [516] Stegeman J, 1974, Bijdragen tot de Dierkunde source

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    Premisecitation

    The risk of cardiovascular disease in adult men in relation to the birth weight to placental weight ratio is U-shaped, with heart-related death rates lowest when placental weight is about 19% of birth weight.

    “The risk of cardiovascular disease in adult men in relation to the birth weight to placental weight ratio does not follow a linear fashion as one might expect, but rather a “U” shaped pattern with heart-related death rates being lowest when placental weight is ~19% of birth weight (Figure 5) (25, 217, 361).”
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    Interpretationcitation

    Placental efficiency changes over time in any given population and is likely influenced by the nutritional environment.

    “There is increasing evidence that placental efficiency changes over time in any given population, and is likely to be influenced by the nutritional environment.”
    Quote in the paperSubstantial claim

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    Premisecitation

    The placental efficiency index is not related to the histological type of the placenta but to the relative geometries of maternal and fetal blood flows.

    “The index is not related to the histological type of the placenta, but to the relative geometries of the maternal and fetal blood flows (137), emphasizing the importance of flow-limited transport.”
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    • cites [137] Dantzer V, 1988, Trophoblast Res

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    The human placenta is generally described as discoid, but in large populations it has often been found on average to be slightly elliptical.

    “The human placenta is generally described as discoid, but in large populations it has often been found on average to be slightly elliptical (435).”
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    Premisecitation

    Senescence has only recently been considered a potential feature of the syncytiotrophoblast in human placenta.

    “Senescence has only recently been considered a potential feature of the syncytiotrophoblast in human placenta (220).”
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    Interpretationnone given

    The vascular arrangement of the early embryo plays an important mechanical role in regulating gene expression in the developing heart.

    “Thus, there is accumulating evidence that the vascular arrangement of the early embryo plays an important mechanical role in regulating gene expression in the developing heart.”
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    Premisecitation

    Cells in the common ventricle and outflow tract of the embryonic heart are sensitive to wall and shear forces, and increases in these forces can lead to heart defects.

    “Cells in the common ventricle and the outflow tract of the embryonic heart are sensitive to wall and shear forces (342, 442), and increases in these forces can lead to heart defects (135, 260, 379).”
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  • May combine two claims.

    Premisecitation

    The vitelline and allantoic vascular beds offer mechanical resistance to blood flow, and their inadequate growth promotes mechanical signals in the heart that result in structural defects.

    “These vascular beds offer mechanical resistance to blood flow, and there is increasing evidence that their inadequate growth promotes mechanical signals in the heart that result in structural defects (218, 260, 341, 379).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [218] source

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    • cites [260] source

      Not checked in the free run.

    • cites [341] source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Placental shape may reflect the site of implantation or events taking place during the transition of the early placenta to its definitive form.

    “As described in section IV.A.2, placental shape may reflect the site of implantation, or events taking place during the transition of the early placenta to its definitive form.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    For each cm increase in placental width, birth weight increased by 125 g (95% CI 88 to 162, p < 0.001), but only by 20 g for each cm increase in placental length (-13 to 53, p = 0.2).

    “For each cm increase in placental width, birth weight increased by 125 g (95% confidence interval 88 to 162, p < 0.001) but only by 20 g for each cm increase in placental length (-13 to 53, p= 0.2).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [12] source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Nutritional conditions across the life of a woman are highly influential in the establishment and growth of the placenta, and thus impact the lifelong health risks of her offspring.

    “This finding suggests that the nutritional conditions across the life of a woman are highly influential in the establishment and growth of the placenta, and thus impact the lifelong health risks of her offspring.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationcitation

    Excessive villous regression at the time of onset of the maternal circulation may indicate deficient extravillous trophoblast invasion, which may mean that the remaining spiral arteries are not fully remodeled, compromising placental blood flow.

    “For the latter, excessive villous regression at the time of onset of the maternal circulation may be indicative of deficient extravillous trophoblast invasion (77), which may mean that the remaining spiral arteries are not fully remodeled, compromising placental blood flow.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [77] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Simultaneous regression revealed that increasing ponderal index and the circumferences of the head, chest, abdomen and thigh among newborns are all highly associated with placental width, but none are related to placental length.

    “For example, simultaneous regression revealed that increasing ponderal index and the circumferences of the head, chest, abdomen and thigh among newborns are all highly associated with placental width; however, none are related to placental length (12).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [12] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Elevated levels of placental inflammation have been associated independently with slower post-natal growth in pre-term infants, and so may have long-lasting effects for adult health.

    “Elevated levels of placental inflammation have been associated independently with slower post-natal growth in pre-term infants, and so may have long-lasting effects for adult health (377).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [377] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Standard definitions of inflammation do not fit findings in the placenta in non-infectious cases such as obesity and diabetes, because inflammatory pathways can be activated without classic infiltration of granulocytes.

    “It is becoming increasing clear that standard definitions of inflammation do not fit the findings in the placenta in non-infectious cases, such as obesity and diabetes, for it is possible for inflammatory pathways to be activated without the classic infiltration of granulocytes (418).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [418] source

      Not checked in the free run.

  • May combine two claims.

    Premiseown data

    Although placental length and width correlate in any sample, the two measurements often have independent associations with fetal growth parameters and with postnatal disease.

    “A frequent finding is that although length and width correlate in any sample of placentas, the two measurements often have independent associations with fetal growth parameters as well as with postnatal disease.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    UPR signaling cascades are activated in placentas from cases of growth restriction and early-onset pre-eclampsia, but no data are yet available for pregnancies complicated by maternal obesity or other metabolic disorders.

    “These cascades are activated in placentas from cases of growth restriction and early-onset pre-eclampsia (595, 596), but no data are yet available for pregnancies complicated by maternal obesity or other metabolic disorders.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [595] Yung HW, 2014, J Pathol source

      Not checked in the free run.

    • cites [596] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Animal studies have confirmed that HIFs are expressed at the blastocyst stage of development and are essential for normal placental development.

    “Animal studies have confirmed that HIFs are expressed at the blastocyst stage of development (243), and that they are essential for normal placental development.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [243] source

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    For most primary or transformed mammalian cells, the critical oxygen threshold is within the range of about 0.15-1.5% oxygen.

    “For most primary or transformed mammalian cells it is within the range of ~0.15 -1.5% oxygen (225).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [225] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Among boys, the number of lobes was directly associated with higher systolic and diastolic pressure, but not with an increased pulse pressure.

    “However, among boys, the number of lobes was directly associated with higher systolic and diastolic pressure, but not with an increased pulse pressure.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [24] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    A high placental/birth weight ratio also predicted sudden death among women, but not men.

    “A high placental/birth weight ratio also predicted sudden death among women, but not men.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [30] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In girls, a greater number of lobes was associated with higher systolic pressure and pulse pressure, but not with higher diastolic pressure.

    “A greater number of lobes was associated with higher systolic pressure and pulse pressure, but not with higher diastolic pressure, in girls.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [24] source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Central to oxygen sensing in any cell is the family of hypoxia-inducible basic Helix-Loop-Helix transcription factors, the HIFs, of which there are three members, HIF-1-3.

    “Central to oxygen sensing in any cell is the family of hypoxia-inducible basic Helix-Loop-Helix transcription factors, the HIFs, of which there are three members, HIF-1-3 (297).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [297] source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    Both large and small placentas can limit the flow of nutrients, and poor placentation occurs more often in women who are short in stature.

    “These data indicate that both large and small placentas can limit the flow of nutrients, and that poor placentation occurs more often in women who are short in stature.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Knockout of HIFs in mice results in failure of allantoic attachment with the chorion, impaired vascularization in the labyrinth, and abnormal differentiation of the trophoblast subpopulations.

    “Knockout in mice results in failure of allantoic attachment with the chorion, impaired vascularization in the labyrinth, and abnormal differentiation of the trophoblast subpopulations (161).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [161] source

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  • May combine two claims.

    Premisecitation

    Lung cancer cases were characterized by having a short mother and a high ponderal index at birth, and the delivered placenta had either a small or a large surface area in three separate phenotypes.

    “The cases were characterized by having a short mother and a high ponderal index (weight/length 3 ) at birth, and the delivered placenta had either a small or a large surface area in three separate phenotypes (38).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [38] source

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  • May combine two claims.

    Interpretationcitation

    The HIF signaling machinery is competent in the human early placenta and can respond to acute changes in oxygenation.

    “There is no doubt, however, that the HIF signaling machinery is competent in the human early placenta and can respond to acute changes in oxygenation.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    HIF-1 provides a very rapid mechanism for responding within seconds or minutes to acute changes in oxygenation, whereas HIF-2 is thought to mediate longer-term adaptations to relatively modest changes.

    “HIF-1 thus provides a very rapid mechanism for responding within seconds or minutes to acute changes in oxygenation, whereas HIF-2 is thought to mediate longer-term adaptations to relatively modest changes (444).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [444] source

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  • May combine two claims.

    Premisereasoning

    The actual oxygen sensors are the prolyl-4-hydroxylase enzymes, which require molecular oxygen and hydroxylate conserved proline residues on the HIF alpha subunit.

    “The actual oxygen sensors are the prolyl-4-hydroxylase (PHDs) enzymes that have an absolute requirement for molecular oxygen and hydroxylate conserved proline residues on the alpha subunit.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Hydroxylation enables binding of the von Hippel-Lindau protein, which targets the HIF alpha subunit for ubiquitination and subsequent degradation.

    “This enables binding of the von Hippel-Lindau protein (pVHL), which targets the subunit for ubiquitination and subsequent degradation (493).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [493] source

      Not checked in the free run.

  • May combine two claims.

    Premisereasoning

    HIF alpha subunits are oxygen dependent; under well-oxygenated conditions they turn over rapidly and do not accumulate, whereas under hypoxia they are stabilized and combine with beta subunits to form an effective transcription factor.

    “All members consist of an alpha and beta subunit, and it is the former that is oxygen dependent.In well-oxygenated conditions this sub-unit turns over rapidly and does not accumulate, whereas under hypoxia it is stabilized and the two subunits are able to combine to form an effective transcription factor.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisereasoning

    HIF binds to hypoxia response elements on a wide range of genes, including VEGF, glucose transporters and glycolytic enzymes, and can inhibit mTOR signaling and regulate protein synthesis.

    “This binds to hypoxia response elements on a wide range of genes, the most important of which in the current context include those encoding VEGF, glucose transporters and glycolytic enzymes.It can also inhibit mTOR signaling, and hence regulate protein synthesis.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    The placenta accounts for about 40% of the oxygen consumption of the fetal-placental unit, of which about 33% is utilized in active transport and about 33% in protein synthesis.

    “Thus, it has been estimated that the placenta accounts for ~40% of the oxygen consumption of the fetal-placental unit, and of that ~33% is utilized in active transport and ~33% in protein synthesis (97).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [97] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Colorectal cancer was unrelated to other placental measurements or to body size at birth.

    “Colorectal cancer was unrelated to other placental measurements or to body size at birth.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [36] source

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  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Ontogenetic studies have reported contrasting results, with peaks of HIF-1α at 7-10 weeks and then again at 14-18 weeks, or a steady decline in HIF-1α from 5-8 weeks to 18-21 weeks and a rapid decline of HIF-2α between 5-8 weeks and 9-11 weeks.

    “Ontogenetic studies have reported contrasting results, with peaks of HIF-1α at 7-10 weeks and then again at 14-18 weeks (269), or a steady decline in HIF-1α from 5-8 weeks to 18-21 weeks and a rapid decline of HIF-2α between 5-8 weeks and 9-11 weeks (447).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [269] source

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    • cites [447] source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    First trimester placental tissues are not energetically compromised, most likely due to the high activity of glycolytic metabolism.

    “The tissues are therefore not energetically compromised, most likely due the high activity of glycolytic metabolism (284).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [284] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    HIF-1 and HIF-2 can be stabilized in chorionic villus sampling samples by stress and activate downstream targets, including VEGF.

    “Equally, HIF-1 and HIF-2 can be stabilized in CVS samples by stress and activate downstream targets, including VEGF (112).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [112] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The half-life of the mRNA encoding VEGF is more than doubled under hypoxic conditions, favoring angiogenesis.

    “By contrast, the half-life of the mRNA encoding VEGF is more than doubled under hypoxic conditions (334), again favoring angiogenesis.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [334] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    More severe UPR activation is seen in human placentas from growth-restricted pregnancies, particularly early-onset pre-eclampsia.

    “More severe activation is seen in human placentas from growth-restricted pregnancies (596), and particularly in cases of early-onset pre-eclampsia (595).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [596] source

      Not checked in the free run.

    • cites [595] Yung HW, 2014, J Pathol source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    PERK upregulates ATF4, which along with ATF6 and IRE1 pathways selectively regulates gene expression to assist the cell to tolerate hypoxia.

    “It also upregulates the transcription factor ATF4, which along with the ATF6 and IRE1 pathways selectively regulates gene expression to assist the cell to tolerate hypoxia (180, 343, 585).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [180] source

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    • cites [343] source

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    • cites [585] source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    GCN2 is activated by the presence of uncharged tRNAs.

    “One of these is GCN2, which is activated by the presence of uncharged tRNAs (153).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [153] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Leakage of electrons from complexes I and III of the electron transport chain generates the superoxide ion, which is converted to hydrogen peroxide; hydrogen peroxide can diffuse out of the organelle and stabilize HIFs.

    “Leakage of electrons from the complexes of the electron transport chain, in particular complexes I and III, generates the superoxide ion, which is then converted to hydrogen peroxide.Being non-polar hydrogen peroxide diffuses out of the organelle and can stabilize HIFs (48).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [48] source

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    A number of other transcription factors and co-activators respond to changes in the redox potential of a cell rather than to oxygen directly, including AP-1, CREB, Mash2, NFκB, p53, PCC-1α, SP-1 and STAT3.

    “A number of other transcription factors and co-activators have been identified that respond to changes in the redox potential of a cell rather than to oxygen directly.These include AP-1, CREB, Mash2, NFκB, p53, PCC-1α, SP-1 and STAT3 (16, 106, 155, 277).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [16] source

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    • cites [106] source

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    • cites [155] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Folding capacity may be compromised if oxygen or ATP concentrations are limiting, but this is likely a secondary mechanism.

    “Folding capacity may therefore be compromised if oxygen or ATP concentrations are limiting, but this is likely to be a secondary mechanism (315).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [315] source

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  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Under hypoxia, accumulation of ROS leads to opening of the mitochondrial permeability transition pore and efflux of Ca2+ from the mitochondrial endoplasmic reticulum complex.

    “In the former, it is proposed that under hypoxia the accumulation of ROS leads to opening of the mitochondrial permeability transition pore and the efflux of Ca 2+ from the mitochondrial endoplasmic reticulum complex.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [324] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    UPR activation can be replicated in trophoblast cell lines by hypoxia-reoxygenation, with activation of the three pathways dependent on the severity of the stress.

    “These findings can be replicated in trophoblast cell lines by exposure to hypoxiareoxygenation, with activation of the three pathways being dependent on the severity of the stress (596).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [596] source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Nuclei within the syncytiotrophoblast exhibit contrasting patterns of chromatin and different epigenetic states.

    “The significance for the placenta is still unknown, although it is well recognized that nuclei within the syncytiotrophoblast exhibit contrasting patterns of chromatin and different epigenetic states (187).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [187] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Another study of placentas from the same high-altitude region found enhanced vascularization, consistent with a hypoxic response, but HIF-DNA binding was less than in low-altitude controls.

    “Another study of placentas from the same region found enhanced vascularization, consistent with a hypoxic response, but paradoxically HIF-DNA binding was less than in the lowaltitude controls (533).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [533] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The IRE1 pathway is essential for normal placental development in mice; knockout leads to downregulation of VEGF and abnormal angiogenesis within the labyrinth.

    “Manipulations in mice have confirmed that the IRE1 pathway is essential for normal placental development, for knockout leads to downregulation of VEGF and abnormal angiogenesis within the labyrinth (273).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [273] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Complex I and III are downregulated at the protein level in the placenta at high altitude, which may be interpreted as an adaptation to reduce production of ROS and so limit HIF signaling.

    “It is notable that complex I and III are downregulated at the protein level in the placenta at high altitude, which may be interpreted as an adaptation to reduce production of ROS and so limit HIF signaling (121).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [121] source

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationcitation

    An excessive hypoxic response may account for the increased incidence of chorangiomas in placentas from altitudes greater than 4,000 m.

    “An excessive hypoxic response may account for the increased incidence of chorangiomas in placentas from altitudes greater than 4,000 m (459, 510), but no data are available as to whether this is HIF-mediated..”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [459] source

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    • cites [510] source

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  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    The UPR has been implicated in regulating the inflammatory response and stemness within the intestinal epithelium.

    “the UPR has been implicated in regulating processes as diverse as the inflammatory response (609) and stemness within the intestinal epithelium (251).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [609] source

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    • cites [251] source

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Micro-RNAs identified as being differentially expressed under hypoxia include miR-93, miR-205, miR-224, MiR-335, MiR-424, miR-451, miR-491 and mIR-34a.

    “Many of these Other micro-RNAs identified as being differentially expressed under hypoxia include miR-93, miR-205, miR-224, MiR-335, MiR-424, miR-451 and miR-491 (396, 397), and mIR-34a (154), but little is known regarding their functional significance at present.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [396] source

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    • cites [397] source

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    • cites [154] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Aberrant HIF signaling has been implicated in the pathophysiology of pre-eclampsia, in particular the early-onset form when the PHDs do not appear to sense oxygen, and may be responsible for abnormal placental secretion of angiogenic regulatory factors.

    “Aberrant HIF signaling has been implicated in the pathophysiology of pre-eclampsia, in particular of the early-onset form when the PHDs do not appear to sense oxygen (90, 448, 467), and may be responsible for the abnormal placental secretion of angiogenic regulatory factors that is thought to precipitate the clinical syndrome (413).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [90] source

      Not checked in the free run.

    • cites [448] source

      Not checked in the free run.

    • cites [467] source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Nuclei that display particularly condensed chromatin aggregate in syncytial knots and are transcriptionally inactive.

    “Nuclei that display particularly condensed chromatin aggregate in syncytial knots and are transcriptionally inactive (188).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [188] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    UPR adaptations include increased amino acid transporter activity and enzyme expression to boost glutathione, stimulation of hematopoiesis, and upregulation of VEGF.

    “These adaptations include increased amino acid transporter activity and enzyme expression to boost the concentration of glutathione, the principal intracellular antioxidant, stimulation of hematopoiesis, and upregulation of the angiogenic growth factor VEGF.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [180] source

      Not checked in the free run.

    • cites [343] source

      Not checked in the free run.

    • cites [585] source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The heavily condensed nuclei within syncytial knots stain particularly strongly for 5-hydroxymethylcytosine.

    “The heavily condensed nuclei within syncytial knots stain particularly strongly for 5hydroxymethylcytosine (187).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [187] source

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  • May combine two claims.

    Premisecitation

    The mRNA encoding Angiopoietin-1 becomes less stable under low oxygen conditions, shifting the balance of angiopoietin-1:angiopoietin-2 in favor of angiopoietin-2 and vessel growth.

    “A notable example is the mRNA encoding Angiopoietin-1, which becomes less stable under low oxygen conditions, shifting the balance of angiopoietin-1:angiopoietin-2 in favor of angiopoietin-2 and vessel growth (608).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [608] source

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  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

    Interpretationreasoning

    Such fluctuations may arise from either variations in maternal diet or compromise of utero-placental blood flow secondary to deficient trophoblast invasion.

    “Such fluctuations may arise from either variations in maternal diet or compromise of utero-placental blood flow secondary to deficient trophoblast invasion.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    A reduction of AKT and mTOR at the protein level, and reduced phosphorylation of mTOR, TSC1/2, 4E-BP1 and GSK-3β, have been reported in growth restricted human placentas associated with maternal vascular compromise, but there was no effect on S6Ks and eEF2K.

    “Equally, a reduction of AKT and mTOR at the protein level, and reduced phosphorylation of mTOR, TSC1/2, 4E-BP1 and GSK-3β have been reported in growth restricted human placentas associated with maternal vascular compromise, but there was no effect on S6Ks and eEF2K (596).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [596] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Reduced p-S6K1, but no change in p-4E-BP1, was observed in placentas with growth restriction of unknown origin.

    “Reduced p-S6K1, but no change in p-4E-BP1, was observed in placentas with growth restriction of unknown origin (468).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [468] source

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    AMPK acts as a key metabolic sensor to match energy demand with supply.

    “Hence, it acts as a key metabolic sensor to match energy demand with supply (240).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [240] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Data from over-nutrition models are conflicting: an obesogenic diet causes activation of mTOR in rat placentas, but the opposite was found following over-nutrition in sheep and mice fed an obesogenic diet.

    “Thus, whilst an obesogenic diet has been shown to cause activation of mTOR in rat placentas (205), the opposite was found following over-nutrition in sheep (150% of control diet) and mice fed an obesogenic diet (323, 615).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [205] source

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    • cites [323] source

      Not checked in the free run.

    • cites [615] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Hydrogen sulfide can scavenge ROS and act as a defense against ischemia-reperfusion injury, affect redox balance, and inhibit enzymes including NADPH oxidase and nitric oxide synthase.

    “In addition, it can scavenge ROS and so act as a defense against ischemia-reperfusion injury (310), affect the redox balance, and also inhibit a number of related enzymes, including NADPH oxidase and nitric oxide synthase.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [310] source

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  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    TRP channels responsive to ROS have been identified in a number of cell types and provide another route of entry for calcium.

    “In addition, transient receptor potential (TRP) channels that are responsive to ROS have been identified in a number of cell types, and provide another route of entry for calcium (589).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [589] source

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  • May combine two claims.

    Premisecitation

    Disruption of just Akt1 causes placental and fetal growth restriction in the mouse, with a particularly severe effect on the development of the glycogen cells.

    “Disruption of just Akt1 causes placental and fetal growth restriction in the mouse, with a particularly severe effect on the development of the glycogen cells (592).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [592] source

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  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationnone given

    These networks combine with the UPR to regulate protein synthesis over short and long term periods to promote cell survival.

    “These networks combine with the UPR to regulate protein synthesis over the short and long term periods to promote cell survival.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Activity of system A, but not system L, transporters in the apical membrane of the syncytiotrophoblast correlates positively with birth weight, and may contribute to fetal overgrowth in cases of maternal obesity.

    “Thus, activity of system A, but not system L, transporters in the apical membrane of the syncytiotrophoblast correlates positively with birth weight, and may contribute to fetal overgrowth in cases of maternal obesity (279).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [279] source

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  • May combine two claims.

    Premisecitation

    TSC1/2 plays a major role in integrating insulin and growth factor signaling through the PI3K and AKT pathway, although recent data suggest growth factors may also stimulate mTORC1 by enhancing delivery of amino acid-laden macropinosomes to the Ragulator complex.

    “This complex plays a major role in integrating insulin and growth factor signaling through the PI3K and AKT pathway (Figure 10), although recent data suggest growth factors may also stimulate mTORC1 by enhancing the delivery of amino acid-laden macropinosomes to the Ragulator complex (593).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [593] source

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    REDD involves phosphorylation of HIF-1α.

    “The latter involves phosphorylation of HIF-1α (88), illustrating again the overlap between these pathways.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [88] source

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  • May combine two claims.

    Premisecitation

    Ca2+-activated K+ channels have recently been demonstrated to be important for trophoblast syncytialization and for syncytial volume homeostasis.

    “In addition, Ca 2+ -activated K + channels have recently been demonstrated to be important for trophoblast syncytialization and for syncytial volume homeostasis (145).”
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    • cites [145] source

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  • May combine two claims.

    Premisecitation

    Nutrient restriction leads to reduced mTOR activity, along with reduced insulin and AKT signaling, in rats fed a low protein diet and mice fed 80% of the control ad libitum diet.

    “Evidence from downstream signaling indicates that nutrient restriction leads to reduced mTOR activity, along with reduced insulin and AKT signaling, in rats fed a low protein diet (470), and mice fed 80% of the control ad libitum diet (495), as might be expected.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [470] source

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    • cites [495] source

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  • May combine two claims.

    Premisecitation

    Hydrogen sulfide is metabolized principally in the mitochondria by oxidation to thiosulfate, but if oxygen availability is limited then its concentration in the cytosol increases.

    “Hydrogen sulfide is metabolized principally in the mitochondria by oxidation to thiosulfate, but if oxygen availability is limited then the concentration in the cytosol will increase (423).”
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    • cites [423] source

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  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    AMPK comprises three sub-units, each of which have multiple isoforms and confer tissue specificity.

    “It comprises three sub-units, each of which have multiple isoforms and confer tissue specificity (549).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [549] source

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  • May combine two claims.

    Premisecitation

    mTOR/AKT signaling is essential for maintenance of embryonic and hematopoietic stem cells.

    “mTOR/AKT signaling is essential for maintenance of embryonic and hematopoietic stem cells (419), and the same is likely to be true for trophoblast.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [419] source

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  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    TSC1/2 acts on mTORC2, which in turn regulates the activity and substrate specificity of AKT through phosphorylation.

    “TSC1/2 also acts on mTORC2, which in turn regulates the activity and substrate specificity of AKT through phosphorylation (597).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [597] source

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  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    AMPK has a direct inhibitory action on raptor, the adaptor protein for mTORC1, and can also stimulate TSC1/2.

    “AMPK has a direct inhibitory action on raptor, the adaptor protein for mTORC1, and can also stimulate the tuberous sclerosis complex TSC1/2 (164).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [164] source

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  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Interpretationreasoning

    This could account for the different growth rates displayed by male and female placentas, and the variations in their adaptations observed in response to stress.

    “This could account for the different growth rates displayed by male and female placentas, and the variations in their adaptations observed in response to stress.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    GSK-3β is a major regulator of protein synthesis through its actions on eIF2B.

    “It is also a major regulator of protein synthesis through its actions on eIF2B (568).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [568] source

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  • May combine two claims.

    Premisecitation

    mTOR expression is inversely correlated with levels of maternal exercise and total sugar content in her diet.

    “mTOR expression is also inversely correlated with levels of maternal exercise, and total sugar content in her diet (60).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [60] source

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  • May combine two claims.

    Premisecitation

    While the mother also benefits from resource investment, a balance must be struck as maternal investment in the current fetus leaves less reserves for future pregnancies.

    “While the mother also benefits from this resource investment as her genes too are transmitted to the next generation, a balance must be struck as maternal investment in the current fetus leaves less reserves for future pregnancies (193).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [193] source

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  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    AMPK may also regulate more physiological functions as it has been implicated in stimulating endothelial nitric oxide production and regulating vascular smooth muscle tone.

    “It may also regulate more physiological functions as it has been implicated in stimulating endothelial nitric oxide production and regulating vascular smooth muscle tone (219).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [219] source

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  • May combine two claims.

    Premisecitation

    These changes can be recapitulated by exposing trophoblast cell lines to hypoxia (1% O2), when they are associated with reduced cell proliferation.

    “These changes can be recapitulated by exposing trophoblast cell lines to hypoxia (1% O2), when they are associated with reduced cell proliferation.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [598] source

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  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Selected mRNAs must be able to bypass translational arrest, and it has been suggested that those containing small upstream open reading frames (uORFs) within their 5'-UTR regions or internal ribosome entry site (IRES) sequences are able to do so.

    “Selected mRNAs must therefore be able to bypass this translational arrest, and it has been suggested that those containing small upstream open reading frames (uORFs) within their 5'-UTR regions or internal ribosome entry site (IRES) sequences are able to do so (278, 349).”
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    • cites [278] source

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    • cites [349] source

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationreasoning

    The secretory output of the trophoblast might change both quantitatively and qualitatively under conditions of stress.

    “It is to expected, therefore, that the secretory output of the trophoblast might change both quantitatively and qualitatively under conditions of stress.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    These high-altitude placentas displayed increased phosphorylation of eIF2α, reduced phosphorylation of AKT and 4E-BP1, and an increase in total 4E-BP1 that will favor sequestration of eIF4E.

    “These placentas displayed increased phosphorylation of eIF2α, reduced phosphorylation of AKT and 4E-BP1, and an increase in total 4E-BP1 that will favor sequestration of eIF4E.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [598] source

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  • May combine two claims.

    Premisecitation

    There is both co-operation and conflict between the mother and her fetus, and between siblings in litter-bearing species, in resource allocation at the placental interface.

    “There is, therefore, both co-operation and conflict between the mother and her fetus, and between siblings in litter-bearing species, in resource allocation at the placental interface (193).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [193] source

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  • May combine two claims.

    Premisecitation

    Marked increased phosphorylation of eIF2α and decreased phosphorylation of 4E-BP1 were observed, and all three isoforms of AKT were reduced at the protein, but not mRNA, level.

    “Marked increased phosphorylation of eIF2α and decreased phosphorylation of 4E-BP1 were observed, and more significantly, all three isoforms of AKT were reduced at the protein, but not at the mRNA, level.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [596] source

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  • May combine two claims.

    Premisecitation

    Protein synthesis is essential for normal development, and blocking dephosphorylation of eIF2α in mice results in severe growth restriction and early embryonic lethality.

    “Protein synthesis is essential for normal development, and blocking dephosphorylation of eIF2α in mice results in severe growth restriction and early embryonic lethality (241).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [241] source

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  • May combine two claims.

    Premisecitation

    This leads to differential selection pressures on maternally and paternally inherited alleles in the conceptus with respect to resource allocation and is manifested as genomic imprinting, a mechanism for monoallelically regulating gene dosage in a parent-of-origin fashion.

    “This leads to differential selection pressures on maternally and paternally inherited alleles in the conceptus with respect to resource allocation and is manifested as genomic imprinting, a mechanism for monoallelically regulating gene dosage in a parent-of-origin fashion (305, 391).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [305] source

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    • cites [391] source

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    HIF-2α is able to combine with RBM4 at hypoxia response elements within the 3'UTR of a selective sub-set of mRNAs to initiate translation under hypoxic conditions.

    “More recently, it has been proposed that HIF-2α is able to combine with RBM4 at hypoxia response elements within the 3'UTR of a selective sub-set of mRNAs to initiate translation under hypoxic conditions (539).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [539] source

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  • May combine two claims.

    Premisecitation

    The importance of the balance to the successful outcome of pregnancy depends on the total uterine mass relative to maternal body size both within and between species, and on the particular mix of nutrients required by the fetus(es) relative to the metabolic ability of the mother to supply these nutrients in the correct proportions and absolute amounts.

    “The importance of this balance to the successful outcome of pregnancy also depends on the total uterine mass relative to maternal body size both within and between species, and on the particular mix of nutrients required by the fetus(es) relative to the metabolic ability of the mother to supply these nutrients in the correct proportions and absolute amounts (193).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [193] source

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  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Classically, AMPK acts to promote glucose uptake and mitochondrial biogenesis, while reducing energy demands by inhibiting mTORC1.

    “Classically, it acts to promote glucose uptake and mitochondrial biogenesis, while reducing energy demands by inhibiting mTORC1 (239).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [239] source

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  • May combine two claims.

    Premisecitation

    Inter- and intra-species crosses between breeds of several species have shown that the mother can constrain the fetal genetic drive for growth while the fetal genome can influence the mother to provide more resources with consequences for fetal growth and pregnancy outcome.

    “Inter-and intra-species crosses between breeds of several species have shown that the mother can constrain the fetal genetic drive for growth while, conversely, the fetal genome can influence the mother to provide more resources with consequences for fetal growth and pregnancy outcome (8,457,551).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [8] source

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    • cites [457] source

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    • cites [551] source

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  • May combine two claims.

    Interpretationcitation

    Sheep evolved at higher altitudes than human populations and may be better adapted to pregnancy in hypoxic conditions.

    “Sheep evolved at higher altitudes than human populations and, hence, may be better adapted to pregnancy in hypoxic conditions (600).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [600] source

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  • May combine two claims.

    Premisecitation

    In pregnant sheep at high altitude, the luminal cross sectional area, but not the number, of maternal vessels in the placentomes is increased, which results in a greater percentage area of maternal blood vessels and normal fetal growth.

    “In pregnant sheep at high altitude, the luminal cross sectional area, but not the number, of maternal vessels in the placentomes is increased, which results in a greater percentage area of maternal blood vessels and normal fetal growth (317, 437).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [317] source

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    • cites [437] source

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  • May combine two claims.

    Premisecitation

    In some studies of Andeans, absolute oxygen delivery to the gravid uterus at high altitude is maintained or even increased above lowland values despite low maternal pO2, while in others the uterine oxygen supply is less at high than low altitude irrespective of ancestry.

    “Thus, in some studies of Andeans, absolute oxygen delivery to the gravid uterus at high altitude is maintained or even increased above lowland values, despite the low maternal pO2, while in others the uterine oxygen supply is less at high than low altitude irrespective of ancestry (69, 295, 443, 604).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [69] source

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    • cites [295] source

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    • cites [443] source

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  • May combine two claims.

    Premisecitation

    On average, there is a 100g decrease in birth weight per 1000m elevation in altitude, although the exact figure varies with the ethnicity of the population.

    “On average, there is a 100g decrease in birth weight per 1000m elevation in altitude, although the exact figure varies with the ethnicity of the population (387).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [387] source

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  • May combine two claims.

    Premisecitation

    In some studies, the protective effect of Andean ancestry on uterine artery haemodynamics is only seen at high altitude while in others, the ethnic differences are also evident at sea level.

    “In some studies, the protective effect of Andean ancestry on uterine artery haemodynamics is only seen at high altitude while in others, the ethnic differences are also evident at sea level (295, 604).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [295] source

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    • cites [604] source

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  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Hypoxia is one of the most common complications of human pregnancy, occurring in 9-10% of pregnancies at sea level and all pregnancies at high altitude.

    “Hypoxia is one of the most common complications of human pregnancy, occurring in 9-10% of pregnancies at sea level and all pregnancies at high altitude (484, 600).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [484] source

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    • cites [600] source

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  • May combine two claims.

    Premisecitation

    Pregnant Tibetan women have higher uterine artery diameters and blood velocity than Han women at high altitude, while Andean women have twice the increment in uterine artery diameter during pregnancy than European women at high altitude.

    “Pregnant Tibetan women have higher uterine artery diameters and blood velocity than Han women at high altitude (107, 389), while Andean women have twice the increment in uterine artery diameter during pregnancy than European women at high altitude (295, 577, 604).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [107] Chen D, 2002, Zhonghua fu chan ke za zhi

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    • cites [389] source

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    • cites [295] source

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  • May combine two claims.

    Premisecitation

    Hypoxia affects both the placenta and fetus and is associated with impaired trophoblast invasion, poor villous development, altered vascularity, reduced spiral artery remodelling and low blood flow on both sides of the placenta.

    “It affects both the placenta and fetus and is associated with impaired trophoblast invasion, poor villous development, altered vascularity, reduced spiral artery remodelling and low blood flow on both sides of the placenta (387, 543, 600).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [387] source

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    • cites [543] source

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    • cites [600] source

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  • May combine two claims.

    Interpretationcitation

    Male placentas showed more resistance to oxidative stress, and fetal growth restriction was significantly less than in female littermates, suggesting the placentas had been able to compensate.

    “Male placentas also showed more resistance to oxidative stress, and fetal growth restriction was notably significantly less than in their female littermates, suggesting the placentas had been able to compensate.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [363] source

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  • May combine two claims.

    Interpretationreasoning

    This suggests that remodelling of the uterine arteries during human pregnancy is impaired at high altitude, in line with the greater incidence of preeclampsia in these populations.

    “This suggests that remodelling of the uterine arteries during human pregnancy is impaired at high altitude (532), in line with the greater incidence of preeclampsia in these populations (429).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [532] source

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    • cites [429] source

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  • May combine two claims.

    Premisecitation

    In human infants near term, the diameters of the umbilical vein and artery are both smaller at high than low altitude, which results in a lower absolute blood flow in the umbilical circulation, irrespective of ethnicity.

    “In human infants near term, the diameters of the umbilical vein and artery are both smaller at high than low altitude, which results in a lower absolute blood flow in the umbilical circulation, irrespective of ethnicity (295, 443).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [295] source

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    • cites [443] source

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  • May combine two claims.

    Interpretationcitation

    Since the percentage decrease in fetal glucose delivery appears to be greater than the percentage reduction in net fetal glucose consumption measured as umbilical glucose uptake at high altitude, there may also be activation of gluconeogenesis from lactate and amino acids by the high-altitude fetus near term.

    “Since the percentage decrease in fetal glucose delivery appears to be greater than the percentage reduction in net fetal glucose consumption measured as umbilical glucose uptake at high altitude (605), there may also be activation of gluconeogenesis from lactate and amino acids by the high-altitude fetus near term.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [605] source

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  • May combine two claims.

    Premisecitation

    Similar increases in fetal vascularity are seen in ovine placentomes at high altitude, but, in contrast to the findings in the human placenta, these are accompanied by an increase in the total surface area of fetal-maternal contact for gas exchange.

    “Similar increases in fetal vascularity are seen in ovine placentomes at high altitude, but, in contrast to the findings in the human placenta, these are accompanied by an increase in the total surface area of fetal-maternal contact for gas exchange (317, 431).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [317] source

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    • cites [431] Parraguez VH, 2010, Can J Vet Res

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  • May combine two claims.

    Premisecitation

    The placental content of glucose and lactate tend to be lower and higher, respectively, at high relative to low altitude.

    “The placental content of glucose and lactate also tend to be lower and higher, respectively, at high relative to low altitude (534).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [534] source

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  • May combine two claims.

    Premisecitation

    In the mouse placenta, vascularity has been shown to be increased in late gestation by 48h of hypoxia, but decreased by longer exposures.

    “In the mouse placenta, vascularity has been shown to be increased in late gestation by 48h of hypoxia, but decreased by longer exposures (133, 212) (Table 3).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [133] source

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    • cites [212] source

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  • May combine two claims.

    Premisecitation

    At high altitude, there is increased branching and reduced coiling of the fetal capillaries in the placenta with more densely packed capillary loops in the terminal villi responsible for gas exchange.

    “At high altitude, there is increased branching and reduced coiling of the fetal capillaries in the placenta with more densely packed capillary loops in the terminal villi responsible for gas exchange (7,532).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [7] source

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    • cites [532] source

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  • May combine two claims.

    Premisecitation

    Per kg of fetus, placental oxygen delivery to the human fetus and its rate of oxygen consumption near term are normal at high altitude, although the fetuses are smaller.

    “Indeed, per kg of fetus, placental oxygen delivery to the human fetus and its rate of oxygen consumption near term are normal at high altitude, although the fetuses are smaller (443, 605).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [443] source

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    • cites [605] source

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  • May combine two claims.

    Interpretationcitation

    Collectively, these observations suggest that the chronically hypoxic placenta at high altitude may switch from oxidative phosphorylation to a greater dependence on anaerobic glycolysis to meet its ATP requirements, which may increase fetal oxygen availability albeit at the expense of the fetal glucose supply.

    “Collectively, these observations suggest that the chronically hypoxic placenta at high altitude may switch from oxidative phosphorylation to a greater dependence on anaerobic glycolysis to meet its ATP requirements, which may increase fetal oxygen availability albeit at the expense of the fetal glucose supply (271, 403).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [271] source

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    • cites [403] source

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  • May combine two claims.

    Interpretationcitation

    Fetal oxygen consumption must therefore be maintained by oxidation of substrates other than glucose, such as amino acids and/or fats, which will then reduce their availability for other purposes.

    “Fetal oxygen consumption must, therefore, be maintained by oxidation of substrates other than glucose, such as amino acids and/or fats, which will then reduce their availability for other purposes (403).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [403] source

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  • May combine two claims.

    Premisecitation

    This is achieved through selective dilation of the capillary sinusoids at the vasculosyncytial membranes, a mechanism that increases placental diffusing capacity but has minimal effects on extracorporeal blood volume and the load on the fetal heart.

    “This is achieved through selective dilation of the capillary sinusoids at the vasculosyncytial membranes (78), a mechanism that increases placental diffusing capacity but has minimal effects on extracorporeal blood volume and the load on the fetal heart.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [78] source

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  • May combine two claims.

    Interpretationcitation

    Overall amongst species, the morphological adaptations of the placenta will increase its oxygen diffusion capacity and aid oxygen delivery to the fetus at low maternal pO2.

    “Overall amongst species, the morphological adaptations of the placenta will increase its oxygen diffusion capacity and aid oxygen delivery to the fetus at low maternal pO2 (370, 387, 431).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [370] source

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    • cites [387] source

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    • cites [431] Parraguez VH, 2010, Can J Vet Res

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  • May combine two claims.

    Premisecitation

    There is an increase in the fetal arterial concentration of lactate in these fetuses, but little is known about their rate of lactate consumption or about the rates of placental production and delivery of lactate at high altitude.

    “There is an increase in the fetal arterial concentration of lactate in these fetuses, but little is known about their rate of lactate consumption or about the rates of placental production and delivery of lactate at high altitude (534, 605).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [534] source

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    • cites [605] source

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  • May combine two claims.

    Interpretationcitation

    The proposed metabolic switch in the high altitude placenta will have consequences for fetal metabolism because, although fetal oxygen consumption is maintained on a weight specific basis, the fetus has lower than normal glucose concentrations and uses less glucose per kg body weight measured as umbilical glucose uptake.

    “The proposed metabolic switch in the high altitude placenta will have consequences for fetal metabolism because, although fetal oxygen consumption is maintained on a weight specific basis, the fetus has lower than normal glucose concentrations and uses less glucose per kg body weight measured as umbilical glucose uptake (605).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [605] source

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  • May combine two claims.

    Premisecitation

    Altered placental endocrine function is seen in response to both chronic and acute hypoxia and reflects changes in gene expression, protein synthesis, and in metabolism and secretion of hormones.

    “Altered placental endocrine function is seen in response to both chronic and acute hypoxia and reflects changes in gene expression, protein synthesis, and in metabolism and secretion of hormones (Table 4).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Table 4

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  • May combine two claims.

    Premisecitation

    In human placentas in vitro, exposure to acute episodes of hypoxia reduces expression and/or activity of accumulative System A amino acid transporters but increases activity of System L amino acid transport.

    “In human placentas in vitro, exposure to acute episodes of hypoxia reduces expression and/or activity of accumulative System A amino acid transporters but increases activity of System L amino acid transport (313, 412, 547).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [313] source

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    • cites [412] source

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    • cites [547] Versen-Hoynck FMV, 2008, Geburtshilfe Frauenheilkd

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  • May combine two claims.

    Premisecitation

    The placenta tolerates hypoxemia well but adapts its metabolism and transport characteristics to cope with reduced oxygen availability.

    “Collectively, the studies show that the placenta tolerates hypoxemia well, but adapts its metabolism and transport characteristics to cope with the reduced oxygen availability (485).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [485] source

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  • May combine two claims.

    Premisenone given

    In fetal sheep exposed to 4 h or more of acute hypoxia, normal rates of glucose and oxygen consumption are maintained, coupled with fetal glucogenesis and altered amino acid turnover.

    “In the high-altitude human fetus there is reduced glucose consumption but normal oxygen consumption, while in fetal sheep exposed to 4 h or more of acute hypoxia, normal rates of glucose and oxygen consumption are maintained coupled with fetal glucogenesis and altered amino acid turnover.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Initially, fetal oxygen consumption decreases in line with placental delivery but then recovers to normal values despite sustained low delivery by increasing oxygen extraction.

    “Initially, fetal oxygen consumption decreases in line with placental delivery but then recovers to normal values despite the sustained low delivery by increasing oxygen extraction (230, 263, 380).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [230] source

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    • cites [263] source

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    • cites [380] source

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  • May combine two claims.

    Premisecitation

    With shorter episodes of severe hypoxia (<48h) in pregnant sheep, there is evidence for activation of fetal glucogenesis and increased delivery of glucose and lactate to the placenta from the fetal circulation.

    “With shorter episodes of severe hypoxia (<48h) in pregnant sheep, there is evidence for activation of fetal glucogenesis and increased delivery of glucose and lactate to the placenta from the fetal circulation (230, 263, 292).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [230] source

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    • cites [263] source

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    • cites [292] Jones CT, 1983, J Dev Physiol

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  • May combine two claims.

    Premisenone given

    In the high-altitude human fetus, glucose consumption is reduced but oxygen consumption is normal.

    “In the high-altitude human fetus there is reduced glucose consumption but normal oxygen consumption, while in fetal sheep exposed to 4 h or more of acute hypoxia, normal rates of glucose and oxygen consumption are maintained coupled with fetal glucogenesis and altered amino acid turnover.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    In the human placenta, concentrations of several key essential amino acids were unaffected by altitude, with the exception of glutamine and the antioxidant taurine, which were higher in concentration at high altitude than sea level.

    “In the human placenta, concentrations of several key essential amino acids were unaffected by altitude, with the exception of glutamine and the antioxidant, taurine, which were higher in concentration at high altitude than sea level (534).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [534] source

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  • May combine two claims.

    Premisecitation

    In pregnant sheep, acute hypoxia for 4 h decreases the placental supply and fetal use of leucine in association with a general increase in amino-nitrogen availability in the fetal circulation and reduced rates of fetal protein synthesis and proteolysis.

    “In pregnant sheep, acute hypoxia for 4 h decreases the placental supply and fetal use of leucine in association with a general increase in amino-nitrogen availability in the fetal circulation and reduced rates of fetal protein synthesis and proteolysis (380).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [380] source

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  • May combine two claims.

    Premisenone given

    At low altitude in response to acute hypoxia and fetal hypoxemia, the sheep placenta maintains its rate of oxygen consumption but reduces its use of glucose, while increasing uptake of lactate from the fetal circulation.

    “At low altitude in response to acute hypoxia and fetal hypoxemia, the sheep placenta maintains its rate of oxygen consumption but reduces its use of glucose, while increasing uptake of lactate from the fetal circulation.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    In the high-altitude human placenta, GLUT1 is reduced at the basal but not the microvillous membranes, consistent with the decreased placental transfer of glucose to the fetus in conditions of chronic maternal hypoxia.

    “By contrast, in the high-altitude human placenta, GLUT1 is reduced at the basal but not the microvillous membranes, consistent with the decreased placental transfer of glucose to the fetus in conditions of chronic maternal hypoxia (601, 605).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [601] source

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    • cites [605] source

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  • May combine two claims.

    Premisecitation

    At high altitude with chronic maternal hypoxemia but mild fetal hypoxemia, the human placenta reduces oxygen consumption but increases glucose use.

    “At high altitude with chronic maternal hypoxemia but mild fetal hypoxemia, the human placenta reduces consumption of oxygen but increases use of glucose (271).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [271] source

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  • May combine two claims.

    Premisecitation

    In the mouse placenta, maternal hypoxia for 2-4 days in late pregnancy leads to reduced expression of an isoform of the y+ system of cationic amino acid transporters and increased expression of the Slc38a1 isoform of the System A amino acid transporters.

    “In the mouse placenta, maternal hypoxia for 2-4 days in late pregnancy leads to reduced expression of an isoform of the y+ system of cationic amino acid transporters and increased expression of the Slc38a1 isoform of the System A amino acid transporters (Table 3).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Table 3

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  • May combine two claims.

    Premisecitation

    In non-human primates, feeding a high fat diet increases placental infarction and reduces utero-placental blood flow, more pronounced in mothers that become obese than in those who remained lean on the diet.

    “In non-human primates, there are increases in placental infarction and reductions in utero-placental blood flow in response to feeding a high fat diet, which are more pronounced in mothers that become obese than in those who remained lean on the diet (200).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [200] source

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  • May combine two claims.

    Premisecitation

    Maternal nutrition is a major determinant of placental development and alters the morphological, transport and endocrine characteristics of the placenta with consequences for fetal nutrient supply in a wide range of species including laboratory and farm species as well as human and non-human primates.

    “In addition, maternal nutrition is a major determinant of placental development and alters the morphological, transport and endocrine characteristics of the placenta with consequences for the fetal nutrient supply in a wide range of species including laboratory and farm species as well as human and non-human primates (47, 144, 204, 522, 550).”
    Quote in the paperSubstantial claim0 of 5 sources checked
    • cites [47] source

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    • cites [144] source

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    • cites [204] source

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    • cites [522] source

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    • cites [550] source

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  • May combine two claims.

    Premisecitation

    Variations in the balance between protein and carbohydrate intake at different stages of human pregnancy are related to placental and infant size at birth, with reduced protein intake in late gestation associated with a smaller placenta.

    “Variations in the balance between protein and carbohydrate intake at different stages of human pregnancy are related to placental and infant size at birth, with reduced protein intake in late gestation associated with a smaller placenta (216).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [216] source

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  • May combine two claims.

    Premisecitation

    Women who gain weight between pregnancies are more likely to have a large placenta subsequently, whereas those with significant inter-pregnancy weight loss are more prone to placental growth restriction in their second pregnancy.

    “Women who gain weight between pregnancies are more likely to have a large placenta subsequently whereas those with significant inter-pregnancy weight loss are more prone to placental growth restriction in their second pregnancy (553).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [553] source

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  • May combine two claims.

    Premisecitation

    In mice, nutritional manipulations before and during pregnancy cause changes in the relative proportions of placental zones and reductions in surface area of the labyrinth and thickness of the interhemal membrane, irrespective of calorie intake or maternal adiposity.

    “There are also changes in the relative proportions of the placental zones and reductions in surface area of the labyrinth and thickness of the interhemal membrane in response to nutritional manipulations before, and during, mouse pregnancy, irrespective of the level of calorie intake or maternal adiposity (Table 5).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Table 5

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  • May combine two claims.

    Premisecitation

    In Dutch hunger winter populations, placental weight at term was increased when the famine occurred in the 1st trimester but was reduced, along with infant birth weight, in women who were in their 3rd trimester at the time of the famine.

    “In the Dutch hunger winter populations, placental weight at term was increased when the famine occurred in the 1 st trimester but was reduced, along with infant birth weight, in women who were in their 3 rd trimester at the time of the famine (350, 471).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [350] source

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    • cites [471] source

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  • May combine two claims.

    Premisecitation

    Similar increases in placental efficiency are seen in human populations fasting for Ramadan and in underweight women delivering small infants with a small placenta.

    “Similar increases in placental efficiency are seen in the human populations fasting for Ramadan and in underweight women delivering small infants with a small placenta (10,556).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [10] source

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    • cites [556] source

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  • May combine two claims.

    Interpretationreasoning

    Taken together, these observations suggest that the human placenta either has a significant reserve capacity or can adapt its nutrient transport capacity during nutritional compromise to support fetal growth.

    “Taken together, these observations suggest that the human placenta either has a significant reserve capacity or can adapt its nutrient transport capacity during nutritional compromise to support fetal growth.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    In obese women delivering larger infants, placental GLUT1 expression and System A activity are higher in the basal and microvillous membranes, respectively, than in women with a lean BMI.

    “By contrast, in obese women delivering larger infants, placental GLUT1 expression and System A activity are higher in the basal and microvillous membranes, respectively, than seen in women with a lean BMI (1,279).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [1] source

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    • cites [279] source

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  • May combine two claims.

    Premisecitation

    Feeding a diet high in fat and sugar reduces fetalplacental growth at day 16 of mouse pregnancy yet upregulates placental glucose and amino acid clearance with the result that fetal weight is restored to normal by D19, despite persisting placental growth restriction.

    “For instance, feeding a diet high in fat and sugar reduces fetalplacental growth at day 16 of mouse pregnancy yet upregulates placental glucose and amino acid clearance with the result that fetal weight is restored to normal by D19, despite persisting placental growth restriction (496).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [496] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In sheep, undernutrition during the early stages of pregnancy when the placenta is growing most rapidly leads to an increase in term placental weight, whereas nutrient restriction later in pregnancy once the placenta is fully formed leads to reduced placental weight at term.

    “In sheep, undernutrition during the early stages of pregnancy when the placenta is growing most rapidly leads to an increase in term placental weight, whereas nutrient restriction later in pregnancy once the placenta is fully formed leads to reduced placental weight at term (198).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [198] source

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  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

    Interpretationnone given

    The mechanisms that regulate the responses to under- or over-nutrition are unknown, but likely involve the mTOR pathway and/or the generation of ROS.

    “At present, the mechanisms that regulate the responses to under-or over-nutrition are unknown, but likely involve the mTOR pathway and/or the generation of ROS.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Reduced taurine and System A transport activity, and lower SNAT4 expression, are seen in placental villous fragments from obese women delivering infants of normal birth weight.

    “Reduced taurine and System A transport activity, and lower SNAT4 expression, are also seen in placental villous fragments from obese women delivering infants of normal birth weight (151, 184).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [151] source

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    • cites [184] source

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  • May combine two claims.

    Interpretationreasoning

    Taken together, these observations suggest that nutritional state and obesity, in particular, alter the energetics and nutrient transport capacity of the human placenta, which will have consequences for fetal development.

    “Taken together, these observations suggest that nutritional state and obesity, in particular, alter the energetics and nutrient transport capacity of the human placenta, which will have consequences for fetal development.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    These changes in weight are accompanied by alterations in the gross morphology of the ovine placentomes and in their vascularity.

    “These changes in weight are accompanied by alterations in the gross morphology of the ovine placentomes and in their vascularity (454, 463).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [454] source

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    • cites [463] source

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  • May combine two claims.

    Premisecitation

    In overnourished obese adolescent ewes, there is no evidence for a change in the placental glucose transfer capacity, despite feto-placental growth restriction, as placental glucose consumption and transfer vary normally with maternal glucose concentrations on a weight-specific basis.

    “Similarly, in overnourished obese adolescent ewes, there is no evidence for a change in the placental glucose transfer capacity, despite feto-placental growth restriction, as placental glucose consumption and transfer vary normally with maternal glucose concentrations on a weight-specific basis (554).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [554] source

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  • May combine two claims.

    Premisecitation

    Ovine placental GLUT expression is altered in response to longer term variations in maternal glycaemia with decreases in GLUT1 abundance in hypoglycaemia conditions, and in both GLUT1 and GLUT3 abundance in response to hyperglycaemia.

    “Ovine placental GLUT expression is altered in response to longer term variations in maternal glycaemia with decreases in GLUT1 abundance in hypoglycaemia conditions, and in both GLUT1”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [138] source

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    • cites [139] source

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    • cites [247] Hay WW, 2006, Trans Am Clin Climatol Assoc

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    • cites [353] source

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  • May combine two claims.

    Premisecitation

    With prolonged maternal hypoglycaemia, distribution of uterine glucose uptake between the ovine uteroplacental and fetal tissues shifts to favour the utero-placental tissues, although absolute rates of glucose consumption remain lower than normal.

    “With prolonged maternal hypoglycaemia, distribution of uterine glucose uptake between the ovine uteroplacental and fetal tissues shifts to favour the utero-placental tissues, although absolute rates of glucose consumption remain lower than normal (99).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [99] source

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  • May combine two claims.

    Premisecitation

    Production of ovine placental lactogen (oPL) is nutritionally responsive and is increased in late gestation by short-term fasting and periconceptional undernutrition.

    “In addition, production of ovine placental lactogen (oPL) is nutritionally responsive and is increased in late gestation by short-term fasting and periconceptional undernutrition (421, 422).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [421] source

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    • cites [422] source

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  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Interpretationcitation

    This may reflect the ability of the sheep fetus to supplement its own glucose supply by activating gluconeogenesis, thereby reducing its demand for maternal glucose and sparing glucose for placental functions essential to maintaining pregnancy.

    “This too, may reflect the ability of the sheep fetus to supplement its own glucose supply by activating gluconeogenesis, thereby reducing its demand for maternal glucose and sparing glucose for placental functions essential to maintaining pregnancy (148,194).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [148] source

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    • cites [194] source

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  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Interpretationcitation

    This may reflect the switch of hypoglycaemic placental tissues from glucose to fat metabolism, and the concomitant increase in availability of arachidonic acid, the prostaglandin precursor.

    “This may reflect the switch of hypoglycaemic placental tissues from glucose to fat metabolism, and the concomitant increase in availability of arachidonic acid, the prostaglandin precursor (195).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [195] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Undernutrition of ewes from early to mid-gestation increases expression of several molecules involved in transplacental fatty acid transport at mid-gestation, although few of these changes persist until late gestation.

    “In addition, undernutrition of ewes from early to mid-gestation increases expression of several molecules involved in transplacental fatty acid transport at mid-gestation, although few of these changes persist until late gestation (353).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [353] source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationnone given

    Changes in placental size due to variations in maternal nutrition or obesity are likely to affect placental hormone synthesis, and hence circulating hormone concentrations.

    “Changes in placental size due to variations in maternal nutrition or obesity are likely to affect placental hormone synthesis, and hence circulating hormone concentrations.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    Taken together, these observations suggest that maternal constraint is an important factor in regulating placental phenotype, not only when maternal nutritional resources are limited but also when fetal demands increase rapidly in late gestation.

    “Taken together, these observations suggest that maternal constraint is an important factor in regulating placental phenotype, not only when maternal nutritional resources are limited but also when fetal demands increase rapidly in late gestation due either to”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationcitation

    The effect on the developing heart will be exaggerated in pathological pregnancies, where poor placental development is associated with absent-or reversed-end diastolic umbilical arterial flow.

    “The effect on the developing heart will be exaggerated in pathological pregnancies, where poor placental development is associated with absent-or reversed-end diastolic umbilical arterial flow (513).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [513] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Placental weight does not distinguish between maternal blood and placental tissue, and is heavily influenced by the mode of delivery and processing of the organ.

    “At the crudest levels it does not distinguish between maternal blood and placental tissue, and is heavily influenced by the mode of delivery and processing of the organ (57).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [57] source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    This upregulation is not maintained into late gestation, probably due to the decreased fetal demand associated with the direct growth inhibitory effects of excess glucocorticoids on fetal tissues late in gestation.

    “However, this upregulation is not maintained into late gestation, probably due to the decreased fetal demand associated with the direct growth inhibitory effects of excess glucocorticoids on fetal tissues late in gestation (191, 587).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [191]

      Not checked in the free run.

    • cites [587] source

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  • May combine two claims.

    Premisecitation

    When fetal demand and supply are mismatched in the naturally small placenta, there are changes in expression of several imprinted genes, including Igf2 in association with sparing of the labyrinth zone, increased MeAIB and glucose transport and upregulated expression of the Slc38a2 amino acid transporters.

    “When the fetal demand and supply are mismatched in the naturally small placenta, there are changes in expression of several imprinted genes, including Igf2 in association with sparing of the labyrinth zone, increased MeAIB and glucose transport and upregulated expression of the Slc38a2 amino acid transporters (114).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [114] source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    The placenta plays a critical role in the maternal-fetal supply line, but its potential influence on programming must be set in the context of other non-placental candidates, including gametogenesis in both parents, fertilization, transport of the conceptus in the oviduct, lactation and post-natal nutrition.

    “The placenta clearly plays a critical role in the maternal-fetal supply line, but it's potential influence on programming must be set in the context of other non-placental candidates, including gametogenesis in both parents, fertilization, transport of the conceptus in the oviduct, lactation and post-natal nutrition.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

    Interpretationnone given

    Placental prostaglandins or the release of pro-inflammatory cytokines, such as TNFα in response to oxidative or ER stress, may influence fetal cardiovascular development through their effects on the ductus venosus and endothelial cells respectively.

    “For example, placental prostaglandins or the release of pro-inflammatory cytokines, such as TNFα in response to oxidative or ER stress, may influence fetal cardiovascular development through their effects on the ductus venosus and endothelial cells respectively.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    Deficient remodeling leads to malperfusion of the placenta, causing loss of function through oxidative and ER stress, diminished surface area through reduced growth and increased infarction, mechanical damage to the syncytiotrophoblast, and hypoxemia.

    “Deficient remodeling leads to malperfusion of the placenta, causing loss of function through oxidative and ER stress, diminished surface area through reduced growth and increased infarction, mechanical damage to the syncytiotrophoblast, and hypoxemia.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationcitation

    Changes in placental Igf2P0 expression occur in response to maternal undernutrition and feeding an obesogenic diet, so this gene transcript may have an important role in adapting placental phenotype to environmental cues.

    “Since changes in placental Igf2P0 expression occur in response to maternal undernutrition and feeding an obesogenic diet (120, 496), this gene transcript may have an important role in adapting placental phenotype to environmental cues.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [120] source

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    • cites [496] source

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  • May combine two claims.

    Premisecitation

    Imprinted genes are known to have a disproportionately important role in fetal-placental development and are involved in resource allocation more widely.

    “These studies have tended to concentrate on the imprinted genes, which are known to have a disproportionately important role in fetal-placental development and are involved in resource allocation more widely (126, 189, 385, 544).”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [126] source

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    • cites [189] source

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    • cites [385] source

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    • cites [544] source

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  • May combine two claims.

    Interpretationcitation

    As a result, the naturally small placenta also supports more fetal growth per gram and maintains a normal fetal growth rate in late gestation.

    “As a result, the naturally small placenta also supports more fetal growth per gram and maintains a normal fetal growth rate in late gestation (114).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [114] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    There is often an increased fetal to placental weight ratio that is accompanied by up-regulation of glucose and amino acid transfer per gram of placenta, particularly when placental growth is restricted early in mouse development.

    “There is often an increased fetal to placental weight ratio that is accompanied by up-regulation of glucose and amino acid transfer per gram of placenta, particularly when placental growth is restricted early in mouse development (Table 6).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Table 6

      Not checked in the free run.

  • May combine two claims.

    Interpretationnone given

    The placenta is in a key position to modulate signals coming from the mother before they are transduced to the embryo/fetus, and can influence programming in at least four ways.

    “Nonetheless, the placenta is in a key position to modulate signals coming from the mother before they are transduced to the embryo/fetus, and can influence programming in at least four ways (Figure 11).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Figure 11

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    Placental hormones, such as the IGFs, stimulate fetal organ growth, and impact on maternal nutrient supply through their actions on appetite, the endometrial glands, pancreatic β cells and peripheral insulin resistance.

    “Equally, placental hormones, such as the IGFs, stimulate fetal organ growth, and impact on maternal nutrient supply through their actions on appetite, the endometrial glands, pancreatic ß cells and peripheral insulin resistance as discussed in section III.B.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Interpretationcitation

    Placental changes may be secondary to programming within the embryo/fetus, or simply a parallel response to the same insult independent of that of the offspring.

    “In addition, the placental changes may be secondary to programming within the embryo/fetus, or simply a parallel response to the same insult independent of that of the offspring (58).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [58] Boyd R, 2011

      Not checked in the free run.

  • May combine two claims.

    Interpretationnone given

    All these factors will interact with the fetal drive for growth determined by its genotype, and the outcome will depend on the timing and severity of the insult.

    “All these factors will interact with the fetal drive for growth determined by its genotype, and the outcome will depend on the timing and severity of the insult (Figure 11).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Figure 11

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In the large H19-/+ mutant placenta, restriction of its transport capacity by simultaneous deletion of the Igf2P0 transcript leads to upregulation of MeAIB transport and Slc38a4 expression to meet the larger demand of the overgrown mutant fetus, with increased Igf2 expression in all its other tissues.

    “Even in the large H19 -/+ mutant placenta, restriction of its transport capacity by simultaneous deletion of the Igf2P0 transcript leads to upregulation of MeAIB transport and Slc38a4 expression to meet the larger demand of the overgrown mutant fetus, with increased Igf2 expression in all its other tissues (14).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [14] source

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  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationnone given

    Their impact will also be influenced by the placenta's ability to adapt and compensate, for example by increasing vascularity, enzyme or transporter expression.

    “Their impact will also be influenced by the placenta's ability to adapt and compensate, for example by increasing vascularity, enzyme or transporter expression.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    There are clearly differences in placental efficiency within healthy pregnancies that deliver babies within the normal birth weight range, but placental weight is an uninformative proxy measure for placental function.

    “They are clearly differences in placental efficiency within healthy pregnancies that deliver babies within the normal birth weight range, but placental weight is an uninformative proxy measure for placental function.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisenone given

    The maternal circulation to the placenta is dependent on remodeling of the spiral arteries, which in turn is reliant on invasion of the endometrium by extravillous trophoblast cells during the first and early second trimesters.

    “The maternal circulation to the placenta is dependent on remodeling of the spiral arteries, which in turn is reliant on invasion of the endometrium by extravillous trophoblast cells during the first and early second trimesters.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisenone given

    Most attention has focused on mir-210, which is HIF-dependent.

    “Most attention has focused on mir-210, which is HIF-dependent.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Upregulation of placental amino acid transport is maintained until D19 in mice with complete Igf2P0null litters but not in Igf2P0 mutants of dams with mixed litters of mutants and wild types, which have a greater total conceptus mass and, thus, demand for nutrients in late gestation.

    “Certainly, upregulation of placental amino acid transport is maintained until D19 in mice with complete Igf2P0null litters but not in Igf2P0 mutants of dams with mixed litters of mutants and wild types, which have a greater total conceptus mass and, thus, demand for nutrients in late gestation (124, 495).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [124] source

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    • cites [495] source

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  • May combine two claims.

    Premisecitation

    Inhibition of CSE activity inhibits trophoblast invasion from first trimester explants in vitro, and increases the release of anti-angiogenic factors from umbilical vein endothelial cells.

    “Inhibition of CSE activity also inhibits trophoblast invasion from first trimester explants in vitro, and increases the release on anti-angiogenic factors from umbilical vein endothelial cells (559).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [559] source

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationreasoning

    The speed with which physiological adaptations on both the maternal and fetal sides can occur makes it difficult to determine if any reserve capacity exists.

    “The speed with which these and many other physiological adaptations on both the maternal and fetal sides can occur makes it difficult to determine if any reserve capacity exists.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisereasoning

    Both of these mechanisms regulate cap-dependent mRNA translation.

    “Both of these mechanisms regulate cap-dependent mRNA translation.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Hydrogen sulfide is a powerful vasodilator of the fetal placental vasculature, and its effects are mediated through actions on both ATP-sensitive K+ channels and nitric oxide.

    “Perfusion experiments ex vivo have demonstrated that hydrogen sulfide is a powerful vasodilator of the fetal placental vasculature, and that its effects are mediated through actions on both ATP-sensitive K + channels and nitric oxide (111).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [111] source

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  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationreasoning

    There might be detrimental effects for the fetus of building too large a placenta for its immediate needs, as this will consume extra resources and place an additional burden on the extracorporeal circulation.

    “There might also be detrimental effects for the fetus of building too large a placenta for its immediate needs, as this will consume extra resources and place an additional burden on the extracorporeal circulation.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Similar inhibition of AMPK signaling has been reported in the placenta of rats fed an obesogenic diet of high-saturated fats.

    “Similar inhibition of AMPK signaling has been reported in the placenta of rats fed an obesogenic diet of high-saturated fats (205).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [205] source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    The complexes of the electron transport chain are reduced in high-altitude placentas, as is the ATP/ADP ratio, suggesting energetic compromise that could adversely affect transport and synthetic activities of the organ.

    “Consistent with this action, the complexes are reduced in these high-altitude placentas (121), as is the ATP/ADP ratio (534), suggesting energetic compromise that could adversely affect transport and synthetic activities of the organ.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [121] source

      Not checked in the free run.

    • cites [534] source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisenone given

    A common, immediate response of cells to oxygen or nutrient deprivation is to suppress non-essential energy-demanding processes in order to harbor what resources are remaining and maximize the chance of survival.

    “A common, immediate response of cells to oxygen or nutrient deprivation is to suppress non-essential energy-demanding processes in order to harbor what resources are remaining and maximize the chance of survival.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisenone given

    Within the placental field there are limited data concerning the involvement of AMPK in placental development and function.

    “Within the placental field there are limited data concerning the involvement of AMPK in placental development and function.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Interpretationreasoning

    Stimulation of mTORC1 promotes protein synthesis, increases cell mass and leads to cell proliferation and growth.

    “Hence, stimulation of mTORC1 promotes protein synthesis, increases cell mass and leads to cell proliferation and growth.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    AMPK has recently been implicated in controlling uterine blood flow, and in adaptations to pregnancy at high altitude.

    “It has recently been implicated in controlling uterine blood flow, and in adaptations to pregnancy at high altitude (505).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [505] source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing).

    Interpretationcitation

    These two extremes of placental efficiency may represent different kinds of programming.

    “These two extremes of efficiency may represent different kinds of programming.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationnone given

    The placenta is sending signals in the form of growth factors, hormones and potentially exosomes, into the maternal and fetal circulations to modify the maternal ability to support the pregnancy and fetal growth.

    “The placenta is also sending signals in the form of growth factors, hormones and potentially exosomes, into the maternal and fetal circulations to modify the maternal ability to support the pregnancy and fetal growth.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

    Premisenone given

    Protein synthesis represents one of these processes, for incorporation of a single amino acid into a polypeptide chain involves four high-energy bonds, two ATP and two GTP.

    “Protein synthesis represents one of these processes, for incorporation of a single amino acid into a polypeptide chain involves four high-energy bonds, two ATP and two GTP.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

    Premisenone given

    The placenta receives signals from the mother regarding her nutritional resources and reserves, and from the fetus relating to its demands.

    “The placenta clearly receives signals from the mother regarding her nutritional resources and reserves, and from the fetus relating to its demands, but what is the nature of those signals and how are they integrated?”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisereasoning

    mTORC1 has the most direct effect on cell proliferation due to its actions on capdependent RNA translation mediated through phosphorylation of the binding protein 4E-BP1, and the ribosomal protein S6.

    “mTORC1 has the most direct effect on cell proliferation due to its actions on capdependent RNA translation mediated through phosphorylation of the binding protein 4E-BP1, and the ribosomal protein S6.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    There are two principal mechanisms that operate in response to hypoxia: a rapid response involving phosphorylation of eIF2α through PERK and the UPR, and a longer term response dependent on suppression of the mTOR pathway.

    “There are two principal mechanisms that operate, a rapid response involving phosphorylation of eIF2α through PERK and the UPR, and a longer term response dependent on suppression of the mTOR pathway (181, 585).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [181] source

      Not checked in the free run.

    • cites [585] source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisenone given

    Such analyses cannot take into account changes in placental blood flows, maternal-fetal concentration gradients, hemoglobin binding affinities, transporter activity and placental metabolism.

    “But such analyses cannot take into account changes in, for example, placental blood flows, maternal-fetal concentration gradients, hemoglobin binding affinities, transporter activity and placental metabolism.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

    Premisenone given

    mTOR comprises two major complexes, mTORC1 and mTORC2, which share the same core kinase but have the different adaptor proteins, raptor and rictor respectively.

    “mTOR comprises two major complexes, mTORC1 and mTORC2, which share the same core kinase but have the different adaptor proteins, raptor and rictor respectively.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationcitation

    This dynamic adaptation in placental phenotype optimises fetal fitness in the prevailing conditions while maintaining sufficient maternal resource for lactation and subsequent pregnancies.

    “This dynamic adaptation in placental phenotype optimises fetal fitness in the prevailing conditions while maintaining sufficient maternal resource for lactation and subsequent pregnancies (144, 193).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [144] source

      Not checked in the free run.

    • cites [193] source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S2 (checkable), S4 (based).

    Interpretationnone given

    The placenta plays a pivotal role in developmental programming as it represents the platform on which the individual is constructed.

    “The placenta plays a pivotal role in this process as it represents the platform on which the individual is constructed.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    The statistical associations between placental phenotype and chronic disease predisposition are so strong, and have been confirmed in so many different cohorts across the globe, that they are incontrovertible.

    “The statistical associations are so strong, and have been confirmed in so many different cohorts across the globe, that they are incontrovertible.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

    Interpretationnone given

    Both pathways receive input at various levels regarding oxygen and nutrient availability, and will influence cell proliferation and growth.

    “Both pathways receive input at various levels regarding oxygen and nutrient availability, and will influence cell proliferation and growth.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisereasoning

    mTORC1 is regulated by amino acid availability.

    “mTORC1 is regulated by amino acid availability, although for many years the mechanism has been uncertain.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Knockdown of AMPKα1 and AMPKα2 inhibits cell proliferation and cytokine-induced differentiation.

    “In addition, knockdown inhibits cell proliferation and cytokine-induced differentiation.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [93] source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationnone given

    The response pathway may interact with the mTOR/AKT pathway to modulate protein synthesis within the placenta.

    “Response pathway may interact with the mTOR/AKT pathway to modulate protein synthesis within the placenta.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Dietary restriction during early to mid-gestation in ewes resulted in increased activation of AMPK in the fetal cotyledonary tissues at d78 but not later on d135, whereas over-nutrition resulted in the reverse.

    “Dietary restriction (50% of controls) during early to mid-gestation in ewes resulted in increased activation of AMPK in the fetal cotyledonary tissues at d78 but not later on d135 (353), whereas the reverse was the case with over-nutrition (150% of controls) (615).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [353] source

      Not checked in the free run.

    • cites [615] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Knockdown of the isoforms AMPKα1 and AMPKα2 in murine SM10 trophoblast progenitor cells affects cell nutrient transport, inhibiting expression of Glut3 and blocking translocation of the protein to the cell surface, but increasing the activity of system A transporters.

    “Knockdown of the isoforms AMPKα1 and AMPKα2 in murine SM10 trophoblast progenitor cells has been shown to affect cell nutrient transport, inhibiting expression of Glut3 and blocking translocation of the protein to the cell surface, but increasing the activity of system A transporters(93).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [93] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    MiR-210 is increased in normal placentas from pregnancies at high altitude, and in placentas from pregnancies complicated by pre-eclampsia.

    “It is increased in normal placentas from pregnancies at high altitude (121), and in placentas from pregnancies complicated by pre-eclampsia (272, 351, 401, 611).”
    Quote in the paperSubstantial claim0 of 5 sources checked
    • cites [121] source

      Not checked in the free run.

    • cites [272] source

      Not checked in the free run.

    • cites [351] source

      Not checked in the free run.

    • cites [401] source

      Not checked in the free run.

    • cites [611] source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Interpretationreasoning

    The associations are complex, for they integrate the long-term nutritional status of the mother, environmental cues and stressors, the demands of the fetus, and development of the placenta.

    “However, the associations are complex, for they integrate the long-term nutritional status of the mother, environmental cues and stressors, the demands of the fetus, and development of the placenta.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Other targets identified for miR-210 include the steroidogenic enzyme hydroxysteroid (17-ß) dehydrogenase 1, ephrin-A3 and homeobox-A9 which are involved in trophoblast cell migration and vascular remodeling, and thrombospondin type 1 domain containing 7A in the placental vasculature.

    “Besides mitochondria, other targets identified for miR-210 include the steroidogenic enzyme hydroxysteroid (17-ß) dehydrogenase 1 (272), ephrin-A3 and homeobox-A9 which are involved in trophoblast cell migration and vascular remodeling (611), and thrombospondin type 1 domain containing 7A in the placental vasculature (351).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [272] source

      Not checked in the free run.

    • cites [611] source

      Not checked in the free run.

    • cites [351] source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    A Ragulator-RAG GTPases multiprotein complex associated with the lysosomal surface regulates mTOR activity by controlling its sub-cellular location, recruiting it to the lysosome.

    “More recent research has identified a Ragulator-RAG GTPases multiprotein complex associated with the lysosomal surface that regulates mTOR activity by controlling its sub-cellular location, recruiting it to the lysosome (164).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [164] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Activation of AMPK has been demonstrated to be a key step in the differentiation of mouse trophoblast stem cells under stress conditions, confirming that the pathway is functional in this cell type.

    “Activation has been demonstrated to be a key step in the differentiation of mouse trophoblast stem cells under stress conditions (613), confirming that the pathway is functional in this cell type.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [613] source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    It is likely that in rodents embryogenesis and early placental development take place in a low oxygen environment, as in the human, because at E6 the antimesometrial decidual cells form an avascular zone around the conceptus, separating it from the maternal blood.

    “It is likely that in rodents embryogenesis and early placental development take place in a low oxygen environment, as in the human, for at E6 the antimesometrial decidual cells form an avascular zone around the conceptus, separating it from the maternal blood (430).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [430] source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    The value expressed per kg of fetus remains constant across gestation, suggesting that development of the placenta and fetus are closely interlinked.

    “The fact that the value expressed per kg of fetus remains constant across gestation suggests that development of the placenta and fetus are closely interlinked (368).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [368] source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    The human placenta expresses a wide variety of non-coding RNAs, but few data are available regarding their responsiveness to hypoxia.

    “The human placenta expresses a wide variety of non-coding RNAs (398), but few data are available regarding their responsiveness to hypoxia.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [398] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Within mitochondria, miR-210 targets regulatory proteins that assist in the assembly of the complexes of the electron transport chain, and suppresses respiration.

    “Within mitochondria it targets regulatory proteins that assist in the assembly of the complexes of the electron transport chain, and suppresses respiration (103, 108).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [103] source

      Not checked in the free run.

    • cites [108] source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationreasoning

    Differences in the nature of the interhemal interface mean that extrapolation of transport data from one species to another may not always be justified.

    “Differences in the nature of the interhemal interface mean that extrapolation of transport data from one species to another may not always be justified.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    Because the vascular plexuses of the secondary yolk sac and the chorioallantoic placenta account for a substantial portion of the total vascular impedance to flow sensed by the embryonic heart, poor vascularity in these organs would offer an increased load to the heart, altering gene expression patterns and leading to congenital defects or a myocardium that is vulnerable for later disease.

    “Because these two beds account for a substantial portion of the total vascular impedance to flow sensed by the embryonic heart, poor vascularity in these organs would offer an increased load to the heart, altering gene expression patterns and leading to congenital defects or a myocardium that is vulnerable for later disease.”
    Quote in the paperNot a substantial claim
254 of 254

  • The authors state this as an assumption.

    Little research has addressed developmental plasticity within the placenta.

    “Developmental plasticity is a well-described process in nature (43), but little research has addressed the phenomenon within the placenta.”

  • The paper relies on this without support.

    The placenta evolved to transfer nutrients to the fetus and to create a stable milieu in which the fetus can develop, isolated as far as possible from maternal and environmental stressors.

    “The placenta evolved to transfer nutrients to the fetus, and also to create a stable milieu in which the fetus can develop, isolated as far as possible from maternal and environmental stressors.”

  • The paper relies on this without support.

    The placenta is a remarkably plastic organ, capable of considerable structural and functional adaptations that help to mitigate adverse maternal insults such as nutrient deprivation, and exposure to drugs, toxins or hypoxia.

    “As well as being multifunctional, the placenta is also a remarkably plastic organ, capable of considerable structural and functional adaptations that help to mitigate adverse maternal insults, such as nutrient deprivation, and exposure to drugs, toxins or hypoxia.”

  • The paper relies on this without support.

    Amino acid transport across the placenta is a key determinant of fetal growth.

    “Amino acid transport across the placenta is a key determinant of fetal growth as it provides the essentials for protein synthesis.”

  • The paper relies on this without support.

    The placenta acts as a selective barrier to create an internal milieu in which the fetus, and in particular its endocrine systems, can develop independently.

    “It therefore acts as a selective barrier to create an internal milieu in which the fetus, and in particular its endocrine systems, can develop independently.”

  • The paper relies on this without support.

    Glucocorticoids are powerful inhibitors of cell proliferation for most fetal organs, except the heart and kidney.

    “Glucocorticoids are powerful inhibitors of cell proliferation for most fetal organs, except the heart and kidney, and the importance of this enzyme for normal development is demonstrated by the fact that there is a significant correlation between its activity in the human placenta and birth weight (497, 518).”

  • The paper relies on this without support.

    The placenta is of the same genotype as the fetus.

    “The placenta is of the same genotype of the fetus, and there is increasing evidence that sexual dimorphism in terms of its gene expression may modulate its responses to environmental stimuli, and so influence the likelihood of fetal developmental programming.”

  • The paper relies on this without support.

    The placenta does not function in isolation, and the mother's nutritional status has a powerful modifying influence on allocation of resources.

    “The placenta does not function in isolation, however, and the mother's nutritional status has a powerful modifying influence on allocation of resources.”

  • The paper relies on this without support.

    Low birth weight usually implies inadequate placental function, either as a primary or secondary cause.

    “Low birth weight usually implies inadequate placental function, either as a primary or secondary cause.”

  • The paper relies on this without support.

    The intraplacental oxygen concentration is about 2.5% during the first trimester.

    “In addition, the intraplacental oxygen concentration of ~2.5% during the first trimester exceeds the evolutionary conserved range of maximal HIF activity of 0.5 -2.0% oxygen (225, 286).”
10 of 10

Cites

Flagged first, then by citations

Research works printed but not linked: 27

  1. Bartelmez GW, 1933, Contrib Embryol, 24, 141
  2. Bocking AD, 1992, J Dev Physiol, 17, 169
  3. Brosens IA, 1988, Trophoblast Res, 3, 61
  4. Burton GJ, 1987, Scanning Microsc, 1, 1811
  5. Burton GJ, 1976, Q J Exp Physiol Cogn Med Sci, 61, 275
  6. Chen D, 2002, Zhonghua fu chan ke za zhi, 37, 69
  7. Dantzer V, 1988, Trophoblast Res, 3, 235
  8. Hardy DB, 2002, J Clin Endocrinol Metab, 87, 3696
  9. Hauguel-de Mouzon S, 1997, J Clin Endocrinol Metab, 82, 2689
  10. Hay WW, 2006, Trans Am Clin Climatol Assoc, 117, 321
  11. Jansson T, 1993, J Clin Endocrinol Metab, 77, 1554
  12. Jones CT, 1983, J Dev Physiol, 5, 223
  13. 10.1002/(SICI)1097-0029(19970701/15)38:1/2<52::AID-JEMT7>3.0.CO;2-W · DOI
  14. Loke YW, 1982, J Reticuloendothel Soc, 31, 317
  15. Marinoni E, 2007, J Reprod Med, 52, 831
  16. Mayhew TM, 1991, J Anat, 175, 187
  17. Molteni RA, 1978, J Reprod Med, 21, 327
  18. Parraguez VH, 2010, Can J Vet Res, 74, 193
  19. Perazzolo S, 2015, Conf Proc IEEE Eng Med Biol Soc, 2015, 8054
  20. Spencer TE, 2004, J Anim Sci, 82, E4
  21. Stewart PM, 1995, J Clin Endocrinol Metab, 80, 885
  22. Thornburg K, 2011, The Placenta and Human Developmental Programming, 201
  23. Vatnick I, 1991, J Dev Physiol, 15, 351
  24. Versen-Hoynck FMV, 2008, Geburtshilfe Frauenheilkd, 68
  25. Wild AE, 1981, Placenta Suppl, 1, 165
  26. Wilson ME, 2001, Reprod Suppl, 58, 223
  27. Zhao XX, 2007, Zhonghua Yi Xue Za Zhi, 87, 894

Cited by

Sorted by citations

Related

Authors
Burton, G. J., Fowden, A. L., & Thornburg, K. L.
Affiliations
Oregon Health & Science University (US)
ORCID
Venue
Physiological Reviews
Publisher
American Physiological Society
Published
2016-10
Volume
96
Issue
4
Pages
1509-1565
ISSN
  • 0031-9333 (ISSN-L)
  • 1522-1210
DOI
10.1152/physrev.00029.2015
PMC
PMC5504455
OpenAlex
W2510028748
Cited by
717
References
623
Citations by year
2026: 60 · 2025: 74 · 2024: 96 · 2023: 82 · 2022: 91 · 2021: 105 · 2020: 83 · 2019: 46 · 2018: 52 · 2017: 28
FWCI
6.50
Type
journal article
Language
en
Open access
Locations
  • Physiological Reviews (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • Apollo (University of Cambridge) (submittedVersion)
  • Apollo
Funders
  • Wellcome Trust (084804/2/08/Z)
  • HHS | NIH | National Institute of Child Health and Human Development (NICHD)
  • Nation Heart Lung and Blood Institute
Topics
  • Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Birth, Development, and Health
  • Health Sciences › Medicine › Obstetrics and Gynecology › Pregnancy and preeclampsia studies
  • Health Sciences › Medicine › Obstetrics and Gynecology › Gestational Diabetes Research and Management
Keywords
placenta, developmental origins of health and disease, fetal programming, placental function, placental adaptation, fetal development, placental endocrine function, placental barrier, glucocorticoids, cardiovascular disease, diabetes mellitus, obesity, disease prevention
MeSH terms
Animals, Chronic Disease, Female, Humans, Maternal-Fetal Exchange, Placenta, Placentation, Pregnancy, Prenatal Exposure Delayed Effects, Fetal Development

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-10.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-10.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

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