Objectives:Umbilical-placental embolization with microspheres has been used as a model of placental insufficiency and intrauterine growth restriction (IUGR). However, the effects of embolization on placental structure and organ morphology of the resulting IUGR fetus are relatively unexplored. In this study using ovine fetuses, we determined the location and distribution of microspheres within the placenta and explored the extent of placental and fetal organ morphologic changes induced by placental embolization. We hypothesized that microspheres administered into the umbilical circulation over 4 days would cause placental damage without significant morphologic alterations in fetal kidney or liver.
Methods:Eleven pregnant sheep at 118 ± 1 (SE) days' gestation were studied. In six fetuses, embolization was induced by injection of 15-μm diameter microspheres on 4 successive days into the fetal descending aorta proximal to the umbilical arteries. Five fetuses served as time controls.
Results:In embolized fetuses, microspheres were detected in the placenta embedded in the fetal cytotrophoblastic layer on maternal parenchyma adjacent to villous cytotrophoblasts. Fetal cytotrophoblasts appeared normal except for loss of distinct separation between fetal and maternal cell layers. Microspheres were also detected in the fetal membranes within capillaries. The body weights of embolized fetuses were lower than controls, as were the body weight-normalized liver but not kidney weights. In the liver of the embolized fetuses, the number of hematopoietic cell clusters was markedly reduced, whereas the fetal kidneys appeared normal.
Conclusions:We conclude that after 5 days of umbilical-placental embolization, microspheres were concentrated at the fetal villi proximal to the apical maternal-fetal interface and in the membranes. There were noticeable morphologic changes in the embolized placentas, with no apparent gross damage to the placenta. The reduction in fetal liver weight and liver extramedullary hematopoietic cell abundance associated with embolization may predispose the fetus to alterations in liver function that could persist after birth.
1. Bekedam DJ, Visser GHA, van der Zee AGJ, Sniders RJM, Poelmann-Weesjes G. Abnormal velocity waveforms of the umbilical artery in growth retarded fetuses: Relationship to antepartum late heart rate decelerations and outcome. Early Hum Dev1990;24:79-89.
2.
2. Murotsuki J, Gagnon R, Matthews SG, Challis JRG. Effects of long-term hypoxemia on pituitary-adrenal function in fetal sheep. Am J Physiol1996;271:E678-E685.
3.
3. Gagnon R, Rundle H, Johnston L, Han VKM. Alterations in fetal and placental deoxyribonucleic acid synthesis rates after chronic fetal placental embolization. Am J Obstet Gynecol1995;172:1451-1458.
4.
4. Duncan JR, Cock ML, Harding R, Rees SM. Relation between damage to the placenta and the fetal brain after late-gestation placental embolization and fetal growth restriction in sheep. Am J Obstet Gynecol2000;183:1013-1022.
5.
5. Murotsuki J, Challis JRG, Han Victor KM, Fraher LJ, Gagnon R. Chronic fetal placental embolization and hypoxemia cause hypertension and myocardial hypertrophy in fetal sheep. Am J Physiol1997;272:R201-R207.
6.
6. Gagnon R, Harding R, Brace RA. Amniotic fluid and fetal urinary responses to severe placental insufficiency in sheep. Am J Obstet Gynecol2002;186:1076-1084.
7.
7. Louey S, Cock ML, Stevenson KM, Harding R. Placental insufficiency and fetal growth restriction lead to postnatal hypotension and altered postnatal growth in sheep. Pediatr Res2000;48:808-814.
8.
8. Block BS, Schlafer DH, Wentworth RA, Kreitzer LA, Nathanielsz PW. Regional blood flow distribution in fetal sheep with intrauterine growth retardation produced by decreased umbilical placental perfusion. J Dev Physiol1990;13:81-85.
9.
9. Murotsuki J, Bocking AD, Gagnon R. Fetal heart rate patterns in growth-restricted fetal sheep induced by chronic fetal placental embolization. Am J Obstet Gynecol1997;176:282-290.
10.
10. Murotsuki J, Challis JRG, Johnston L, Gagnon R. Increased fetal plasma prostaglandin E2 concentrations during fetal placental embolization in pregnant sheep. Am J Obstet Gynecol1995;173:30-35.
11.
11. Gagnon R, Challis J, Johnston L, Fraher L. Fetal endocrine responses to chronic placental embolization in the late-gestation ovine fetus. Am J Obstet Gynecol1994;170:929-938.
12.
12. Gagnon R, Lamb T, Richardson B. Cerebral circulatory responses of near-term ovine fetuses during sustained fetal placental embolization. Am J Physiol1997;273:H2001-H2008.
13.
13. Harding R, Tester ML, Moss TJ, et al. Effects of intra-uterine growth restriction on the control of breathing and lung development after birth. Clin Exp Pharmacol Physiol2000;27:114-119.
14.
14. Makowski EL, Meschia G, Droegemueller W, Battaglia FC. Measurement of umbilical arterial blood flow to the sheep placenta and fetus in utero: Distribution to cotyledons and the intercotyledonary chorion. Circ Res1968;23:623-631.
15.
15. Benirschke K. Normal development. In: Creasy RK, Resnik R, eds. Maternal Fetal Medicine, Philadelphia: Saunders, 1999:63-63.
16.
16. Huppertz B, Kertschanska S, Demir AY, Frank H-G, Kaufmann P. Immunohistochemistry of matrix metalloproteinases (MMP), their substrates, and their inhibitors (TIMP) during trophoblast invasion in the human placenta. Cell Tissue Res1998;291:133-148.
17.
17. Huppertz B, Kertschanska S, Frank H-G, Gaus G, Funayama H, Kaufmann P. Extracellular matrix components of placental extravillous trophoblast: immunocytochemistry and ultra-structural distribution. Histochem Cell Biol1996;106:291-301.
19. Fox H. The placenta in maternal disorders. In: Livolsi V, ed. Major problems in pathology. Philadelphia: Saunders, 1997:206-216.
20.
20. Ghidini A. Idiopathic fetal growth restriction: A pathophysiological approach. Obstet Gynecol Surv1996;51:376-382.
21.
21. Robinson JS, Owens JA, Owens PC. Fetal growth and fetal growth restriction. In: Thorburn GD, Harding R, eds. Textbook of fetal physiology. Oxford: Oxford University Press, 1994:83-94.
22.
22. Brace RA, Langendorfer C, Song T-B, Mock, DM. Red blood life span in the ovine fetus. Am J Physiol2000;279:R1196-R1204.
23.
23. Cock ML, Harding R. Renal and amniotic fluid responses to umbilicoplacental embolization for 20 days in fetal sheep. Am J Physiol1997;273:R1094-R1102.
24.
24. Itskovitz J, Goetzman BW, Rudolph AM. Effects of hemorrhage on umbilical venous return and oxygen delivery in fetal lambs. Am J Physiol1982;242:H543-H548.
25.
25. Soothill PW, Nicolaides KH, Campbell S. Parental asphyxia, hyperlacticaemia, hypoglycemia and erythroblastosis in growth retarded fetuses. Br Med J1987;294:1051-1053.
26.
26. Salafia CM, Weigl CA, Foye GJ. Correlation of placental erythrocyte morphology and gestational age. Pediatr Pathol1988;8:495-502.
27.
27. Maier RF, Gunther A, Vogel M, Dudenhausen JW, Obladen M. Umbilical venous erythropoietin and umbilical arterial pH in relation to morphologic placental abnormalities. Obstet Gynecol1994;84:81-87.
28.
28. Qian J, Ramroop K, McLeod A, et al. Induction of hypoxia-inducible factor-1α andactivation of caspase-3 in hypoxia-reoxygenated bone marrow stroma is negatively regulated by the delayed production of substance P. J Immunol2001;167:4600-4608.
29.
29. McLellan KC, Bocking AD, White SE, Han KM. Placental and fetal hepatic growth are selectively inhibited by prolonged reductions of uterine blood flow in pregnant sheep. Reprod Fertil Dev1995;7:405-410.
30.
30. Gagnon R, Murotsuki J, Challis JRG, Fraher L, Richardson BS. Fetal sheep endocrine responses to sustained hypoxemic stress after chronic fetal placental embolization. Am J Physiol1997;272:E817-E823.
31.
31. Gagnon R, Johnston L, Murotsuki J. Fetal placental embolization in the late-gestation ovine fetus: Alterations in umbilical blood flow and fetal heart rate patterns. Am J Obstet Gynecol1996;175:63-72.
