Bands of migrating glial cells in the germinal matrix visualized by MRI ( left ) and at histologic evaluation ( right ; reprinted from Coupes macroscopiques fontales. In: Atlas d’IRM du cerveau foetal. de C Adamsbaum, A Gelott, C Andre ` , J-M Baron (eds). Paris; Masson; 2001. p. 48 with permission from Masson) at 21 weeks’ gestation. 

Contexts in source publication

Context 1

... Bands of migrating glia can be visualized and represent very important markers of normal brain development, in particular of the white matter. 59 The uniform appearance of periventricular bands and their relationship to the infants' maturity is consistent with the results of histologic studies (Figure 7). 60 These MRI studies demonstrate the presence of migrating glial cells within the periventricular white matter of infants beyond 20 weeks' gestation, when neuronal migration to the cortex is complete. ...

Context 2

... chain amino acids, independently from the degree of severity, 28,52 with significantly reduced fetal-maternal ratios. The kinetics of these mechanisms have been investi- gated in vivo under steady state conditions by giving a constant infusion of 1-13C leucine to the mother before fetal blood sampling. 53 Figure 6 presents these results in normal pregnancies and in IUGR divided according to severity. In normal pregnancies, because leucine is an essential amino acid, the dilution (by approximately 20%) of the tracer in the fetal circulation is accounted for by protein catabolism. This component, however, is significantly and progressively increased in IUGR pregnancies, indicating that, besides a reduction in placental transport, also protein catabolism is proportionally increased in IUGR; and maybe considered a sign of fetal decompensation. These evidences have led to the concept that the alterations in the human placenta can be grouped into patterns, or phenotypes, associated with specific types of fetal growth. 47 Identifying the placental phenotypes of different fetal growth patterns should improve the comprehension of fetal growth and also help clinicians to identify pregnancies at risk for fetal growth abnormalities. Fifty years ago, Dawes calculated that cardiac output in the fetal lamb is 315 mL/kg/min. Of these, 142 mL/ kg/min (45%) originate from the right ventricle and 174 mL/kg/min (55%) from the left ventricle. 54 In the human fetus, by measuring peak velocities in the heart vessels, we have calculated a blood flow of 600 mL/ min in the pulmonary artery and 450 mL/min in the aorta. The sum of these 2 measures yields an approxi- mate value of 1050 mL/min, or approximately 300 mL/min/kg, remarkably similar to the values reported by Dawes in the fetal lamb. Besides cardiac output, today we are able to evaluate the distribution of blood to the different organs in the human fetus, such as the umbilical, cerebral, hepatic, and cardiac districts. By these means, the temporal sequence of abnormal Doppler changes in the fetal circulation has been described in a subset of early and severely growth- restricted fetuses. 55 In this study, severely growth- restricted fetuses followed a progressive sequence of acquiring Doppler abnormalities that were categorized into ‘‘early’’ and ‘‘late’’ Doppler changes. Early changes occurred in peripheral vessels (umbilical and middle cerebral arteries; 50% of patients affected 15-16 days before delivery). Late changes included umbilical artery reverse flow, and abnormal changes in the ductus venosus, aortic and pulmonary outflow tracts (50% of patients affected 4-5 days before delivery). These progressive alterations represent the natural history that in fetal diseases associated to growth restriction starts with fetal adaptation and then proceeds into failure. Late changes are indeed significantly associated with perinatal death and should prompt delivery. Most of the knowledge that we have today about intrauterine life has been built around the placenta and the fetal heart and circulation. This is principally the result of availability of tissues (for the placenta) and of techniques (evaluation of fetal heart rate and Doppler evaluation of blood flows). However, new technologic tools open new perspec- tives in the study of fetal organs development and function. We now focus and report available data about brain and liver, 2 of the most important fetal organs. The relevance of fetal brain growth and development is evident from the simple observation that the ratio between brain and body weight is significantly higher in newborn infants than in adults in all species, but particularly in the human. 56 The growth of the brain has been evaluated by measuring its volume through 3D ultrasound, showing that median brain weight represents approximately 15% of total fetal weight. Sonographic measurement of fetal brain volume demonstrated a nearly 10-fold increase during the second half of gestation. 57 In fetal diseases such as IUGR, brain growth is preserved even when there is a reduction in umbilical blood flow, with a reduction in brain volume growth proportionally much less of what occurs to other organs like the liver. 8 Magnetic resonance imaging (MRI) represents a powerful technique for evaluation of fetal brain development and function. In particular, the measurement of water apparent diffusion coefficient in the human brain by means of diffusion-weighted (DW) MRI has provided valuable information in normal cerebral development providing information about the size and course of unmyelinated as well as myelinated tracts in the fetal brain in the second half of pregnancy. 58 Bands of migrating glia can be visualized and represent very important markers of normal brain development, in particular of the white matter. 59 The uniform appear- ance of periventricular bands and their relationship to the infants’ maturity is consistent with the results of histologic studies (Figure 7). 60 These MRI studies demonstrate the presence of migrating glial cells within the periventricular white matter of infants beyond 20 weeks’ gestation, when neuronal migration to the cortex is complete. Moreover, although prenatal ultrasound has a low sensitivity in the detection of hypoxic-ischemic damage, recently prenatal DW MRI has been shown to allow the diagnosis of acute fetal brain ischemic lesions in utero. 61 Today, however, the best available tool for the evaluation of neurologic integrity is still represented by fetal heart rate analysis. Fetal heart rate variability must indeed be considered as an indicator of neurologic rather than of cardiac function. A mean variability below 1 beat/min strongly suggests the disappearance of heart rate control by the autonomic nervous system and must be viewed as a sign of central nervous system lesion. 62 As already discussed in the section on Heart and circulation, the fetal liver is located at a very special circulatory crossing. Moreover, the fetal liver is involved in numerous metabolic processes, as well in metabolic and endocrine cycles with the placenta. The evaluation of fetal liver growth and function is therefore of outmost importance in understanding fetal physiology and in the evaluation of fetal well being. Fetal liver volume has recently been evaluated in utero by 3D ultrasound, as shown in Figure 8. By these means, the growth of liver volume in normal fetuses from 18 weeks to term has been shown to follow an exponential curve. 7 At the same time, evidence has been provided that fetal diseases that lead to alterations of fetal growth are associated with proportional changes of fetal liver volumes. De- creased and increased fetal liver volumes have been measured in IUGR and in insulin-dependent diabetes mellitus (IDDM) pregnancies, respectively. 8 The blood supply to the fetal liver has been evaluated by color Doppler ultrasound as shown in Figure 9, that presents the distribution of umbilical blood flow to the ductus venosus and to the liver with increasing gestation. 63 The percentage of umbilical blood flow shunted through the ductus venosus decreases significantly (from 40%-15%); consequently, the percentage of flow to the liver increases. The right lobe flow changes from 20% to 45%, whereas the left lobe flow is approximately constant (40%). These changes are related to different patterns of growth of the umbilical veins and ductus venosus diameters and support the hypothesis that the ductus venosus plays a less important role in shunting well-oxygenated blood to the brain and myocardium in late normal pregnancy than in early gestation, which leads to increased fetal liver perfusion. However, when growth restriction occurs, after the initial stage of adaptation, ductus venosus shunting is increased, representing an intermediate stage before failure. 9 In more severe IUGR, the percentage of umbilical blood flow shunted through the ductus venosus is greater than the 90th percentile of control fetuses. This is accomplished with a concomitant reduction in the percentage of blood flow to the right lobe of the liver, with evidence of reversed blood flow from the right lobe and portal system into the ductus venosus evaluated both by volume blood flow calculations and by direct pulsed Doppler wave- form direction. 9 These changes provide therefore a relatively constant blood flow to the heart and brain at the expense of fetal hepatic perfusion. Supporting these data, the normal fetal brain/liver volume ratio shows a significant reduction with gestational age, and is significantly higher in growth restricted fetuses, with a significant inverse relationship between fetal weight-related umbilical venous volume flow and fetal brain/liver volume ratio. 7 In these 50 years, we have known the human fetus as a healthy person with a big brain. It will be very important in the future to complete our knowledge about morphologic and functional development of single fetal organs: we know something but much more is needed. The placenta is a fetal organ that plays a key role: it regulates fetal growth and development. Therefore, many fetal diseases originate much earlier in the placenta, and only later develop in the fetus. It is very important that every fetal disease has a staging, an evaluation of degree of severity. The expression ‘‘fetal distress’’ should no longer be used as such because it is a big basket, a container of different disease entities. We sincerely thank Fred Battaglia for his teaching, Anna Maria Marconi and Enrico Ferrazzi for all their work with us throughout these years, Simona Boito and Jury Wladimiroff for their expertise, and Tatjana Radaelli and Patrizio Antonazzo for their help in preparing the manuscript. We also give a big hug to Ron Gibbs, a mentor in the field of ...