Uteroplacental Blood Flow

Sexual reproduction in the ocean necessitates only the combination of gametes, followed by absorption of nutrients and oxygen from the surrounding watery medium. As life moved from the sea to the land, reproductive strategies required compensation for the loss of this aquatic environment. For mammals and a few other animals, the solution to this problem was the development of the placenta, the means by which the fetus extracts nutrients from its environment. As the animals that used the placenta evolved from small rodent-like creatures with short gestations to larger animals with prolonged gestations, the demands of the developing fetus grew. Whereas the placenta of the fetal pig, with a gestational period of a little less than 4 months, can extract sufficient nutrients from the mother by simple diffusion across the uterus to the placenta, the human fetus needs a far more complex uteroplacental relationship. Several evolutionary solutions to the increased demands of fetuses can be observed.1Benirschke K Kaufmann P Pathology of the Human Placenta. 3d edition. Springer-Verlag, New York1995Crossref Google Scholar One approach was a larger placenta. For example, the chinchilla has a neonatal:placental weight ratio of 30:1, whereas the human has a 6:1 ratio. Another means to greater nutritional support for the fetus was to increase the surface area of contact between fetal circulation in the placenta and maternal circulation. The pig fetus has a diffuse placenta that makes contact with the mother's uterus by a simple folded contact. The human placenta, on the other hand, has a complex villous structure, similar to the sea anemone's tentacles waving in the sea, that greatly increases the contact surface area between the mother's blood space and the fetal circulation. Despite this increased fetal-maternal contact, the system is still rather inefficient. We can quantify this by considering the amount of oxygen in the maternal blood that enters the human placenta and the amount of oxygen in the fetal blood that leaves the placenta. Maternal blood has a pO2 of around 100, whereas the pO2 of umbilical vein blood is around 35 to 40. This represents an efficiency of only 35 to 40%. Therefore, it also became necessary to greatly increase the flow of maternal blood into the intervillous space during pregnancy.2Thornburg KL Jacobson SL Giraud GD Morton MJ Hemodynamic changes in pregnancy.Semin Perinatol. 2000; 24: 11-14Abstract Full Text PDF PubMed Google Scholar, 3Duvekot JJ Peeters LL Maternal cardiovascular hemodynamic adaptation to pregnancy.Obstet Gynecol Surv. 1994; 49: S1-S14Crossref PubMed Google Scholar Without this increased maternal blood flow, preterm birth and fetal loss occur.4Naeye RL Pregnancy hypertension, placental evidences of low uteroplacental blood flow, and spontaneous premature delivery.Hum Pathol. 1989; 20: 441-444Abstract Full Text PDF PubMed Google Scholar One of two mechanisms can increase maternal flow. increased total body blood flow or increased blood flow to the placental bed through the uterine spiral arteries. For the human, evolution has selected the latter mechanism, limiting the overall systemic effects that increased total body blood flow would produce. In the nonpregnant state the uterine vessels carry <1% of the maternal cardiac output.5Silver M Barnes RJ Comline RS Burton GJ Placental blood flow: some fetal and maternal cardiovascular adjustments during gestation.J Reprod Fertil Suppl. 1982; 31: 139-160PubMed Google Scholar This is not surprising in light of the fact that a nonpregnant women needs to maintain a uterus that weighs only 50 g. At term, these same vessels must support a uterus, placenta, and fetus that can weigh up to 5000 g. How can these vessels meet such a hemodynamic challenge? Doubling the number of vessels in the uterus, for example, would have only doubled the total amount of flow into the placenta. An understanding of fluid mechanics gives us insight into how such a significant increase in total blood flow can be achieved without increasing the total number of vessels in the uterus. Poiseuille's law of fluid flow in a cylinder states that flow is proportional to the radius to the fourth power.6Poston L The control of blood flow to the placenta.Exp Physiol. 1997; 82: 377-387PubMed Google Scholar Applying this law to the situation in the uterus, doubling the radius of a uterine vessel will increase the flow through that vessel 16 times. Comparison of vessels in the nonpregnant uterus to those at term reveals that these vessels can increase their radii by as much as tenfold. According to Poiseuille's law, this results in an increase in blood flow by a factor of 10,000! Clearly, the ability of uterine vessels to vary in diameter is a great advantage. The evolutionary problem then became how to convert small-caliber vessels in the nonpregnant state to large-caliber vessels during pregnancy, and then return them to their nonpregnant state and size when the pregnancy is completed. The answer lies in the relationship between the endometrium, uterine vessels, and invasive trophoblasts. Invasive trophoblasts are the key to the modulation of the state of the uterine vessels.7Kliman HJ Trophoblast infiltration.Reprod Med Rev. 1994; 3: 137-157Crossref Google Scholar These unique cells leave the placenta, penetrate the endometrium and upper layers of the myometrium, selectively permeate the uterine spiral arteries, and modify these vessels to yield widened, low-resistance vascular channels that carry the markedly increased maternal blood flow to the placenta. Enacting this scenario takes a very delicate balancing of conflicting biological needs between the mother and fetus. The fetus, on the one hand, requires its invasive trophoblasts to penetrate the mother's uterus aggressively in search of vessels to modify. The mother, on the other hand, must protect herself from the invasive trophoblasts, lest they completely penetrate her uterus, causing her to hemorrhage and bleed to death. Traditionally, two types of trophoblasts have been described: the cytotrophoblast and the syncytiotrophoblast. With the development of reproducible methods of trophoblast culture,8Kliman HJ Nestler JE Sermasi E Sanger JM Strauss JF Purification, characterization, and in vitro differentiation of cytotrophoblasts from human term placentae.Endocrinology. 1986; 118: 1567-1582Crossref PubMed Google Scholar improved markers of trophoblast synthetic activity,9Kliman HJ Feinberg RF Trophoblast differentiation.in: Barnea E Hustin J Jauniaux E The First Twelve Weeks of Gestation. Springer-Verlag, New York1992: 3-25Crossref Google Scholar and a deeper understanding of the functions that trophoblasts play in the uteroplacental unit,10Feinberg RF Kliman HJ Lockwood CJ Oncofetal fibronectin: a trophoblast "glue" for human implantation?.Am J Pathol. 1991; 138: 537-543PubMed Google Scholar, 11Feinberg RF Kao LC Haimowitz JE Queenan Jr, JT Wun TC Strauss JF Kliman HJ Plasminogen activator inhibitor types 1 and 2 in human trophoblasts: PAI-1 is an immunocytochemical marker of invading trophoblasts.Lab Invest. 1989; 61: 20-26PubMed Google Scholar, 12Damsky CH Fitzgerald ML Fisher SJ Distribution patterns of extracellular matrix components and adhesion receptors are intricately modulated during first trimester cytotrophoblast differentiation along the invasive pathway, in vivo.J Clin Invest. 1992; 89: 210-222Crossref PubMed Google Scholar, 13Fernandez PL Merino MJ Nogales FF Charonis AS Stetler Stevenson W Liotta L Immunohistochemical profile of basement membrane proteins and 72 kilodalton type IV collagenase in the implantation placental site: an integrated view.Lab Invest. 1992; 66: 572-579PubMed Google Scholar, 14Zhou Y Damsky CH Chiu K Roberts JM Fisher SJ Preeclampsia is associated with abnormal expression of adhesion molecules by invasive cytotrophoblasts.J Clin Invest. 1993; 91: 950-960Crossref PubMed Google Scholar we now can identify more specific subsets of trophoblasts. These include the undifferentiated mononuclear precursor of all trophoblast forms, the cytotrophoblast; the endocrinologically active villous syncytiotrophoblast; the junctional trophoblast that attaches the anchoring villi to the maternal decidua at Nitabuch's layer; and the invasive intermediate trophoblast that migrates into the decidua, the myometrium, and finally the spiral arteries of the uterus (Figure 1).15Kliman HJ Trophoblast to human placenta.in: Knobil E Neill JD Encyclopedia of Reproduction. vol 4.. Academic Press, San Diego1999: 834-846Google Scholar The presence of invasive trophoblasts within the decidua and myometrium has been appreciated for some time,16Pijnenborg R Robertson WB Brosens I Dixon G Review article: trophoblast invasion and the establishment of haemochorial placentation in man and laboratory animals.Placenta. 1981; 2: 71-91Abstract Full Text PDF PubMed Google Scholar, 17Pijnenborg R Bland JM Robertson WB Brosens I Uteroplacental arterial changes related to interstitial trophoblast migration in early human pregnancy.Placenta. 1983; 4: 397-413Abstract Full Text PDF PubMed Google Scholar, 18Pijnenborg R The placentae bed.Hypertens Preg. 1996; 15: 7-23Crossref Google Scholar, 19Pijnenborg R Vercruysse L Verbist L Van Assche FA Interaction of interstitial trophoblast with placental bed capillaries and venules of normotensive and pre-eclamptic pregnancies.Placenta. 1998; 19: 569-575Abstract Full Text PDF PubMed Google Scholar but it is only relatively recently that researchers have attributed specific markers, and hence specific functional characteristics, to these cells. The first clear marker of the invasive trophoblast was described by Kurman and colleagues,20Kurman RJ Main CS Chen HC Intermediate trophoblast: a distinctive form of trophoblast with specific morphological, biochemical and functional features.Placenta. 1984; 5: 349-369Abstract Full Text PDF PubMed Google Scholar who demonstrated that first-trimester invasive trophoblasts react with anti-human placental lactogen antibodies. They coined the term "intermediate" invasive trophoblasts partly because of their intermediate size between cyto. and syncytiotrophoblasts. Feinberg et al11Feinberg RF Kao LC Haimowitz JE Queenan Jr, JT Wun TC Strauss JF Kliman HJ Plasminogen activator inhibitor types 1 and 2 in human trophoblasts: PAI-1 is an immunocytochemical marker of invading trophoblasts.Lab Invest. 1989; 61: 20-26PubMed Google Scholar demonstrated that these same cells express plasminogen activator inhibitor type 1, suggesting that intermediate invasive trophoblasts may use, in addition to the collagenases, the plasminogen activator system to perform their invasive function. More recently, Zhou et al14Zhou Y Damsky CH Chiu K Roberts JM Fisher SJ Preeclampsia is associated with abnormal expression of adhesion molecules by invasive cytotrophoblasts.J Clin Invest. 1993; 91: 950-960Crossref PubMed Google Scholar, 21Zhou Y Fisher SJ Janatpour M Genbacev O Dejana E Wheelock M Damsky CH Human cytotrophoblasts adopt a vascular phenotype as they differentiate: a strategy for successful endovascular invasion?.J Clin Invest. 1997; 99: 2139-2151Crossref PubMed Google Scholar, 22Zhou Y Damsky CH Fisher SJ Preeclampsia is associated with failure of human cytotrophoblasts to mimic a vascular adhesion phenotype: one cause of defective endovascular invasion in this syndrome?.J Clin Invest. 1997; 99: 2152-2164Crossref PubMed Google Scholar have shown that as trophoblasts leave the cell columns and enter the maternal space, they lose integrins for basement membrane interactions (possibly laminin) and gain integrins for fibronectin and type I collagen interactions. To protect the mother from the onslaught of invasive trophoblasts migrating toward the uterine spiral arteries, the endometrial stroma transforms itself into a dense cellular matrix known as the decidua.23Kearns M Lala PK Life history of decidual cells: a review.Am J Reprod Immunol. 1983; 3: 78-82Crossref PubMed Google Scholar The decidua impedes the movement of invasive trophoblasts both by forming a physical barrier to cell penetration and by generating a local cytokine milieu that promotes trophoblast attachment rather than invasion.7Kliman HJ Trophoblast infiltration.Reprod Med Rev. 1994; 3: 137-157Crossref Google Scholar, 24Graham CH Lala PK Mechanisms of placental invasion of the uterus and their control.Biochem Cell Biol. 1992; 70: 867-874Crossref PubMed Google Scholar, 25Graham CH Lysiak JJ McCrae KR Lala PK Localization of transforming growth factor-beta at the human fetal-maternal interface: role in trophoblast growth and differentiation.Biol Reprod. 1992; 46: 561-572Crossref PubMed Google Scholar, 26Clark DA Cytokines, decidua, and early pregnancy.Oxf Rev Reprod Biol. 1993; 15: 83-111PubMed Google Scholar, 27Roth I Fisher SJ IL-10 is an autocrine inhibitor of human placental cytotrophoblast MMP-9 production and invasion.Dev Biol. 1999; 205: 194-204Crossref PubMed Scopus (96) Google Scholar, 28Tabibzadeh S Lessey B Satyaswaroop PG Temporal and site-specific expression of transforming growth factor-beta4 in human endometrium.Mol Hum Reprod. 1998; 4: 595-602Crossref PubMed Scopus (25) Google Scholar The fate of the invasive trophoblasts is, in part, likely the result of the balancing of the invasive promoting proteases made by the trophoblasts and the inhibitors of invasion made by the decidua.7Kliman HJ Trophoblast infiltration.Reprod Med Rev. 1994; 3: 137-157Crossref Google Scholar, 11Feinberg RF Kao LC Haimowitz JE Queenan Jr, JT Wun TC Strauss JF Kliman HJ Plasminogen activator inhibitor types 1 and 2 in human trophoblasts: PAI-1 is an immunocytochemical marker of invading trophoblasts.Lab Invest. 1989; 61: 20-26PubMed Google Scholar, 29Graham CH Lala PK Mechanism of control of trophoblast invasion in situ.J Cell Physiol. 1991; 148: 228-234Crossref PubMed Google Scholar, 30Strickland S Richards WG Invasion of the trophoblasts.Cell. 1992; 71: 355-357Abstract Full Text PDF PubMed Scopus (0) Google Scholar Fisher and colleagues have recently proposed that local oxygen tension in the decidua and upper myometrium also plays a role in regulating trophoblast invasion by forming a cytotactic gradient within the placental bed.31Zhou Y Genbacev O Damsky CH Fisher SJ Oxygen regulates human cytotrophoblast differentiation and invasion: implications for endovascular invasion in normal pregnancy and in pre-eclampsia.J Reprod Immunol. 1998; 39: 197-213Abstract Full Text Full Text PDF PubMed Scopus (67) Google Scholar, 32Genbacev O Zhou Y Ludlow JW Fisher SJ Regulation of human placental development by oxygen tension.Science. 1997; 277: 1669-1672Crossref PubMed Scopus (480) Google Scholar, 33Zhou Y Chiu K Brescia RJ Combs CA Katz MA Kitzmiller JL Heilbron DC Fisher SJ Increased depth of trophoblast invasion after chronic constriction of the lower aorta in rhesus monkeys.Am J Obstet Gynecol. 1993; 169: 224-229Abstract Full Text PDF PubMed Google Scholar Thus, the ultimate disposition of any particular invasive trophoblast appears to be determined by the sum of the proinvasive factors (intrinsic invasive proteases made by the trophoblasts and the activators and attractants within the decidua. and the inhibitors of invasion (the physical barrier and the inhibitors of invasion made by decidua).7Kliman HJ Trophoblast infiltration.Reprod Med Rev. 1994; 3: 137-157Crossref Google Scholar, 27Roth I Fisher SJ IL-10 is an autocrine inhibitor of human placental cytotrophoblast MMP-9 production and invasion.Dev Biol. 1999; 205: 194-204Crossref PubMed Scopus (96) Google Scholar, 30Strickland S Richards WG Invasion of the trophoblasts.Cell. 1992; 71: 355-357Abstract Full Text PDF PubMed Scopus (0) Google Scholar, 34Bischof P Friedli E Martelli M Campana A Expression of extracellular matrix-degrading metalloproteinases by cultured human cytotrophoblast cells: effects of cell adhesion and immunopurification.Am J Obstet Gynecol. 1991; 165: 1791-1801Abstract Full Text PDF PubMed Google Scholar, 35Fisher SJ Damsky CH Human cytotrophoblast invasion.Semin Cell Biol. 1993; 4: 183-188Crossref PubMed Google Scholar, 36Bass KE Morrish D Roth I Bhardwaj D Taylor R Zhou Y Fisher SJ Human cytotrophoblast invasion is up-regulated by epidermal growth factor: evidence that paracrine factors modify this process.Dev Biol. 1994; 164: 550-561Crossref PubMed Scopus (146) Google Scholar, 37Damsky CH Librach C Lim KH Fitzgerald ML McMaster MT Janatpour M Zhou Y Logan SK Fisher SJ Integrin switching regulates normal trophoblast invasion.Development. 1994; 120: 3657-3666PubMed Google Scholar, 38Bischof P Haenggeli L Campana A Gelatinase and oncofetal fibronectin secretion is dependent on integrin expression on human cytotrophoblasts.Hum Reprod. 1995; 10: 734-742PubMed Google Scholar, 39Huppertz B Kertschanska S Demir AY Frank HG Kaufmann P Immunohistochemistry of matrix metalloproteinases (MMP), their substrates, and their inhibitors (TIMP) during trophoblast invasion in the human placenta.Cell Tissue Res. 1998; 291: 133-148Crossref PubMed Scopus (147) Google Scholar Imbalances on either side of this equation can lead to abnormally limited or abnormally excessive invasion.23Kearns M Lala PK Life history of decidual cells: a review.Am J Reprod Immunol. 1983; 3: 78-82Crossref PubMed Google Scholar, 26Clark DA Cytokines, decidua, and early pregnancy.Oxf Rev Reprod Biol. 1993; 15: 83-111PubMed Google Scholar, 33Zhou Y Chiu K Brescia RJ Combs CA Katz MA Kitzmiller JL Heilbron DC Fisher SJ Increased depth of trophoblast invasion after chronic constriction of the lower aorta in rhesus monkeys.Am J Obstet Gynecol. 1993; 169: 224-229Abstract Full Text PDF PubMed Google Scholar, 40Lala PK Kearns M Immunobiology of the decidual tissue.Contrib Gynecol Obstet. 1985; 14: 1-15PubMed Google Scholar, 41Genbacev O Bass KE Joslin RJ Fisher SJ Maternal smoking inhibits early human cytotrophoblast differentiation.Reprod Toxicol. 1995; 9: 245-255Crossref PubMed Scopus (55) Google Scholar, 42DiFederico E Genbacev O Fisher SJ Preeclampsia is associated with widespread apoptosis of placental cytotrophoblasts within the uterine wall.Am J Pathol. 1999; 155: 293-301Abstract Full Text Full Text PDF PubMed Google Scholar, 43Genbacev O DiFederico E McMaster M Fisher SJ Invasive cytotrophoblast apoptosis in pre-eclampsia.Hum Reprod. 1999; 14: 59-66Crossref PubMed Google Scholar The first signs of the decidualization reaction can be seen as early as day 23 (10 days after the peak of the luteinizing hormone surge. of the normal menstrual cycle, when the spiral arteries of the endometrium first become prominent.44Hendrickson MR Kempson RL Surgical pathology of the uterine corpus.Major Probl Pathol. 1979; 12: 36-98Google Scholar Over the next few days, the stromal cells surrounding the spiral arteries become increasingly eosinophilic and enlarged as the differentiating effect of progesterone transforms these cells into predecidual cells.45Tabanelli S Tang B Gurpide E In vitro decidualization of human endometrial stromal cells.J Steroid Biochem Mol Biol. 1992; 42: 337-344Crossref PubMed Google Scholar The progressive decidualization of the endometrial stroma in the later part of the menstrual cycle prepares the uterine lining for the presence of the invasive trophoblasts, but simultaneously closes the door to implantation.46Lessey BA Castelbaum AJ Buck CA Lei Y Yowell CW Sun J Further characterization of endometrial integrins during the menstrual cycle and in pregnancy.Fertil Steril. 1994; 62: 497-506Abstract Full Text PDF PubMed Google Scholar, 47Lessey BA The use of integrins for the assessment of uterine receptivity.Fertil Steril. 1994; 61: 812-814PubMed Google Scholar Though the state of the endometrium in the later part of the cycle is ideal to protect the mother from the invasive trophoblasts in the event of a pregnancy, it is entirely unsuited for implantation. But how can a nonreceptive decidualized endometrium be returned to a receptive nondecidualized endometrium if pregnancy The solution is CA women and evolutionary J Obstet Gynecol Reprod Biol. 1996; 70: Full Text PDF PubMed Scopus Google Scholar, The evolution of endometrial and Rev Biol. 1996; 71: PubMed Google Scholar, CA a of uterine Rev Biol. 1998; PubMed Google Scholar the and of the endometrial lining at the of a cycle, is seen only in and CA women and evolutionary J Obstet Gynecol Reprod Biol. 1996; 70: Full Text PDF PubMed Scopus Google Scholar these same are the only animals that evidence of trophoblast invasion of uterine vessels, the that is a biological in that trophoblast Thus, it appears that is the by which the endometrium a receptive a cycle without This would to the complex of the menstrual cycle with an the endometrial followed by a differentiation first the of and later closes this with the of LL and control of the normal menstrual Gynecol Clin Google Scholar, C P Regulation of the human menstrual 1998; 19: PubMed Scopus Google Scholar The of human trophoblast invasion have been in great the RF Kao LC Haimowitz JE Queenan Jr, JT Wun TC Strauss JF Kliman HJ Plasminogen activator inhibitor types 1 and 2 in human trophoblasts: PAI-1 is an immunocytochemical marker of invading trophoblasts.Lab Invest. 1989; 61: 20-26PubMed Google Scholar, 17Pijnenborg R Bland JM Robertson WB Brosens I Uteroplacental arterial changes related to interstitial trophoblast migration in early human pregnancy.Placenta. 1983; 4: 397-413Abstract Full Text PDF PubMed Google Scholar, Y Genbacev O Damsky CH Fisher SJ Oxygen regulates human cytotrophoblast differentiation and invasion: implications for endovascular invasion in normal pregnancy and in pre-eclampsia.J Reprod Immunol. 1998; 39: 197-213Abstract Full Text Full Text PDF PubMed Scopus (67) Google Scholar, 39Huppertz B Kertschanska S Demir AY Frank HG Kaufmann P Immunohistochemistry of matrix metalloproteinases (MMP), their substrates, and their inhibitors (TIMP) during trophoblast invasion in the human placenta.Cell Tissue Res. 1998; 291: 133-148Crossref PubMed Scopus (147) Google Scholar, 43Genbacev O DiFederico E McMaster M Fisher SJ Invasive cytotrophoblast apoptosis in pre-eclampsia.Hum Reprod. 1999; 14: 59-66Crossref PubMed Google Scholar, R Bland JM Robertson WB Dixon G Brosens I The of interstitial invasion of the myometrium in early human pregnancy.Placenta. 1981; 2: Full Text PDF PubMed Scopus Google Scholar, R Robertson WB Brosens I Trophoblast invasion and of the in the human 1982; Google Scholar, WB Brosens I R The of the placental J Obstet Gynecol Reprod Biol. 1984; Full Text PDF PubMed Google Scholar, WB Brosens I Gynecol 1985; 14: Google Scholar, E Human trophoblast invasion and spiral the role of J Pathol. 1999; Full Text Full Text PDF PubMed Google Scholar, KH Zhou Y Janatpour M McMaster M Bass K Fisher SJ Human cytotrophoblast is abnormal in J Pathol. 1997; Google Scholar it is to human 4 of much of understanding of the of trophoblast invasion has been from invasion and the development of uteroplacental arteries in the of type IV and Tissue Res. 1993; PubMed Scopus Google Scholar, invasion and of uterine during placental development in Tissue Res. 1993; PubMed Google Scholar, interactions of trophoblast and uterus during placenta 1993; PubMed Google Scholar, of invasion of the maternal vascular system during implantation in the and J 1991; PubMed Scopus Google Scholar of implantation has that trophoblasts to into the maternal spiral arteries as early as days after and at days, of the spiral arteries the are of invasion of the maternal vascular system during implantation in the and J 1991; PubMed Scopus Google Scholar The of this vascular is by the fact that such invasion takes in the human trophoblasts in the same This has been more to and it has Hustin and and that is in fact trophoblast of the maternal spiral arteries and a in maternal of intervillous space of J and of the during the first trimester of J Obstet Gynecol. Full Text PDF PubMed Google Scholar et P C Jauniaux E Oxygen in endometrial and during early pregnancy.Obstet Gynecol. 1992; Google Scholar then that it is that maternal blood flow to the be limited very early in to protect the from oxygen during early of This was by et M P M P of uteroplacental and umbilical blood flow changes in normal early Obstet Gynecol. 1996; PubMed Google Scholar of on normal women between and uteroplacental blood flow in the first trimester but a significant increase at which at More recently, Burton et the from to days of in the of at the of and that was significant of the maternal spiral by trophoblasts at of contact with the intervillous space between and but that this was between and of GJ Jauniaux E Maternal arterial to the placental intervillous space during the first trimester of human the J Obstet Gynecol. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar Despite its the first trimester has not been A S M L D on intervillous circulation in early 1997; PubMed Google Scholar, L P R K Uteroplacental and circulation in normal first-trimester and J Obstet Gynecol. 1996; Full Text Full Text PDF PubMed Scopus Google Scholar, W of intervillous blood flow in the first trimester of human pregnancy.Placenta. 1995; Full Text PDF PubMed Google Scholar The this to have been recently with the use of an oxygen In this of The of Jauniaux et E J Burton GJ of maternal arterial and placental a factor in human early pregnancy J Pathol. 2000; Full Text Full Text PDF Google Scholar the of a significant increase in placental intervillous oxygen and hence maternal of the placenta, between and of This also with this increased and oxygen tension within the placenta between and is a