Trophoblast Plugs Research Articles

Hyperhomocysteinemia and pregnancy: about a case and literature review

Homocysteine ​​(Hct) is a substance produced in the metabolism of methionine that can be found in our daily diet. Mutation of the methylenetetrahydrofolate reductase (MTHFR) gene, especially in women with low folate intake. Hyperhomocysteinemia (HHct) can be caused by several factors, such as lack of folic acid, vitamin B6 and B12 deficiency, hypothyroidism, medications, genetic abnormalities, aging and kidney dysfunction. Increased homocysteine ​​in peripheral blood can lead to vascular disease, coronary artery dysfunction, atherosclerotic changes, and embolic disease. Thus, upstream of the trophoblastic plugs, any increase in the thrombogenic power of pregnant women will lead to the formation of a clot and the termination of pregnancy. Recent studies have reported that hyperhomocysteinemia is associated with numerous pregnancy complications, including abortion disease, preeclampsia, preterm birth, hematoma placentae, fetal growth restriction, and gestational diabetes. To avoid thrombosis, the treatment will therefore be based on anticoagulants, sometimes combined with low-dose aspirin because of the anti-aggregating action of the latter. In this article, we report the case of a patient with a history of abortive disease on hyperhomocysteinemia who carried a pregnancy to term, while recalling the metabolism of homocysteine, its impact on pregnancy, and the interest of supplementation folic acid to prevent complications due to hyperhomocysteinemia.

Maternal platelets pass interstices of trophoblast columns and are not activated by HLA-G in early human pregnancy

In early human gestation, maternal arterial blood flow into the intervillous space of the developing placenta is obstructed by invaded trophoblasts, which form cellular plugs in uterine spiral arteries. These trophoblast plugs have recently been described to be loosely cohesive with clear capillary-sized channels into the intervillous space by 7 weeks of gestation. Here, we analysed localisation of maternal platelets at the maternal-foetal interface of human first trimester pregnancy, and tested the hypothesis whether HLA-G, which is primarily expressed by extravillous trophoblasts, affects aggregation and adhesion of isolated platelets. Immunohistochemistry of first trimester placental sections localised maternal platelets in vessel-like channels and adjacent intercellular gaps of extravillous trophoblasts in distal parts of columns. Furthermore, this localisation was confirmed by transmission electron microscopy. Neither co-incubation of HLA-G overexpressing JAR cells with isolated platelets, nor incubation with cell-derived soluble HLA-G or recombinant HLA-G affected platelet adhesion and aggregation. Our study suggests that maternal platelets flow through vessel-like channels of distal trophoblast columns and spread into adjacent lateral intercellular gaps, where platelet-derived factors could contribute to trophoblast differentiation into the invasive phenotype.

Something old, something new: digital quantification of uterine vascular remodelling and trophoblast plugging in historical collections provides new insight into adaptation of the utero-placental circulation.

What is the physiological extent of vascular remodelling in and trophoblast plugging of the uterine circulation across the first half of pregnancy? All levels of the uterine vascular tree (arcuate, radial and spiral arteries (SAs)) dilate ∼2.6- to 4.3-fold between 6 and 20 weeks of gestation, with significant aggregates of trophoblasts persisting in the decidual and myometrial parts of SAs beyond the first trimester. In early pregnancy, endovascular trophoblasts form 'plugs' in the SAs, transiently inhibiting blood flow to the placenta, whilst concurrently the uterine vasculature undergoes significant adaption to facilitate increased blood delivery to the placenta later in gestation. These processes are impaired in pregnancy disorders, but quantitative understanding of the anatomical changes even in normal pregnancy is poor. Serial sections of normal placentae in situ (n = 22) of 6.1-20.5 weeks of gestation from the Boyd collection and Dixon collection (University of Cambridge, UK) were digitalized using a slide scanner or Axio Imager.A1 microscope. Spiral (n = 45), radial (n = 40) and arcuate (n = 39) arteries were manually segmented. Using custom-written scripts for Matlab® software, artery dimensions (Feret diameters; major axes; luminal/wall area) and endovascular trophoblast plug/aggregate (n = 24) porosities were calculated. Diameters of junctional zone SAs within the myometrium (n = 35) were acquired separately using a micrometre and light microscope. Decidual thickness and trophoblast plug depth was measured using ImageJ. By all measures, radial and arcuate artery dimensions progressively increased from 6.1 to 20.5 weeks (P < 0.01). The greatest increase in SA calibre occurred after 12 weeks of gestation. Trophoblast aggregates were found to persist within decidual and myometrial parts of SA lumens beyond the first trimester, and up to 18.5 weeks of gestation, although those present in the second trimester did not appear to prevent the passage of red blood cells to the intervillous space. Trophoblasts forming these aggregates became more compact (decreased in porosity) over gestation, whilst channel size between cells increased (P = 0.01). Decidual thickness decreased linearly over gestation (P = 0.0003), meaning plugs occupied an increasing proportion of the decidua (P = 0.02). N/A. Although serial sections were assessed, two-dimensional images cannot completely reflect the three-dimensional properties and connectivity of vessels and plugs/aggregates. Immersion-fixation of the specimens means that vessel size may be under-estimated. Uterine vascular remodelling and trophoblast plug dispersion is a progressive phenomenon that is not completed by the end of the first trimester. Our quantitative findings support the concept that radial arteries present a major site of resistance until mid-gestation. Their dimensional increase at 10-12 weeks of gestation may explain the rapid increase in blood flow to the placenta observed by others at ∼13 weeks. Measured properties of trophoblast plugs suggest that they will impact on the resistance, shear stress and nature of blood flow within the utero-placental vasculature until mid-gestation. The presence of channels within plugs will likely lead to high velocity flow streams and thus increase shear stress experienced by the trophoblasts forming the aggregates. Quantitative understanding of utero-placental vascular adaptation gained here will improve in silico modelling of utero-placental haemodynamics and provide new insights into pregnancy disorders, such as fetal growth restriction. This work was supported by a Royal Society Te Aparangi Marsden Grant [18-UOA-135]. A.R.C. is supported by a Rutherford Discovery Fellowship [14-UOA-019]. The authors have no conflict of interest to declare.

Changes in Placental Morphology and their Association with Embryonic Skin Development

Abstract Histogenesis and organogenesis in mammals normally transpires in a hypoxic environment. Oxygen diffusing capacity is dependent on diffusion distance, which may vary with the thickness of placental barrier and with the level of tissue vascularity. Since the epidermis is avascular, its development fully depends on dermal blood vessels. Despite the large number of studies focusing on uteroplacental circulation and embryogenesis, it is clear that the current knowledge of how placental changes in pregnancy contribute to skin development is incomplete. The aim of this study was to evaluate the association between structural changes in the placental barrier and development of the integumentary system, with special reference to dermal angiogenesis. The study included specimens of six embryos and ten foetuses from 5 to 24 developmental weeks, and 21 specimens of placental tissue 6–40 weeks gestational age. The panel of antibodies used was S- 100, SMA, CD31, CD34, AE1/AE3 (PCKT), CKRT7, CD 56 and hCG. During the first trimester, maternal blood flow to the placenta appears to be initially restricted by trophoblast plugs. Natural killer cells appear in great abundance in subendothelium of decidual blood vessels, potentially stimulating extensive angiogenesis. By the end of the first trimester, new capillary beds organise to supply the developing epidermal derivatives. During the second trimester, the placental barrier becomes progressively thinner, and uteroplacental circulation is established due to dissolution of endovascular trophoblast plugs. Progression of the formation of skin appendages, hypodermal adipose tissue, demarcation of papillary and reticular dermis, and keratinisation of interfollicular epidermis in the second trimester strongly accompanies the dermal angiogenesis and placental maturation.

Trophoblast plugs: impact on utero-placental haemodynamics and spiral artery remodelling.

How does trophoblast plugging impact utero-placental haemodynamics? Physiological trophoblast plug structures are dense enough to restrict flow of oxygenated blood to the intervillous space (IVS) in the first trimester, and result in a shear stress environment upstream of the plugs that promotes spiral artery remodelling. Trophoblast plugging of the uterine spiral arteries is thought to be the dominant factor restricting the flow of oxygenated maternal blood to the placenta in the first trimester of pregnancy. However, the extent of plugging, the timing of plug break up, and the impact of plug structure on pregnancy outcomes is debated. A computational model of the uterine radial and spiral arteries, incorporating arteriovenous anastomoses was developed. The model was parameterized with our own histological data and previous literature descriptions of the dimensions of the spiral arteries, and the structural properties (porosity) of trophoblast plugs. Structural data were acquired from the literature, and supplemented by images of the spiral arteries acquired by standard thin-section 2D immunohistochemistry, and whole mount immunohistochemistry imaged in 3D by micro-CT. Computational models were solved using Matlab software, via custom written scripts. We confirm that physiological lengths (>0.1 mm) and porosities (0.2-0.6) of trophoblast plugs are sufficient to restrict the flow of oxygenated maternal blood flow to the placental surface. Trophoblast plugs also have important haemodynamic consequences upstream in the spiral arteries by generating shear stress conditions of <2 dyne/cm2 that promote trophoblast-induced spiral artery remodelling. Structural changes in plugs as they dislodge are likely to result in rapid increases in blood flow to the IVS, and it is likely at this stage of gestation that the major source of resistance in the utero-placental circulation transitions from the spiral arteries to the radial arteries, which then act as a the 'rate-limiting' step to IVS flow. Structural descriptions of the spiral arteries, radial arteries and trophoblast plugs largely rely on 2D histological sections, or historical measurements. Increased focus on quantitatively assessing the 3D structure of the uterine arteries using more modern imaging technologies in the future will strengthen model predictions. Our work suggests that trophoblast plugs play a previously under-appreciated role in regulating spiral artery remodelling in the first trimester of human pregnancy. This creates the possibility that inadequate trophoblast plugging in the first trimester may contribute to the inadequate artery remodelling observed in pregnancy pathologies such as pre-eclampsia. The incorporation of arteriovenous anastomoses in our model highlights the important influence that shunted blood can play in utero-placental haemodynamics, and together with the emerging role of radial arteries in regulating blood flow to the placenta, the influence of arteriovenous anastomoses on radial artery haemodynamics in normal and pathological pregnancies warrants further investigation. This research was supported by a Royal Society of New Zealand Marsden Fund award (13-UOA-032). A.R.C. is supported by a Royal Society of New Zealand Rutherford Discovery Fellowship (14-UOA-019). R.S. was supported by a Gravida (National Centre for Growth and Development) postgraduate scholarship. The authors have no conflicts of interest. N/A.

Early first trimester uteroplacental flow and the progressive disintegration of spiral artery plugs: new insights from contrast-enhanced ultrasound and tissue histopathology.

Does the use of a vascular contrast agent facilitate earlier detection of maternal flow to the placental intervillous space (IVS) in the first trimester of pregnancy? Microvascular filling of the IVS was demonstrated by contrast-enhanced ultrasound from 6 weeks of gestation onwards, earlier than previously believed. During placental establishment and remodeling of maternal spiral arteries, endovascular trophoblast cells invade and accumulate in the lumen of these vessels to form 'trophoblast plugs'. Prior evidence from morphological and Doppler ultrasound studies has been conflicting as to whether the spiral arteries are completely plugged, preventing maternal blood flow to the IVS until late in the first trimester. Uteroplacental flow was examined across the first trimester in human subjects given an intravenous infusion of lipid-shelled octofluoropropane microbubbles with ultrasound measurement of destruction and replenishment kinetics. We also performed a comprehensive histopathological correlation using two separately archived uteroplacental tissue collections to evaluate the degree of spiral artery plugging and evaluate remodeling of the upstream myometrial radial and arcurate arteries. Pregnant women (n = 34) were recruited in the first trimester (range: 6+3 to 13+6 weeks gestation) for contrast-enhanced ultrasound studies with destruction-replenishment analysis of signal intensity for assessment of microvascular flux rate. Histological samples from archived in situ (Boyd Collection, n = 11) and fresh first, second, and third trimester decidual and post-hysterectomy uterine specimens (n = 16) were evaluated by immunohistochemistry (using markers of epithelial, endothelial and T-cells, as well as cell adhesion and proliferation) and ultrastructural analysis. Contrast agent entry into the IVS was visualized as early as 6+3 weeks of gestation with some variability in microvascular flux rate noted in the 6-7+6 week samples. Spiral artery plug canalization was observed from 7 weeks with progressive disintegration thereafter. Of note, microvascular flux rate did not progressively increase until 13 weeks, which suggests that resistance to maternal flow in the early placenta may be mediated more proximally by myometrial radial arteries that begin remodeling at the end of the first trimester. Gestational age was determined by crown-rump length measurements obtained by transvaginal ultrasound on the day of contrast-enhanced imaging studies, which may explain the variability in the earliest gestational age samples due to the margin of error in this type of measurement. Our comprehensive in situ histological analysis, in combination with the use of an in vivo imaging modality that has the sensitivity to permit visualization of microvascular filling, has allowed us to reveal new evidence in support of increasing blood flow to the IVS from 6 weeks of gestation. Histologic review suggested the mechanism may be blood flow through capillary-sized channels that form through the loosely cohesive 'plugs' by 7 weeks gestation. However, spiral artery remodeling on its own did not appear to explain why there is significantly more blood flow at 13 weeks gestation. Histologic studies suggest it may be related to radial artery remodeling, which begins at the end of the first trimester. This project was supported by the Oregon Health and Science University Knight Cardiovascular Institute, Center for Developmental Health and the Struble Foundation. There are no competing interests.

The influence of trophoblast plugs on spiral artery hemodynamics

The influence of trophoblast plugs on spiral artery hemodynamics

The trophoblast plug during early pregnancy: a deeper insight.

During the first trimester of pregnancy, foetal endovascular trophoblasts invade into maternal spiral arteries, accumulate and form plugs in the lumen of the vessels. These plugs only allow blood plasma to seep through. Hence, during the first trimester of pregnancy, a first flow of fluids through the placental intervillous space is established, resulting in a physiological oxygen gradient between mother and foetus. The trophoblast plugs block spiral arteries until the beginning of the second trimester (11–14 weeks). In parallel, uterine glands are invaded and opened by endoglandular trophoblasts towards the intervillous space of the placenta, without showing the formation of plugs (Moser et al. in Hum Reprod 25:1127–1136, 2010, Hum Reprod Oxf Engl 30:2747–2757, 2015). This enables histiotrophic nutrition of the embryo prior to onset of maternal blood flow into the placenta. Failure of these endovascular and endoglandular invasion processes may lead to miscarriage or pregnancy disorders such as intrauterine growth restriction (IUGR). After dissolution of the plugs, the onset of maternal blood flow allows maternal blood cells to enter the intervillous space and oxygen concentrations rise up. In this study, we demonstrate for the first time serial cross sections through a trophoblast plug in a first trimester placental bed specimen. Invaded and plugged arteries as well as invaded uterine glands in week 11 of gestation are visualized with specific immunohistochemical double staining techniques. We show that spiral artery plugs appear throughout the placental invasion zone and illustrate erythrocytes stowed due to trophoblast plugs. In addition, we give evidence of the presence of MMP-1 in plugs of invaded spiral arteries. The results reveal a better understanding and a closer insight into the morphological appearance of trophoblast plugs and the consequences for placental and uterine blood flow.

Does high-density lipoprotein protect vascular function in healthy pregnancy?

The maternal adaptation to pregnancy includes hyperlipidaemia, oxidative stress and chronic inflammation. In non-pregnant individuals, these processes are usually associated with poor vascular function. However, maternal vascular function is enhanced in pregnancy. It is not understood how this is achieved in the face of the adverse metabolic and inflammatory environment. Research into cardiovascular disease demonstrates that plasma HDL (high-density lipoprotein), by merit of its functionality rather than its plasma concentration, exerts protective effects on the vascular endothelium. HDL has vasodilatory, antioxidant, anti-thrombotic and anti-inflammatory effects, and can protect against endothelial cell damage. In pregnancy, the plasma HDL concentration starts to rise at 10 weeks of gestation, peaking at 20 weeks. The initial rise in plasma HDL occurs around the time of the establishment of the feto-placental circulation, a time when the trophoblast plugs in the maternal spiral arteries are released, generating oxidative stress. Thus there is the intriguing possibility that new HDL of improved function is synthesized around the time of the establishment of the feto-placental circulation. In obese pregnancy and, to a greater extent, in pre-eclampsia, plasma HDL levels are significantly decreased and maternal vascular function is reduced. Wire myography studies have shown an association between the plasma content of apolipoprotein AI, the major protein constituent of HDL, and blood vessel relaxation. These observations lead us to hypothesize that HDL concentration, and function, increases in pregnancy in order to protect the maternal vascular endothelium and that in pre-eclampsia this fails to occur.

The six stages of pre-eclampsia.

For many years pre eclampsia has been considered to be a two-stage disease. The first stage comprises poor placentation. The second stage is the clinical expression of the disease namely new hypertension and new proteinuria. The first stage is preclinical and symptomless, which evolves between weeks 8 and 18 of pregnancy, when the uteroplacental circulation is established by spiral artery remodelling. Its consequence is dysfunctional perfusion of the intervillous space of the placenta with oxidative and haemodynamic stress. The damaged placenta releases excessive pro-inflammatory and antiangiogenic factors into the maternal circulation. With increasing knowledge, this model has become inadequate. First the antecedents of poor placentation have become clearer and are immunological in origin, reflecting the mother's ability to accommodate to the genetic foreignness of her unborn child. They begin, as discussed already in this meeting, with preconceptual tolerisation of the mother to the semen of the prospective father of her child. A lack of tolerisation, arising from a short interval between first coitus and conception increases the likelihood of poor placentation and pre-eclampsia (Stage 1). This is presumed to affect the health and growth of the embryo immediately after implantation but there is little evidence of this at the moment (Stage 2). Placentation begins after week 8 when the uteroplacental circulation, which previously has been closed by trophoblast plugs in the spiral arteries, begins to open. Defective placentation may arise from premature opening, and perfusion of the intervillous space by oxygenised arterial blood before the placenta is equipped to cope with the stress. Placentation extends over about 10 weeks and, when it is defective, constitutes stage 3 of pre-eclampsia. Stages 4-6 all occur in the second half of pregnancy. Stage 4 is associated with excessive or deficient placental derived factors in the mother's blood, secondary to placental damage, before the appearance of clinical signs. When the diagnosis of pre-eclampsia can be made stage 5 has begun. Stage 6 affects less than half of women with pre-eclampsia. It is the superimposition of a second and later spiral artery lesion called acute atherosis, which has some resemblance to atherosclerosis, which is suffered by middle and old-aged, non-pregnant adults. Its importance is that it further reduces uteroplacental perfusion and predisposes to spiral artery thrombosis, which underlies the occurrence of placental infarcts. The evidence for and the mechanisms of these multiple stages will be briefly presented.

LAIR2-expressing extravillous trophoblasts associate with maternal spiral arterioles undergoing physiologic conversion

Leukocyte-associated immunoglobulin-like receptor 2 (LAIR2) was identified on a global gene expression microarray analysis of surplus chorionic villus sampling (CVS) tissues as down-regulated in the first trimester of preeclampsia pregnancies. LAIR2 is the soluble receptor counterpart to LAIR1, an inhibitory receptor found on multiple immune cell subsets. In situ and immunohistochemical studies have previously shown that placental expression of LAIR2 expression is highly restricted, confined to the more distal portions of extravillous trophoblast (EVT) cell columns. This study examines LAIR2 expression in deeper layers of trophoblasts in the placental implantation site, maternal decidua and maternal spiral arterioles. Immunohistochemical staining detected LAIR2 expression on a subset of EVT within the implantation site. This trophoblast included the invasive EVT infiltrating the maternal decidual vessels and the EVT forming the endovascular trophoblastic plugs. More specifically, LAIR2-positive EVT showed a striking predilection for maternal decidual arterioles and the immediately surrounding decidua. Moreover, the appearance of EVT expressing LAIR2 in these areas was contemporaneous with the process of spiral arteriole remodeling. Based on these findings, we suggest that LAIR2-expressing EVT may play an important role in the remodeling of maternal spiral arterioles.

Comparative expression of hCG β-genes in human trophoblast from early and late first-trimester placentas

Human chorionic gonadotropin (hCG) displays a major role in pregnancy initiation and progression and is involved in trophoblast differentiation and fusion. However, the site and the type of dimeric hCG production during the first trimester of pregnancy is poorly known. At that time, trophoblastic plugs present in the uterine arteries disappear, allowing unrestricted flow of maternal blood to the intervillous space. The consequence is an important modification of the trophoblast environment, including a rise of oxygen levels from about 2.5% before 10 wk of amenorrhea (WA) to ∼8% after 12 WA. Two specific β-hCG proteins that differ from three amino acids have been described: type 1 (CGB7) and type 2 (CGB3, -5, and -8). Here, we demonstrated in situ and ex vivo on placental villi and in vitro in primary cultures of human cytotrophoblasts that type 1 and 2 β-hCG RNAs and proteins were expressed by trophoblasts and that these expressions were higher before blood enters in the intervillous space (8-9 vs. 12-14 WA). hCG was immunodetected in villous mononucleated cytotrophoblasts (VCT) and syncytiotrophoblast (ST) at 8-9 WA but only in ST at 12-14 WA. Furthermore, hCG secretion was fourfold higher in VCT cultures from 8-9 WA compared with 12-14 WA. Interestingly, VCT from 8-9 WA placentas were found to exhibit more fusion features. Taken together, we showed that type 1 and type 2 β-hCG are highly expressed by VCT in the early first trimester, contributing to the high levels of hCG found in maternal serum at this term.

Development and hormonal functions of the human placenta.

The human placenta is characterized by the intensity of the trophoblast invasion into the uterus wall and the specificity of its hormonal functions. Placental hormones are required for the establishment and maintenance of pregnancy, adaptation of the maternal organism to pregnancy and fetal growth. In the early placenta at the maternofetal interface, the human trophoblast differentiates along two pathways: 1/ the villous trophoblast pathway including the cytotrophoblastic cells which differentiate by fusion to form the syncytiotrophoblast that covers the entire surface of the villi; 2/ the extravillous trophoblast pathway. The cytotrophoblastic cells of the anchoring villi in contact with the uterus wall proliferate and then migrate into the decidua and the myometrium but also participate to the remodeling of the spiral arteries. During the first trimester of pregnancy the spiral arteries are plugged by trophoblastic cells, allowing the development of the fetoplacental unit in low oxygen environment. At this stage of pregnancy the extravillous trophoblast secretes a large amount of hormones such as particular hyperglycosylated forms of hCG directly involved in the quality of the placentation. At 10-12 weeks of pregnancy, the trophoblastic plugs are progressively dislocated and the syncytiotrophoblast starts to bath in maternal blood. It secretes the major part of its polypeptide hormones in maternal circulation taking over the maternal metabolism in order to increase the energetic flux to the fetus. As example the placental GH (growth hormone) secreted continuously by the syncytiotrophoblast is directly involved in the insulino-resistance of pregnancy. Capturing the cholesterol from the maternal lipoproteins, the syncytiotrophoblast synthesizes also large amount of progesterone essential for the uterine quiescence. Deprived of cytochrome P450 17alpha-hydroxylase-17:20 lyase, it uses the maternal and fetal adrenal androgens to synthesize estrogens. The differentiation and hormonal functions of the human trophoblast are regulated by the environmental O2 and reflect mammalian evolution.

The regulation of trophoblast differentiation by oxygen in the first trimester of pregnancy

In the first trimester of human pregnancy villous cytotrophoblasts are able to differentiate to form either the overlying syncytiotrophoblast layer or, in anchoring villi, extravillous trophoblasts which grow out from the villi and invade into the maternal decidua, acting to both physically attach the placenta to the decidua, and modify the maternal spiral arteries to sustain pregnancy. During the first 10-12 weeks of gestation, extravillous trophoblast plugs block the spiral arteries and prevent maternal blood flow entering the intervillous space, thereby creating an environment of physiological hypoxia in which placental and fetal development occur. As extravillous trophoblasts migrate away from the villus they differentiate from a proliferative to an invasive phenotype. The hypoxic environment of the first trimester is believed to play an important role in the regulation of trophoblast differentiation. However, there is currently a large body of conflicting experimental evidence concerning this topic. This review examines the experimental evidence to date on the role of oxygen in trophoblast differentiation.

Pre-eclampsia: An overview in placentation, endothelial dysfunction and flow-mediated vasodilation

AbstractThe blastocyst–endometrium interaction requires the perfect synchronization between the development of the embryo and the maturation of the endometrium. The trophoblast starts to invade the decidua and the spiral arteries, forming trophoblastic plugs. These plugs explain why the beginning of placentation and the development of the fetus occur in a hypoxic environment with trophoblastic invasion of the inner third of the myometrium and the physiological transformation of the spiral arteries in this region. Recent studies indicate that many abnormalities in the physiopathology of pre-eclampsia are similar to those in atherosclerosis. The risk factors of this disorder are heterogeneous and are, once more, frequently associated with atherosclerosis. Pre-eclampsia is currently regarded as a two-stage disease: the uteroplacental circulation remains in a high-pressure regimen, corresponding to the first stage of the disease. The second stage includes the maternal response in which there is global activat...

Placental Transport in Early Pregnancy—A Workshop Report

Most studies concerning placental transport in humans have concentrated on term placenta, undoubtedly because this tissue is more readily available than from earlier in pregnancy. As a result, our understanding of placental transport in early pregnancy is somewhat limited. Certainly this aspect of placental physiology needs exploring, not least because in early pregnancy both the fetus and the developing placenta will have changing metabolic demands for nutrients/metabolites. Additionally, the uterine environment in which the placenta is developing in early pregnancy is also changing concomitantly. This is especially notable with respect to the partial pressure of oxygen (pO 2 ) in the intervillous space (IVS), which is raised following the onset of blood flow to the IVS after progressive dislocation of trophoblast plugs from the openings of the spiral arterioles at 10‐12 weeks of pregnancy [1]. This leads us to consider several questions. How is fetal nutrition mediated in early pregnancy before the onset of blood flow to the IVS? What is the impact of the changing oxygen environment on placental transport processes? What placental transporters are expressed in first trimester and how might these be regulated? What is the relative importance of transcellular and paracellular pathways of transport during early pregnancy and how might these change with advancing gestation? The aim of this workshop was to address these issues with a view to gaining a better understanding of placental transport events in early pregnancy. Graham Burton (Cambridge) started by reviewing the placental environment during the first trimester. During the first week of development, the embryo most likely obtains nutrients by simple diffusion from blood pooled in the trophoblastic lacunae. However, the metabolic demands of the developing embryo soon outstrip this means of nutrient delivery and progressive placental development and the establishment of uteroplacental and fetoplacental circulations provides a more efficient means of maternofetal exchange. However, before 8 weeks of pregnancy, no maternal arterial connections with the IVS space exist, and endovascular extravillous trophoblast occlude the openings of spiral arteries. But from 10 weeks onwards direct communication between the spiral arteries and the IVS could be delineated [2]. The intervillous circulation is, however, not continuous over the whole placenta until about after 12 weeks [1]. So, how does the fetus obtain nutrients prior to the establishment of the maternal circulation through the placenta allowing haemotrophic nutrition to occur? One possibility is that a plasma filtrate percolates through the arterial plugs into the IVS providing a source of nutrients for histiotrophic nutrition [2]. Another proposal is that carbohydrate-rich uterine glandular secretions, discharged into the IVS are taken up by trophoblastic tissue [2].

Maternal circulation in the first-trimester human placenta—Myth or reality?

The classic theory of development of the uteroplacental and intervillous circulation determined that maternal blood enters the intervillous space in high-pressure streams from the early first trimester. This theory has recently been challenged and our hypothesis to be presented is that the intervillous circulation is not fully established until the end of the first trimester. Ex vivo studies of hysterectomy specimens have demonstrated that trophoblastic plugs obstruct blood flow into the intervillous space in early pregnancy and only at 12 to 13 weeks do these plugs become loose and allow for continuous maternal blood flow into the intervillous space. This concept is supported by many other experimental findings. In complicated early pregnancies the uteroplacental circulation demonstrates flow characteristics that are strikingly different from those of normal early pregnancies. In abnormal pregnancies increased flow within the intervillous space is demonstrated by color Doppler imaging. Our hypothesis supports other studies that have shown that the embryo favors an environment low in oxygen during early development and that oxygen levels in placental tissue are low in the early first trimester. The classic drawing of placental circulations is based on second- and third-trimester studies, and its applicability to the early first trimester should be revisited because we will show that new data support the hypothesis that the development of the early intervillous circulation is a progressive phenomenon. (Am J Obstet Gynecol 1997;176:695-705.)

Longitudinal evaluation of uteroplacental and umbilical blood flow changes in normal early pregnancy.

The hemodynamic changes in the uteroplacental circulation and the umbilical artery were evaluated in normal pregnancy from 8 to 14 weeks' gestation. A 6-9-MHz broad-band transvaginal sonographic transducer combined with pulsed color Doppler was used to scan 37 healthy volunteer pregnant women at weekly intervals. Vascular impedance to blood flow in all examined vessels decreased significantly throughout the first gestational trimester. Resistance to flow was highest in the main uterine artery and decreased towards the spiral artery. When the flow velocity waveform patterns of the arteries under investigation were analyzed, specific changes were observed. The diastolic notch was present in the spiral artery flow velocity waveform in all cases until 10 weeks' gestation. From then, the diastolic notch disappeared progressively and was absent in 100% of cases at 13 weeks. The diastolic notch in the arcuate artery disappeared within 2 weeks of its disappearance in the spiral artery. We could not detect intervillous blood flow during the first 12 weeks. From then on, intervillous flow was observed in most pregnancies, reaching 100% at 14 weeks' gestation. These changes reflect the growth and development of the uteroplacental circulation. The absence of detectable intervillous flow during most of the first trimester confirms the concept that, during the first 3 months of gestation, blood flow to the intervillous space is inhibited by trophoblastic plugs.

Uteroplacental and luteal circulation in normal first-trimester pregnancies: Doppler ultrasonographic and morphologic study

OBJECTIVE: Our purpose was to establish reference data representative of normal findings at transvaginal color and spectral Doppler ultrasonographic examination of the uteroplacental and luteal circulation in the first trimester and to relate the Doppler findings to morphologic data. STUDY DESIGN: A cross-sectional study was performed of 64 uncomplicated pregnancies of 5 to 11 completed gestational weeks terminated by legal abortion for psychosocial reasons. Doppler examinations of the main uterine arteries, subchorionic arteries, intrachorionic area, and corpus luteum were performed. Abortion material was examined morphologically. RESULTS: In the uterine and subchorionic arteries blood flow velocity increased and pulsatility index values decreased with advancing gestation. Arterial or venous Doppler shift spectra were recorded from the intrachorionic area in 91% (58/64) of the pregnancies. Intrachorionic arterial blood flow velocities and pulsatility index values were low and did not change with advancing gestation; the mean time-averaged maximum velocity, peak systolic velocity, and pulsatility index values were 4.6 cm/sec, 6.0 cm/sec, and 0.47, respectively. Morphologic examination showed trophoblast plugs in the spiral arteries to consistently manifest multiple spaces containing red blood cells at the choriodecidual junction. CONCLUSION: Blood flow velocity in the uteroplacental arteries increases and pulsatility index values decrease with advancing gestation, indicating a steady increase in uterine perfusion during the first trimester. Our findings suggest intervillous flow to be present as early as the first trimester. (A M J O BSTET G YNECOL 1996;174:768-75.)