Chapter 1 Fetal Asphyxia: Section F Ovine model

Sheep studies of umbilical cord occlusion



In the 1980’s -1990’s several laboratories produced elegant and detailed studies of fetal asphyxia in the lamb using implanted devices to measure fetal blood pressure, blood chemistries, fetal heart rate and EKG, and to occlude the umbilical cord with a controllable inflatable ring around the cord. They repeated the primate studies using variables of time and completeness of occluded blood flow both to the uterus and through the umbilical cord. They confirmed many of the conclusions from primate research including the significance of partial asphyxia and the contribution of cardiovascular collapse and hypotension.

The sheep experiments could track the physiologic changes in experimental hypoxemia produced by administration of maternal nitrogen, and maternal aortic occlusion. Hypoxemia sufficient to produce fetal acidosis (essentially intrauterine asphyxia) redistributed fetal blood flow to maintain perfusion of the brain, heart and adrenal, but that with cardiovascular collapse (in one study at pH6.86 an BE -20) heart and brain perfusion became inadequate1. This model of maternal aortic occlusion did sometimes produce neuronal necrosis (and fetal death) not unlike short episodes of complete asphyxia in the monkey model2.

While studies did not usually examine long-term follow up of the lamb for neurological symptoms, some did look at pathologic changes in the brain72 hours after the asphyxia. For example, one study found that when partial umbilical cord occlusion that was continued until pH fell below 6.90 and base excess below -20 mEq/L over a range of 55 to 65 minutes, neither the fetal heart rate nor the fetal blood gases predicted the degree of brain injury although there was correlation with the degree of fetal hypotension3. The brain lesions varied from mild white matter changes to severe infarction of the gray and white matter. The low-grade white matter changes were subtle with loss of myelin sheaths. They also found that while renal tubular damage was seen with all degrees of asphyxia, liver and myocardial necrosis were only seen in lambs with severe brain injury4 This finding correlates with the redistribution of blood flow to the heart and brain, and likely liver, and away form the kidney in asphyxia. When this adaptation is overwhelmed, the heart, brain and liver suffer ischemic injury.

One frequently used ovine model duplicates the stress of labor by completely and repetitively occluding umbilical cord blood flow for given intervals such as 1 minute every 2.5 minutes5. In one study, after 1 -1.5 hours of repetitive, complete umbilical cord occlusions, the lambs developed a severe lactic acidosis (pH<6.8, lactate > 10mM/L). The variable decelerations of fetal heart rate from the cord occlusions did not change with the development of severe acidosis. Even details of the EKG (the ratio of the PR interval to the RR wave interval) did not distinguish the lambs with acidosis6. There was an imperfect correlation of unstable heart rate variability and fetal acidosis7. The fetal heart rate monitor was not a predictor of the onset of severe acidosis.

This intermittent model of umbilical cord occlusion demonstrated the same redistribution of flow with preservation of brain oxidative metabolism as with maternal aortic occlusion8. Intermittent umbilical cord occlusion that lowered blood pressure below 20 mm Hg between occlusions produced neuronal necrosis and cerebral infarctions generally in watershed zones (that is between the perfusion areas of the larger cerebral arteries and hence more at risk with shock)9. Interestingly there was a persistence of elevated impedance to brain blood flow after the occlusions were stopped in the brain injured animals, which may have contributed to infarction after the initial insult was terminated.

A more recent ovine study of intermittent complete umbilical cord occlusion found that the base deficit increased 0.56 mEq/L for each minute of occlusion and normalized afterward at a rate of 0.1 mEq/L/min10. The authors suggest given a starting base excess of 2mEq/L, that an algorithm based on these rates could predict the onset of a base deficit of -12 mEq, a threshold value for brain injury. However, the actual experiments demonstrated some animal-to-animal variability even in their controlled model. The umbilical cord was occluded with increasing severity until the fetus reached an arterial pH below 7.0. Two animals reached this level with only the moderate protocol (1 minute of occlusion every 3 minutes) while 8 sheep continued to the severe protocol (1 minute of occlusion very 2 minutes), but one of these died on reaching the pH threshold. The same model was modified to demonstrate that less complete umbilical cord occlusion that inhibited only 50% and 75% of umbilical blood flow failed to cause significant fetal acidosis11. In earlier studies, fetal lambs that were already partially hypoxic required fewer occlusions to produce severe acidosis and hypotension than normoxic lambs12.

Other studies of intermittent umbilical cord inclusion often produced either white matter lesions or fetal death13,14. Together, these studies suggest that brain perfusion was being maintained but that the intermittent hypoxia was causing white matter injury until the point at which cardiac and brain perfusion were not being maintained an circulatory collapse occurred with either death or with gray and white matter brain infarction in survivors.

The sheep studies did demonstrate that intermittent occlusions with a labor like recurrence could produce severe fetal acidosis, hypotension and brain injury without a change in the FHR pattern beyond the expected deep variable decelerations. Despite a consistent change in base excess in controlled conditions of complete occlusion, the change in fetal acidosis with repetitive deep variable decelerations in the clinical setting is likely to depend on the prior state of the fetus and on the completeness of the episodes of hypoxia. The lamb brain lesions produced showed similar variability to those in the monkey and occurred with the sudden onset of circulatory collapse that was not predictable. The bottom line from the sheep models was that with a repeat umbilical cord compression pattern of the fetal heart rate, the obstetrician would not be able to predict when the infant or which infant would go on to succumb or have brain injury.


  1. Block BS, Schlafer DH, Wentworth RA, Kreitzer LA, Nathanielsz PW. Intrauterine asphyxia and the breakdown of physiologic circulatory compensation in fetal sheep. Am J Obstet Gynecol 1990;162:1325-31.
  2. Gunn A, Parer J, Mallard E, Williams C, Gluckman P. Cerebral histologic and electrophysiologic changes after asphyxia in fetal sheep. Pediatr Res 1992;31:486-91.
  3. Ikeda T, Murata Y, Quilligan EJ, et al. Physiologic and histologic changes in near-term fetal lambs exposed to asphyia by partial umbilical cord occlusion. Am J Obstet Gynecol 1998;178:24-32.
  4. Ikeda T, Murata Y, Quilligan EJ, Parer JT, Murayama T, Koono M. Histologic and biochemical study of the brain, heart, kidney, and liver in asphyxia caused by occlusion of the umbilical cord in near-term fetal lambs. Am J Obstet Gynecol 2000;182:449-57.
  5. deHann H, Gunn A, Gluckman P. Fetal heart rate changes do not reflect cardiovascular deterioration during brief repeated umbilical cord occlusions in near-term fetal lambs. Am J Obstet Gynecol 1997;176:8-17.
  6. Westgate JA, Gunn AJ, Bennet L, Gunning MI, de Haan HH, Gluckman PD. Do fetal electrocardiogram PR-RR changes reflect progressive asphyxia after repeated umbilical cord occlusion in fetal sheep? Pediatr Res 1998;44:297-303.
  7. Westgate JA, Bennet L, Gunn AJ. Fetal heart rate variability changes during brief repeated umbilical cord occlusion in near term fetal sheep. Br J Obstet Gynaecol 1999;106:664-71.
  8. Richardson B, Carmichael L, Homan J, Johnston L, R G. Fetal cerebral; circulatory; and metabolic responses during heart rate decelerations with umbilical cord compression. Am J Obstet Gynecol 1996;175:929-36.
  9. De Haan HH, Gunn AJ, Williams CE, Gluckman PD. Brief repeated umbilical cord occlusions cause sustained cytotoxic cerebral edema and focal infarcts in near-term fetal lambs. Pediatr Res 1997;41:96-104.
  10. Frasch MG, Mansano RZ, McPhaul L, Gagnon R, Richardson BS, Ross MG. Measures of acidosis with repetitive umbilical cord occlusions leading to fetal asphyxia in the near-term ovine fetus. Am J Obstet Gynecol 2009;200:200 e1-7.
  11. Ross MG, Jessie M, Amaya K, et al. Correlation of arterial fetal base deficit and lactate changes with severity of variable heart rate decelerations in the near-term ovine fetus. Am J Obstet Gynecol 2013;208:285 e1-6.
  12. Westgate JA, Wassink G, Bennet L, Gunn AJ. Spontaneous hypoxia in multiple pregnancies is associated with early fetal decompensation and enhanced T-wave elevation during brief repeated cord occlusion in near-term fetal sheep. Am J Obstet Gynecol 2005;193:1526-33.
  13. III JFC, Peress NS, Wesley M, Mann LI. Brain damage after intermittent partial cord occlusion in the chronically instrumented fetal lamb. Am J Obstet Gynecol 1988;159:504-9.
  14. Ohyu J, Marumo G, Ozawa H, et al. Early axonal and glial pathology in fetal sheep brains with leukomalacia induced by repeated umbilical cord occlusion [In Process Citation]. Brain Dev 1999;21:248-52.


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