The fetal dilemma: spare the brain and spoil the liver

Extensive studies conducted in chronically instrumented fetal sheep have demonstrated pronounced redistribution of blood throughout the fetal and placental vasculature in response to challenges such as hypoxaemia. By redistributing blood flow, the fetus attempts to maintain the oxygen and nutrient supply to vital organs especially the brain, heart and adrenal glands. Since the major beneficiary of redistribution is the brain, these flow alterations have been designated as achieving ‘brain sparing‘. Sparing of the brain is only relative brain sparing since the brain does experience the insult as oxygen delivery usually falls. Nonetheless, redistribution of blood flow towards the brain, coupled with a reduction in cerebral metabolism, allows the brain to be less affected than other organs such as skeletal muscle, gastrointestinal tract and kidneys that are of lesser importance to immediate survival.

The neural and hormonal mechanisms responsible for this redistribution of blood flow are complex. Redistribution involves altered responses in the different fetal organs to vasoconstrictors such as catecholamines, arginine vasopressin and endothelin, and vasodilators such as nitric oxide. While extensive studies have evaluated the effects of catecholamines on the redistribution of blood flow in the maternal circulation (Rosenfeld & West, 1977) no studies have directly addressed this question in the fetus. There are also pronounced changes in the response of the fetal hypothalamo-pituitary-adrenal axis to various challenges such as hypoxaemia in late gestation, which might play direct and indirect roles in blood flow redistribution. Exogenous administration of glucocorticoids to the fetus alters regional blood flow both at rest and in response to hypercarbia (Schwab et al. 2000). Similar studies need to be performed with catecholamines.

Organ-specific vasoconstrictor and vasodilator function is central to the redistribution of blood flow. In addition, the fetal vasculature contains three shunts, the ductus arteriosus, foramen ovale and ductus venosus (DV), that bypass selective regions of the circulation. Active regulation of flow through these shunts would provide significant mechanisms for altering brain blood flow. There is no evidence for active regulation of flow through the foramen ovale. The pulmonary circulation receives only 7 % of cardiac output and decreased fetal pulmonary flow is unlikely to play a major role.

Flow through the fetal sheep DV comprises about one-third of umbilical return from the placenta (Bristow et al. 1983), a value similar to that of the late gestation human fetus (Haugen et al. 2002). In this issue of The Journal of Physiology, Tchirikov and colleagues provide evidence for a role for catecholamines in regulating DV flow. Umbilical vein blood returning from the placenta can take one of two routes. It can return to the inferior vena cava via intrahepatic veins that branch from the umbilical vein to supply the liver before passing into the hepatic veins that drain the liver lobules into the vena cava. Alternatively, umbilical venous blood can bypass the liver via the DV, passing directly to the right atrium and thence to the cerebral circulation without giving up any oxygen or nutrient.

The study by Tchirikov and colleagues (2003) demonstrates that catecholamines exert a greater constrictor effect on smooth muscle of the intrahepatic veins than on muscle of the narrowest (isthmic) portion of the DV. As a result, situations in which fetal catecholamine concentrations are elevated will alter the pressure differential across these two vessels, thereby causing more blood to bypass the liver. Tchirikov et al. (2003) call this ‘DV sparing’. Since the function is not to spare the DV from hypoxia, this term is confusing by analogy with ‘brain sparing’. The study shows that the DV is relatively unresponsive to catecholamines in early gestation. Thus, changes in response to hypoxaemia and other challenges that occur in the circulation may vary with gestational age. The study of endogenous catecholamines will no doubt be expanded using specific adrenergic agonists and antagonists.

Maturation of function throughout gestation reflects the development of structural competence of the tissues. Kiserud (2001) found that gestational age had a significant effect on blood velocity in the umbilical vein and DV. In this regard it is of interest that Tchirikov and colleagues (2003) demonstrate that the DV in early gestation does not respond to potassium chloride-induced depolarization and that force development increases with gestational age. Maximum force generation in intrahepatic veins is sixfold higher than in the DV in response to both noradrenaline (norepinephrine) and adrenaline (epinephrine). The sensitivity to noradrenaline-induced constriction is also greater in the intrahepatic veins. The tension responses correlate with a greater density of α-adrenergic receptors in the media of the intrahepatic veins compared with the DV. The intrahepatic veins also contain more muscle. Thus, differences in response have both anatomical and functional origins. Studies on the redistribution of fetal blood flow under intra-uterine conditions that challenge fetal survival have often ignored hepatic flow, which is difficult to measure. Whilst hepatic arterial flow is still difficult to measure, the venous circulation, especially that in the DV and portal veins, provides an increasingly valuable opportunity for clinical evaluation (see Kiserud et al. 2001).

Further information on hepatic perfusion will be of considerable value. Of particular interest is the distribution of umbilical flow between the left and right liver lobes, as the former receives little portal supply. The functional consequences of this lobar difference are not known. Future work in this area should evaluate the effects of other vasoconstrictors and vasodilators, responses to different challenges to the fetus such as under-nutrition and growth retardation as well as hypoxaemia, document gestational age-dependent changes and demonstrate similarities and differences across species.