Manuela Cardellicchio

Long chain fatty acids and dietary fats in fetal nutrition

Long chain polyunsaturated fatty acids are essential nutrients for a healthy diet. The different kinds consumed by the mother during gestation and lactation may influence pregnancy, fetal and also neonatal outcome. The amount of fatty acids transferred from mother to fetus depends not only on maternal metabolism but also on placental function, i.e. by the uptake, metabolism and then transfer of fatty acids to the fetus. The third trimester of gestation is characterized by an increase of long chain polyunsaturated fatty acids in the fetal circulation, in particular docosahexaenoic acid, especially to support brain growth and visual development. These mechanisms may be altered in pathological conditions, such as intrauterine growth restriction and diabetes, when maternal and fetal plasma levels of long chain polyunsaturated fatty acids undergo significant changes. The aim of this review is to describe the maternal and placental factors involved in determining fetal fatty acid availability and metabolism, focusing on the specific role of long chain polyunsaturated fatty acids in normal and pathological pregnancies.

PlGF in a clinical setting of pregnancies at risk of preeclampsia and/or intrauterine growth restriction

Abstract Placental growth factor (PlGF) is an angiogenic molecule produced by the placenta and implicated in the pathogenesis of preeclampsia (PE) and intrauterine growth restriction (IUGR). We have evaluated utility and applicability of the PlGF test in a clinical setting of pregnancies at risk of PE or complicated by IUGR in order to assess its relationship with pregnancy outcomes. Seventy-three pregnancies were enrolled between 19 and 35 weeks: 57 pregnancies at risk of PE and 16 at diagnosis of IUGR. Maternal circulating PlGF levels were measured by the Triage PlGF test (Alere, San Diego, CA). Pregnancy outcomes were evaluated in relation to three categories of plasma PlGF levels: very low (<12 pg/ml), low (12–100 pg/ml) and normal (≥100 pg/ml). Uterine artery Doppler velocimetry (UADV) pulsatility index (PI) was measured in the same patients on the day of maternal sampling. Pregnancies at risk with very low plasma PlGF levels had significantly lower gestational age at delivery than patients with low or normal PlGF. The rate of emergency C-section was significantly higher in the group with PlGF <12 pg/ml. IUGR pregnancies with very low and low PlGF delivered earlier than patients with normal PlGF. All IUGR with very low and low PlGF had UADV PI > 95th percentile. Our data indicate that PlGF may provide useful information to identify fetuses requiring increased surveillance and possibly urgent delivery in pregnancies at risk of adverse outcomes. Furthermore, in IUGR, PlGF can predict adverse pregnancy outcomes that may be secondary to placental insufficiency.

Mitochondrial Content and hepcidin are increased in Obese pregnant mothers

Abstract Objective: Maternal obesity is characterized by systemic low-grade inflammation and oxidative stress (OxS) with the contribution of fetal sex dimorphism. We recently described increased mitochondrial content (mtDNA) in placentas of obese pregnancies. Here, we quantify mtDNA and hepcidin as indexes of OxS and systemic inflammation in the obese maternal circulation. Methods: Forty-one pregnant women were enrolled at elective cesarean section: 16 were normal weight (NW) and 25 were obese (OB). Obese women were further classified according to the presence/absence of maternal gestational diabetes mellitus (GDM); [OB/GDM(–)]: n = 15, [OB/GDM(+)]: n = 10. mtDNA and hepcidin were evaluated in blood (real-time PCR) and plasma (ELISA). Results: mtDNA and hepcidin levels were significantly increased in OB/GDM(–) versus NW, significantly correlating with pregestational BMI. Male/female (M/F) ratio was equal in study groups, and overall F-carrying pregnancies showed significantly higher mtDNA and hepcidin levels than M-carrying pregnancies both in obese and normal weight mothers. Conclusions: Our results indicate a potential compensatory mechanism to increased obesity-related OxS and inflammation, indicated by the higher hepcidin levels found in obese mothers. Increased placental mitochondrial biogenesis, due to lipotoxic environment, may account for the greater mtDNA amount released in maternal circulation. This increase is namely related to F-carrying pregnancies, suggesting a gender-specific placental response.

Physiology of Pregnancy: Interaction between Mother and Child

In the last years evidence has shown how lifelong well-being strongly depends on intrauterine growth and development during intrauterine life. Fetal growth can achieve its full potential only with an adequate and fine-tuned interaction between mother, placenta and fetus. Several environmental and maternal factors like maternal diet, body composition and endocrine status may alter this delicate equilibrium. Moreover, placental function and metabolism contribute and regulate the availability of fetal nutrients. Changes in this complex mechanism may compromise the pregnancy outcome. In this chapter we wish to elucidate the physiologic mechanisms that regulate this interaction and how also little modifications may predispose to pathologies like intrauterine growth restriction and gestational diabetes with important consequences on fetal and adult health.

Inflammatory and Oxidative Responses in Pregnancies With Obesity and Periodontal Disease

Background: Maternal obesity is related to immunologic and inflammatory systemic modifications that may worsen the pregnancy inflammatory status. Hormonal changes during pregnancy can adversely affect oral biofilms and oral health initiating or worsening periodontal diseases, with enhanced local and systemic oxidative stress and inflammation. Objective: The aim of this study was to examine the relationship between local salivary and systemic parameters of oxidative stress and inflammation in relation to obesity and periodontal diseases. Study Design: Sixty-two women with singleton pregnancies were enrolled. Twenty-seven women were normal weight (NW; 18.5< body mass index [BMI] <25 kg/m2) and 35 obese (BMI ≥30 kg/m2). Seventeen of the obese had gestational diabetes mellitus (GDM). During third trimester, periodontal status was evaluated, saliva (s) was collected to assess total antioxidant capacity (s-TAC) and C-reactive protein (s-CRP) levels, and venous plasma (p) was used to measure CRP levels (p-CRP). Maternal, fetal, and placental data were registered at delivery. Results: Levels of s-TAC, s-CRP, and p-CRP were significantly higher in obese, particularly in the presence of GDM, compared to NW and related to each other (P = .000; r > 0.59), to maternal BMI (P = .000; r > 0.52), and fasting glycemia (P < .002; r > 0.47). Periodontal disease was more frequent in obese groups (80%) versus NW (52%; P = .04), particularly when GDM was diagnosed (P = .009). A significant interaction effect between maternal BMI and oral condition was found for s-TAC levels. Obese with periodontitis showed significant increase in local and systemic parameters versus NW. Conclusion: Obesity and periodontal disease could synergistically amplify the inflammatory and oxidative status, resulting in increased local and systemic biomarkers particularly when GDM is diagnosed.

Alterations of mitochondrial content in obese placentas

Figures will be available only online at UNIV OF PITTSBURGH on June 19, 2015 rsx.sagepub.com Downloaded from at UNIV OF PITTSBURGH on June 19, 2015 rsx.sagepub.com Downloaded from Thrsday O als Scientific Abstracts Reproductive Sciences Vol. 22, Supplement 1, March 2015 57AINTRODUCTION: Statin use inadvertently during pregnancy and proposed use of statins for the treatment of preeclampsia, led us to question the evidence behind their current contraindicated status. Several studies have evaluated the relationship between statin use in pregnancy with fetal outcome but their results have not been quantitatively assessed by meta-analysis. Our objective was to undertake a systematic review of all published clinical evidence to assess the effects of statin use in pregnancy on subsequent fetal wellbeing. METHODS: A comprehensive search strategy was performed of all electronic databases and the Merck reporting database for studies published from 1966 to 2014. Two reviewers independently screened citations and undertook study quality assessment and data extraction. We obtained summary estimates of adverse fetal events that were classified as potentially fatal, clinically significant morbidity or minor adverse event. We identified 602 titles and reviewed 30 articles for inclusion and exclusion criteria. Meta-analysis was performed on seven studies (3 cohort, 3 case-series and 1 case-control). RESULTS: Of the 922 cases of statin exposure in pregnancy, 27 exposures were associated with lethal or clinically significant fetal morbidity and 10 with minor adverse events. Statin exposure was limited to the first trimester in all but two cases. The pooled rate of lethal or clinically significant fetal abnormalities in pregnant women exposed to statins was 0.01 (95% CI 0.00-0.04), less than the European rate of 0.026 (95% CI 2.54- 2.57)EUROCAT. The rate of fetal abnormality for simvastatin was 0.03 (95% CI 0.00-0.08), atorvostatin 0.11 (95% CI 0.00-0.52), pravastatin 0.01 (95% CI 0.00-0.2) and lovastatin use 0.04 (95% CI 0.00-0.28). Systems based anomalies were also calculated, congenital heart disease was 0.8 (95% CI 0.02-0.12) compared with the background rate of 0.79 (95% CI 0.78- 0.80). CONCLUSIONS: The published data suggests that statins may not be teratogenic when given inadvertently during pregnancy and prospective studies such as The StAmP Trial may provide more dataIntroduction. Being born small increases cardio-renal disease risk, with males exhibiting more se vere phenotypes than females. These disease risks are not limited to the first generation (F1) but may be transmitted to subsequent generations (F2 and F3). The F3 maternal line represents the first generation that is not directly exposed to the initial insults. There is limited evidence of paternal line transmission. W e characterized nephron number and cardio-renal phenotype of F3 of fspring born to normally grown and growth restricted (F1) mothers or fathers. Methods. Late gestation rat uteroplacental insuf ficiency was induced (Restricted) or sham (Control) surgery in F0. Rats were anaesthetized with 4% isoflurane and 650ml.min -1 oxygen flow (reduced to 3.2% isoflurane and 250ml.min -1 oxygen flow when suturing). T o generate F3 paternal line offspring, F1 Control and Restricted males were mated with normal females and the F2 Control and Restricted males were then mated with normal females. F3 maternal line of fspring were similarily generated. F3 body weights were measured from birth to 12 months. Nephron number w as quantified using unbiased sterology at postnatal day 35. 24h renal excretions, creatinine clearance and tail cuf f blood pressure were measured at 6 (maternal and paternal lines) and 12 (maternal line only) months of age. All data were analysed by t-test within a gender and line. Results. Although F1 offspring were born small, F2 and F3 offspring (both maternal and paternal lines) had normal birth weights. F3 body weight was not dif ferent from birth to 12 months of age with no dif ferences in kidney, heart or adipose weights at 6 months between groups or lines. F3 male and female nephron endowment and blood pressure w as not different between groups for paternal and maternal lines. F3 maternal line renal function was normal at 6 months of age. Ho wever, at 12 months, although creatinine clearance (eGFR) was normal, renal dysfunction emerged in F3 maternal line males (proteinuria) and females (increased urinary creatinine excretion). F3 offspring from fathers born small had e vidence of impaired eGFR (reduced creatinine clearance). Conclusions. F3 offspring, born to F1 growth restricted mothers or f athers are not programmed to be born of low birth weight but de veloped renal dysfunction in the absence of obesity . The proteinuria that emerged with aging in the F3 maternal line male of fspring in the absence of nephron deficits, hypertension and reduced eGFR, suggests tubulointerstitial injury mediated either through podocyte dysfunction/depletion or solely via proteinuria. In contrast, F3 paternal line of fspring had glomerular dysfunction (reduced eGFR), indicati ve of glomerular filtration deficits. Our paternal line results highlight sustained transgenerational inheritance of renal dysfunction. Since nephron number was preserved our results propose the progression of renal dysfunction via the “fibrosis hypothesis” rather than the “Brenner h ypothesis”. Our findings provide no vel evidence of transgenerational transmission of renal dysfunction to F3 offspring from both maternal and paternal lines.INTRODUCTION: Preeclampsia is a vascular disorder in pregnancyand is biochemical characterization by high soluble Flt-1 and lowplacenta growth factor as well as an imbalance in redox homeostasis.During conditions of high oxidative stress, cysteine residues on keyproteins are reversibly altered by S-glutathionylation, modifying theirfunction. Glutaredoxin-1 (Glrx) enzymatically catalyzes the removal of S-glutathione adducts, conferring reversible signaling dynamics toproteins with redox-sensitive cysteines. The role of Glrx in preeclampsiais unknown.METHODS: Immunohistochemistry and Western blot analysis for Glrx orglutathione were conducted on human placenta samples collected pre-termfrom early onset preeclamptic patients (n=10) or non-preeclamptic induceddeliveries (n=9). Human endothelial cells were infected with adenovirusencoding Glrx or LacZ prior to the cells being exposed to hypoxia (0.1%O2, 24h) to measure changes in soluble Flt-1 (sFlt-1). Quantitative PCRand ELISA were used to measure sFlt-1 at mRNA and protein level.RESULTS: Immunohistochemical staining for GSH revealed lowerS-glutathionylation adducts in preeclampsia placenta in comparison tocontrols. Glrx expression, which catalyses de-glutathionylation wasenhanced in early onset preeclampsia compared to pre-term controlsamples. In contrast, no change was observed in preeclamptic and IUGRplacentas at full term. In endothelial cells overexpressing Glrx, sFlt-1expression was dramatically enhanced at mRNA (3-fold P 0.01, n=4) after hypoxia andoverexpressing Glrxin mice enhanced levels of circulating sFlt-1 during in vivo ischemia.CONCLUSIONS: Enhanced Glrx expression in preeclamptic placentain line with an apparent decrease in S-glutathionylation may leavekey proteins susceptible to irreversible oxidation in conditions of highoxidative stress.

Physiologie de la grossesse: Interactions entre la mère et l’enfant

Ces dernières années, il a été démontré à quel point la croissance et le développement pendant la vie intra-utérine influaient sur le bien-être futur. La croissance du fœtus ne peut atteindre son plein potentiel qu’avec une interaction adéquate et finement régulée entre la mère, le placenta et le fœtus. Plusieurs facteurs environnementaux et maternels comme l’alimentation de la mère, sa composition corporelle et son statut endocrine peuvent modifier cet équilibre fragile. De plus, la fonction et le métabolisme du placenta contribuent à réguler la disponibilité des nutriments pour le fœtus et toute modification de ce mécanisme complexe peut compromettre le déroulement de la grossesse. Dans ce chapitre, nous souhaitons éclaircir les mécanismes physiologiques qui régulent cette interaction mère, fœtus, placenta, et aussi montrer comment de petites modifications peuvent engendrer des pathologies (tels qu’un retard de croissance intra-utérine ou un diabète gestationnel) ayant des conséquences importantes sur la santé du fœtus et de l’adulte qu’il deviendra.

Proteinuria in pregnancy: Clinically driven considerations:

Introduction:Proteinuria assessment is a key test in pregnancy to evaluate renal and systemic well-being. The finding of proteinuria may allow diagnosis and ready intervention for pre-eclampsia and glomerulonephritis, which may compromise a favorable delivery. Moreover, pathological-range isolated proteinuria is a risk factor by itself for adverse outcomes during pregnancy. An appropriate interpretation of pathologic values of proteinuria is therefore of crucial importance.Patient presentation:We present the case of a 33-year-old apparently healthy woman at her first pregnancy who developed a clinically significant proteinuria during the first trimester; we describe the clinical workup and the management of the patient up to delivery.Conclusion:Urine analysis with dipstick or protein-to-creatinine ratio is part of the routine prenatal clinical care during pregnancy. Detection of a pathological proteinuria (>300 mg/24 h or equivalent) should never be underestimated, and timed urine collection is required, ...

L6. Placental oxygenation and respiration in preeclampsia

difficult by the nature of the condition, which occurs only in women who reproduce. It is not clear whether the maternal genotype, the fetal genotype, or some combination of both is responsible. Recent genome-wide studies have independently shown the association of the 12q24.12 locus with different diseases or traits: this locus seems to be involved in the control of blood pressure and microcirculation, platelet count, hemoglobin concentration and hematocrit but also in severe diseases like coronary heart disease, chronic kidney disease or immune-related disease (celiac disease, type 1 diabetes and rheumatoid arthritis). An abnormally functioning microcirculation is a common feature of diseases like type 1 diabetes, coronary heart disease, and preeclampsia. As the derangement of endothelial function and microcirculation is a key element in development of preeclampsia. We focused one on the study analysis focus single nucleotide polymorphisms (SNPs), situated on SH2B3 and ATXN2 genes in the 12q24 locus, with the aim of verifying a possible role of chromosome 12q24 in hypertensive disorders of pregnancy. We investigated the presence of aplotypes (combination of SNPs) specific for preeclampsia and chronic hypertension, and whether these aplotypes are able to increase or reduce the risk of developing hypertensive disorders. A case-control study was performed with 175 preeclamptic women, 194 women with chronic hypertension and 212 women with normal pregnancy. DNA was extracted from blood leucocytes with Salting-out technique, and the genetic analysis of the samples was done with TaqMan genotyping method with predesigned probes. One of the SNPs (rs648997) is out of Hardy-Weinberg equilibrium: this could suggest a possible association between our selected SNP and preeclampsia, as observed heterozygosity is significantly different from the expected heterozygosity (p < 0.005). The same SNP is highly associated with preeclampsia independently from maternal age, diabetes, twin pregnancy or parity according to logistic regression analysis. The analysis of the most frequent aplotypes in our population shows that one of them, CATC, is significantly associated with preeclampsia: being present in 3,7% of preeclamptic women versus 1.4% of controls (p = 0.0421). Our study confirms the importance of a genetic predisposition to preeclampsia, in which the multiple variants each play a small part in boosting the risk factor. In the future these data may be able stratify the pregnant population into different groups of genetic risk to develop preeclampsia.

Fisiología del embarazo: Interacción materno-infantil

En los últimos años los datos han demostrado de qué manera el bienestar vitalicio depende considerablemente del crecimiento y el desarrollo intrauterinos durante la vida dentro del útero. El crecimiento fetal puede alcanzar únicamente su potencial íntegro mediante una interacción adecuada y armonizada entre la madre, la placenta y el feto. Este delicado equilibrio puede ser alterado por varios factores ambientales y maternos, como la dieta, la composición corporal y la situación endocrina maternas. Por otra parte, la función y el metabolismo de la placenta contribuyen y regulan la disponibilidad de nutrientes fetales. Los cambios en este mecanismo complejo pueden comprometer el desenlace del embarazo. En este capítulo pretendemos aclarar los mecanismos fisiológicos que regulan esta interacción y de qué modo, incluso pequeñas modificaciones pueden predisponer a patologías como la limitación del crecimiento intrauterino y la diabetes gravídica, con importantes consecuencias sobre la salud fetal y adulta.