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Interaction between Metformin, Folate and Vitamin B12 and the Potential Impact on Fetal Growth and Long-Term Metabolic Health in Diabetic Pregnancies.
Owen, MD, Baker, BC, Scott, EM, Forbes, K
International journal of molecular sciences. 2021;(11)
Abstract
Metformin is the first-line treatment for many people with type 2 diabetes mellitus (T2DM) and gestational diabetes mellitus (GDM) to maintain glycaemic control. Recent evidence suggests metformin can cross the placenta during pregnancy, thereby exposing the fetus to high concentrations of metformin and potentially restricting placental and fetal growth. Offspring exposed to metformin during gestation are at increased risk of being born small for gestational age (SGA) and show signs of 'catch up' growth and obesity during childhood which increases their risk of future cardiometabolic diseases. The mechanisms by which metformin impacts on the fetal growth and long-term health of the offspring remain to be established. Metformin is associated with maternal vitamin B12 deficiency and antifolate like activity. Vitamin B12 and folate balance is vital for one carbon metabolism, which is essential for DNA methylation and purine/pyrimidine synthesis of nucleic acids. Folate:vitamin B12 imbalance induced by metformin may lead to genomic instability and aberrant gene expression, thus promoting fetal programming. Mitochondrial aerobic respiration may also be affected, thereby inhibiting placental and fetal growth, and suppressing mammalian target of rapamycin (mTOR) activity for cellular nutrient transport. Vitamin supplementation, before or during metformin treatment in pregnancy, could be a promising strategy to improve maternal vitamin B12 and folate levels and reduce the incidence of SGA births and childhood obesity. Heterogeneous diagnostic and screening criteria for GDM and the transient nature of nutrient biomarkers have led to inconsistencies in clinical study designs to investigate the effects of metformin on folate:vitamin B12 balance and child development. As rates of diabetes in pregnancy continue to escalate, more women are likely to be prescribed metformin; thus, it is of paramount importance to improve our understanding of metformin's transgenerational effects to develop prophylactic strategies for the prevention of adverse fetal outcomes.
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Prenatal Air Pollution Exposure and Placental DNA Methylation Changes: Implications on Fetal Development and Future Disease Susceptibility.
Ghazi, T, Naidoo, P, Naidoo, RN, Chuturgoon, AA
Cells. 2021;(11)
Abstract
The Developmental Origins of Health and Disease (DOHaD) concept postulates that in utero exposures influence fetal programming and health in later life. Throughout pregnancy, the placenta plays a central role in fetal programming; it regulates the in utero environment and acts as a gatekeeper for nutrient and waste exchange between the mother and the fetus. Maternal exposure to air pollution, including heavy metals, can reach the placenta, where they alter DNA methylation patterns, leading to changes in placental function and fetal reprogramming. This review explores the current knowledge on placental DNA methylation changes associated with prenatal air pollution (including heavy metals) exposure and highlights its effects on fetal development and disease susceptibility. Prenatal exposure to air pollution and heavy metals was associated with altered placental DNA methylation at the global and promoter regions of genes involved in biological processes such as energy metabolism, circadian rhythm, DNA repair, inflammation, cell differentiation, and organ development. The altered placental methylation of these genes was, in some studies, associated with adverse birth outcomes such as low birth weight, small for gestational age, and decreased head circumference. Moreover, few studies indicate that DNA methylation changes in the placenta were sex-specific, and infants born with altered placental DNA methylation patterns were predisposed to developing neurobehavioral abnormalities, cancer, and atopic dermatitis. These findings highlight the importance of more effective and stricter environmental and public health policies to reduce air pollution and protect human health.
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DNA methylation changes in genes coding for leptin and insulin receptors during metabolic-altered pregnancies.
Stolzenbach, F, Valdivia, S, Ojeda-Provoste, P, Toledo, F, Sobrevia, L, Kerr, B
Biochimica et biophysica acta. Molecular basis of disease. 2020;(2):165465
Abstract
The overwhelming rates of obesity worldwide are a major concern due to the elevated medical costs associated and the poor quality of life of obese patients. In the recent years, it has become evident that the intrauterine milieu can have a long-term impact on the foetus health. The placenta is a highly dynamic organ; whose primary function is to carry nutrients from the mother to the foetus and to remove waste products from the foetus. Any alteration in maternal circulating metabolites elicits a response in order to ensure the developing foetus an adequate growth environment. This response can be translated into epigenetic modifications in coding genes for metabolic-related receptors located in the placenta and foetal tissues. The most studied receptors involved in the metabolic sensing are the leptin and the insulin receptors. A maternal metabolic disease-like state can alter the expression of these receptors in different organs, including placenta. There is evidence that these alterations not only affect the expression level of these receptors, but there are also differences in epigenetic marks in regulatory elements of these genes that may become permanent despite the mother's treatment. This review provides evidence about possible mechanisms involved in the foetal programming of metabolic diseases originated from the pre-natal environment that could contributive to increasing levels of obesity in the world.
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Iron deficiency in pregnancy.
Georgieff, MK
American journal of obstetrics and gynecology. 2020;(4):516-524
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Abstract
Iron is essential for the function of all cells through its roles in oxygen delivery, electron transport, and enzymatic activity. Cells with high metabolic rates require more iron and are at greater risk for dysfunction during iron deficiency. Iron requirements during pregnancy increase dramatically, as the mother's blood volume expands and the fetus grows and develops. Thus, pregnancy is a condition of impending or existing iron deficiency, which may be difficult to diagnose because of limitations to commonly used biomarkers such as hemoglobin and ferritin concentrations. Iron deficiency is associated with adverse pregnancy outcomes, including increased maternal illness, low birthweight, prematurity, and intrauterine growth restriction. The rapidly developing fetal brain is at particular risk of iron deficiency, which can occur because of maternal iron deficiency, hypertension, smoking, or glucose intolerance. Low maternal gestational iron intake is associated with autism, schizophrenia, and abnormal brain structure in the offspring. Newborns with iron deficiency have compromised recognition memory, slower speed of processing, and poorer bonding that persist despite postnatal iron repletion. Preclinical models of fetal iron deficiency confirm that expected iron-dependent processes such as monoamine neurotransmission, neuronal growth and differentiation, myelination, and gene expression are all compromised acutely and long term into adulthood. This review outlines strategies to diagnose and prevent iron deficiency in pregnancy. It describes the neurocognitive and mental health consequences of fetal iron deficiency. It emphasizes that fetal iron is a key nutrient that influences brain development and function across the lifespan.
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The impact of maternal obesity in pregnancy on placental glucocorticoid and macronutrient transport and metabolism.
Johns, EC, Denison, FC, Reynolds, RM
Biochimica et biophysica acta. Molecular basis of disease. 2020;(2):165374
Abstract
Maternal obesity is the most common metabolic disturbance in pregnancy affecting >1 in 5 women in some countries. Babies born to obese women are heavier with more adiposity at birth, and are vulnerable to obesity and metabolic disease across the lifespan suggesting offspring health is 'programmed' by fetal exposure to an obese intra-uterine environment. The placenta plays a major role in dictating the impact of maternal health on prenatal development. Maternal obesity impacts the function of integral placental receptors and transporters for glucocorticoids and nutrients, key drivers of fetal growth, though mechanisms remain poorly understood. This review aims to summarise current knowledge in this area, and considers the impact of obesity on the epigenetic machinery of the placenta at this vital juncture in offspring development. Further research is required to advance understanding of these areas in the hope that the trans-generational cycle of obesity can be alleviated.
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The Role of microRNAs Identified in the Amniotic Fluid.
Fasoulakis, Z, Theodora, M, Tsirkas, I, Tsirka, T, Kalagasidou, S, Inagamova, L, Papamanolis, V, Blontzos, N, Kontomanolis, EN
MicroRNA (Shariqah, United Arab Emirates). 2020;(1):8-16
Abstract
AIM: The study aimed to provide an overall view of current data considering the presence of microRNAs in amniotic fluid. METHODS The available literature in MEDLINE, regarding the role of the amniotic fluid in pregnancy and fetal development, was searched for related articles including terms such as "microRNA", "Amniotic fluid", "Adverse outcome" and others. RESULTS The amniotic fluid has an undoubtedly significant part in fetal nutrition, with a protecting and thermoregulatory role alongside. MicroRNAs have proven to be highly expressed during pregnancy in many body liquids including amniotic fluid and are transferred between cells loaded in exosomes, while they are also implicated in many processes during fetal development and could be potential biomarkers for early prediction of adverse outcomes. CONCLUSION Current knowledge reveals that amniotic fluid microRNAs participate in many developmental and physiological processes of pregnancy including proliferation of fibroblasts, fetal development, angiogenesis, cardioprotection, activation of signaling pathways, differentiation and cell motility, while the expression profile of specific microRNAs has a potential prognostic role in the prediction of Down syndrome, congenital hydronephrosis and kidney fibrosis.
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Mineral and bone physiology in the foetus, preterm and full-term neonates.
Sethi, A, Priyadarshi, M, Agarwal, R
Seminars in fetal & neonatal medicine. 2020;(1):101076
Abstract
Mother is the major source of minerals in foetal life with placenta actively transporting against a concentration and electrochemical gradient. The foetal serum mineral concentration is thereby higher as compared to maternal values, which possibly help in its rapid accretion in developing bones and for counteracting postnatal fall in calcium levels at birth. Parathyroid hormone related peptide (PTHrP) and parathyroid hormone (PTH) play a major role in mineral physiology during foetal life with hormones like calcitriol, calcitonin, FGF-23 and sex steroids having minimal role. PTHrP and PTH also play a major role in endochondral bone formation and mineralization of skeleton. At the birth, as the cord is clamped, there is loss of active transport of minerals through placenta and the neonate has to rely on enteral intake of minerals to meet the demands of growing bones and metabolisms. The calcium levels fall after birth, reaching a nadir at 24-48 h and gradually rise to adult values over several days, probably resulting from a fall in PTHrP levels and hyporesponsiveness of parathyroid glands. As PTH and calcitriol levels increase postnatally, there is a rise in calcium levels with maturation in functioning of kidneys and intestines. However, there may be significant delay in intestinal maturation in preterm infants along with an increased demand for mineral accretion, which predispose them to osteopenia of prematurity.
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Clinical consequences of developmental programming of low nephron number.
Luyckx, VA, Brenner, BM
Anatomical record (Hoboken, N.J. : 2007). 2020;(10):2613-2631
Abstract
Nephron number in humans varies up to 13-fold, likely reflecting the impact of multiple factors on kidney development, including inherited body size and ethnicity, as well as maternal health and nutrition, fetal exposure to gestational diabetes or preeclampsia and other environmental factors, which may potentially be modifiable. Such conditions predispose to low or high offspring birth weight, growth restriction or preterm birth, which have all been associated with increased risks of higher blood pressures and/or kidney dysfunction in later life. Low birth weight, preterm birth, and intrauterine growth restriction are associated with reduced nephron numbers. Humans with hypertension and chronic kidney disease tend to have fewer nephrons than their counterparts with normal blood pressures or kidney function. A developmentally programmed reduction in nephron number therefore enhances an individual's susceptibility to hypertension and kidney disease in later life. A low nephron number at birth may not lead to kidney dysfunction alone except when severe, but in the face of superimposed acute or chronic kidney injury, a kidney endowed with fewer nephrons may be less able to adapt, and overt kidney disease may develop. Given that millions of babies are born either too small, too big or too soon each year, the population impact of altered renal programming is likely to be significant. Many gestational exposures are modifiable, therefore urgent attention is required to implement public health measures to optimize maternal, fetal, and child health, to prevent or mitigate the consequences of developmental programming, to improve the health future generations.
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Updates on Assessment and Monitoring of the Postnatal Growth of Preterm Infants.
Cordova, EG, Belfort, MB
NeoReviews. 2020;(2):e98-e108
Abstract
Assessing and monitoring the physical growth of preterm infants is fundamental to NICU care. The goals of nutritional care are to approximate the growth and body composition of the healthy fetus and to support optimal brain development while minimizing future cardiometabolic risk. Both poor and excessive growth predict adverse long-term health outcomes. Growth curves are clinical tools used to assess the preterm infant's growth status. Several growth curves for preterm infants were developed in the past decade. To use them effectively, clinicians need to understand how each growth curve was developed; the underlying reference population; intended use; and strengths and limitations. Intrauterine growth curves are references that use size at birth to represent healthy fetal growth. These curves serve 2 purposes-to assign size classifications at birth and to monitor postnatal growth. The INTERGROWTH-21 st preterm postnatal growth standards were developed to compare the postnatal growth of preterm infants to that of healthy preterm infants rather than the fetus. Individualized weight growth curves account for the water weight loss that frequently occurs after birth. In addition, body mass index (BMI) curves are now available. In this review, we discuss the main characteristics of growth curves used for preterm infants as well as the use of percentiles, z scores, and their change over time to evaluate size and growth status. We also review the differences in body composition between preterm infants at term-equivalent age and term-born infants and the potential role of monitoring proportionality of growth using BMI curves.
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Role of the microbiome in human development.
Dominguez-Bello, MG, Godoy-Vitorino, F, Knight, R, Blaser, MJ
Gut. 2019;(6):1108-1114
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Abstract
The host-microbiome supraorganism appears to have coevolved and the unperturbed microbial component of the dyad renders host health sustainable. This coevolution has likely shaped evolving phenotypes in all life forms on this predominantly microbial planet. The microbiota seems to exert effects on the next generation from gestation, via maternal microbiota and immune responses. The microbiota ecosystems develop, restricted to their epithelial niches by the host immune system, concomitantly with the host chronological development, providing early modulation of physiological host development and functions for nutrition, immunity and resistance to pathogens at all ages. Here, we review the role of the microbiome in human development, including evolutionary considerations, and the maternal/fetal relationships, contributions to nutrition and growth. We also discuss what constitutes a healthy microbiota, how antimicrobial modern practices are impacting the human microbiota, the associations between microbiota perturbations, host responses and diseases rocketing in urban societies and potential for future restoration.