Disorders of Placentation

Lead: Professor Eric Jauniaux

Main aims

Research in disorders of placentation is focussed on four strongly interrelated themes:

1. Investigation of cellular and molecular mechanisms of early placental development and their role in the pathophysiology of placental-related complication.

2. Identification of the molecular causes of placental-related pregnancy disorders.

3. Developing new screening and therapeutic strategies to prevent or reduce placental damage in cases of pre-eclampsia, recurrent and threatened miscarriages.

4. To investigate the link between maternal diet, placental development and gestational diabetes.

Background

Normal placental development is essential to normal fetal development. Placental-related disorders of pregnancy are almost unique to the human species. These disorders, which affect around a third of human pregnancies, primarily include miscarriage and preeclampsia. Recent changes in human lifestyle, such as delayed childbirth and hypercaloric diets, may have increased the global incidence of placental-related disorders over the last decades. There is mounting evidence that oxidative stress or an imbalance in the oxidant/antioxidant activity in utero-placental tissues plays a pivotal role in the development of placental-related diseases.

Pre-eclampsia is a disorder that occurs only during pregnancy and the postpartum period and affects both the mother and the unborn baby. Affecting at least 5-8% of all pregnancies, it is a rapidly progressive condition characterised by high blood pressure and the presence of protein in the urine. Proper prenatal care is essential to diagnose and manage pre-eclampsia. Pre-eclampsia and other hypertensive disorders of pregnancy are a leading global cause of maternal and infant illness and death. By conservative estimates, these disorders are responsible for 76,000 maternal deaths each year. There are no predictive markers for this disease in early pregnancy yet but it has been recently shown that in patient suffering from preeclampsia there is abnormal blood supply with pulse/bursts of blood and oxygen supply to some parts of the placenta causing a chronic placental damage. In some ways this oxidative stress phenomenon is similar to that we have observed in miscarriages but is more progressive in pre-eclampsia.

At the other end of placental-related disorders, are the spontaneous miscarriages, which are the most common complication of pregnancy and this phenomenon is extremely rare in other mammalian species. Around 250,000 couples are affected by miscarriages every year in the UK. About 50% of miscarriages are linked to a chromosomal abnormality of the fetus. The other miscarriages have been classified as idiopathic and until recently there has been no research on the causes of this very large group of pregnancy complication.

Current Projects

General projects

The role of oxidative stress in placental remodelling during the first trimester of human pregnancy.
The biochemistry of fetal fluids in normal and abnormal early pregnancies.
The evaluation of placental hormones and markers of oxidative stress in screening for placental-related pregnancy disorders.
The development of the utero-placental circulation and placental volume in relation with changes in maternal serum levels of placental proteins.

Main Achievements

Our original combined in vivo in vitro investigations have resulted in a new understanding of the materno-fetal relationship during the first trimester of pregnancy and led to the now internationally accepted concept that in humans the early placenta limits, rather than facilitates, oxygen supply to the fetus during the period of organogenesis. Our studies have demonstrated that, contrary to classical anatomy teaching, human placentation is in fact not truly haemochorial in early pregnancy and that the earliest stages of development therefore take place in a low oxygen environment, reflecting the evolutionary path.

In close collaboration with Professor GJ Burton (Department of Anatomy, University of Cambridge), we were the first to demonstrate that the placental syncytiotrophoblast is extremely sensitive to oxidative stress, partly because it is the outermost tissue of the conceptus and so exposed to the highest concentrations of oxygen coming from the mother, and partly because it contains surprisingly low concentrations of the principal antioxidant enzymes. This has lead us to conclude that that the architecture of the human first trimester gestational sac is designed to limit fetal exposure to oxygen to that which is strictly necessary for its development. Within this context, we have also shown for the first time that, different nutritional pathways to those operating during most of pregnancy serve the first-trimester fetus.

The question of the formation of placental membranes in humans had been the subject of numerous debates among anatomists over the last century and was considered by Boyd and Hamilton as a fundamental question to answer in understanding human evolution as it allows for women to give birth vaginally. Our original studies have demonstrated that at the end trimester, there is a burst of oxidative stress in the periphery of the early placenta. This leads focal trophoblastic oxidative damage and progressive villous degeneration, triggering the formation of the fetal membranes.

As a result of the above studies a new understanding of the early materno-fetal relationship has, and with it new insight into the pathogenesis of placental-related pregnancy disorders emerged. Unifying the two is the concept of placental oxidative stress. In miscarriage, development of the placento-decidual interface is severely impaired leading to early and widespread onset of maternal blood flow and major oxidative degeneration. This mechanism is common to all miscarriages, the time at which it occurs in the first trimester depending on the aetiology. By contrast, in preeclampsia the trophoblastic invasion is sufficient to allow early pregnancy phases of placentation but too shallow for complete transformation of the arterial utero-placental circulation, predisposing to a repetitive ischemia-reperfusion phenomenon. We have recently suggested that preeclampsia is a three-stage disorder with the primary pathology being an excessive or atypical maternal immune response. This would impair the placentation process leading to chromic oxidative stress in the placenta and finally to diffuse maternal endothelial cell dysfunction.

Our basic science and translational research have also suggested some potential useful clinical applications. We have shown that specific placental proteins hCG, inhibin A and activin A could be useful in predicting subsequent development of pre eclampsia in early pregnancy. Inhibin A could be useful in predicting subsequent miscarriage in recurrent miscarriage patients and threatened miscarriage patients. We were the first to show that serum and urine inhibin A and activin A are predictive of pre-eclampsia and miscarriages in pregnancy. We have developed Real time PCR gene expression assays to quantitative inhibin and related proteins and receptor gene expression in the placental tissue.

Finally our pioneering work on the physiology of materno-fetal molecular transfer in early pregnancy has shown that that the secondary yolk sac has an absorptive role and that the exocoelomic cavity is a reservoir of nutrients for the embryo and an important zone of transfer between the extraembryonic and embryonic compartments. The study of placental transfer of inulin, diazepam, fentanyl and propofol has been successfully studied our exocolomic model in collaboration with Professor B Gulbis (Universite Libre de Bruxelles).

In 2001 we were awarded the International Spa Foundation Biennial Prize for our research on the role of placental oxygenation and generation of free radicals in the pathogenesis of miscarriage and preeclampsia and in 2002 E Jauniaux was laureate of the International Prize for Research in Placentology of the International Placental Federations Association (IPFA) for his contribution to placental research. A complete list of related publications since 2001 and current funding is listed below.

Overall this research and other linked-research programs on fetal physiology, placentology and clinical materno-fetal medicine has lead to 261 Peer-reviewed publications (indexed Pub-Med; Jan 2007); 54 book chapters and 7 international textbooks (as main editor or co-editor).

Key staff

Shanthi Muttukrishna- Non Clinical Lecturer in Reproductive Science

Future Plans

First trimester Placental Development: investigating the role of oxygen tension on angiogenesis and trophoblast invasion.

Current Funding

Publications (2001-2006: 101 published papers and 10 in press in peer-reviewed international journals)

Jauniaux E, Gulbis B. Placental transfer of cotinine at 12-17 weeks of gestation and at term in heavy smokers. Reprod Biomed Online 2001; 3: 30-33.
Moore GE, Abu-Amero S, Bell G, Wakeling EL, Wilson A, Stanier P, Jauniaux E, Bennett ST. Insulin is imprinted in the human yolk sac. Diabetes 2001; 50: 199-203.
Watson A, Burton G. Evaluation of respiratory gases and acid-base gradients in human fetal fluids and uteroplacental tissue between 7 and 16 weeks. AJOG 2001; 184: 998-1003.
Burton GJ, Hempstock J, Jauniaux E. Nutrition of the human fetus during the first trimester: A review. Placenta-Trophoblast Research 2001; 22: S70-S76.
Kiserud T, Jauniaux E, West D, Ozturk O, Hanson MA. Circulatory responses to acute maternal hyperoxemia and hypoxemia assessed non-invasively by ultrasound in fetal sheep at 0.3-0.5 gestation. Brit J Obstet Gynaecol 2001; 108:359-364.
Cooper J, Jauniaux E, Gulbis B, Bromley L. Placental transfer of fentanyl and temazepam in the first and second trimesters of human pregnancy. Reprod BioMed Online 2001; 2: 165-171.
Mohan, A, Asselin, J., Sargent, I.L., Groome, N. P. and Muttukrishna, S. Effect of Cytokines and growth factors on the secretion of inhibin A, activin A and follistatin by term placental villous trophoblasts in culture. Europ J Endocrinol 2001;145:505-511.
Bersinger, N.A., Groome, N.P. and Muttukrishna, S. Pregnancy-associated and placental proteins in the placental tissue of normal and pre-eclamptic women at delivery. Europ J Endocrinol 2002;147:785-793.
Bobrow, C. S., Holmes, R. P., Muttukrishna, S., Mohan, A, Groome, N. P., Murphy, D. Soothill, P.W. Maternal serum activin A, inhibin A and follistatin in pregnancies with appropriately grown and small for gestational age fetuses classified by umbilical artery Doppler. AJOG 2002; 186:283-287.
Muttukrishna S, Jauniaux E, Greenwold N, McGarrigle H, Jivraj S, Carter S, Elgaddal S, Groome N, Regan L. Circulating levels of inhibin A, activin A and follistatin in missed and recurrent miscarriages. Hum Reprod 2002; 17: 3072-3078.
Calvo RM, Jauniaux E, Gulbis B, Asuncion M, Gervy C, Contempre B, Morreale de Escobar M. Fetal tissues are exposed to biologically relevant free tryroxine concentrations during early phases of development. JCEM 2002; 87: 1768-1777.
Burton GJ, Watson AL, Hempstock J, Skepper JN, Jauniaux E. Uterine glands provide histiotrophic nutrition for the human fetus during the first trimester of pregnancy. JCEM 2002; 87: 2954-2959.
Maymon R, Jauniaux E, Moroz C. Enhanced expression of the immunoregulator p43-placental isoferritin in Down’s syndrome conceptus. Molec Hum Reprod 2002; 8: 1125-1128.
Burton GJ, Hempstock J, Jauniaux E. Oxygen, early embryonic metabolism and radical mediated embryopathies. Reprod Biomed Online 2003; 6: 84-96.
Jauniaux E, Greenwold N, Hempstock J, Burton GJ. Comparison of ultrasound and Doppler mapping of the intervillous circulation in normal and abnormal early pregnancies. Fertil Steril 2003; 79: 100-106.
Greenwold N, Jauniaux E, Gulbis B, Hempstock J, Gervy C, Burton G. Relationships between maternal serum, endocrinology, placental karyotype and intervillous circulation in early pregnancy failure. Fertil Steril 2003; 79: 1373-1379.
Jauniaux E, Hempstock J, Greenwold N, Burton GJ. Trophoblastic oxidative stress in relation to temporal and regional differences in maternal placental blood flow in normal and abnormal early pregnancy. Am J Pathol 2003; 162: 115-125.
Hempstock J, Bao YP, Bar-Issac M, Segaren N, Watson AL, Charnock-Jones DS, Jauniaux E, Burton GJ. Intralobular differences in antioxidant enzyme expression and activity reflect oxygen gradients within the human placenta. Placenta 2003; 24: 517-523.
Jauniaux E, Gulbis B, Burton GJ. The human first trimester gestational sac limitsrather than facilities oxygen transfer to the foetus: A review. Placenta-Trophoblast Research 2003; 24: S86-S93.
Burton GJ, Skepper JN, Hempstock J, Cindrova T, Jones CJP, Jauniaux E. A reappraisal of the contrasting morphological appearances of villous cytotrophoblast cells during early human pregnancy: Evidence for both apoptosis and primary necrosis. Placenta 2003; 24: 297-305.
Jauniaux E, Gulbis B, Burton GJ. Physiological implications of the materno-fetal oxygen gradient in human early pregnancy. Reprod Biomed Online 2003; 7: 250-253.
Hempstock J, Jauniaux E, Greenwold N, Burton GJ. The contribution of placental oxidative stress to early pregnancy failure. Hum Pathol. 2003; 34: 1265-1275.
Tannetta, D.S., Muttukrishna, S., Groome, N.P., Redman, C.W.G. and Sargent, I.L Endothelial cells and Peripheral mononuclear cells are a potential source of extraplacental activin A in pre eclampsia. JCEM 2003; 88:5995-6001.
Bersinger, N.A. Smárason, A.K., Muttukrishna S., Groome, N.P. and Redman, C.W. Women with pre-eclampsia have increased serum levels of pregnancy-associated plasma protein A (PAPP-A), inhibin A, activin A and soluble E-selectin. Hypertension in Pregnancy 2003; 22: 45-55.
Casagrandi, D., Bearfield, C., Geary, J., Redman, C. W. and Muttukrishna, S. Inhibin, Activin, Follistatin, Activin Receptors and Betaglycan Gene Expression in the Placental Tissue of Pre eclampsia Patients. Molec Hum Reprod 2003; 9:199-203.
Muttukrishna, S. Role of inhibin in normal and high-risk pregnancy. Seminars Reprod Med. 2004; 22: 227-234.
Muttukrishna, S., Tannetta, D.S., Groome, N.P. and Sargent, I.L () Activin and Follistatin in female reproduction. Molec Cell Endocrinol 2004; 15:45-56.
Burton GJ, Jauniaux E. Placental oxidative stress: from miscarriage to preeclampsia. J Soc Gynecol Investig 2004; 11: 342-352.
Jauniaux E, Burton GJ. Pathophysiology of histological changes in early pregnancy loss. Placenta 2005; 26: 114-123.
Abdallah MA, Lei ZM, Greenwold N, Nakajima ST, Jauniaux E, Rao CV. Human fetal nongonadal tissues contain human chorionic gonadotropin/luteinizing hormone receptors. JCEM 2004; 89: 952-956.
Jauniaux E, Cindrova-Davies T, Johns T, Dunster C, Hempstock J, Kelly F, Burton GJ. Distribution and transfer pathways of antioxidant molecules inside the first trimester human gestational sac. JCEM 2004; 89: 1452-1458.
Muttukrishna S, Jauniaux E, McGarrigle H, Groome N, Rodeck CH. In-vivo concentrations of inhibins, activin A and follistatin in human early pregnancy. Reprod Biomed Online 2004 ;8: 712-719.
Hempstock J, Cindrova-Davies T, Jauniaux E, Burton GJ. Endometrial glands as a source of nutrients, growth factors and cytokines during the first trimester of human pregnancy: a morphological and immunohistochemical study. Reprod Biol Endocrinol 2004; 20: 58.
Jauniaux E, Hempstock J, Teng C, Battaglia FC, Burton GJ.Polyol concentrations in the fluid compartments of the human conceptus during the first trimester of pregnancy: maintenance of redox potential in a low oxygen environment. JCEM 2005; 90: 1171-1175.
Bearfield JC, Jauniaux E, Groome N, Sargent IL, Muttukrishna S. The secretion and effect of inhibin A, activin A and follistatin on first-trimester trophoblasts in vitro. Eur J Endocrinol. 2005;152:909-16.
Burton GJ, Charnock-Jones DS, Jauniaux E . Working with oxygen and oxidative stress in vitro. Methods Mol Med. 2006;122:413-25.
Raijmakers MT, Burton GJ, Jauniaux E, Seed PT, Peters WH, Steegers EA, Poston L. Placental NAD(P)H oxidase mediated superoxide generation in early pregnancy. Placenta. 2006;27:158-63.
Jauniaux E, Burton GJ. Villous Histomorphometry and Placental Bed Biopsy Investigation in Type I Diabetic Pregnancies. Placenta. 2006; 27:468-74.
Johns J, Jauniaux E. Threatened miscarriage as a predictor of obstetric outcome. Obstet Gynecol. 2006; 107: 845-50.
Muttukrishna, S., Hyett, J., Paine, M, Moodley, J., Groome, N. and C. Rodeck () Levels of Activin A and inhibin A in the Maternal Urine as Possible Markers of Pre-eclampsia? J Clin Endocrinol 2006; 64: 469-473.
Jauniaux E, Poston L, Burton GJ. Placental-related diseases of pregnancy: Involvement of oxidative stress and implications in human evolution. Hum Reprod Update. 2006; 12: 747-55.

Google School Search Results (Results 1 - 10 of about 4,400 for Jauniaux E.)

Oxygen measurements in endometrial and trophoblastic tissues during early pregnancy F Rodesch, P Simon, C Donner, E Jauniaux Obstetrics & Gynecology, 1992; Placental and endometrial partial pressures of oxygen (PO2) were measured using a polarographic oxygen electrode during the first trimester of pregnancy. ... Cited by 169 SFX@UCL