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  • Print publication year: 2007
  • Online publication date: September 2009

9 - Placental hypoxia, hyperoxia and ischemia–reperfusion injury in pre-eclampsia

from Part I - Basic science



Oxidative stress of the placenta is a key element in the pathogenesis of pre-eclampsia, although its precise contribution remains uncertain (Hubel, 1999; Redman and Sargent, 2000). The aim of this chapter is to address the origin of that oxidative stress and, as the title suggests, to consider the effects of different oxygen concentrations on placental tissues. In the past it has widely been assumed that the vascular abnormalities in the endometrial arteries of women with pre-eclampsia result in reduced placental perfusion, and hence chronic hypoxia within the feto-placental unit. More recently, the converse has been proposed, and that in pre-eclampsia associated with intrauterine growth restriction (IUGR) the placenta is in fact hyperoxic due to less oxygen than normal being extracted from the intervillous space by the smaller fetus (Kingdom and Kaufmann, 1997). Hypoxia and hyperoxia are relative terms, however, and these assessments have of necessity been based on data obtained at the time of delivery, which, in the majority of cases, represents the end-stage of a process that may have been developing over many weeks. It is therefore difficult to separate primary from secondary effects, and to elucidate earlier stages in the pathogenesis of the disorder. The situation is further complicated by the fact that pre-eclampsia varies widely in severity. Late onset pre-eclampsia is often associated with normal birthweight, whereas early onset of the disease is generally linked with IUGR (Douglas and Redman, 1994).

Adamsons, K. and Myers, R. E. (1975). Circulation in the intervillous space; obstetrical considerations in fetal deprivation. In The Placenta and its Maternal Supply Line. Effects of Insufficiency on the Fetus, ed. Gruenwald, P.. Lancaster: Medical and Technical Publishing Co. Ltd., pp. 158–77.
Adamsons, K., Mueller-Heubach, E. and Myers, R. E. (1971). Production of fetal asphyxia in the rhesus monkey by administration of catecholamines to the mother. Am. J. Obstet. Gynecol., 109, 248–62.
Allaire, A. D., Ballenger, K. A., Wells, S. R., McMahon, M. J. and Lessey, B. A. (2000). Placental apoptosis in preeclampsia. Obstet. Gynecol., 96, 271–6.
Bloxham, D. L., Bullen, B. E., Walters, B. N. J. and Lao, T. T. (1987). Placental glycolysis and energy metabolism in preeclampsia. Am. J. Obstet. Gynecol., 157, 97–101.
Borell, U., Fernström, I., Ohlson, L. and Wiqvist, N. (1965a). An arteriographic study of the blood flow through the uterus and the placenta at midpregnancy. Acta Obstet. Gynecol. Scand., 44, 22–31.
Borell, U., Fernström, I., Ohlson, L. and Wiqvist, N. (1965b). Influence of uterine contractions on the uteroplacental blood flow at term. Am. J. Obstet. Gynecol., 93, 44–57.
Brosens, I. (1964). A study of the spiral arteries of the decidua basalis in normotensive and hypertensive pregnancies. J. Obstet. Gynaecol. Br. Commonwlth, 71, 222–30.
Brosens, I. A. (1988). The utero-placental vessels at term – the distribution and extent of physiological changes. Trophoblast Res., 3, 61–7.
Brosens, J. J., Pijnenborg, R. and Brosens, I. A. (2002). The myometrial junctional zone spiral arteries in normal and abnormal pregnancies. Am. J. Obstet. Gynecol., 187, 1416–23.
Burton, G. J. (1997). On ‘Oxygen and placental villous development: origins of fetal hypoxia’. Placenta, 18, 625–6.
Carden, D. L. and Granger, D. N. (2000). Pathophysiology of ischaemia–reperfusion injury. J. Pathol., 190, 255–66.
Carter, A. M. (2000). Placental oxygen consumption. Part I: in vivo studies – a review. Placenta, 21 (Suppl A), S31–7.
Collard, C. D. and Gelman, S. (2001). Pathophysiology, clinical manifestations, and prevention of ischemia–reperfusion injury. Anesthesiology, 94, 1133–8.
Critchley, G. R. and Burton, G. J. (1987). Intralobular variations in barrier thickness in the mature human placenta. Placenta, 8, 185–94.
Crompton, M. (1999). The mitochondrial permeability transition pore and its role in cell death. Biochem. J., 341, 233–49.
Wolf, F., Robertson, W. B. and Brosens, I. (1975). The ultrastructure of acute atherosis in hypertensive pregnancy. Am. J. Obstet. Gynecol., 123, 164–74.
Douglas, K. A. and Redman, C. (1994). Eclampsia in the United Kingdom. Br. Med. J., 309, 1395–400.
Espinoza, J., Sebire, N. J., McAuliffe, F., Krampl, E. and Nicolaides, K. H. (2001). Placental villus morpholgy in relation to maternal hypoxia at high altitude. Placenta, 22, 606–8.
Francis, S. T., Duncan, K. R., Moore, R. J., Baker, P. N. and Johnson, I. R. (1998). Non-invasive mapping of placental perfusion. Lancet, 351, 1397–9.
Freeman, B. A. and Crapo, J. D. (1981). Hyperoxia increases oxygen radical production in rat lungs and lung mitochondria. J. Biol. Chem., 256, 10,986–92.
Grace, P. A. and Mathie, R. T. (1999). Ischaemia–Reperfusion Injury. Oxford: Blackwell Science. 384 pp.
Halliwell, B. and Gutteridge, J. M. C. (1999). Free Radicals in Biology and Medicine. Oxford: Oxford Science Publications. 936 pp.
Hempstock, J., Bao, Y.-P., Bar-Issac, M., et al. (2003a). Intralobular differences in antioxidant enzyme expression and activity reflect oxygen gradients within the human placenta. Placenta, 24, 517–23.
Hempstock, J., Jauniaux, E., Greenwold, N. and Burton, G. J. (2003b) The contribution of placental oxidative stress to early pregnancy failure. Hum. Pathol., 34, 1265–75.
Hockenbery, D. (1995). Defining apoptosis. Am. J. Pathol., 146, 16–19.
Hubel, C. A. (1999). Oxidative stress in the pathogenesis of preeclampsia. Proc. Soc. Exp. Biol. Med., 222, 222–35.
Hung, T.-H., Charnock-Jones, D. S., Skepper, J. N. and Burton, G. J. (2004). Secretion of tumour necrosis factor-α from human placental tissues induced by hypoxia–reoxygenation causes endothelial cell activation in vitro: a potential mediator of the inflammatory response in preeclampsia. Am. J. Pathol., 164, 1049–61.
Hung, T.-H., Skepper, J. N. and Burton, G. J. (2001). In vitro ischemia–reperfusion injury in term human placenta as a model for oxidative stress in pathological pregnancies. Am. J. Pathol., 159, 1031–43.
Hung, T.-H., Skepper, J. N., Charnock-Jones, D. S. and Burton, G. J. (2002). Hypoxia/reoxygenation. A potent inducer of apoptotic changes in the human placenta and possible etiological factor in preeclampsia. Circ. Res., 90, 1274–81.
Huppertz, B., Kingdom, J., Caniggia, I., et al. (2003). Hypoxia favours necrotic versus apoptotic shedding of placental syncytiotrophoblast into the maternal circulation. Placenta, 24, 181–90.
Ishihara, N., Matsuo, H., Murakoshi, H., Laoag-Fernandez, J., Samoto, T. and Maruo, T. (2002). Increased apoptosis in the syncytiotrophoblast in human term placentas complicated by either preeclampsia or intrauterine growth retardation. Am. J. Obstet. Gynecol., 186, 158–66.
Jauniaux, E. and Nicolaides, K. H. (1996). Placental lakes, absent umbilical artery diastolic flow and poor fetal growth in early pregnancy. Ultras. Obstet. Gynecol., 7, 141–4.
Jauniaux, E., Ramsay, B. and Campbell, S. (1994). Ultrasonographic investigation of placental morphologic characteristics and size during the second trimester of pregnancy. Am. J. Obstet. Gynecol., 170, 130–7.
Jauniaux, E., Watson, A. L. and Burton, G. J. (2001). Evaluation of respiratory gases and acid-base gradients in fetal fluids and uteroplacental tissue between 7 and 16 weeks. Am. J. Obstet. Gynecol., 184, 998–1003.
Jauniaux, E., Hempstock, J., Greenwold, N. and Burton, G. J. (2003). Trophoblastic oxidative stress in relation to temporal and regional differences in maternal placental blood flow in normal and abnormal early pregnancies. Am. J. Pathol., 162, 115–25.
Jauniaux, E., Watson, A. L., Hempstock, J., Bao, Y.-P., Skepper, J. N. and Burton, G. J. (2000). Onset of maternal arterial bloodflow and placental oxidative stress; a possible factor in human early pregnancy failure. Am. J. Pathol., 157, 2111–22.
Kam, E. P. Y., Gardner, L., Loke, Y. W. and King, A. (1999). The role of trophoblast in the physiological change in decidual spiral arteries. Hum. Reprod., 14, 2131–8.
Karimu, A. L. and Burton, G. J. (1994). The effects of maternal vascular pressure on the dimensions of the placental capillaries. Br. J. Obstet. Gynaecol., 101, 57–63.
Kingdom, J. C. P. and Kaufmann, P. (1997). Oxygen and placental villous development: origins of fetal hypoxia. Placenta, 18, 613–21.
Krampl, E., Lees, C., Bland, J. M., Espinoza Dorado, J., Moscoso, G. and Campbell, S. (2000). Fetal biometry at 4300 m compared to sea level Peru. Ultras. Obstet. Gynaecol., 16, 9–18.
Leist, M., Single, B., Castoldi, A. F., Kühnle, S. and Nicotera, P. (1997). Intracellular adenosine triphosphate (ATP) concentration: a switch in the decision between apoptosis and necrosis. J. Exp. Med., 185, 1481–6.
Leung, D. N., Smith, S. C., To, K. F., Sahota, D. S. and Baker, P. N. (2001). Increased placental apoptosis in pregnancies complicated by preeclampsia. Am. J. Obstet. Gynecol., 184, 1249–50.
Majno, G. and Joris, I. (1995). Apoptosis, oncosis, and necrosis. An overview of cell death. Am. J. Pathol., 146, 3–15.
Malek, A., Sager, R. and Schneider, H. (2001). Effect of hypoxia, oxidative stress and lipopolysaccharides on the release of prostaglandins and cytokines from human term placental explants. Placenta, 22 (Suppl A), S45–50.
Manes, C. (2001). Human placental NAD(P)H oxidase: solubilization and properties. Placenta, 22, 58–63.
Many, A. and Roberts, J. M. (1997). Increased xanthine oxidase during labour-implications for oxidative stress. Placenta, 18, 725–6.
Many, A., Hubel, C. A., Fisher, S. J., Roberts, J. M. and Zhou, Y. (2000). Invasive cytotrophoblasts manifest evidence of oxidative stress in preeclampsia. Am. J. Pathol., 156, 321–31.
Martin, C. B., McGaughey, H. S., Kaiser, I. H., Donner, M. W. and Ramsey, E. M. (1964). Intermittent functioning of the uteroplacental arteries. Am. J. Obstet. Gynecol., 90, 819–23.
Matsubra, S. and Tamada, T. (1991). Ultracytochemical localisation of NAD(P)H oxidase activity in the human placenta. Acta Obstet. Gynaecol. Jap., 43, 117–21.
Mayhew, T. M., Ohadike, C., Baker, P. N., Crocker, I. P., Mitchell, C. and Ong, S. S. (2003). Stereological investigation of placental morphology in pregnancies complicated by pre-eclampsia with and without intrauterine growth restriction. Placenta, 24, 219–26.
Meekins, J. W., Pijnenborg, R., Hanssens, M., McFadyen, I. R. and Assche, F. A. (1994). A study of placental bed spiral arteries and trophoblast invasion in normal and severe pre-eclamptic pregnancies. Br. J. Obstet. Gynaecol., 101, 669–74.
Moll, W., Künzel, W. and Herberger, J. (1975). Hemodynamic implications of hemochorial placentation. Eur. J. Obstet. Gynecol. Reprod. Biol., 5, 67–74.
Myatt, L., Rosenfield, R. B., Eis, A. L. W., Brockman, D. E., Greer, I. and Lyall, F. (1996). Nitrotyrosine residues in placenta. Evidence of peroxynitrite formation and action. Hypertension, 28, 488–93.
Raha, S., McEachern, G. E., Myint, A. T. and Robinson, B. H. (2000). Superoxides from mitochondrial complex III: the role of manganese superoxide dismutase. Free Radi. Biol. Med., 29, 170–80.
Ramsey, E. M. and Donner, M. W. (1980). Placental Vasculature and Circulation. Anatomy, Physiology, Radiology, Clinical Aspects, Atlas and Textbook. Stuttgart: Georg Thieme. 101 pp.
Ramsey, E. M. and Donner, M. W. (1988). Placental vasculature and circulation in primates. Trophoblast Res., 3, 217–33.
Ramsey, E. M., Corner, G. W. and Donner, M. W. (1963). Serial and cineradiographic visualization of the maternal circulation in the primate (hemochorial) placenta. Am. J. Obstet. Gynecol., 86, 213–25.
Redman, C. W. G. and Sargent, I. L. (2000). Placental debris, oxidative stress and pre-eclampsia. Placenta, 21, 597–602.
Reshetnikova, O. S., Burton, G. J. and Milovanov, A. P. (1994). Effects of hypobaric hypoxia on the feto-placental unit; the morphometric diffusing capacity of the villous membrane at high altitude. Am. J. Obstet. Gynecol., 171, 1560–5.
Richart, R. M., Doyle, G. B. and Ramsay, G. C. (1964). Visualisation of the entire maternal placental circulation in the rhesus monkey. Am. J. Obstet. Gynecol., 90, 334–9.
Rodesch, F., Simon, P., Donner, C. and Jauniaux, E. (1992). Oxygen measurements in endometrial and trophoblastic tissues during early pregnancy. Obstet. Gynecol., 80, 283–5.
Schneider, H. (2000). Placental oxygen consumption. Part II: in vitro studies – a review. Placenta, 21 (Suppl A), S38–44.
Schuhmann, R., Stoz, F. and Maier, M. (1988). Histometric investigations in placentones (materno-fetal circulation units) of human placentae. Trophoblast Res., 3, 3–16.
Serkova, N., Bendrick-Peart, J., Alexander, B. and Tissot van Patot, M. C. (2003). Metabolite concentrations in human term placentae and their changes due to delayed collection after delivery. Placenta, 24, 227–35.
Sheppard, B. L. and Bonnar, J. (1988). The maternal blood supply to the placenta in pregnancy complicated by intrauterine fetal growth retardation. Trophoblast Res., 3, 69–81.
Soothill, P. W., Nicolaides, K. H., Rodeck, C. H. and Campbell, S. (1986). Effect of gestational age on fetal and intervillous blood gas and acid–base values in human pregnancy. Fetal Therapy, 1, 168–75.
Teasdale, F. (1985). Histomorphometry of the human placenta in maternal preeclampsia. Am. J. Obstet. Gynecol., 152, 25–31.
Teasdale, F. (1987). Histomorphometry of the human placenta in pre-eclampsia associated with severe intra-uterine growth retardation. Placenta, 8, 119–28.
Teixeira, J. M., Fisk, N. M. and Glover, V. (1999) Association between maternal anxiety in pregnancy and increased uterine artery resistance index: cohort based study. Br. Med. J., 318, 153–7.
Watson, A. L., Skepper, J. N., Jauniaux, E. and Burton, G. J. (1998). Susceptibility of human placental syncytiotrophoblastic mitochondria to oxygen-mediated damage in relation to gestational age. J. Clin. Endocrinol. Metab., 83, 1697–705.
Watson, A. L, Skepper, J. N., Jauniaux, E. and Burton, G. J. (1999). Reducing oxidative stress effects in early human placental villi during in vitro culture. Placenta, 20, A69.
Wigglesworth, J. S. (1969). Vascular anatomy of the human placenta and its significance for placental pathology. J. Obstet. Gynaecol. Br. Commonwlth, 76, 979–89.
Woods, J. R. Jr., Cavanaugh, J. L., Norkus, E. P., Plessinger, M. A. and Miller, R. K. (2002). The effect of labor on maternal and fetal vitamins C and E. Am. J. Obstet. Gynecol., 187, 1179–83.