Thinning of the intervascular tissue layers of the human placenta is an adaptive response to passive diffusion in vivo and may help to predict the origins of fetal hypoxia
Abstract
Objectives To test the hypothesis that thinning of the placental intervascular layers, and greater variability in thickness, are positive adaptations to facilitate passive diffusion and may help to resolve different categories of fetal hypoxia.Study design Placentas from 12-41 weeks of normal gestation and from pregnancies associated with fetal hypoxic stress (high altitude, diabetes mellitus) were sampled systematically, fixed in formalin, wax-embedded and quantified using stereological methods. Arithmetic and harmonic mean distances across villous trophoblast, stroma and fetal plasma were estimated by measuring randomly sampled intercept lengths. In each case, an index of variability of layer thickness was calculated by dividing the arithmetic by harmonic mean distance. This index has the value I when a tissue layer is uniformly thick but increases in value as local layer thickness becomes more variable. Comparisons between groups were drawn using variance and regression analysis.Results During pregnancy, there were significant negative correlations between layer thickness (trophoblast, stroma) and gestational age and fetal weight, and significant positive correlations between thickness irregularity and age and weight. Compared with lowland controls, high-altitude placentas possessed thinner layers but only the trophoblast and stroma (and not fetal plasma) were more variably thick. In maternal diabetes, only fetal plasma distance was reduced but fetal and stromal layers appeared to be more irregular in thickness.Conclusions Alterations in placental intervascular layer thicknesses occur in normal and abnormal pregnancies and represent real adaptations leading to improved diffusive conductances. Differences in the tissue location of the adaptive response may depend on the nature and origins of the fetal hypoxia.
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There is thinning of the interhemal membrane in the human placenta at high altitude.
“In addition, there is thinning of the interhemal membrane in the human placenta at high altitude (276, 366, 458).”
From Placental Origins of Chronic Disease (2016) · cites this paper as [366]
Cites
The efficiency of systematic sampling in stereology and its prediction *
Gundersen, H., & Jensen, E. B. V. (1987) · Journal of Microscopy · doi:10.1111/j.1365-2818.1987.tb02837.x · Cited by 3,586 · see citing works
Oxygen and placental villous development: Origins of fetal hypoxia
Kingdom, J. C., & Kaufmann, P. (1997) · Placenta · doi:10.1016/s0143-4004(97)90000-x · Cited by 581 · see citing works
Clinical significance of absent or reversed end diastolic velocity waveforms in umbilical artery
Karsdorp, V. H. M., van Vugt, J. M. G., van Geijn, H. P., Kostense, P. J., Arduim, D., Montenegro, N., & Todros, T. (1994) · The Lancet · doi:10.1016/s0140-6736(94)90457-x · Cited by 445 · see citing works
Macara, L., Kingdom, J. C., Kaufmann, P., Kohnen, G., Hair, J., More, I. A. R., Lyall, F., & Greer, I. A. (1996) · Placenta · doi:10.1016/s0143-4004(05)80642-3 · Cited by 352 · see citing works
Widness, J. A., Susa, J. B., García, J. F., Singer, D. B., Sehgal, P. K., Oh, W., Schwartz, R., & Schwartz, H. C. (1981) · Journal of Clinical Investigation · doi:10.1172/jci110078 · Cited by 222 · see citing works
Jackson, M., Mayhew, T. M., & Boyd, P. A. (1992) · Placenta · doi:10.1016/0143-4004(92)90060-7 · Cited by 158 · see citing works
Self-citationBurton, G. J., Reshetnikova, O. S., Milovanov, A. P., & Teleshova, O. V. (1996) · Placenta · doi:10.1016/s0143-4004(05)80643-5 · Cited by 149 · see citing works
Reshetnikova, O. S., Burton, G. J., & Milovanov, A. P. (1994) · American Journal of Obstetrics and Gynecology · doi:10.1016/0002-9378(94)90402-2 · Cited by 127 · see citing works
Distribution of Membrane Thickness Determined By Lineal Analysis
Gundersen, H. J. G., Jensen, T. B., & Østerby, R. (1978) · Journal of Microscopy · doi:10.1111/j.1365-2818.1978.tb00091.x · Cited by 127 · see citing works
Infant birth weight is related to maternal arterial oxygenation at high altitude
MOORE, L. G., Rounds, S., Jahnigen, D. W., Grover, R. F., & Reeves, J. Τ. (1982) · Journal of Applied Physiology · doi:10.1152/jappl.1982.52.3.695 · Cited by 126 · see citing works
Boyd, P. A., & SCOTT, A. (1985) · BJOG An International Journal of Obstetrics & Gynaecology · doi:10.1111/j.1471-0528.1985.tb01454.x · Cited by 115 · see citing works
Morphometric differences between the placental vasculature of non‐smokers, smokers and ex‐smokers
Burton, G. J., Palmer, M. E., & Dalton, K. J. (1989) · BJOG An International Journal of Obstetrics & Gynaecology · doi:10.1111/j.1471-0528.1989.tb03344.x · Cited by 109 · see citing works
Quantitative structure of the normal human placenta from 10 weeks of gestation to term
Boyd, P. A. (1984) · Early Human Development · doi:10.1016/0378-3782(84)90074-4 · Cited by 89 · see citing works
Placental changes in gestational diabetes. An ultrastructural study.
Jones, C., & Fox, H. (1976) · PubMed · Cited by 84 · see citing works
Mayhew, T. M., Jackson, M. R., & Haas, J. D. (1986) · Placenta · doi:10.1016/s0143-4004(86)80003-0 · Cited by 83 · see citing works
Self-citationHistomorphometry of the human placenta in class B diabetes mellitus
Teasdale, F. (1983) · Placenta · doi:10.1016/s0143-4004(83)80012-5 · Cited by 82 · see citing works
Reshetnikova, O. S., Burton, G. J., & Васильевна, Т. О. (1995) · American Journal of Obstetrics and Gynecology · doi:10.1016/0002-9378(95)90330-5 · Cited by 82 · see citing works
Growth and maturation of villi in placentae from well-controlled diabetic women
Mayhew, T. M., Sørensen, F. B., Klebe, J. G., & Jackson, M. (1994) · Placenta · doi:10.1016/s0143-4004(05)80236-x · Cited by 81 · see citing works
Self-citationMayhew, T. M., Jackson, M. R., & Boyd, P. A. (1993) · Placenta · doi:10.1016/s0143-4004(05)80248-6 · Cited by 80 · see citing works
Self-citationOntogenic changes in the nutritive function of the placenta
Schneider, H. (1996) · Placenta · doi:10.1016/s0143-4004(05)80639-3 · Cited by 79 · see citing works
Oxygen diffusive conductances of human placentae from term pregnancies at low and high altitudes
Mayhew, T. M., Jackson, M. R., & Haas, J. D. (1990) · Placenta · doi:10.1016/s0143-4004(05)80195-x · Cited by 77 · see citing works
Self-citationJackson, M., Mayhew, T. M., & Haas, J. D. (1987) · PubMed · Cited by 72 · see citing works
Self-citationTeasdale, F. (1987) · Placenta · doi:10.1016/0143-4004(87)90015-4 · Cited by 68 · see citing works
Hematologic evidence of fetal hypoxia among newborn infants at high altitude in Bolivia
Ballew, C., & Haas, J. D. (1986) · American Journal of Obstetrics and Gynecology · doi:10.1016/0002-9378(86)90104-3 · Cited by 66 · see citing works
Jackson, M. R., Joy, C. F., Mayhew, T. M., & Haas, J. D. (1985) · Placenta · doi:10.1016/s0143-4004(85)80054-0 · Cited by 65 · see citing works
Self-citationMayhew, T. M. (1996) · European Journal of Obstetrics & Gynecology and Reproductive Biology · doi:10.1016/0301-2115(96)02486-4 · Cited by 64 · see citing works
Self-citationJackson, M. R., Mayhew, T. M., & Haas, J. D. (1988) · Placenta · doi:10.1016/0143-4004(88)90068-9 · Cited by 57 · see citing works
Self-citationMayhew, T. M., Wadrop, E., & Simpson, R. A. (1994) · PubMed · Cited by 51 · see citing works
Self-citationJackson, M. R., Mayhew, T. M., & Haas, J. D. (1988) · Placenta · doi:10.1016/0143-4004(88)90067-7 · Cited by 51 · see citing works
Self-citationHistomorphometry of the human placenta in class C diabetes mellitus
Teasdale, F. (1985) · Placenta · doi:10.1016/s0143-4004(85)80034-5 · Cited by 48 · see citing works
Oxygen diffusive conductance in placentae from control and diabetic women
Mayhew, T. M., Sørensen, F. B., Klebe, J. G., & Jackson, M. (1993) · Diabetologia · doi:10.1007/bf02374479 · Cited by 46 · see citing works
Self-citationAli, K. Z. M. (1997) · Placenta · doi:10.1016/s0143-4004(97)80046-x · Cited by 42 · see citing works
Placental Changes in Gestational Diabetes
Fox, H. (1979) · Springer eBooks · doi:10.1007/978-3-642-66972-9_7 · Cited by 37 · see citing works
Morphological Changes in the Placentas of Smoking Mothers: A Histomorphometric Study
Teasdale, F., & Ghislaine, J.-J. (2009) · Biology of the Neonate · doi:10.1159/000242926 · Cited by 31 · see citing works
Ong, P. J. L., & Burton, G. J. (1991) · European Journal of Obstetrics & Gynecology and Reproductive Biology · doi:10.1016/0028-2243(91)90072-s · Cited by 27 · see citing works
Basal lamina thickening in the placentae of smoking mothers
van der Velde, W. J., Peereboom-Stegeman, J. H. J. C., STEGEMAN, P., Treffers, P. E., & James, J. (1985) · Placenta · doi:10.1016/s0143-4004(85)80042-4 · Cited by 24 · see citing works
Placental Function and Fetal Nutrition
Battaglia, F. C., & Services, N. N. (1997) · Cited by 19 · see citing works
Morphometric diffusing capacity of the human placenta in cases of preeclampsia
(1995) · Placenta · doi:10.1016/s0143-4004(05)80119-5 · Cited by 3 · see citing works
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Burton, G. J., Fowden, A. L., & Thornburg, K. L. (2016) · Physiological Reviews · doi:10.1152/physrev.00029.2015 · Cited by 717 · see citing works
Human Genetic Adaptation to High Altitude
MOORE, L. G. (2001) · High Altitude Medicine & Biology · doi:10.1089/152702901750265341 · Cited by 335 · see citing works
Ilekis, J. V., Tsilou, E. T., Fisher, S. J., Abrahams, V. M., Soares, M. J., Cross, J. C., Zamudio, S., Illsley, N. P., Myatt, L., Colvis, C. M., et al. (2016) · American Journal of Obstetrics and Gynecology · doi:10.1016/j.ajog.2016.03.001 · Cited by 291 · see citing works
Colson, A., Sonveaux, P., Debiève, F., & Sferruzzi-Perri, A. N. (2020) · Human Reproduction Update · doi:10.1093/humupd/dmaa053 · Cited by 145 · see citing works
Bush, P. G., Mayhew, T. M., Abramovich, D. R., Aggett, P. J., Burke, M. D., & Page, K. (2000) · Placenta · doi:10.1053/plac.1999.0470 · Cited by 138 · see citing works
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Browne, V. A., Julian, C. G., Toledo-Jaldin, L., Cioffi-Ragan, D., Vargas, E., & Moore, L. G. (2015) · Philosophical Transactions of the Royal Society B: Biological Sciences · doi:10.1098/rstb.2014.0068 · Cited by 127 · see citing works
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Torry, D. S., Hinrichs, M., & Torry, R. J. (2004) · American Journal of Reproductive Immunology · doi:10.1111/j.1600-0897.2004.00154.x · Cited by 118 · see citing works
Dokras, A., Hoffmann, D. S., Eastvold, J. S., Kienzle, M. F., Gruman, L. M., Kirby, P., Weiss, R. M., & Davisson, R. L. (2006) · Biology of Reproduction · doi:10.1095/biolreprod.106.053603 · Cited by 118 · see citing works
Semenov, O. V., Koestenbauer, S., Riegel, M., Zech, N., Zimmermann, R., Zisch, A. H., & Malek, A. (2009) · American Journal of Obstetrics and Gynecology · doi:10.1016/j.ajog.2009.10.869 · Cited by 112 · see citing works
Higgins, J., Vaughan, O. R., de Liger, E. F., Fowden, A. L., & Sferruzzi-Perri, A. N. (2015) · The Journal of Physiology · doi:10.1113/jp271057 · Cited by 102 · see citing works
Placental structural abnormalities in gestational diabetes and when they develop: A scoping review
Ehlers, E., Talton, O. O., Schust, D. J., & Schulz, L. C. (2021) · Placenta · doi:10.1016/j.placenta.2021.04.005 · Cited by 100 · see citing works
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Bose, P., Kadyrov, M., Goldin, R. D., Hahn, S., Backos, M., Regan, L., & Huppertz, B. (2005) · Placenta · doi:10.1016/j.placenta.2005.09.007 · Cited by 69 · see citing works
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van Patot, M. C. T., Valdez, M., Becky, V., Cindrová‐Davies, T., Johns, J., Zwerdling, L., Jauniaux, E. R. M., & Burton, G. J. (2009) · Placenta · doi:10.1016/j.placenta.2009.04.002 · Cited by 42 · see citing works
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Regnault, T. R. H., Limesand, S. W., & Hay, W. W. (2006) · Cambridge University Press eBooks · doi:10.1017/cbo9780511544712.004 · Cited by 4 · see citing works
Understanding pre‐eclampsia and fetal growth restriction at high altitude: A narrative review
Rangel, V. S., Castillo, J. M., Duarte, J. D., Barreto, M. A., Ramirez, A. V., Daza, J. A., & Ruiz-Sternberg, Á. M. (2026) · International Journal of Gynecology & Obstetrics · doi:10.1002/ijgo.70800 · Cited by 3 · see citing works
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Saga, Z., & Liaqat Ali Minhas, L. A. M. (2009) · Journal of Rawalpindi Medical College · Cited by 1 · see citing works
Perinatal mortality and severe morbidity of term infants
Evers, A. C. C. (2012) · Utrecht University Repository (Utrecht University)
Kasdaglis, T. L., & Baschat, A. (2012) · doi:10.1002/9781118477076.ch5
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- Authors
- Mayhew, T. M.
- Affiliations
- University of Nottingham (GB)
- Corresponding author
- Mayhew, Terry M
- Venue
- European Journal of Obstetrics & Gynecology and Reproductive Biology
- Publisher
- Elsevier BV
- Published
- 1998-10
- Volume
- 81
- Issue
- 1
- Pages
- 101-109
- ISSN
- 0028-2243 (ISSN-L)
- 0301-2115
- OpenAlex
- W2126980346
- Cited by
- 46
- References
- 38
- Citations by year
- 2026: 2 · 2023: 1 · 2021: 3 · 2020: 1 · 2018: 1 · 2017: 1 · 2016: 2 · 2015: 3 · 2013: 2 · 2012: 3
- FWCI
- 3.55
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- European Journal of Obstetrics & Gynecology and Reproductive Biology (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Obstetrics and Gynecology › Pregnancy and preeclampsia studies
- Life Sciences › Immunology and Microbiology › Immunology › Reproductive System and Pregnancy
- Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Birth, Development, and Health
- Keywords
- layer thickness, fetal hypoxia, passive diffusion, placental adaptation, trophoblast, placental stroma, fetal plasma, high altitude, maternal diabetes, gestational age, fetal weight, stereology
- MeSH terms
- Adaptation, Physiological, Altitude, Anemia, Diffusion, Female, Fetal Hypoxia, Gestational Age, Humans, Infant, Newborn, Male, Placenta, Pre-Eclampsia, Pregnancy, Pregnancy Complications, Pregnancy in Diabetics, Regression Analysis, Smoking, Trophoblasts, Stromal Cells
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