Perinatal Hypoxia

Implications for Mammalian Development
  • Charles F. Mactutus
  • Laurence D. Fechter


The literature contains many studies of the effects of acute hypoxia, anoxia, and asphyxia, as induced by a variety of techniques, on measures of the cardiovascular, pulmonary, and nervous systems. These studies have provided an important information base for healthcare professionals in instances of cardiorespiratory pathology, acute toxic exposure, or other acute life-threatening situations. However, the literature dealing with responses of the immature organism to hypoxic conditions is much less complete. One explanation for this relative paucity of data on the developing organism is that, classically, the immature organism has been regarded as relatively insensitive to hypoxia. This view stems largely from experiments such as those of Adolph (1969), which show an inverse relationship between age and survival following asphyxiation (Figure 1). Similar results showing an inverse relationship between age and survival of anoxia have been obtained in various mammalian species (Fazekas, Alexander, & Himwich, 1941). Such data led to the early belief that the immature organism relies predominantly on anaerobic metabolism, but they are probably more accurately interpreted as reflecting the lower brain-oxygen consumption of the fetus and the newborn than of the adult (Himwich, Baker, & Fazakas, 1939). As we unfortunately know from clinical experience and from a variety of experiments with animal subjects, the immature organism, under certain conditions, will survive hypoxia, but the central nervous system shows profound injury. Survival is clearly an inexact measure of resistance to injury. Still to be determined are the boundary conditions under which the immature brain first suffers hypoxic injury and the brain regions and the developmental processes that are most vulnerable.


Retention Interval Litter Size Hypobaric Hypoxia Simulated Altitude Hypoxic Hypoxia 
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  1. Abbatiello, E. R., & Mohrmann, K. Effects on the offspring of chronic low exposure carbon monoxide during mice pregnancy. Clinical Toxicology, 1979, 14, 401–406.PubMedCrossRefGoogle Scholar
  2. Adolph, E. F. Regulations during survival without oxygen in infant mammals. Respiratory Physiology, 1969, 7, 356–368.CrossRefGoogle Scholar
  3. Ashwal, S., Majcher, J. S., & Longo, L. D. Patterns of fetal lamb regional cerebral blood flow during and after prolonged hypoxia: Studies during the posthypoxic recovery period. American Journal of Obstetrics and Gynecology, 1981, 139, 365–372.PubMedGoogle Scholar
  4. Astrup, P., Trolle, D., Olsen, H. M., & Kjeldsen, K. Effects of moderate carbon-monoxide exposure on fetal development. Lancet, 1972, 2, 1220–1222.PubMedCrossRefGoogle Scholar
  5. Astrup, P., Trolle, D., Olsen, H. M., & Kjeldsen, K. Moderate hypoxia exposure and fetal development. Archives of Environmental Health, 1975, 30, 15–16.PubMedGoogle Scholar
  6. Bailey, C. J., & Windle, W. F. Neurological, psychological and neurohistological defects following asphyxia neonatorum in the guinea pig. Experimental Neurology, 1959, 1, 467–482.CrossRefGoogle Scholar
  7. Bauer, R. H. Ontogeny of two-way avoidance in male and female rats. Developmental Psychobiology, 1978, 11, 103–116.PubMedCrossRefGoogle Scholar
  8. Becker, R. F., & Donnell, W. Learning behavior in guinea pigs subjected to asphyxia at birth. Journal of Comparative and Physiological Psychology, 1952, 45, 153–162.PubMedCrossRefGoogle Scholar
  9. Behrman, R. E., Lees, M. H., Peterson, E. N., de Lannoy, C. W., & Seeds, A. E. Distribution of the circulation in the normal and asphyxiated fetal primate. American Journal Obstetrics and Gynecology, 1970, 108, 956–969.Google Scholar
  10. Bornschein, R. L., Hastings, L., & Manson, J. M. Behavioral toxicity in the offspring of rats following maternal exposure to dichloromethane. Toxicology and Applied Pharmacology, 1980, 52, 29–37.PubMedCrossRefGoogle Scholar
  11. Bunch, M. E. The effects of pre- and postnatal anoxia upon learning and memory at maturity. Science, 1952, 116, 517–518.Google Scholar
  12. Choi, K. D., & Oh, Y. K. A teratological study on the effects of carbon monoxide exposure upon the fetal development of albino rats. Korean Central Journal of Medicine, 1975, 29, 209–212.Google Scholar
  13. Coyle, J. T. Development of the central catecholaminergic neurons in the rat. In E. Usdin & S. H. Snyder (Eds.), Frontiers in catecholamine research. New York: Pergamon Press, 1973.Google Scholar
  14. Culver, B., & Norton, S. Juvenile hyperactivity in rats after acute exposure to carbon monoxide. Experimental Neurology, 1976, 50, 80–98.PubMedCrossRefGoogle Scholar
  15. Curley, F. J., & Ingalls, T. H. Hypoxia at normal atmospheric pressure as a cause of congenital malformations in mice. Proceedings of the Society for Experimental Biology and Medicine, 1957, 94, 87–88.PubMedGoogle Scholar
  16. Darke, R. A. Late effects of severe asphyxia neonatorum. Journal of Pediatrics, 1944, 24, 148–158.CrossRefGoogle Scholar
  17. Daughtrey, W. C., & Norton, S. Caudate morphology and behavior of rats exposed to carbon monoxide in utero. Experimental Neurology, 1983, 80, 265–278.PubMedCrossRefGoogle Scholar
  18. Degenhardt, K. H., & Knoche, E. Analysis of intrauterine malformations of the vertebral column induced by oxygen deficiency. Canadian Medical Association Journal, 1959, 80, 441–445.PubMedGoogle Scholar
  19. Dobbing, J. Undernutrition and the developing brain. In W. A. Himwich (Ed.), Developmental neurobiology. Springfield, IL: Thomas, 1970.Google Scholar
  20. Faro, M. D., & Windle, W. F. Transneuronal degeneration in brains of monkeys asphyxiated at birth. Experimental Neurology, 1969, 24, 38–53.PubMedCrossRefGoogle Scholar
  21. Fazekas, J. F., Alexander, F. A. D., & Himwich, H. E. Tolerance of the newborn to anoxia. American Journal of Physiology, 1941, 134, 281–287.Google Scholar
  22. Fechter, L. D., & Annau, Z. Effects of prenatal carbon monoxide exposure on neonatal rats. In M. Horvath (Ed.), Adverse effects of environmental chemicals and psychotropic drugs: Neurophysiological and behavioral tests, Vol 2. Amsterdam: Elsevier Scientific, 1976.Google Scholar
  23. Fechter, L. D., & Annau, Z. Toxicity of mild prenatal carbon monoxide exposure. Science, 1977, 197, 680–682.PubMedCrossRefGoogle Scholar
  24. Fechter, L. D., & Annau, Z. Prenatal carbon monoxide exposure alters behavioral development. Neurobehavioral Toxicology, 1980, 2, 7–11.PubMedGoogle Scholar
  25. Fechter, L. D., Thakur, M., Miller, B., Annau, Z., & Srivastava, U. Effects of prenatal carbon monoxide exposure on cardiac development. Toxicology and Applied Pharmacology, 1980, 56, 370–375.PubMedCrossRefGoogle Scholar
  26. Feigley, D. A., & Spear, N. E. Effect of age and punishment condition on long-term retention by the rat of active- and passive-avoidance learning. Journal of Comparative and Physiological Psychology, 1970, 73, 515–526.PubMedCrossRefGoogle Scholar
  27. File, S. E., & Wardhill, A. G. Validity of head-dipping as a measure of exploration in a modified hole board. Psychopharmacologia, 1975, 44, 53–59.PubMedCrossRefGoogle Scholar
  28. Garvey, D. J., & Longo, L. D. Chronic low level maternal carbon monoxide and fetal growth and development. Biology of Reproduction, 1978, 19, 8–14.PubMedCrossRefGoogle Scholar
  29. Ginsberg, M. D., & Myers, R. E. Fetal brain damage following maternal carbon monoxide intoxication: An experimental study. Acta Obstetricia et Gynecologicia Scandinavica, 1974, 53, 309–317.CrossRefGoogle Scholar
  30. Graessle, C. A. Prenatal influence of mild decompressions on hooded rats. Developmental Psychobiology, 1980, 13, 399–407.PubMedCrossRefGoogle Scholar
  31. Graessle, C. A., Ahbel, K., & Porges, S. W. Effects of mild prenatal decompressions on growth and behavior in the rat. Bulletin of the Psychonomic Society, 1978, 12, 329–331.Google Scholar
  32. Hardin, B. D., & Manson, J. M. Absence of dichloromethane teratogenicity with inhalation exposure in rats. Toxicology and Applied Pharmacology, 1980, 52, 22–28.PubMedCrossRefGoogle Scholar
  33. Harned, H. S., Jr. Respiration and the respiratory system. In U. Stave (Ed.), Perinatal physiology, New York: Plenum Press, 1978.Google Scholar
  34. Hershkowitz, M., Grimm, V. E., & Speiser, Z. The effects of postnatal anoxia on behavior and on the muscarinic and beta-adrenergic receptors in the hippocampus of the developing rat. Developmental Brain Research, 1983, 7, 147–155.CrossRefGoogle Scholar
  35. Hill, E. P., Power, G. G., & Longo, L. D. A mathematical model of placental 02 transfer with consideration of hemoglobin reaction rates. American Journal of Physiology, 1972, 222, 721–729.PubMedGoogle Scholar
  36. Hill, E. P., Power, G. G., & Longo, L. D. A mathematical model of carbon dioxide transfer in the placenta and its interaction with oxygen. American Journal of Physiology, 1973, 224, 283–299.PubMedGoogle Scholar
  37. Himwich, H. E., Baker, Z., & Fazekas, J. F. The respiratory metabolism of infant brain. American Journal of Physiology, 1939, 125, 601–606.Google Scholar
  38. Hurder, W. P., & Sanders, A. F. The effects of neonatal anoxia on the maze performance of adult rats. Journal of Comparative and Physiological Psychology, 1953, 46, 61–63.PubMedCrossRefGoogle Scholar
  39. Hyman, A., Parker, B., Berman, D., & Berman, A. J. Delayed response deficits in neonatally asphyxiated Rhesus monkeys. Experimental Neurology, 1970, 28, 420–425.PubMedCrossRefGoogle Scholar
  40. Hyman, A., Berman, D., & Berman, A. J. Deficits in unsignaled avoidance behavior in Rhesus monkeys asphyxiated at birth. Experimental Neurology, 1971, 30, 362–366.PubMedCrossRefGoogle Scholar
  41. Ingalls, T. H., Curley, F. J., & Prindle, R. A. Anoxia as a cause of fetal death and congenital defect in the mouse. American Journal of the Diseases of Children, 1950, 80, 34–45.Google Scholar
  42. Ingalls, T. H., Curley, F. J., & Prindle, R. A. Experimental production of congenital abnormalities: Timing and degree of anoxia as factors causing deaths and congenital abnormalities in the mouse. New England Journal of Medicine, 1952, 247, 758–768.PubMedCrossRefGoogle Scholar
  43. Kalter, H., & Warkany, J. Experimental production of congenital malformations in mammals by metabolic procedure. Physiological Reviews, 1959, 39, 69–115.PubMedGoogle Scholar
  44. Kellogg, C., & Lundborg, P. Ontogenic variations in responses to /-DOPA and monoamine receptor-stimulating agents. Psychopharmacologia, 1972, 23, 187–200.PubMedCrossRefGoogle Scholar
  45. Kimble, G. Hilgard and Marquis’ conditioning and learning ( 2nd ed. ). New York: Appleton-Century-Crofts, 1961.Google Scholar
  46. King, F. A. Effects of septal and amygdaloid lesions on emotional behavior and conditioned avoidance responses in the rat. Journal of Nervous and Mental Diseases, 1958, 126, 57–63.CrossRefGoogle Scholar
  47. Longo, L. D. Carbon monoxide in the pregnant mother and fetus and its exchange across the placenta. Annals of the New York Academy of Sciences, 1970, 174, 313–341.CrossRefGoogle Scholar
  48. Longo, L. D. The biological effect of carbon monoxide on the pregnant woman, fetus, and newborn infant. American Journal of Obstetrics and Gynecology, 1977, 129, 69–103.PubMedGoogle Scholar
  49. Longo, L. D., & Hill, E. P. Carbon monoxide uptake and elimination in fetal and maternal sheep. American Journal of Physiology, 1977, 232, H324–H330.PubMedGoogle Scholar
  50. Longo, L. D., Hill, E. P., & Power, G. G. Theoretical analysis of factors affecting placental 02 transfer. American Journal of Physiology, 1972, 222, 730–739.PubMedGoogle Scholar
  51. Mactutus, C. F., & Fechter, L. D. Prenatal exposure to carbon monoxide: Learning and memory deficits. Science, 1984, 223, 409–411.PubMedCrossRefGoogle Scholar
  52. Mactutus, C. F., & Fechter, L. D. Moderate carbon monoxide exposure produces persistent, and apparently permanent, memory deficits in rats. Teratology, 1985, 31, 1–12.PubMedCrossRefGoogle Scholar
  53. McCullough, M. L., & Blackman, D. E. The behavioral effects of prenatal hypoxia in the rat. Developmental Psychobiology, 1976, 9, 335–342.PubMedCrossRefGoogle Scholar
  54. Meier, G. W. Hypoxia. In E. Furchtgott (Ed.), Pharmacological and biophysical agents and behavior. New York: Academic Press, 1971.Google Scholar
  55. Meier, G. W., & Bunch, M. E. The effects of natal anoxia upon learning and memory at maturity. Journal of Comparative and Physiological Psychology, 1950, 43, 436–441.PubMedCrossRefGoogle Scholar
  56. Meier, G. W., Bunch, M. E., Nolan, C. Y., & Scheidler, C. H. Anoxia, behavioral development, and learning ability: A comparative-experimental approach. Psychological Monographs, 1960, 74, 1–48. (Whole No. 488).Google Scholar
  57. Metcalf, J., Bartels, H., & Moll, W. Gas exchange in the pregnant uterus. Physiological Reviews, 1967, 47, 782–838.Google Scholar
  58. Murakami, U., & Kameyama, Y. Vertebral malformations in the mouse foetus caused by maternal hypoxia during early stages of pregnancy. Journal of Embryology and Experimental Morphology, 1963, 11, 107–118.Google Scholar
  59. Myers, R. E. A unitary theory of casuation of anoxic and hypoxic brain pathology. In S. Fahn, J. N. Davis, & L. P. Roland (Eds.), Advances in neurology, Vol. 26. New York: Raven Press, 1979.Google Scholar
  60. Norton, S., & Culver, B. A Golgi analysis of caudate neurons in rats exposed to carbon monoxide. Brain Research, 1977, 132, 455–465.PubMedCrossRefGoogle Scholar
  61. O’Keefe, J., & Nadel, L. The hippocampus as a cognitive map. London: Oxford University Press, 1978.Google Scholar
  62. Pokorny, J., & Trojan, S. Chronic changes in the receptive field of the pyramidal cells of the rat hippocampus after intermittent postnatal hypoxia. Physiologia Bohemoslovaca, 1983, 32, 393–402.PubMedGoogle Scholar
  63. Power, G. G., & Longo, L. D. Fetal circulation times and their implications for tissue oxygenation. Gynecological Investigation, 1975, 6, 342–355.CrossRefGoogle Scholar
  64. Ranck, J. B., Jr., & Windle, W. F. Brain damage in the monkey, Macaca mulatta by asphyxia neonatorum. Experimental Neurology, 1959, 1, 130–154.PubMedCrossRefGoogle Scholar
  65. Reiter, L. W., & MacPhail, R. C. Motor activity: A survey of methods with potential use in toxicity testing. Neurobehavioral Toxicology, 1979, 1, 53–66. (Supplement 1).PubMedGoogle Scholar
  66. Riccio, D. C., Rohrbaugh, M., & Hodges, L. A. Developmental aspects of passive and active avoidance learning in rats. Developmental Psychobiology, 1968, 1, 108–111.CrossRefGoogle Scholar
  67. Robertson, G. G. Embryonic development following maternal hypoxia in the rat. Anatomical Record, 1959, 133, 420–421.Google Scholar
  68. Rodier, P. M. Chronology of neuron development: Animal studies and their clinical implications. Developmental Medicine and Child Neurology, 1980, 22, 525–545.PubMedCrossRefGoogle Scholar
  69. Saxon, S. V. Effects of asphyxia neonatorum on behavior in the Rhesus monkey. Journal of Genetic Psychology, 1961, 99, 277–282. (a)PubMedGoogle Scholar
  70. Saxon, S. V. Differences in reactivity between asphyxial and normal Rhesus monkeys. Journal of Genetic Psychology, 1961, 99, 283–287. (b)PubMedGoogle Scholar
  71. Saxon, S. V., & Ponce, C. G. Behavioral defects in monkeys asphyxiated during birth. Experimental Neurology, 1961, 4, 460–469.PubMedCrossRefGoogle Scholar
  72. Scheidler, C. The effects of prenatal anoxia on learning of white rats. Unpublished doctoral dissertation, Washington University, St. Louis, 1953. (Reproduced in G. W. Meier et al, article appearing in Psychological Monographs, 1960, 74.)Google Scholar
  73. Schwetz, B. A., Smith, F. A., Leong, B. K. J., & Staples, R. E. Teratogenic potential of inhaled carbon monoxide in mice and rabbits. Teratology, 1979, 19, 385–392.PubMedCrossRefGoogle Scholar
  74. Sechzer, J. A. Behavioral responses of Rhesus monkeys seven years after neonatal asphyxia. Anatomical Record, 1968, 160, 425–426.Google Scholar
  75. Sechzer, J. A. Memory deficit in monkeys brain damaged by asphyxia neonatorum. Experimental Neurology, 1969, 24, 497–507.PubMedCrossRefGoogle Scholar
  76. Sechzer, J. A., Faro, M. D., Barker, J. N., Barsky, D., Gutierrez, S., & Windle, W. F. Developmental behaviors: Delayed appearance in monkeys asphyxiated at birth. Science, 1971, 171, 1173–1175.PubMedCrossRefGoogle Scholar
  77. Shellenberger, K. M., & Norton, S. Factors influencing the persistent effects of carbon monoxide exposure on rat motor activity. Neurotoxicology, 1980, 1, 541–550.Google Scholar
  78. Simon, N., & Volicer, L. Neonatal asphyxia in the rat: Greater vulnerability of males and persistent effects on brain monoamine synthesis. Journal of Neurochemistry, 1976, 26, 893–900.PubMedCrossRefGoogle Scholar
  79. Speiser, Z., Korczyn, A. D., Teplitzky, I., & Gitter, S. Hyperactivity in rats following postnatal anoxia. Behavioral Brain Research, 1983, 7, 379–382.CrossRefGoogle Scholar
  80. Tapp, J. T., Zimmerman, R. S., & D’Encarnacao, P. S. Intercorrelational analysis of some common measures of rat activity. Psychological Reports, 1968, 23, 1047–1050.CrossRefGoogle Scholar
  81. Tolman, E. C. Principles of performance. Psychological Review, 1955, 62, 315–326.PubMedCrossRefGoogle Scholar
  82. Tominaga, T., & Page, E. W. Accommodation of the human placenta to hypoxia. American Journal of Obstetrics and Gynecology, 1966, 94, 679–691.PubMedGoogle Scholar
  83. Towbin, A. Cerebral hypoxic damage in fetus and newborn: Basic patterns and clinical significance. Archives of Neurology, 1969, 20, 35–43.PubMedGoogle Scholar
  84. Towbin, A. Organic causes of minimal brain dysfunction. Journal of the American Medical Association, 1971, 217, 1207–1214.PubMedCrossRefGoogle Scholar
  85. Vierck, C. J., Jr., & Meier, G. W. Effects of prenatal hypoxia upon locomotor activity of the mouse. Experimental Neurology, 1963, 7, 418–425.PubMedCrossRefGoogle Scholar
  86. Vierck, C. J., Jr., King, F. A., & Ferm, V. H. Effects of prenatal hypoxia upon activity and emotionality of the rat. Psychonomic Science, 1966, 4, 87–88.Google Scholar
  87. Weasner, M. H., Finger, F. W., & Reid, L. S. Activity changes under food deprivation as a function of recording device. Journal of Comparative and Physiological Psychology, 1960, 53, 470–474.PubMedCrossRefGoogle Scholar
  88. Wells, L. L. The prenatal effect of carbon monoxide on albino rats and the resulting neuropathology. Biologist, 1933, 15, 80–81.Google Scholar
  89. Williams, I. R., & Smith, E. Blood picture, reproduction and general condition during daily exposure to illuminating gas. American Journal of Physiology, 1935, 110, 611–615.Google Scholar
  90. Windle, W. F. Brain damage at birth. Journal of the American Medical Association, 1968, 206, 1967–1972.PubMedCrossRefGoogle Scholar
  91. Windle, W. F., & Becker, R. F. Effects of anoxia at birth on central nervous system of the guinea pig. Proceedings of the Society for Experimental Biology and Medicine, 1942, 51, 213–215.Google Scholar
  92. Windle, W. F., & Becker, R. F. Asphyxia neonatorum. An experimental study in the guinea pig. American Journal of Obstetrics and Gynecology, 1943, 45, 183–200.Google Scholar
  93. Windle, W. F., Becker, R. F., & Weil, A. Alterations in brain structure after asphyxiation at birth: An experimental study in the guinea pig. Journal of Neuropathology and Experimental Neurology, 1944, 3, 224–238.CrossRefGoogle Scholar

Copyright information

© Plenum Press, New York 1986

Authors and Affiliations

  • Charles F. Mactutus
    • 1
  • Laurence D. Fechter
    • 2
  1. 1.Developmental Neurobiology Group, Laboratory of Behavioral and Neurological ToxicologyNational Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle ParkUSA
  2. 2.Department of Environmental Health Sciences, School of Hygiene and Public HealthJohns Hopkins UniversityBaltimoreUSA

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