The fetal brain sparing response to hypoxia: physiological mechanisms

Abstract

How the fetus withstands an environment of reduced oxygenation during life in the womb has been a vibrant area of research since this field was introduced by Joseph Barcroft, a century ago. Studies spanning five decades have since used the chronically instrumented fetal sheep preparation to investigate the fetal compensatory responses to hypoxia. This defence is contingent on the fetal cardiovascular system, which in late gestation adopts strategies to decrease oxygen consumption and redistribute the cardiac output away from peripheral vascular beds and towards essential circulations, such as those perfusing the brain. The introduction of simultaneous measurement of blood flow in the fetal carotid and femoral circulations by ultrasonic transducers has permitted investigation of the dynamics of the fetal brain sparing response for the first time. Now we know that major components of fetal brain sparing during acute hypoxia are triggered exclusively by a carotid chemoreflex and that they are modified by endocrine agents and the recently discovered vascular oxidant tone. The latter is determined by the interaction between nitric oxide and reactive oxygen species. The fetal brain sparing response matures as the fetus approaches term, in association with the prepartum increase in fetal plasma cortisol, and treatment of the preterm fetus with clinically relevant doses of synthetic steroids mimics this maturation. Despite intense interest into how the fetal brain sparing response may be affected by adverse intrauterine conditions, this area of research has been comparatively scant, but it is likely to take centre stage in the near future.

Figure 1. Fetal cardiovascular responses to acute hypoxia

The data show the means ± SEM for the change in fetal carotid blood flow (A), fetal femoral blood flow (B) and fetal heart rate (C) in intact (○, n = 14) and carotid body denervated (●, n = 12) chronically instrumented sheep fetuses at 0.8 of gestation during a 1 h episode of acute hypoxia ($P_{{\mathrm{aO}}_2}$ reduced from ca 23 to 13 mmHg, box). Calculation of the ratio between simultaneous measurements of carotid and femoral blood yields the fetal brain sparing index (D). Carotid body denervation prevents the fetal bradycardia and diminishes the fall in fetal femoral blood flow and the increase in the fetal brain sparing index during acute hypoxia. However, carotid body denervation does not affect the increment in carotid blood flow during acute hypoxia. *P < 0.05, intact vs. denervated. Redrawn from Giussani et al. (1993), with permission.

Figure 2. Physiology of fetal brain sparing during hypoxia

The fetal brain sparing response to acute hypoxia is triggered by a carotid chemoreflex that leads to bradycardia and an increase in peripheral vasoconstriction. The bradycardia is mediated by a dominant vagal influence on the fetal heart. The neurally triggered peripheral vasoconstriction is maintained by the release of constrictor hormones into the fetal circulation as well as a local vascular oxidant tone, determined by the interaction between nitric oxide (·NO) and reactive oxygen species (ROS), such as the superoxide anion (·O₂ ⁻). Numbers represent some of the evidence available in the literature. 1, Kjellmer et al. (1989); 2, van Bel et al. (1995); 3, Pearce (1995); 4, Green et al. (1996); 5, Blood et al. (2002); 6, Hunter et al. (2003); 7, Nishida et al. (2006); 8, Giussani et al. (1993); 9, Bartelds et al. (1993); 10, Giussani et al. (2001); 11, Parer (1984); 12, Court & Parer (1984); 13, Lewis et al. (1980); 14, Reuss et al. (1982); 15, Iwamoto et al. (1983); 16, Robillard et al. (1986); 17, Thakor et al. (2005); 18, Booth et al. (2012); 19, Broughton‐Pipkin et al. (1974); 20, Jones & Robinson (1975); 21, Rurak (1978); 22, Peréz et al. (1989); 23, Giussani et al. (1994 b); 24, Giussani et al. (1994 c); 25, Fletcher et al. (2000); 26, Fletcher et al. (2006); 27, Morrison et al. (2003); 28, Thakor et al. (2010 b); 29, Kane et al. (2012); 30, Kane et al. (2014); 31, Thakor et al. (2015).

Figure 3. Ontogeny of the fetal cardiovascular responses to acute hypoxia

The data show mean ± SEM calculated every minute for the fetal heart rate, fetal arterial blood pressure, fetal femoral blood flow and fetal femoral vascular resistance during a 1 h episode of acute hypoxia (box) in 13 fetuses between 125 and 130 days of gestation, 6 fetuses between 135 and 140 days of gestation and 6 fetuses >140 days (term is ca 145 days). Basal fetal heart rate and basal fetal femoral blood flow decrease with advancing gestation. In addition, during acute hypoxia, the bradycardia becomes enhanced and persistent and the femoral vasoconstriction is more intense as the fetus approaches term. Redrawn from Fletcher et al. (2006), with permission.

Figure 4. Anteanatal glucocorticoid therapy and maturation of the fetal cardiovascular defence to acute hypoxia

The data show mean ± SEM calculated every minute for the fetal heart rate, fetal arterial blood pressure, fetal femoral blood flow and fetal femoral vascular resistance during a 1 h episode of acute hypoxia (box) in 14 fetuses at 127 ± 1 days of gestation (term is ca 145 days) following 2 days of continuous fetal i.v. infusion with saline or with dexamethasone treatment. Fetal treatment with dexamethasone switches the pattern and the magnitude of the fetal heart rate and the femoral vascular resistance responses to acute hypoxia towards those seen in fetuses close to term (see Fig. 3). This indicates accelerated maturation of the fetal cardiovascular defence to acute hypoxia by antenatal glucocorticoid treatment. Redrawn from Fletcher et al. (2003), with permission.