Placental Vascular Function Research Articles

Circulating cord blood HDL-S1P complex preserves the integrity of the feto-placental vasculature

Perinatal and long-term offspring morbidities are strongly dependent on the preservation of placental vascular homeostasis during pregnancy. In adults, the HDL-apoM-S1P complex protects the endothelium and maintains vascular integrity. However, the metabolism and biology of cord blood-derived HDLs (referred to as neonatal HDL, nHDL) strikingly differ from those in adults. Here, we investigate the role of neonatal HDLs in the regulation of placental vascular function. We show that nHDL is a major carrier of sphingosine-1-phosphate (S1P), which is anchored to the particle through apoM (rs = 0.90, p < 0.0001) in the fetal circulation. Furthermore, this complex interacts with S1P receptors on the feto-placental endothelium and activates specifically extracellular signal-regulated protein kinases 1 and 2 (ERK) and phospholipase C (PLC) downstream signaling, promotes endothelial cell proliferation and calcium flux. Notably, the nHDL-S1P complex triggers actin filaments reorganization, leading to an enhancement of placental endothelial barrier function. Additionally, nHDL induces vasorelaxation of isolated placental chorionic arteries. Taken together, these results suggest that circulating nHDL exerts vasoprotective effects on the feto-placental endothelial barrier mainly via S1P signaling.

EP18.24: Thrombophillia in pregnant patients: ultrasound evaluation for the assessment of the fetal‐placental unit

There is currently a small number of studies regarding the complications that may occur in a pregnant woman with thrombophillia. Due to low quality of the case-control studies and cohort type studies conducted to date, it has been shown that there is a relatively high risk of complications in pregnant women with thrombophillia, but the absolute risk remains very small. We aim to study the influence of pregnancy-associated thrombophilia in IUGR determininsm and the risk of damage to the utero-placental vasculature in these pregnant women. We propose the evaluation of changes in the uteroplacental and foetal system by prenatal monitoring of the Doppler parameters in the case of pregnant women wirh thrombophilia. We conducted a study that included 32 pregnant patients with thrombophilia from January 2016 to December 2017 at the Obstetrics and Ginecology Clinic of the Cuza Voda Maternity in Iasi. These were evaluated both clinically and by ultrasound. Four cases were found that showed a ratio of the mean cerebral artery pulse rate / umbilical artery index less than 1, representing cases of high risk for mortality and maternal-fetal morbidity. Also, intrauterine growth restriction was more common in the mentioned group (58%) compared to the rest of the patients (7%). This study highlights the causal relationship between maternal thrombophilia and obstetric complications due to impaired normal placental vascular function and demonstrates the need for individualised ultrasound monitoring in this group of patients in order to improve the maternal-fetal prognosis. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

The Impact of Infection in Pregnancy on Placental Vascular Development and Adverse Birth Outcomes.

Healthy fetal development is dependent on nutrient and oxygen transfer via the placenta. Optimal growth and function of placental vasculature is therefore essential to support in utero development. Vasculogenesis, the de novo formation of blood vessels, and angiogenesis, the branching and remodeling of existing vasculature, mediate the development and maturation of placental villi, which form the materno-fetal interface. Several lines of evidence indicate that systemic maternal infection and consequent inflammation can disrupt placental vasculogenesis and angiogenesis. The resulting alterations in placental hemodynamics impact fetal growth and contribute to poor birth outcomes including preterm delivery, small-for-gestational age (SGA), stillbirth, and low birth weight (LBW). Furthermore, pathways involved in maternal immune activation and placental vascularization parallel those involved in normal fetal development, notably neurovascular development. Therefore, immune-mediated disruption of angiogenic pathways at the materno-fetal interface may also have long-term neurological consequences for offspring. Here, we review current literature evaluating the influence of maternal infection and immune activation at the materno-fetal interface and the subsequent impact on placental vascular function and birth outcome. Immunomodulatory pathways, including chemokines and cytokines released in response to maternal infection, interact closely with the principal pathways regulating placental vascular development, including the angiopoietin-Tie-2, vascular endothelial growth factor (VEGF), and placental growth factor (PlGF) pathways. A detailed mechanistic understanding of how maternal infections impact placental and fetal development is critical to the design of effective interventions to promote placental growth and function and thereby reduce adverse birth outcomes.

Expression of ECE1, IGFBP7 and CALR in a porcine model for von Willebrand disease (VWD) type 1 and 3

To characterise Chorionic Plate Artery (CPA) function in maternal obesity, and investigate whether leptin exposure reproduces the obese CPA phenotype in normal-BMI women.CPA responses to the thromboxane-A2 mimetic U46619 (pre/post leptin incubation), to the nitric oxide donor sodium nitroprusside (SNP) and the occurrence of tone oscillations (pre/post leptin incubation) were assessed in 46 term placentas from women of normal (18.5–24.9) or obese (>30) Body Mass Index (BMI).Area Under the dose response Curve (AUC), maximum response (Vmax), sensitivity (EC50) to U46619 (pre/post leptin) and SNP; average vessel tone, oscillation amplitude and frequency (pre/post leptin).U46619 vasoconstriction was similar between BMI categories (p > 0.05), however vasodilatation to SNP was reduced in obesity (AUC p = 0.02, Vmax p = 0.04) compared to normal-BMI women. Leptin incubation altered responses to U46619 in both normal-BMI (EC50 at 100 ng/ml leptin; p < 0.05) and obese women (AUC at 50 ng/ml; p < 0.05) but vasomotion was unaffected (p > 0.05).Maternal obesity is associated with altered placental vascular function which may adversely affect placental oxygen and nutrient transport, placing the fetus at risk. Leptin incubation altered CPA vascular function but did not reproduce the obese phenotype.

Ursodeoxycholic acid inhibits uptake and vasoconstrictor effects of taurocholate in human placenta.

Intrahepatic cholestasis of pregnancy (ICP) causes increased transfer of maternal bile acids to the fetus and an increased incidence of sudden fetal death. Treatment includes ursodeoxycholic acid (UDCA), but it is not clear if UDCA protects the fetus. This study explores the placental transport of the bile acid taurocholate (TC) by the organic anion–transporting polypeptide, (OATP)4A1, its effects on the placental proteome and vascular function, and how these are modified by UDCA. Various methodological approaches including placental villous fragments and Xenopus laevis oocytes were used to investigate UDCA transport. Placental perfusions and myography investigated the effect of TC on vasculature. The effects of acute TC exposure on placental tissue were investigated using quantitative proteomics. UDCA inhibited OATP4A1 activity in placental villous fragments and oocytes. TC induced vasoconstriction in placental and rat vasculature, which was attenuated by UDCA. Quantitative proteomic analysis of villous fragments showed direct effects of TC on multiple placental pathways, including oxidative stress and autophagy. The effects of TC on the placental proteome and vasculature demonstrate how bile acids may cause fetal distress in ICP. UDCA inhibition of OATP4A1 suggests it will protect the mother and fetus against the vascular effects of TC by inhibiting its cellular uptake. UDCA may protect the fetus in ICP by inhibiting OATP4A1-mediated bile acid transfer and TC-induced placental vasoconstriction. Understanding the physiologic mechanisms of UDCA may allow better therapeutic interventions to be designed specifically for the fetus in the future.—Lofthouse, E. M., Torrens, C., Manousopoulou, A., Nahar, M., Cleal, J. K., O’Kelly, I. M., Sengers, B. G., Garbis, S. D., Lewis, R. M. Ursodeoxycholic acid inhibits uptake and vasoconstrictor effects of taurocholate in human placenta.

Inherited thrombophilia and pregnancy loss. Study of an Argentinian cohort

Background and objectivesThrombophilia might increase the risk of suffering from obstetric complications by adversely affecting the normal placental vascular function. Our aim was to study the distributions of five thrombosis-associated genetic variants: factor V Leiden, prothrombin G20210A, −675 4G/5G PAI-1, 10034C/T gamma fibrinogen and 7872C/T factor XI and the frequencies of the deficiencies of protein C, S and antithrombin in Argentinian patients with recurrent pregnancy loss (RPL) and, therefore, to analyse their association with the risk and timing of RPL and the risk of suffering other vascular obstetric pathologies. Patients and methodsWe performed a case–control study that included 247 patients with idiopathic RPL (cases), 107 fertile controls and 224 subjects from general population (reference group). Cases were stratified according to the gestational time of the losses (early RPL, n=89; late losses, n=158; foetal losses, n=107) and according to the type of vascular obstetric pathologies. ResultsNo differences were found in the distribution of the genetic variants among RPL group vs. control/reference group (p>.05). Similarly, no differences were observed in their distributions when analysing RPL patients stratified according to gestational times or vascular obstetric pathologies (p>.05), except for the factor V Leiden carriage in patients with foetal growth retardation vs. controls (11.8%, 4/34 vs. 1.9%, 2/107; p=.04) (OR=7.11 [1.24–40.93], p=.03). ConclusionsFactor V Leiden might have a significant impact on certain obstetric pathologies such as foetal growth retardation. The genetic variants, 10034C/T gamma fibrinogen and 7872C/T factor XI, associated with thromboembolic disease, would not have an impact on PRE.

Study of Human T21 Placenta Suggests a Potential Role of Mesenchymal Spondin-2 in Placental Vascular Development.

Placental development is particularly altered in trisomy of chromosome 21 (T21)-affected pregnancies. We previously described in T21-affected placentae an abnormal paracrine crosstalk between the villus mesenchymal core and villus trophoblasts. T21-affected placentae are known to be characterized by their hypovascularity. However, the causes of this anomaly remain not fully elucidated. Therefore, the hypothesis of an abnormal paracrine crosstalk between fetal mesenchymal core and placental endothelial cells (PLECs) was evocated. Villus mesenchymal cells from control (CMCs) and T21 placentae (T21MCs) were isolated and grown in culture to allow their characterization and collection of conditioned media for functional analyses (CMC-CM and T21MC-CM, respectively). Interestingly, PLEC proliferation and branching ability were less stimulated by T21MC-CM than by CMC-CM. Protein array analysis identified secreted proangiogenic growth factors in CMC-CM, which were reduced in T21MC-CM. Combined mass spectrometry and biochemical analysis identified spondin-2 as a factor decreased in T21MC-CM compared with CMC-CM. We found that exogenous spondin-2 stimulated PLEC proliferation and established that T21MC-CM supplemented with spondin-2 recovered conditioned media ability to induce PLEC proliferation and angiogenesis. Hence, this study demonstrates a crosstalk between villus mesenchymal and fetal endothelial cells, in which spondin-2 secreted from mesenchymal cells plays a central role in placental vascular functions. Furthermore, our results also suggest that a reduction in spondin-2 secretion may contribute to the pathogenesis of T21 placental hypovascularity.

100. The effect of pitavastatin and pravastatin on omental and chorionic plate artery function in normal pregnancy and pre-eclampsia

Introduction There are no effective therapies for pre-eclampsia (PE), which remains a leading cause of considerable materno-fetal morbidity and mortality. Statins, widely utilized in cardiovascular disease, represent a candidate therapy for PE. Determination of statins’ ability to ameliorate the observed endothelial dysfunction in PE is lacking. Objective To determine the effect of short-term pitavastatin and pravastatin exposure on chorionic plate arteries (CPAs) and omental arteries (OAs) from normal and PE pregnancies. Methods CPAs and OAs from normal pregnancy (NP; N = 43 placentas, N = 20 biopsies) and PE (N = 18 placentas, N = 5 biopsies) pregnancies were mounted on a wire myograph. Contraction was assessed with KPSS (120 mM) and thromboxane-mimetic U46619 (0.1 nM–2 μM). Arteries were incubated for 2 h with 1 μM pitavastatin or pravastatin; time-controls in parallel. U46619 dose–response curves were repeated or NO-donor SNP (1 nM–100 μM) or endothelium-dependent bradykinin (0.1–1000 nM/L) following U46619 pre-constriction. All data are mean ± SEM. Results Neither statin significantly altered vascular reactivity in NP CPAs. CPAs show blunted SNP-induced relaxation in PE vs. NP (38 ± 10% vs. 28 ± 12% respectively; p = 0.038; Two-way ANOVA). Additionally, 1μM pitavastatin attenuated PE CPAs vasoconstriction compared to control (Emax, 152 ± 30% and 165 ± 33% respectively; p = 0.013; Two-way ANOVA) but vasodilation was unaffected. In NP OAs, 1μM pravastatin reduced vasoconstriction compared to time-control (111 ± 20% and 123 ± 23% respectively; p = 0.044; Two-way ANOVA) but did not affect vasodilation. Preliminary PE OA data suggests neither statin had a significant effect on vasoconstriction or vasodilatation (P > 0.05; Two-way ANOVA; N = 5). Discussion Data suggests statins are unlikely to be deleterious to placental vascular function in NP. Pitavastatin (PE CPAs) and pravastatin (NP OAs) have the ability to blunt agonist-induced vasoconstriction. Future work will focus on whether pitavastatin and pravastatin improve endothelial function in OAs from women with PE.

317. Do Calcium channel blockers modulate fetoplacental blood flow? A study using parallel wire myography

Introduction Calcium channel blockers treat maternal hypertension in pregnancy. The effect of newer calcium channel blockers on placental vascular function remains unknown. This study aimed to determine the effect of calcium channel blockers on placental chorionic plate proximal resistance arteries in comparison to maternal omental arteries. Methods Chorionic plate and omental arteries from healthy term pregnancies delivered by caesarean section were studied using parallel wire myography (n = 80; N = 10). Arteries were normalised at 0.9 of L5.1 kPa in 5% O2 and L13.3 kPa in 20% O2 respectively, approximating physiologic vascular pressure and oxygen tension. Arteries were contracted with thromboxane-mimetic U46619 to determine and maintain optimal physiologic vascular tone (EC80). Nifedipine, Nicardipine and Clevidipine were added in incremental doses from 10–10 M to 10–5 M to create dose-dependent relaxation curves. Omental arteries were incubated for 30 min at the highest dose (10–5 M) to further evaluate full effect (n = 16; N = 4). Results Omental arteries demonstrated similar contractility to chorionic plate arteries (8.90 kPa ± 0.681 vs 8.85 kPa ± 0.603). Chorionic plate arteries did not relax with Nifedipine, Nicardipine or Clevidipine (110.73%± 7.518 vs 118.88%±9.379 vs 113.16%±5.163). Omental arteries demonstrated a trend towards larger relaxation with all calcium channel blockers at the highest dose of drug concentration. This was confirmed with highest dose incubation of omental arteries, that showed Nifedipine, Nicardipine and Clevidipine relaxed omental arteries (52.31%±16.294 vs 57.12%±8.621 vs 79.95%±14.862; One-way ANOVA, p Conclusion Chorionic plate arteries demonstrated reduced vasodilatory responses to calcium channel blockers compared to omental arteries. This suggests calcium channel blockers show limited effect on placental blood flow through proximal resistance arteries.

Gestational diabetes mellitus modulates cholesterol homeostasis in human fetoplacental endothelium

Gestational diabetes mellitus (GDM) is associated with excessive oxidative stress which may affect placental vascular function. Cholesterol homeostasis is crucial for maintaining fetoplacental endothelial function. We aimed to investigate whether and how GDM affects cholesterol metabolism in human fetoplacental endothelial cells (HPEC). HPEC were isolated from fetal term placental arterial vessels of GDM or control subjects. Cellular reactive oxygen species (ROS) were detected by H2DCFDA fluorescent dye. Oxysterols were quantified by gas chromatography–mass spectrometry analysis. Genes and proteins involved in cholesterol homeostasis were detected by real-time PCR and immunoblotting, respectively. Cholesterol efflux was determined from [3H]-cholesterol labeled HPEC and [14C]-acetate was used as cholesterol precursor to measure cholesterol biosynthesis and esterification. We detected enhanced formation of ROS and of specific, ROS-derived oxysterols in HPEC isolated from GDM versus control pregnancies. ROS-generated oxysterols were simultaneously elevated in cord blood of GDM neonates. Liver-X receptor activation in control HPEC by synthetic agonist TO901319, 7-ketocholesterol, or 7β-hydroxycholesterol upregulated ATP-binding cassette transporters (ABC)A1 and ABCG1 expression, accompanied by increased cellular cholesterol efflux. Upregulation of ABCA1 and ABCG1 and increased cholesterol release to apoA-I and HDL3 (78 ± 17%, 40 ± 9%, respectively) were also observed in GDM versus control HPEC. The LXR antagonist GGPP reversed ABCA1 and ABCG1 upregulation and reduced the increased cholesterol efflux in GDM HPEC. Similar total cellular cholesterol levels were detected in control and GDM HPEC, while GDM enhanced cholesterol biosynthesis along with upregulated 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) and sterol O-acyltransferase 1 (SOAT1) mRNA and protein levels. Our results suggest that in GDM cellular cholesterol homeostasis in the fetoplacental endothelium is modulated via LXR activation and helps to maintain its proper functionality.

Malaria relief, one amino acid at a time

Malaria![Figure][1] Malaria-infected pregnant women in Malawi lack l-arginine. CREDIT: PAUL JEFFREY/ALAMY STOCK PHOTO Malaria infection during pregnancy can disrupt placental vasculature and cause complications. Nitric oxide plays a key role in placental vascular function, and its synthesis

Trombofilia hereditaria y pérdidas de embarazo. Estudio de una cohorte de Argentina

Background and objectivesThrombophilia might increase the risk of suffering from obstetric complications by adversely affecting the normal placental vascular function. Our aim was to study the distributions of five thrombosis-associated genetic variants: factor V Leiden, prothrombin G20210A, -675 4G/5G PAI-1, 10034C/T gamma fibrinogen and 7872C/T factor XI and the frequencies of the deficiencies of protein C, S and antithrombin in Argentinian patients with recurrent pregnancy loss (RPL) and, therefore, to analyse their association with the risk and timing of RPL and the risk of suffering other vascular obstetric pathologies. Patients and methodsWe performed a case-control study that included 247 patients with idiopathic RPL (cases), 107 fertile controls and 224 subjects from general population (reference group). Cases were stratified according to the gestational time of the losses (early RPL, n = 89; late losses, n = 158; foetal losses, n = 107) and according to the type of vascular obstetric pathologies. ResultsNo differences were found in the distribution of the genetic variants among RPL group vs. control/reference group (p >.05). Similarly, no differences were observed in their distributions when analysing RPL patients stratified according to gestational times or vascular obstetric pathologies (p >.05), except for the factor V Leiden carriage in patients with foetal growth retardation vs. controls (11.8%, 4/34 vs. 1.9%, 2/107; p = .04) (OR = 7.11 [1.24-40.93], p = .03). ConclusionsFactor V Leiden might have a significant impact on certain obstetric pathologies such as foetal growth retardation. The genetic variants, 10034C/T gamma fibrinogen and 7872C/T factor XI, associated with thromboembolic disease, would not have an impact on PRE.

Assessment of the fetal-placental unit using clinical and ultrasound evaluation and inherited thrombophilia in pregnant patients

A normal pregnancy progression leads towards a pro­throm­botic phenotype in order to prepare the mother for delivery. When the physiological adaptation overlaps to abnormal changes, such as thrombophilic factor mu­ta­tions, the risk for adverse pregnancy outcome becomes in­crea­singly higher. Doppler ultrasound velocimetry of utero-placental and fetal vessels represents a method of antenatal monitoring, thus being a noninvasive evaluation method. We analyzed 145 pregnant women, recruited over a period of 6 months, from January 2016 to June 2016, in the Obstetrics and Gynecology Department of the Bucharest University Emergency Hospital, who underwent clinical and ultrasound evaluation according to their gestational age. We encountered five cases with middle cerebral artery/umbilical artery pulsatility indices ratio smaller than 1, representing the population at risk for a higher maternal and fetal morbidity and mortality. Also, intrauterine growth restriction was more frequent in the aforementioned group (60%) versus the rest of the patients (7.9%). An extensive literature review highlights the role of inherited thrombophilic disorders and obstetric complications affecting the normal placental vascular function; however, appropriate treatment can improve pregnancy outcome. Future research regarding thrombophilic pregnant patients should focus on close clinical and ultrasound monitoring for the best maternal and fetal results.

Adverse Placental Perfusion and Pregnancy Outcomes in a New Nonhuman Primate Model of Gestational Protein Restriction.

Maternal malnutrition during pregnancy impacts fetal growth, with developmental consequences that extend to later life outcomes. In underdeveloped countries, this malnutrition typically takes the form of poor dietary protein content and quality, even if adequate calories are consumed. Here, we report the establishment of a nonhuman primate model of gestational protein restriction (PR) in order to understand how placental function and pregnancy outcomes are affected by protein deficiency. Rhesus macaques were assigned to either a control diet containing 26% protein or switched to a 13% PR diet prior to conception and maintained on this PR diet throughout pregnancy. Standard fetal biometry, Doppler ultrasound of uteroplacental blood flow, ultrasound-guided amniocentesis, and contrast-enhanced ultrasound (CE-US) to assess placental perfusion were performed mid-gestation (gestational day 85 [G85] where term is G168) and in the early third trimester (G135). Our data demonstrate that a 50% reduction in dietary protein throughout gestation results in reduced placental perfusion, fetal growth restriction, and a 50% rate of pregnancy loss. In addition, we demonstrate reduced total protein content and evidence of fetal hypoxia in the amniotic fluid. This report highlights the use of CE-US for in vivo assessment of placental vascular function. The ability to detect placental dysfunction, and thus a compromised pregnancy, early in gestation, may facilitate the development of interventional strategies to optimize clinical care and improve long-term offspring outcomes, which are future areas of study in this new model.

Assessment of in vivo fetal growth and placental vascular function in a novel intrauterine growth restriction model of progressive uterine artery occlusion in guinea pigs.

Intra-uterine growth restriction (IUGR) is associated with short and long-term metabolic and cardiovascular alterations. Mice and rats have been extensively used to study the effects of IUGR, but there are notable differences in fetal and placental physiology relative to those of humans that argue for alternative animal models. This study proposes that gradual occlusion of uterine arteries from mid-gestation in pregnant guinea pigs produces a novel model to better assess human IUGR. Fetal biometry and in vivo placental vascular function were followed by sonography and Doppler of control pregnant guinea pigs and sows submitted to surgical placement of ameroid constrictors in both uterine arteries (IUGR) at mid-gestation (35 days). The ameroid constrictors induced a reduction in the fetal abdominal circumference growth rate (0.205 cm day(-1) ) compared to control (0.241 cm day(-1) , P < 0.001) without affecting biparietal diameter growth. Umbilical artery pulsatility and resistance indexes at 10 and 20 days after surgery were significantly higher in IUGR animals than controls (P < 0.01). These effects were associated with a decrease in the relative luminal area of placental chorionic arteries (21.3 ± 2.2% vs. 33.2 ± 2.7%, P < 0.01) in IUGR sows at near term. Uterine artery intervention reduced fetal (∼30%), placental (∼20%) and liver (∼50%) weights (P < 0.05), with an increased brain to liver ratio (P < 0.001) relative to the control group. These data demonstrate that the ameroid constrictor implantations in uterine arteries in pregnant guinea pigs lead to placental vascular dysfunction and altered fetal growth that induces asymmetric IUGR.

Periconceptional multiple-micronutrient supplementation and placental function in rural Gambian women: a double-blind, randomized, placebo-controlled trial

Background: Maternal micronutrient deficiencies are commonly associated with clinical indicators of placental dysfunction.Objective: We tested the hypothesis that periconceptional multiple-micronutrient supplementation (MMS) affects placental function.Design: We conducted a double-blind, randomized, placebo-controlled trial of MMS in 17- to 45-y-old Gambian women who were menstruating regularly and within the previous 3 mo. Eligible subjects were pre–randomly assigned to supplementation with the UNICEF/WHO/United Nations University multiple micronutrient preparation (UNIMMAP) or placebo on recruitment and until they reached their first antenatal check-up or for 1 y if they failed to conceive. Primary outcome measures were midgestational indexes of utero-placental vascular-endothelial function [ratio of plasminogen-activator inhibitor (PAI) 1 to PAI-2 and mean uterine-artery resistance index (UtARI)] and placental active transport capacity at delivery [fetal to maternal measles antibody (MMA) ratio].Results: We recruited 1156 women who yielded 415 pregnancies, of which 376 met all of the inclusion criteria. With adjustment for gestational age at sampling, there were no differences in PAI-1 to PAI-2 or MMA ratios between trial arms, but there was a 0.02-unit reduction in UtARI between 18 and 32 wk of gestation (95% CI: −0.03, −0.00; P = 0.040) in women taking UNIMMAP.Conclusions: Placental vascular function was modifiable by periconceptional micronutrient supplementation. However, the effect was small and supplementation did not further affect other variables of placental function. This trial was registered at www.controlled-trials.com as ISRCTN 13687662.

IFPA Gábor Than Award Lecture: Recognition of placental failure is key to saving babies' lives

In high-income countries, placental failure is implicated in up to 65% of cases of stillbirth. Placental failure describes the situation where the placenta cannot meet the fetus' needs and may be the end-result of a variety of underlying pathological processes evident in the placental disc, membranes and umbilical cord. These include lesions with genetic, environmental, infectious, inflammatory, mechanical, metabolic, traumatic or vascular origin. Investigation of placental tissue from stillbirths and from pregnancies at an increased risk of stillbirth has demonstrated changes in macroscopic and microscopic structure which are themselves related to abnormal placental function.A better understanding and identification of placental failure may improve the management of pregnancy complications and of pregnancies after stillbirth (which have a 5-fold increased risk of stillbirth). The majority of current antenatal tests focus on the fetus and its response to the intrauterine environment; few of these investigations reduce stillbirths in low-risk pregnancies. However, some currently used investigations reflect placental development, structure and vascular function, while other investigations employed in clinical research settings such as the evaluation of placental structure and shape have a good predictive value for adverse fetal outcome. In addition, recent studies suggest that biomarkers of placental inflammation and deteriorating placental function can be detected in maternal blood suggesting that holistic evaluation of placental structure and function is possible. We anticipate that development of reliable tests of placental structure and function, coupled to assessment of fetal wellbeing offer a new opportunity to identify pregnancies at risk of stillbirth and to direct novel therapeutic strategies to prevent it.

Does altered placental morphology and function explain increased incidence of poor pregnancy outcome in advanced maternal age

Does altered placental morphology and function explain increased incidence of poor pregnancy outcome in advanced maternal age

The placental pursuit for an adequate oxidant balance between the mother and the fetus.

The placenta is the exchange organ that regulates metabolic processes between the mother and her developing fetus. The adequate function of this organ is clearly vital for a physiologic gestational process and a healthy baby as final outcome. The umbilico-placental vasculature has the capacity to respond to variations in the materno-fetal milieu. Depending on the intensity and the extensity of the insult, these responses may be immediate-, mediate-, and long-lasting, deriving in potential morphostructural and functional changes later in life. These adjustments usually compensate the initial insults, but occasionally may switch to long-lasting remodeling and dysfunctional processes, arising maladaptation. One of the most challenging conditions in modern perinatology is hypoxia and oxidative stress during development, both disorders occurring in high-altitude and in low-altitude placental insufficiency. Hypoxia and oxidative stress may induce endothelial dysfunction and thus, reduction in the perfusion of the placenta and restriction in the fetal growth and development. This Review will focus on placental responses to hypoxic conditions, usually related with high-altitude and placental insufficiency, deriving in oxidative stress and vascular disorders, altering fetal and maternal health. Although day-to-day clinical practice, basic and clinical research are clearly providing evidence of the severe impact of oxygen deficiency and oxidative stress establishment during pregnancy, further research on umbilical and placental vascular function under these conditions is badly needed to clarify the myriad of questions still unsettled.

Is a low level of free thyroxine in the maternal circulation associated with altered endothelial function in gestational diabetes?

Synthesis of thyroid hormones, thyroxine (T4) and tri-iodothyronine (T3), in the human fetus starts from 17 to 19th weeks of gestation. Despite the majority of normal pregnant women reaching adequate levels of circulating thyroid hormones, in some cases, women with normal pregnancies have low level of free T4 during first trimester of pregnancy, suggesting that T4 action may be compromised in those women and their fetuses. In addition, pathological low levels of thyroid hormones are detected in isolated maternal hypothyroxemia (IMH) and clinical hypothyroidism. Nevertheless, human placenta regulates T3/T4 concentration in the fetal circulation by modulating the expression and activity of both thyroid hormone transporters (THT) and deiodinases. Then, placenta can control the availability of T3/T4 in the feto-placental circulation, and therefore may generate an adaptive response in cases where the mother courses with low levels of T4. In addition, T3/T4 might control vascular response in the placenta, in particularly endothelial cells may induce the synthesis and release of vasodilators such as nitric oxide (NO) or vasoconstrictors such as endothelin-1 mediated by these hormones. On the other hand, low levels of T4 have been associated with increase in gestational diabetes (GD) markers. Since GD is associated with impaired placental vascular function characterized by increased NO synthesis in placental arteries and veins, as well as elevated placental angiogenesis, it is unknown whether reduced T4 level at the maternal circulation could result in an altered placental endothelial function during GD. In this review, we analyze available information regarding thyroid hormones and endothelial dysfunction in GD; and propose that low maternal levels of T4 observed in GD may be compensated by increased placental availability of T3/T4 via elevation in the activity of THT and/or reduction in deiodinases in the feto-placental circulation.