Fetal Demand Research Articles

Current Theories on the Prevention of Severe Preeclampsia With Low-Molecular Weight Heparin

During normal pregnancy, the maternal cardiovascular system undergoes important anatomic and functional modifications to establish a low-resistance, high-volume state to support fetal demands for nutrients and gas exchange.1 Cardiac output increases by as much as 30% to 40%, resulting from increases in stroke volume and, to a lesser extent, heart rate. Gestational hormones and alterations in the synthesis of, and reactivity to, vasoactive substances result in systemic vasodilatation.2 Despite increases in cardiac output, maternal blood pressure decreases because of a substantial reduction in systemic vascular resistance. Pregnancy is also associated with an increase in venous capacitance and a parallel large expansion of blood volume.3 The purpose of these maternal changes is to promote blood flow to the implantation site to optimize fetal growth, increase maternal renal excretory functions because of excess maternal, placental, and fetal metabolic demand, and to withstand hemorrhage at delivery. Hemodynamic and vascular adaptations that occur in normal pregnancy are disrupted in women who develop preeclampsia (PE), a hypertensive disorder that affects 2% to 8% of all pregnancies worldwide.4 PE is characterized by new-onset hypertension (blood pressure consistently >140/90 mm Hg) after 20 weeks of gestation, accompanied by evidence of organ injury (proteinuria, thrombocytopenia, renal or liver impairment, pulmonary edema, or cerebral/visual symptoms suggesting cerebral cortical dysfunction), as redefined by the American College of Obstetrics and Gynecology in 2013.5 PE can be subdivided into early-onset PE (before 34 weeks of gestation), the more severe subset of the disease with smaller birthweight neonates and a higher rate of recurrence, and late-onset PE (after 37 weeks of gestation).6 Once established, PE often advances until delivery and may persist for some time in the postpartum period.7–10 Recent population-based cohort studies have concluded that women with a history of PE are at …

Placental hypoxia, endoplasmic reticulum stress and maternal endothelial sensitisation by sFLT1 in pre-eclampsia

The human placenta is a multifunctional organ that grows and adapts to increasing fetal demand and fluctuations in the intrauterine environment. It is subjected to physiological and pathological changes in local oxygenation, both of which induce adaptive changes. In early pregnancy a low PO2 is the normal physiological state and this is not hypoxic—there is no perturbation of ATP/ADP ratios and, if the placenta is sampled very rapidly, little HIF1α is detected in human first-trimester placental villi. Nonetheless, HIF1α can be increased and activated by culture. However, the placenta does show evidence of stress under pathological conditions. For example, in cases of pre-eclampsia where delivery by caesarean section is necessitated for maternal well-being before 34 weeks’ gestation, placental endoplasmic reticulum stress is evident. Cases delivered ≥34 weeks are indistinguishable from normal term controls. One consequence of placental stress, whether oxidative, related to the endoplasmic reticulum or immunological, is that factors are released into the maternal circulation, which affects the endothelium, leading to the maternal syndrome. Soluble FLT1 may contribute directly to this and the most likely mechanism is direct action on the maternal endothelium. sFLT1 is able to form a heterodimer with cell surface VEGF receptors and is therefore able to have a dominant negative effect (in addition to acting as a competitive inhibitor by simply binding vascular endothelial growth factor A [VEGFA] and placental growth factor [PlGF]). This leads in vitro to the sensitisation of endothelial cells to low levels of TNFα.

Maternal pregnancy weight gain and cord blood iron status are associated with eosinophilia in infancy.

Allergic disease is multifactorial in origin. Because iron nutrition affects immune responses and maternal pregnancy weight gain impairs fetal iron delivery while increasing fetal demands for growth, the study examined maternal pregnancy weight gain, newborn iron status and an index of atopic disease, infant eosinophilia. Within a larger prospective study of healthy newborns at risk for developing iron deficiency anemia, umbilical cord iron indicators were compared to infant eosinophil counts. Infants who developed eosinophilia exhibited higher cord reticulocyte-enriched zinc protoporphyrin/heme ratio, P<0.05 and fewer cord ferritin values in the highest (best) quartile, P<0.05. If cord ferritin was in the upper three quartiles, the negative predictive value for infant eosinophilia was 90%. High maternal pregnancy weight gain predicted infant eosinophil counts, P<0.04, and contributed to cord ferritin predicting eosinophilia, P<0.003. Poor fetal iron status may be an additional risk factor for infant eosinophilia.

Thyroid hormone and the developing hypothalamus.

Thyroid hormone (TH) plays an essential role in normal brain development and function. Both TH excess and insufficiency during development lead to structural brain abnormalities. Proper TH signaling is dependent on active transport of the prohormone thyroxine (T4) across the blood-brain-barrier and into brain cells. In the brain T4 undergoes local deiodination into the more active 3,3′,5-triiodothyronine (T3), which binds to nuclear TH receptors (TRs). TRs are already expressed during the first trimester of pregnancy, even before the fetal thyroid becomes functional. Throughout pregnancy, the fetus is largely dependent on the maternal TH supply. Recent studies in mice have shown that normal hypothalamic development requires intact TH signaling. In addition, the development of the human lateral hypothalamic zone coincides with a strong increase in T3 and TR mRNA concentrations in the brain. During this time the fetal hypothalamus already shows evidence for TH signaling. Expression of components crucial for central TH signaling show a specific developmental timing in the human hypothalamus. A coordinated expression of deiodinases in combination with TH transporters suggests that TH concentrations are regulated to prevent untimely maturation of brain cells. Even though the fetus depends on the maternal TH supply, there is evidence suggesting a role for the fetal hypothalamus in the regulation of TH serum concentrations. A decrease in expression of proteins involved in TH signaling towards the end of pregnancy may indicate a lower fetal TH demand. This may be relevant for the thyrotropin (TSH) surge that is usually observed after birth, and supports a role for the hypothalamus in the regulation of TH concentrations during the fetal period anticipating birth.

Placental glucose transfer: a human in vivo study.

ObjectivesThe placental transfer of nutrients is influenced by maternal metabolic state, placenta function and fetal demands. Human in vivo studies of this interplay are scarce and challenging. We aimed to establish a method to study placental nutrient transfer in humans. Focusing on glucose, we tested a hypothesis that maternal glucose concentrations and uteroplacental arterio-venous difference (reflecting maternal supply) determines the fetal venous-arterial glucose difference (reflecting fetal consumption).MethodsCross-sectional in vivo study of 40 healthy women with uncomplicated term pregnancies undergoing planned caesarean section. Glucose and insulin were measured in plasma from maternal and fetal sides of the placenta, at the incoming (radial artery and umbilical vein) and outgoing vessels (uterine vein and umbilical artery).ResultsThere were significant mean (SD) uteroplacental arterio-venous 0.29 (0.23) mmol/L and fetal venous-arterial 0.38 (0.31) mmol/L glucose differences. The transplacental maternal-fetal glucose gradient was 1.22 (0.42) mmol/L. The maternal arterial glucose concentration was correlated to the fetal venous glucose concentration (r = 0.86, p<0.001), but not to the fetal venous-arterial glucose difference. The uteroplacental arterio-venous glucose difference was neither correlated to the level of glucose in the umbilical vein, nor fetal venous-arterial glucose difference. The maternal-fetal gradient was correlated to fetal venous-arterial glucose difference (r = 0.8, p<0.001) and the glucose concentration in the umbilical artery (r = −0.45, p = 0.004). Glucose and insulin concentrations were correlated in the mother (r = 0.52, p = 0.001), but not significantly in the fetus. We found no significant correlation between maternal and fetal insulin values.ConclusionsWe did not find a relation between indicators of maternal glucose supply and the fetal venous-arterial glucose difference. Our findings indicate that the maternal-fetal glucose gradient is significantly influenced by the fetal venous-arterial difference and not merely dependent on maternal glucose concentration or the arterio-venous difference on the maternal side of the placenta.

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Objectives A well-developed placenta is essential for a healthy pregnancy. A widespread oxidative stress and free radical damage and the resultant damage of the maternal endothelial cells have been implicated in preeclampsia. Nuclear factor-erythroid 2-related factor 2 (Nrf2) is a potent transcription activator that regulates the expression a group of antioxidants and detoxication enzymes. Recent discussion about a link between Nrf2 and vascular angiogenic balance in preeclampsia has focused on the downstream target protein, heme oxygenase-1 (HO-1). The effect Nrf2 on placental development has not been yet discussed. In particular, we evaluated the placental and fetal growth, the feto-placental phenotype and oxidative stress status in Nrf2 knockout (Nrf2−/−) mice at different stages of pregnancy. Methods Placentae from Nrf2−/− and wild type Nrf2+/+ were collected on days 13.5, 15.5 and 18.5 post coitum. We performed H&E and Periodeic Acid Schiff on paraffin-embedded samples. Markers of oxidative stress, VEGF, Nrf2, 4-Hydroxynonenal (4-HNE) and HO-1 were assessed by immunohistochemical methods. Results At 18.5 days post coitum the fetal weight in Nrf2−/− was reduced (P In the placentas of Nrf2−/− the labyrinth cells showed increased levels of the lipid peroxidation product 4-hydroxynonenal (4-HNE). Furthermore, in Nrf2−/−-placentas there was a significant decrease in HO-1, an important endogenous antioxidant enzyme and a key regulator of trophoblast invasion and placental function. The labyrinth zones of these placentas were smaller when compared to Nrf2+/+-ones. Conclusions Our results indicated that deficiency in Nrf2 signaling may reduce the placental functions, increase the levels of oxidative stress, which may negatively affect the nutrient transfer capacity to meet fetal growth demands. Disclosures N. Kweider: None. J. Lambertz: None. T. Pufe: None. C.J. Wruck: None. W. Rath: None.

Effect of obesity on human reproduction

Obesity influences human reproduction in several ways. Obesity is associated with sub-fertility and this effect is noticeable already at BMI 25 kg/m2. As many as 6 - 9% of the female population of child-bearing age suffer from polycystic ovary syndrome, i.e. anovulatory infertility, among whom more than half are obese. Bariatric surgery has become increasingly common in women of childbearing ages, and poses specific problem when women later become pregnant. In addition, the obesity epidemic has also reached the pregnant population of developed countries. The challenge for clinicians within the obstetric field is three-fold; first, obesity is associated with a number of obstetric risks that may have fatal or long-term consequences for both mother and offspring such as preeclampsia, preterm birth, intrauterine death, and congenital malformations. Secondly, while the obvious cure for obesity is weight loss, this is not an appropriate strategy during pregnancy when fetal nutritional demands are at stake. Finally, Caesarean section delivery is not the answer to the problem; the adverse neonatal outcomes are unaffected by mode of delivery, and the anesthetic risks, that are generally elevated in pregnant women, are even more imminent in obese pregnant women.

Clinical efficacy of Punarnava Mandura and Dhatri Lauha in the management of Garbhini Pandu (anemia in pregnancy).

Introduction:India is one of the countries with high prevalence of anemia during pregnancy. Anemia in pregnancy is multifactorial. Iron deficiency anemia is the most common conditions in a pregnant woman. As per ayurvedic classics, this condition occurs due to improper Rasa Dhatu in mother and continuously increasing fetal demands and is considered as Rasa Pradoshajavikara. A large number of Lauha preparations have been used widely for centuries to cure Anemia.Aim:To evaluate efficacy of Punarnava Mandura and Dhatri Lauha on Garbhini Pandu.Materials and Methods:A total 24 pregnant women with symptoms of Garbhini Pandu were randomly divided into two groups (A and B). In Group A (n = 15) Punarnava Mandura, two tablets (each of 500 mg) thrice a day with one cup (100 ml) of buttermilk and in Group B (n = 9) Dhatri Lauha, two tablets (each of 500 mg) thrice a day with luke warm water were administered for 90 days. The assessment was done with subjective parameters such as pallor, general weakness, dyspnea, etc., and objective parameters such as hematological parameters. Results were statistically analyzed using Student's t-test.Results:The results revealed that overall clinical improvement was better in Group A when compared to Group B. Hemoglobin was increased in patients of Group A, which was statistically significant. No adverse drug reaction was observed during the treatment period.Conclusion:Punarnava Mandura is more effective on Garbhini Pandu in comparison to Dhatri Lauha.

Uterine Spiral Artery Remodeling: The Role of Uterine Natural Killer Cells and Extravillous Trophoblasts in Normal and High-Risk Human Pregnancies.

The process of uterine spiral artery remodeling in the first trimester of human pregnancy is an essential part of establishing adequate blood perfusion of the placenta that will allow optimal nutrient/waste exchange to meet fetal demands during later development. Key regulators of spiral artery remodeling are the uterine natural killer cells and the invasive extravillous trophoblasts. The functions of these cells as well as regulation of their activation states and temporal regulation of their localization within the uterine tissue are beginning to be known. In this review, we discuss the roles of these two cell lineages in arterial remodeling events, their interaction/influence on one another and the outcomes of altered temporal, and spatial regulation of these cells in pregnancy complications.

Placental amino acid transporter function adapts to maternal and fetal nutrient conditions

s / Placenta 35 (2014) A1eA23 A10 O-026. PLACENTAL AMINO ACID TRANSPORTER FUNCTION ADAPTS TO MATERNAL AND FETAL NUTRIENT CONDITIONS Eiji Shibata David, J. Askew, Yukiyo Aiko, Chiharu Tomonaga, Satoshi Aramaki, Hirohide Inagaki, Toru Hachisuga. Department of Obstetrics and Gynecology, University of Occupational and Environmental Health, Japan Background: Studies suggest that placental nutrient uptake activity is responsive to both maternal and fetal nutrient demands. We hypothesize that under conditions of limited nutrient availability to the fetus, as often present in preeclampsia (PE), IUGR, and insufficient weight-gain during pregnancy, a general adaptive response aimed to increase amino acid transport activity may be observed in the placenta. Method: A total of 40 placentas from full-term (n1⁄410) and pre-term (n1⁄410) normal pregnancies, IUGR (n1⁄410), and PE (n1⁄410) associated pregnancies were looked at by immunohistochemistry followed by relative qualitative scoring to compare expression levels and localization of System L, ASCT2, and mTOR proteins. Result: Syncytiotrophoblast (ST) in placenta of pregnancies complicated by IUGR or PE showed significant increases in the levels of 4F2hc and LAT1 compared to both full-term control and pre-term pregnancies seperately. Elevated mTOR protein was uniquely higher in IUGR placentas compared to full-term controls. Total cellular ASCT2 transporter protein levels were similar in all groups, however, levels of ASCT2 protein localized to the ST microvillous membrane (MVM) were significantly lower in IUGR compared to both full-term and pre-term pregnancies. Additionally, ASCT2 and mTOR protein levels were positively associated with maternal prepregnancy BMI. Conclusion: First, in conditions of limited nutrient availability, such as PE or IUGR, there is an overall increase in the level of System L and mTOR protein expression in the ST, suggestive of an adaptive response. Second, a decrease in ASCT2 protein at the ST MVM suggests a post-translational event that may decrease AAT activity in IUGR placentas. Third, a physiological link between transporter expression and pre-pregnancy BMI is suggested based upon a positive association observed with ASCT2 and mTOR expression values. O-027. ENDOMETRIAL PERIVASCULAR CELLS ESTABLISH UNIQUE CYTOKINE GRADIENTS IN DECIDUAL PROCESS Keisuke Murakami , Keiji Kuroda , Shintaro Makino , Atsuo Itakura , Satoru Takeda , Jan J. Brosens . Department of Obstetrics and Gynaecology, Juntendo University Faculty of Medicine, Japan; Division of Reproductive Health, Clinical Science Research Laboratories, Warwick Medical School, University of Warwick, Japan Aim: The endometrial perivascular microenvironment is rich in mesenchymal stem-like cells that express type 1 integral membrane protein Sushi domain containing 2 (SUSD2) but the role of these cells in the decidual transformation of this tissue in pregnancy is unknown. We used an antibody directed against SUSD2 to isolate perivascular (SUSD2+) and non-perivascular (SUSD2-) fibroblasts from mid-luteal biopsies. Method: SUSD2+ and SUSD2cells were purified from mid-luteal endometrial biopsies by magnetic bead separation and each cell population were expanded in vitro, then, subjected to RNA-seq analysis or differentiation experiments induced by cAMP andMPA to assess secretome profile. Result: On average, positive cells comprised 6.8% of endometrial stromal cells and 6-fold enriched in clonogenic cells. RNA sequencing revealed that cultures derived from SUSD2+ progenitor cells remain phenotypically distinct by the enrichment of novel and established endometrial perivascular signature genes including AOC3, NOTCH3, ELN, MYH11, DES, ACTA2, MCAM, and CSPG4. Decidualization transformed perivascular SUSD2+ -derived cells into the dominant source of a range of chemokines and cytokines, including CCL7, LIF and LTA. Conclusion: Our findings confirmed that SUSD2+ -derived cells remain the expression of perivascular signature genes even after in-vitro culture. Decidual response is spatially organized at the feto-maternal interface with differentiating perivascular cells establishing distinct cytokine and chemokine gradients that could have the key role in decidual process. O-028. LOCALIZATION OF TRPV5 (TRANSIENT RECEPTOR POTENTIAL VANILLOID RECEPTOR 5) PROTEIN IN HUMAN PLACENTAL TROPHOBLASTS Yoko Aoyama, David J. Askew, Yukiyo Aiko, Chiharu Tomonaga, Satoshi Aramaki, Hirohide Inagaki, Toru Hachisuga, Eiji Shibata. Department of Obstetrics and Gynecology, University of Occupational and Environmental

Effects of partial pressure of oxygen on the modulation of syncytiotrophoblast potassium channels by reactive oxygen species

s / Placenta 35 (2014) A1eA112 A97 mouse knockout models of impaired sulfonation of structural molecules important for foetal development. Conclusion: Our novel mouse model is providing valuable insight into the critical role of placental sulphate transporters in meeting foetal nutrient demands during gestation. P2.115-N. PLACENTAL URIC ACID TRANSPORTER GLUT9 IS MODULATED BY FREE IODINE Benjamin P. Luscher , Michael Fine , Camilla Marini , Benjamin Clemencon , Christiane Albrecht , Matthias A. Hediger , Daniel V. Surbek , Marc U. Baumann a,b Department of Obstetrics and Gynecology, University Hospital of Bern, Bern, Switzerland; Department of Clinical Research, University of Bern, Bern, Switzerland; c Institute for Biochemistry and Molecular Medicine, University of Bern, Bern, Switzerland Objectives: Materno-fetal transplacental transport is crucial for the fetal well-being. The altered expression of placental transport proteins under specific pathophysiological conditions may affect the intrauterine environment. Pre-eclampsia is often associated with high maternal uric acid serum levels. The regulation of the placental uric transport system and its transporter glucose transporter (GLUT)-9 are not fully understood yet. The aim of this study was to investigate the placental urate transport and to characterize its transporter GLUT9. Methods: In this study we used a transepithelial transport (Transwell®) model to assess uric acid transport activity. Electrophysiological techniques and radioactive ligand up-take assays were used to measure transport activity of GLUT9 expressed in Xenopus oocytes. Results: In the Transwell/ model uric acid is transported across the BeWo choriocarcinoma cell monolayer with 530 pmol/min at the linear stage. We could successfully over-express GLUT9 using the Xenopus laevis oocytes expression system. Chloride modulates the urate transport system: interestingly replacing chloride with iodine resulted in a complete loss of urate transport activity. We determined the IC50 of iodine at 30uM concentration. In radioactiveup-takeexperiments iodinehadnoeffectonuric acid transport. Conclusions: In vitro the “materno-fetal” transport of uric acid is slow. This indicates that in vivo the child is protected from short-term fluctuations of maternal uric acid serum concentrations. The different results regarding iodine-mediated regulation of GLUT9 transport activity between electrophysiological and radioactive ligand uptake experiments may suggest that iodine does not directly inhibit uric acid transport, but changes the mode of up-take from an electrogenic to an electroneutral transport. GLUT9 is not an uric acid uniporter, there are more ions involved in the transport. This may allow regulating uric acid transport by the change from an active to a passive transport. P2.116. UPTAKE MECHANISM OF AN ESTRIOL PRECURSOR, 16a-HYDROXY DEHYDROEPIANDROSTERONE SULFATE, AT THE BASAL PLASMA MEMBRANE OF HUMAN TERM PLACENTA Masatoshi Tomi , Hiromi Eguchi , Tomohiro Nishimura , Tetsuo Maruyama , Emi Nakashima a Keio University Faculty of Pharmacy, Tokyo, Japan; Keio University School of Medicine, Tokyo, Japan Objectives: Estriol is mostly secreted from placental syncytiotrophoblasts during pregnancy. 16a-Hydroxy dehydroepiandrosterone sulfate (16a-OH DHEAS) is an estriol precursor, which is synthesized by fetal liver-specific CYP3A7 (16a-hydroxylase). To achieve placental estriol synthesis, syncytiotrophoblasts require organic anion transporter(s) for 16a-OH DHEAS uptake at the basal plasma membrane (BM) facing fetal circulation. The purpose of this study is to clarify the mechanism underlying 16a-OH DHEAS uptake at the BM of human placental syncytiotrophoblasts. Methods: The uptake of [3H]16a-OH DHEAS was characterized using basal-enriched plasma membrane vesicles (BMVs) derived from human term placenta. The expression of transporters in BMVs was determined by western blot analysis. Results:Proteinexpressionsof organic anion transporter (OAT)4 (SLC22A11) and organic anion transporting polypeptide 2B1 (SLCO2B1)were enriched in human placental BMVs compared with crude membrane fractions, which is consistent with immunohistochemical observations of the basal localization of these transporters in syncytiotrophoblasts. Uptake of [3H]16a-OH DHEAS by BMVs was sodiumand chloride-independent and was trans-stimulated by preloaded glutarate. The uptake of [3H]16a-OH DHEAS was significantly cis-inhibited byDHEAS, estrone sulfate, andbromosulfophthalein, but not by cyclosporin A, tetraethylammonium, p-aminohippuric acid, and cimetidine. These transport characteristics of [3H]16a-OHDHEAS are in good agreement with those in human OAT4-transfected COS7 cells. Conclusion: OAT4 expressed at the basal plasma membrane of the syncytiotrophoblast appears to play a predominant role in the placental uptake of 16a-OH DHEAS from the fetal circulation and contribute to estriol synthesis during pregnancy. P2.117. NANOPARTICLE INTERACTION WITH EARLY HUMAN PLACENTA: PLACENTAL BARRIER MATTERS? Liudmila Nikitina , Gottfried Dohr , Herbert Juch a,b a Institute of Cell Biology, Histology and Embryology, Medical University of Graz, Graz, Austria; b Institute of Human Genetic, Medical University of Graz, Graz,

Fetal response to maternal hunger and satiation - novel finding from a qualitative descriptive study of maternal perception of fetal movements.

BackgroundMaternal perception of decreased fetal movements is a specific indicator of fetal compromise, notably in the context of poor fetal growth. There is currently no agreed numerical definition of decreased fetal movements, with the subjective perception of a decrease on the part of the mother being the most significant definition clinically. Both qualitative and quantitative aspects of fetal activity may be important in identifying the compromised fetus. Yet, how pregnant women perceive and describe fetal activity is under-investigated by qualitative means. The aim of this study was to explore normal fetal activity, through first-hand descriptive accounts by pregnant women.MethodsUsing qualitative descriptive methodology, interviews were conducted with 19 low-risk women experiencing their first pregnancy, at two timepoints in their third trimester. Interview transcripts were later analysed using qualitative content analysis and patterns of fetal activity identified were then considered along-side the characteristics of the women and their birth outcomes.ResultsThis paper focuses on a novel finding; the description by pregnant women of fetal behaviour indicative of hunger and satiation. Full findings will be presented in later papers. Most participants (74% 14 of 19) indicated mealtimes were a time of increased fetal activity. Eight participants provided detailed descriptions of increased activity around meals, with seven (37% 7 of 19) of these specifying increased fetal activity prior to meals or in the context of their own hunger. These movements were interpreted as a fetal demand for food often prompting the mother to eat. Interestingly, the women who described increased fetal activity in the context of hunger subsequently gave birth to smaller infants (mean difference 364 gm) than those who did not describe a fetal response to hunger.ConclusionsFood seeking behaviour may have a pre-birth origin. Maternal-fetal interaction around mealtimes could constitute an endocrine mediated communication, in the interests of maintaining optimal intrauterine conditions. Further research is warranted to explore this phenomenon and the potential influence of feeding on the temporal organisation of fetal activity in relation to growth.

The role of placental nutrient sensing in maternal-fetal resource allocation.

The placenta mediates maternal-fetal exchange and has historically been regarded as a passive conduit for nutrients. However, emerging evidence suggests that the placenta actively responds to nutritional and metabolic signals from the mother and the fetus. We propose that the placenta integrates a multitude of maternal and fetal nutritional cues with information from intrinsic nutrient-sensing signaling pathways to match fetal demand with maternal supply by regulating maternal physiology, placental growth, and nutrient transport. This process, which we have called placental nutrient sensing, ensures optimal allocation of resources between the mother and the fetus to maximize the chances for propagation of parental genes without jeopardizing maternal health. We suggest that these mechanisms have evolved because of the evolutionary pressures of maternal undernutrition, which result in decreased placental growth and down-regulation of nutrient transporters, thereby limiting fetal growth to ensure maternal survival. These regulatory loops may also function in response to maternal overnutrition, leading to increased placental growth and nutrient transport in cases of maternal obesity or gestational diabetes. Thus, placental nutrient sensing modulates maternal-fetal resource allocation to increase the likelihood of reproductive success. This model implies that the placenta plays a critical role in mediating fetal programming and determining lifelong health.

Placental heme receptor LRP1 correlates with the heme exporter FLVCR1 and neonatal iron status

LDL receptor-related protein 1 (LRP1) is a transmembrane receptor highly expressed in human placenta. It was recently found to be the receptor for heme and its plasma-binding protein hemopexin (Hx) and is integral to systemic heme clearance. Little is known about systemic concentrations of Hx during pregnancy and whether maternal Hx and placental LRP1 contributes to fetal iron (Fe) homeostasis during pregnancy. We hypothesized that placental LRP1 would be upregulated in maternal/neonatal Fe insufficiency and would be related to maternal circulating Hx. Placental LRP1 expression was assessed in 57 pregnant adolescents (14-18 years) in relationship with maternal and cord blood Fe status indicators (hemoglobin (Hb), serum ferritin, transferrin receptor), the Fe regulatory hormone hepcidin and serum Hx. Hx at mid-gestation correlated positively with Hb at mid-gestation (r=0.35, P=0.02) and Hx at delivery correlated positively with cord hepcidin (r=0.37, P=0.005). Placental LRP1 protein expression was significantly higher in women who exhibited greater decreases in serum Hx from mid-gestation to term (r=0.28, P=0.04). Significant associations were also found between placental LRP1 protein with cord hepcidin (r=-0.29, P=0.03) and placental heme exporter feline leukemia virus C receptor 1 (r=0.34, P=0.03). Our data are consistent with a role for placental heme Fe utilization in supporting fetal Fe demands.

Differential levels of amino acid transporters System L and ASCT2, and the mTOR protein in placenta of preeclampsia and IUGR.

BackgroundSufficient amino acid transport activity (AAT) is indispensable for appropriate fetal growth. Studies suggest that placental nutrient uptake activity is responsive to both maternal and fetal nutrient demands. We hypothesize that under conditions of limited nutrient availability to the fetus, as often present in preeclampsia, intrauterine growth restriction (IUGR), and insufficient weight-gain during pregnancy, a general adaptive response aimed to increase amino acid transport activity may be observed in the placenta.MethodA total of 40 placentas from full-term (n = 10) and pre-term (average gestational period = 34.8 weeks, n = 10) normal pregnancies, IUGR (n = 10), and preeclampsia (n = 10) associated pregnancies were looked at by immunohistochemistry followed by relative qualitative scoring to compare expression levels and localization of System L, ASCT2, and mTOR proteins.ResultMicrovillous syncytiotrophoblast (ST) in placenta of pregnancies complicated by IUGR or preeclampsia (PE) showed significant increases in the levels of System L amino acid transport proteins 4F2hc and LAT1 compared to both full-term control and pre-term (early gestation control) pregnancies seperately (p < 0.05). Elevated mTOR protein was uniquely higher in IUGR placentas compared to full-term controls (P = 0.0026). Total cellular ASCT2 transporter protein levels were similar in all groups, however, levels of ASCT2 protein localized to the ST microvillous membrane (MVM) were significantly lower in IUGR compared to both full-term and pre-term pregnancies (P = 0.0006, 0.03, respectively). Additionally, ASCT2 and mTOR protein levels were positively associated with maternal pre-pregnancy BMI (P = 0.046, 0.048, respectively).ConclusionThere are three important findings based upon the present study. First, in conditions of limited nutrient availability, such as PE or IUGR, there is an overall increase in the level of System L and mTOR protein expression in the ST, suggestive of an adaptive response. Second, a decrease in ASCT2 protein at the ST MVM suggests a post-translational event that may decrease AAT activity in IUGR placentas. Third, a physiological link between transporter expression and pre-pregnancy BMI is suggested based upon a positive association observed with ASCT2 and mTOR expression values.

Effect of maternal cardiovascular conditions and risk factors on offspring cardiovascular disease.

Cardiovascular diseases (CVDs) constitute a particular challenge during pregnancy because physiological changes and fetal demands create an additional burden and fetal safety concerns limit treatment options. Other articles of this series review the physiological changes during pregnancy, the management of cardiovascular conditions most likely to endanger maternal and fetal health, and their long-term consequences for the cardiovascular health of the mother. This article focuses on their consequences in offspring. Developmental programming resulting from in utero or early postnatal exposure to specific risk factors is increasingly recognized to determine CVD in later life. Clinically manifest cardiovascular conditions during pregnancy such as preeclampsia/eclampsia and gestational hypertension may not only affect maternal health and pregnancy outcome but also reduce fetal growth, which is associated with increased adult CVD. Furthermore, extensive evidence indicates that maternal cardiovascular risk factors (hypercholesterolemia, smoking, obesity, and diabetes mellitus) program endothelial dysfunction, insulin resistance (IR), hypertension, atherosclerosis, and type 2 diabetes mellitus in offspring. The mechanisms of developmental programming remain largely unknown, but specific factors affecting in utero programming have been identified and experimental models established in which causal relationships, mechanisms, and protective effects of maternal treatment can be explored. These findings suggest that interventions targeting in utero programming may reduce the susceptibility to CVD in offspring, a high priority given the increasing prevalence of obese and dysmetabolic mothers and the concomitant increase in lifestyle risk in children. However, neither the cardiovascular consequences of many maternal risk factors nor the efficacy of maternal prevention and treatment is sufficiently supported by prospective double-blind studies. The present review provides a critical evaluation of the associations between maternal cardiovascular conditions during pregnancy and offspring CVD, the role of low birth weight, and the evidence for developmental programming of CVD by other maternal cardiovascular risk factors. It then proposes an integrated view of …

Docosahexaenoic acid supplementation during pregnancy: a potential tool to prevent membrane rupture and preterm labor.

Polyunsaturated fatty acids (PUFAs) are required to maintain the fluidity, permeability and integrity of cell membranes. Maternal dietary supplementation with ω-3 PUFAs during pregnancy has beneficial effects, including increased gestational length and reduced risk of pregnancy complications. Significant amounts of ω-3 docosahexaenoic acid (DHA) are transferred from maternal to fetal blood, hence ensuring high levels of DHA in the placenta and fetal bloodstream and tissues. Fetal DHA demand increases exponentially with gestational age, especially in the third trimester, due to fetal development. According to the World Health Organization (WHO) and the Food and Agriculture Organization of the United Nations (FAO), a daily intake of DHA is recommended during pregnancy. Omega-3 PUFAs are involved in several anti-inflammatory, pro-resolving and anti-oxidative pathways. Several placental disorders, such as intrauterine growth restriction, premature rupture of membranes (PROM) and preterm-PROM (pPROM), are associated with placental inflammation and oxidative stress. This pilot study reports on a preliminary evaluation of the significance of the daily DHA administration on PROM and pPROM events in healthy pregnant women. Further extensive clinical trials will be necessary to fully elucidate the correlation between DHA administration during pregnancy and PROM/pPROM occurrence, which is related in turn to gestational duration and overall fetal health.

Challenges to human uniqueness: bipedalism, birth and brains

AbstractHistorically, paleoanthropology has focused on explaining human uniqueness. This review paper highlights several recent challenges to key features that have been considered to be exclusive to hominins, testing three long‐standing theories in evolutionary anthropology. The knuckle‐walking quadrupedalism model describes the evolution of modern gorillines, panins and hominins from a common, knuckle‐walking ancestor. But the homology of knuckle‐walking in African apes has been questioned. Although habitual bipedalism is unique to humans, it may have developed from occasional bipedalism in ancestors, without a quadrupedal stage. The obstetric dilemma seeks to explain the helplessness of human infants. The timing of human birth is seen as uniquely constrained by fetal head size and maternal pelvic width. An alternative hypothesis suggests that birth occurs when fetal demand for energy threatens to exceed maternal supply; this mechanism also appears to operate in other mammals. The expensive tissue hypothesis suggests that the expansion of energy‐hungry brain tissue in hominins was offset by a reduction in gut tissue. But although large brains are correlated with both good quality diets and relatively short guts in primates, the causes of this correlation are not clear. An alternative suggestion is that the large human brain is paid for by savings in other functions, such as locomotion and reproduction, and that a concurrent expansion of low‐cost adipose tissue in humans keeps metabolic rate low. In the past, paleoanthropology may have focused on defining a boundary between humans and animals, but recent research has seen a shift of focus to exploring humans as animals. Aspects of bipedalism, birth and brains have been considered to be exclusively human, but in the last few years even these have been eroded. It is the package of features that characterizes Homo sapiens that is unique.

Mammalian viviparity: a complex niche in the evolution of genomic imprinting

Evolution of mammalian reproductive success has witnessed a strong dependence on maternal resources through placental in utero development. Genomic imprinting, which has an active role in mammalian viviparity, also reveals a biased role for matrilineal DNA in its regulation. The co-existence of three matrilineal generations as one (mother, foetus and post-meiotic oocytes) has provided a maternal niche for transgenerational co-adaptive selection pressures to operate. In utero foetal growth has required increased maternal feeding in advance of foetal energetic demands; the mammary glands are primed for milk production in advance of birth, while the maternal hypothalamus is hormonally primed by the foetal placenta for nest building and post-natal care. Such biological forward planning resulted from maternal-foetal co-adaptation facilitated by co-expression of the same imprinted allele in the developing hypothalamus and placenta. This co-expression is concurrent with the placenta interacting with the adult maternal hypothalamus thereby providing a transgenerational template on which selection pressures may operate ensuring optimal maternalism in this and the next generation. Invasive placentation has further required the maternal immune system to adapt and positively respond to the foetal allotype. Pivotal to these mammalian evolutionary developments, genomic imprinting emerged as a monoallelic gene dosage regulatory mechanism of tightly interconnected gene networks providing developmental genetic stability for in utero development.

Knowledge on management of anemia during pregnancy: A descriptive study

Background of the study: The growing fetus depends entirely on its mother's healthy body for all needs. However, sometimes it can be a time of fear of suffering and death, in case women begin pregnancy with low or absent stores of iron because of previous pregnancy, poor iron intake, substance abuse; increased fetal demands of iron leads to iron deficiency anemia. Iron deficiency anemia is the most common form of malnutrition in the world and is the eighth leading cause of death in pregnant women in developing countries leading to the low birth weight, which is in turn an important risk factor for infant mortality. Objectives: To determine the knowledge of antenatal mothers regarding management of anemia during pregnancy. Materials and Methods: Non-experimental descriptive study was conducted to assess the knowledge of antenatal mothers from Yenepoya Medical College Hospital. A sample size consists of 50 antenatal mothers were selected through non-probability purposive sampling. The data was collected by using pretested structured knowledge questionnaire. Data was analyzed using SPSS version 16 and the results expressed as proportions. Results: The majority of the antenatal mothers (54%) had satisfactory knowledge, 38% had poor knowledge, and 8% had good knowledge regarding anemia during pregnancy. Conclusion: The overall knowledge in the study population was 29.9%. Hence, the researcher emphasizes the need for more research to improve the knowledge of antenatal mothers on anemia during pregnancy.