After completing this article, readers should be able to: Deprivation of supplies is the common pathogenic factor for fetuses experiencing placental insufficiency, even if all do not exhibit hypotrophy at birth or accelerated maturation as a response to stress. Nearly one century ago, placental insufficiency was remarkably described by the French obstetrician Pierre Budin: “They are tiny, puny infants with great vitality. Their movements are untiring and their crying lusty, for their organs are quite capable of performing their allotted functions. These infants will live, for although their weight is inferior … their sojourn in the womb was longer.” (1)Since then, normative growth curves and precise determination of gestational age (GA) have permitted consensual categorization of newborns, the last advance being the identification of an intrauterine growth restriction (IUGR) subgroup among the small-for-gestational age (SGA) group (10th percentile). (2) However, this categorization remains unsatisfactory when dealing with the very preterm group for several reasons, including unknown GA in many cases and inadequacy of the current growth curves in the low range of GA.Why is it so important to make a distinction between SGA and IUGR infants? First, the cause is different: genetic factors explain a large proportion of cases in SGA infants and epigenetic factors are involved in IUGR fetuses. This current conception is elegantly summarized by Fowden: “Normal fetal growth depends on an adequate supply of nutrients and on a strict temporal relationship between tissue accretion and differentiation. During early development, the pattern of intrauterine growth is largely determined by the fetal genome but, as size increases, growth may become constrained by environmental or epigenetic factors.” (3) Second, perinatal management should be influenced by the expectation of adaptive phenomena in the IUGR group. Such adaptive phenomena, including acceleration of maturation, have been reported repeatedly in IUGR fetuses. (4)(5)(6) Accelerated maturation of the brain and lung is classically associated with a decrease in perinatal mortality and morbidity as well as in severe brain damage.Both clinical and experimental data (5)(6) have demonstrated the importance of considering GA more than birthweight in terms of the occurrence of adaptive phenomena. Before 29 weeks’ gestation, these mechanisms do not seem to operate, perhaps because the insult is too early or too acute. Moreover, the effects of extreme prematurity could overshadow these mechanisms. Consequently, the neonatal period is very stormy, and an adverse outcome is common. This explains why obstetricians cannot rely on adaptive phenomena as favorable factors in this age group to determine the timing of cesarean section.In discussions of the outcome of newborns who have placental insufficiency, a cut off based on GA is used to distinguish a “modern” group below this threshold (<29 weeks’ gestation) and a “classical” group above this threshold (≥29 weeks’ gestation). For the “modern” group, the data concerning mortality and morbidity can be found in a few recent collaborative studies, with outcome being based on birthweight only. (7)(8) For the “classical” group, the pattern of results is described in our cohort identified on Doppler velocimetry (9)(10) and followed up to the age of 7 years. The results are described for three successive periods: at term, preschool age, and school age.In 1995, a study was initiated to document the usefulness of different pre- and perinatal markers to predict neurodevelopmental outcome in fetuses experiencing uteroplacental insufficiency. To be eligible, all fetuses had to show an abnormal umbilical Doppler velocity waveform (pulsatility index at the fetal end of the cord above the 95th percentile), (10) and delivery had to occur after 28 weeks’ gestation to avoid the potential confounding effects of extreme prematurity. Exclusion criteria were: residence outside the Montreal metropolitan area; families who did not speak French at home (to exclude bias in the developmental assessments, which were carried out in French); chromosome abnormalities; congenital malformations; and evidence of sociofamilial problems, such as drug addiction, alcoholism, mental illness, consanguinity, welfare beneficiary, and history of battered children. The timing of delivery was based on conventional criteria, classified according to two categories: fetal reasons (absence of weight gain, abnormal biophysical profile score, (11) reverse diastolic flow in the umbilical artery) and maternal reasons (severe preeclampsia). IUGR was defined as birthweight below the third percentile for gestational age according to the Canadian growth curves designed by Arbuckle and associates. (12)The neurodevelopmental follow-up, which is still ongoing, involves a neurologic examination at term according to the Amiel-Tison method (13) as well as subsequent annual neurodevelopmental assessments. Up to the age of 5 years, the Griffiths Mental Development Scales (GMDS) are administered. (14) The GMDS are standardized, with a mean of 100 and a standard deviation of 13, and allow the calculation of six different subscores as well as a global developmental quotient (DQ), which is obtained by averaging the six subscores. A nonverbal quotient also may be calculated according to Bowen’s method. (15) At the ages of 6 and 7 years, the WISC-III is used to assess the children’s intellectual performances. (16). The WISC-III has been standardized on a population of children aged 6 to 17 years, with a mean of 100 and a standard deviation of 15. Results are expressed in terms of verbal intelligence quotient (IQ), performance IQ, and full scale IQ.At each annual visit, the neurologic status also is assessed according to the method described by Amiel-Tison and Gosselin. (17) This neurologic examination, which usually is completed within 10 to 15 minutes, includes: growth parameters, cranial suture status, deep tendon reflexes, primary reflexes, and postural reactions as well as muscle tone and qualitative characteristics of motor activity. By emphasizing the evaluation of passive tone and cranial signs, this assessment allows exploration of the integrity of the superior motor control on the brainstem. Three specific neurologic signs, referred to as the Amiel-Tison Triad (ATT), have emerged from extensive clinical observation. (18) Two of these signs refer to passive tone (imbalance in axial tone and phasic stretch reflex in the triceps surae) and the third concerns cranial squamous sutures. A classification based on the severity and clustering of neurologic and cranial signs has been defined into five categories: normal, intermediate, ATT, minimal cerebral palsy (CP), and CP. As shown in Table 1, this categorization takes into account the functional impact of neurologic impairment, primarily on independent walking, which allows distinction between disabling and nondisabling CP. Because the neurologic and cranial signs at 2 years of age recently have been shown to be predictive of problems in coordination, language, or reasoning at both preschool and school age, only the results of neurologic assessment performed at that age are presented here. (19)The initial cohort included 148 infants, including 55 twins. For the purpose of the current study, however, only the singletons who had Doppler tracings recorded no more than 7 days before delivery were retained. On the basis of these criteria, the final sample includes 60 children followed up to the age of 5 years. For 35 of them, results of the intellectual assessment completed at 7 years of age are available and presented here.At birth, 40 (67%) children had IUGR and 33 (55%) were male (Table 2). Most of the children did not experience any medical complications during the neonatal period; only 12 (20%) showed variable signs of respiratory distress. Neurologic status at term (Fig. 1) was optimal in 26% of the infants. At the opposite end of the spectrum, 7% of the cohort showed severe neurologic signs, primarily associated with persistent feeding problems, lethargy, and severe muscle tone abnormalities. Mild or moderate signs, such as mild abnormalities of axial tone or active tone and unstable autoregulation, were found in 67% of the infants.At 2 years corrected age (Fig. 2), only 1 (2%) child had disabling CP with absence of independent walk, 10 (17%) showed signs compatible with nondisabling CP, and 14 (23%) had the triad of neurocranial signs previously described. Finally, 12 (20%) children had isolated neurologic signs (hypotonia and asymmetry), and 23 (38%) had no signs.Later, both average verbal and performance quotients, reflecting developmental and intellectual performances, were within normal limits (Table 3). However, six of 59 children (10%) had a global DQ below 1 standard deviation (SD) at preschool age. This ratio is seven of 35 children (20%) already assessed at school age. It should be noted that 19 children (32%) presented with both neurologic signs and at least one quotient (verbal or performance) below 1 SD.Three conclusions can be reached based on the study data. First, a very low incidence of disabling CP was found in this well-defined IUGR cohort, with only one child being affected (1.7%). These results corroborate previous reports showing that disabling CP is a rare outcome when delivery is decided on abnormal umbilical Doppler velocimetry waveform and nonstress test. (20) Second, some type of developmental impairments were found in 19 (31.7%) children, all of whom received rehabilitation services before the age of 5 years and many of whom still require special education or other forms of educational support now that they are at school. Third, developmental or intellectual performances within normal limits were found in 41 children (68.3%) of the cohort at their last visit, giving strong support for a normal long-term outcome. The higher proportion of low IQ at school age compared with low DQ at preschool age supports the latent nature of some neurodevelopmental impairments already reported in this high-risk population. (21)For years, the primary concern of pediatricians has been restricted to the school-age period and learning disabilities in this population. However, Denckla (22) has demonstrated residua of these learning disabilities in adult life, naming them executive dysfunction. The primary contribution of animal experiments has been to show the negative effects of prenatal stress, more specifically in relation to profound impairment of neurogenesis in the hippocampus. Offspring of prenatally stressed mothers show decreased neurogenesis throughout development, including adult life and aging. (23)(24) Experiments on these issues are reviewed by McEwen (25) and Matthews. (26)The mechanisms underlying the association between prenatal stress and developmental outcome are not yet fully elucidated. Nevertheless, plausible hypotheses may be summarized as follows: maternal stress may reduce uteroplacental blood flow, increase production of placental corticotropin-releasing hormone, and increase fetal concentrations of cortisol by the additional maternal cortisol transported across the placenta. (27) Those three mechanisms result in excessive levels of cortisol, particularly deleterious to brain development in late pregnancy.In the 1990s, a new field of investigation opened when Barker and colleagues (28)(29)(30) suggested long-term effects of fetal undernutrition on the occurrence of chronic adult diseases, based on the findings from historical cohort studies in the United Kingdom. Since then, other studies have supported the Barker hypothesis, indicating that chronic adult diseases may be programmed in utero. Adaptation to malnutrition would have permanent effects on metabolism and organ structure that determine the occurrence of coronary heart diseases, hypertension, and diabetes in adulthood. Such a long-term effect of fetal environment appeared revolutionary in 1993 and raised the question of potential selection bias. Numerous other studies have been performed in various countries that support the association between low birthweight and adult chronic diseases. Underlying mechanisms, however, are yet poorly understood. Twin studies (31)(32) have demonstrated the contribution of genetic factors, though modulated by environmental circumstances. (33)CP is only the tip of the iceberg in the at-risk group of neonates who have experienced uteroplacental insufficiency. Studies have shown a continuum from very severe to mild consequences of placental insufficiency, based on neurologic and cranial signs within the 2 first years after birth.Based on those clinical findings, pediatricians can select the group of children (about 40% of the cohort) who will benefit from close developmental follow-up until school age. Being aware of the noxious role of fetal stress on brain development, pediatricians also can try to reduce postnatal stress in the neonatal intensive care unit.Many uncertainties persist for obstetric management of affected fetuses, despite recent experimental data. The so-called classical criteria to decide that any additional day in utero may be potentially deleterious to the brain are good enough for preventing CP but not for preventing more subtle developmental impairments.The following case illustrates how the expected adaptive phenomena may guide obstetric decisions, especially in developing countries or any place where intensive care is technically minimal. A 30-year-old woman had lost three fetuses at 34 weeks’ gestation in a context of preeclampsia. During her fourth pregnancy, she was hospitalized at 30 weeks’ gestation with signs of preeclampsia. She had generalized edema (Fig. 3), hypertension, and proteinuria. Repeated fetal echographic measurements showed poor fetal growth since 30 weeks’ gestation, with biparietal diameter increasing adequately. Results of nonstress tests were repeatedly normal up to 34 weeks’ gestation. The pediatrician struggled against the proposal of a cesarean section at 34 weeks, fearing respiratory distress syndrome, for which he was not technically equipped. We had to promise that accelerated maturation of brain and lungs very likely had occurred in the last weeks as a response to stress, and consequently, there would be no respiratory distress syndrome and an easy neonatal course. After 48 hours of hesitation, under the pressure of an expected death in utero, cesarean section was performed under epidural analgesia. A boy weighing 1,450 g (<2nd percentile) was born, who exhibited hypotrophy, was active and alert, and had a head circumference at the 25th percentile. The neonatal course was easy and included 48 hours of glucose infusion and phototherapy for mild jaundice. The infant was able to suck and feed independently after a few days. The neurologic maturation at postnatal day 2 was estimated at 38 weeks for a gestational age of 34 weeks. He was discharged 1 month later (Fig. 4) with an optimal neurologic assessment. Due to the fairly late emergent nature of the placental insufficiency, the obstetric decision based on the probability of adaptive phenomena was lifesaving.
To verify whether extra uterine changes in total peripheral vascular resistance and cardiac output, caused by raised haematocrit, occur in fetal life and if they can be documented using conventional ultrasound techniques.
METHODS
An exchange transfusion with packed red cells was performed on five fetal lambs at 140 days of gestation (weight 3.44, SD 0.48 kg); three others were used as controls. The haematocrit was raised from 44 ± 3 to 64 (SD2)%.
RESULTS
Body temperature, blood gas, and pH remained within normal limits. Blood viscosity increased from 5.3 ( 0.3) to 9.6 (1.6) cps. Combined cardiac output fell to 30% of its initial value. The pulsatility index (PI) remained unchanged in the umbilical artery (0.66, SD 0.1) and descending aorta (1.3, SD 0.3). A significant positive correlation was found between haematocrit and PI only in the carotid artery (r=0.67, p<0.01).
CONCLUSION
In the fetus, as in adults, an increase in blood viscosity is associated with a fall in cardiac output. However, the low resistance and the relative inertia of the placental vascular bed blunt the velocimetric changes that could be induced in the lower body vascular system by an increase in resistance. Such changes were observed only in the carotid artery. These results could be of interest in the Doppler monitoring of human fetuses at risk of an abnormal increase in their haematocrit.
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