Irene Cetin

Umbilical amino acid concentrations in normal and growth-retarded fetuses sampled in utero by cordocentesis

Fetal plasma amino acid concentrations were obtained by cordocentesis at midgestation in 11 normal (appropriate for gestational age) fetuses and at late gestation in 12 small-for-gestational-age fetuses, and at cesarean section in 14 normal term infants. In normal fetuses total molar amino acid concentrations and fetal/maternal total molar concentration ratios did not change significantly between the second and third trimesters. Fetal and maternal concentrations of most amino acids were significantly correlated at both midgestation and late gestation. Small-for-gestational-age fetuses had significantly lower concentrations of total alpha-aminonitrogen; this was mainly because of a reduction of the branched chain amino acids valine, leucine, and isoleucine, and of lysine and serine. Maternal arterial concentrations of phenylalanine, arginine, histidine, and alanine were elevated in small-for-gestational-age pregnancies. Thus there are only minor changes in amino acid concentrations between midgestation and late gestation in normal fetuses with a constant fetal/maternal ratio. In small-for-gestational-age infants a significant reduction in alpha-aminonitrogen and in most essential amino acids was demonstrable in utero weeks before delivery.

Role of micronutrients in the periconceptional period

BACKGROUNDnMicronutrient deficiencies have been associated with significantly high reproductive risks, ranging from infertility to fetal structural defects and long-term diseases. In this review we focus on the reproductive risks related to some micronutrients during the periconceptional period, a critical step in determining fetal development and health due to the potential onset of several disorders.nnnMETHODSnEmbase Medline and PubMed databases, Google-indexed scientific literature and periodics from on-line University of Milan Bibliotecary Service were searched to identify relevant publications. In vivo human studies were mainly searched for, but when needed animal studies as well as in vitro and cell culture experiments were also considered.nnnRESULTSnFertility, conception, implantation, fetal organogenesis and placentation are the critical stages potentially affected by nutrition during the periconceptional period. Reactive oxygen species (ROS) and total homocysteine (tHcy) plasma levels are factors involved in the respective mechanisms. The preconceptional period is particularly important since it affects both fertility and the early stages of gestation. Micronutrients dietary intake and maternal status affect the different phases of the onset and development of pregnancy as well as of the conceptus.nnnCONCLUSIONnAlthough human studies are scarce, and conclusive evidence is provided solely for periconceptional folate and prevention of neural tube defects (NTDs), the overall data indicate that micronutrients may affects fertility, embryogenesis and placentation, and the prophylactic use of some micronutrients may be useful in preventing several adverse pregnancy outcomes. Efforts to increase awareness of a healthy diet should be strengthened not only throughout pregnancy but also before. However, further researches in humans are necessary to optimise periconceptional micronutrient requirements.

State of the art: reproduction and pregnancy in rheumatic diseases

Throughout the last decade, increasing awareness has been raised on issues related to reproduction in rheumatic diseases including basic research to clarify the important role of estrogens in the etiology and pathophysiology of immune/inflammatory diseases. Sub- or infertility is a heterogeneous condition that can be related to immunological mechanisms, to pregnancy loss, to disease burden, to therapy, and to choices in regard to family size. Progress in reproductive medicine has made it possible for more patients with rheumatic disease to have children. Active disease in women with rheumatoid arthritis (RA) affects their childrens birth weight and may have long-term effects on their future health status. Pregnancy complications as preeclampsia and intrauterine growth restriction are still increased in patients with systemic lupus erythematosus (SLE) and antiphospholipid syndrome (APS), however, biomarkers can monitor adverse events, and several new therapies may improve outcomes. Pregnancies in women with APS remain a challenge, and better therapies for the obstetric APS are needed. New prospective studies indicate improved outcomes for pregnancies in women with rare diseases like systemic sclerosis and vasculitis. TNF inhibitors hold promise for maintaining remission in rheumatological patients and may be continued at least in the first half of pregnancy. Pre-conceptional counseling and interdisciplinary management of pregnancies are essential for ensuring optimal pregnancy outcomes.

Micronutrients in pregnancy: Current knowledge and unresolved questions

Micronutrient status is increasingly recognized to play an important role in the health and well-being of pregnant women and in the development and long-term health of the offspring. On 26th - 28th February 2009, The Child Health Foundation invited leading experts in this area to a scientific workshop at Obergurgl, Austria to review and critically discuss current knowledge, to identify issues that may need to be addressed in future recommendations, and to highlight priorities and opportunities for future research. This report summarizes updated key conclusions of the workshop with regards to micronutrients intake and physiological role related to mother, placenta and fetus, as well as relevance for adverse pregnancy and long-term outcomes.

Placental mitochondrial content and function in intrauterine growth restriction and preeclampsia

Intrauterine growth restriction (IUGR) and pregnancy hypertensive disorders such as preeclampsia (PE) associated with IUGR share a common placental phenotype called placental insufficiency, originating in early gestation when high availability of energy is required. Here, we assess mitochondrial content and the expression and activity of respiratory chain complexes (RCC) in placental cells of these pathologies. We measured mitochondrial (mt)DNA and nuclear respiratory factor 1 (NRF1) expression in placental tissue and cytotrophoblast cells, gene and protein expressions of RCC (real-time PCR and Western blotting) and their oxygen consumption, using the innovative technique of high-resolution respirometry. We analyzed eight IUGR, six PE, and eight uncomplicated human pregnancies delivered by elective cesarean section. We found lower mRNA levels of complex II, III, and IV in IUGR cytotrophoblast cells but no differences at the protein level, suggesting a posttranscriptional compensatory regulation. mtDNA was increased in IUGR placentas. Both mtDNA and NRF1 expression were instead significantly lower in their isolated cytotrophoblast cells. Finally, cytotrophoblast RCC activity was significantly increased in placentas of IUGR fetuses. No significant differences were found in PE placentas. This study provides genuine new data into the complex physiology of placental oxygenation in IUGR fetuses. The higher mitochondrial content in IUGR placental tissue is reversed in cytotrophoblast cells, which instead present higher mitochondrial functionality. This suggests different mitochondrial content and activity depending on the placental cell lineage. Increased placental oxygen consumption might represent a limiting step in fetal growth restriction, preventing adequate oxygen delivery to the fetus.

Suppression of Mitochondrial Electron Transport Chain Function in the Hypoxic Human Placenta: A Role for miRNA-210 and Protein Synthesis Inhibition

Fetal growth is critically dependent on energy metabolism in the placenta, which drives active exchange of nutrients. Placental oxygen levels are therefore vital, and chronic hypoxia during pregnancy impairs fetal growth. Here we tested the hypothesis that placental hypoxia alters mitochondrial electron transport chain (ETS) function, and sought to identify underlying mechanisms. We cultured human placental cells under different oxygen concentrations. Mitochondrial respiration was measured, alongside levels of ETS complexes. Additionally, we studied placentas from sea-level and high-altitude pregnancies. After 4 d at 1% O2 (1.01 KPa), complex I-supported respiration was 57% and 37% lower, in trophoblast-like JEG3 cells and fibroblasts, respectively, compared with controls cultured at 21% O2 (21.24 KPa); complex IV-supported respiration was 22% and 30% lower. Correspondingly, complex I levels were 45% lower in placentas from high-altitude pregnancies than those from sea-level pregnancies. Expression of HIF-responsive microRNA-210 was increased in hypoxic fibroblasts and high-altitude placentas, whilst expression of its targets, iron-sulfur cluster scaffold (ISCU) and cytochrome c oxidase assembly protein (COX10), decreased. Moreover, protein synthesis inhibition, a feature of the high-altitude placenta, also suppressed ETS complex protein levels. Our results demonstrate that mitochondrial function is altered in hypoxic human placentas, with specific suppression of complexes I and IV compromising energy metabolism and potentially contributing to impaired fetal growth.

Umbilical amino acid uptake at increasing maternal amino acid concentrations : effect of a maternal amino acid infusate

OBJECTIVEnOur purpose was to establish whether, in normal human pregnancies, the maternal intravenous infusion of amino acids can increase fetal amino acid uptake and amino acid concentrations.nnnSTUDY DESIGNnTwenty-six normal pregnancies were studied at the time of cesarean delivery (38-40 weeks gestation). In 10 cases an amino acid formulation (Freamine 8.5% III, Baxter) was infused into a maternal vein before cesarean delivery. Maternal blood samples were obtained during the course of the study. Umbilical venous and arterial samples were obtained from the clamped segment of the cord. There were no differences between the 2 groups for fetal and placental weights and for fetal oxygenation and acid-base balance.nnnRESULTSnMaternal amino acid concentrations increased significantly in the group receiving infusions. Significant increases in umbilical venous concentrations were observed for most amino acids, except for histidine and threonine. The amino acid umbilical arteriovenous differences per mole of oxygen (AA/O(2) ratio) increased significantly for leucine, isoleucine, valine, methionine, phenylalanine, arginine, glycine, serine, alanine, and proline. There were no significant increases for lysine, histidine, and threonine.nnnCONCLUSIONnAn increase in maternal concentrations leads to an increase in the delivery of most amino acids to the fetus.

Maternal predictors of intrauterine growth restriction.

Purpose of review Intrauterine growth restriction (IUGR) occurs when fetal growth rate falls below the genetic potential and affects a significant number of pregnancies, but still no therapy has been developed for this pregnancy disease. This article reviews the most recent findings concerning maternal characteristics and behaviours predisposing to IUGR as well as maternal early markers of the disease. A comprehensive understanding of factors associated with IUGR will help in providing important tools for preventing and understanding adverse outcomes. Recent findings Maternal nutritional status, diet and exposure to environmental factors are increasingly acknowledged as potential factors affecting fetal growth both by altering nutrient availability to the fetus and by modulating placental gene expression, thus modifying placental function. Summary Assessing nutritional and environmental factors associated with IUGR, and the molecular mechanisms by which they may have a role in the disease onset, is necessary to provide comprehensive and common guidelines for maternal care and recommended behaviours. Moreover, maternal genetic predispositions and early serum markers may allow a better and more specific monitoring of high risk pregnancies, optimizing the timing of delivery.

Maternal blood mitochondrial DNA content during normal and intrauterine growth restricted (IUGR) pregnancy.

OBJECTIVEnWe investigated mitochondrial DNA (mtDNA) content in the maternal circulation of normal pregnancies of different gestational ages and in pregnancies complicated by intrauterine growth restriction (IUGR).nnnSTUDY DESIGNnWe examined 70 maternal blood samples: 13 nonpregnant women; 45 normal pregnancies, divided into the 3 trimesters; and 12 pregnancies complicated by IUGR. MtDNA content was determined by real-time quantitative polymerase chain reaction, using a genomic control and a target gene.nnnRESULTSnA highly significant progressive reduction in circulating mtDNA was observed in pregnant women of first, second, and third trimesters and compared to nonpregnant women (mean value: 237, 188, 144, and 283, respectively; P < .001). Moreover, mtDNA was significantly increased in women carrying IUGR fetuses compared to women with normal pregnancies (430 vs 144; P < .001).nnnCONCLUSIONnMtDNA could provide new insight into the mechanisms that occur during physiological gestation. Furthermore, mtDNA content may help recognize the IUGR disease in pregnancy.

Cerebral Maturation in IUGR and Appropriate for Gestational Age Preterm Babies

Intrauterine growth restriction (IUGR) is associated with increased risk of perinatal morbidity and mortality, as well as long-term neurological deficits. However, neurostructural correlations with observed developmental disabilities have not yet been established. Magnetic resonance imaging (MRI) could prove useful for assessing brain development in the early neonatal period. We evaluated cerebral lesions and morphological maturation by MRIs in 59 preterm neonates, in order to verify the hypothesis that IUGR interferes on human brain development. A total of 26 pregnancies were complicated by IUGR and 33 pregnancies delivered preterm at a comparable gestational age with appropriate for gestational age (AGA). Magnetic resonance examination was performed at the completion of 41 weeks gestation. White matter disease studied with MR included periventricular cavitations and punctuate lesions characterized by increased signal on T1-weighted and decreased signal on T2-weighted images. Cerebral maturation was defined by the total maturation score, on the basis of 4 morphological parameters of cerebral maturation: myelination (M), cortical infolding (C), germinal matrix distribution (GM), and glial cell migration pattern (G). No difference in brain lesions and in the level of cerebral maturation was found between preterm AGA and IUGR neonates. However, myelination was significantly reduced in IUGR neonates with brain sparing compared to IUGR neonates with normal Doppler of middle cerebral artery. Our study could not demonstrate any major significant difference between preterm AGA and IUGR neonates in terms of lesion occurrence and cerebral maturation. We observed, however, a mild delay in myelination in IUGR with brain sparing in utero. The relevance of this finding needs to be investigated with long-term follow-up.