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Indeed, recent studies have reported a 10% reduction in oxygen saturation in the ascending aorta in fetuses with complex cardiac defects, not accompanied by the anticipated increased volume flow or oxygen extraction.84 This suggests that, in cardiac disease, cerebral oxygen delivery and consumption is reduced Although it appears that the brains of fetuses with congenital heart defects develop at lower oxygen tension, the impact of this on delivery is more difficult to measure.85 Glucose delivery to the brain plays a vital role in its homeostasis,86 as does the role of chronicity of the altered state Work in animal models suggest responsiveness diminishes with chronicity and the human fetus may adapt and downregulate the brain's requirement for oxygen and metabolic substrates This metabolic alteration may alter gene expression and reduce mitochondrial respiration affecting important regulatory neurohormonal axes (such as the hypothalamic-pituitary axis) and the usual pattern of brain development such as myelination resulting in its permanent alteration.87–89 Flow Across the Aortic Isthmus Only approximately one-third of left ventricular output, or one-tenth of total cardiac output, flows through the aortic isthmus One consequence of this is that the isthmal diameter is smaller than that of the transverse arch and shows a characteristic Doppler pattern (Fig 6.11) Experimental increases in systemic impedance in the lamb, mimicking placental insufficiency in the human, have been shown to reduce or stop isthmal flow.59 In the human, where flow to the brain is 8 to 10 times that of the lamb, the hypoxic-mediated increase allows a reduction in cerebral impedance, with reversal of flow about the aortic arch that can be demonstrated on pulsed wave Doppler.90 FIG 6.11 Doppler flow velocity patterns in the fetal aortic isthmus throughout gestation (A) During the first half of pregnancy, forward flow is present both in systole and diastole (B) During the second half of pregnancy, a brief reversal of flow appears at the end of systole as illustrated in this 32-week fetus (C) In the same fetus a delayed onset and longer acceleration time of the ductal wave are observed at the isthmusductus junction, explaining the late systolic reversal of flow in the isthmus (From Fouron JC The unrecognized physiological and clinical significance of the fetal aortic isthmus Ultrasound Obstet Gynecol 2003;22[5]:441– 447.) The alteration in Doppler flow profile in the isthmus in response to alteration of cerebral and placental impedances has been characterized by five separate profiles termed the isthmic flow index (Fig 6.12).31 Latterly the same group has developed a quantifiable index, the isthmic systolic index, to describe the influence of right and left ventricular performance on the Doppler waveforms measured in this region.91 The index becomes negative during the final weeks of pregnancy, where retrograde isthmic flow is common and correlates with right ventricular output This explains the common finding of reversed flow in the transverse aortic arch in later gestation, attributable to the fall in cerebrovascular resistance, driving blood retrogradely through the isthmus during systole The metabolically active brain responds by vasodilation resulting in an increase in the proportion of left ventricular stroke volume going to the brain, thereby reducing this retrograde flow A plausible alternative explanation is that the fall in cerebrovascular resistance and increased cerebral flow toward term results in increased right heart preload with a subsequent increased ductal flow, leading to retrograde flow about the isthmus Animal studies suggest that ventricular ejection times of both ventricles are similar,92 but these findings may not be applicable in the human fetus because the proportion of cardiac output supplying the brain is relatively greater than most experimental animal species It is true that the opening time of the pulmonary valve exceeds that of the aortic valve due to the longer electromechanical time interval of the right ventricle, but the isthmal flow depends also on the compliance in the pulmonary vasculature (see section later) The higher the right ventricular output, the greater the reversal of branch pulmonary flow and therefore the more negative the end-systolic velocity should be producing greater reversal of transverse arch flow.93 FIG 6.12 Five possible types (I–V) of the isthmic flow index Doppler flow waveforms at the bottom of the figure are taken from fetuses with placental circulatory insufficiency (From Fouron JC The unrecognized physiological and clinical significance of the fetal aortic isthmus Ultrasound Obstet Gynecol 2003;22[5]:441–447.) The ability of the isthmus to function as a true shunt explains why reversal of flow in the transverse arch is often seen in the healthy near-term human fetus It also explains the pathophysiologic mechanisms underlying the reversed aortic arch flow due to the steal phenomenon in cerebral arteriovenous malformations, such as vein of Galen malformation (Video 6.10) However, interpretation of the isthmic systolic index in cardiac defects remains more complex and utility of this index requires determination.94 Flow of Blood to the Lungs The flow of blood in the lungs of the normal human fetus has been calculated noninvasively from the difference in estimated volumes in the arterial duct and in the pulmonary trunk using Doppler ultrasound In this way, an increase with age for pulmonary flow from 13% to 25% has been described in a cross-section