Adaptive changes in the developing brain during intrauterine stress

REVIEW ARTICLE

Adaptive Changes in the Developing Brain during Intrauterine Stress Claudine Amiel-Tison, MD and Alan G Pettigrew, PhD

Maturation of neurological performance in moderately to severely growth-retarded newborn infants (SGA) can be accelerated by 3 to 4 weeks or more when compared to the development of appropriately grown infants (AGA) of the same gestation. This is particularly the case in multiple pregnancies or pregnancies characterized by maternal hypertension. This clinical finding has been confirmed by neurophysiological studies on the maturation of brain stem auditory evoked responses (BAERs). The possible mechanisms which underly this phenomenon are not yet elucidated Glucocorticoids, other steroid hormones and catecholamines are elevated in pregnancies with placental dysfunction, and it is known that these substances have multiple actions on neuronal maturation, particularly on mechanisms of release of neurotransmitters. These observations suggest that the acceleration of brain maturation, and lung maturation, in SGA infants reflects an adaptation of the fetus to early extrauterine life. However, if the placental dysfunction progresses, these mechanisms of adaptation will be overwhelmed by severe malnutrition and anoxia which result in cerebral lesions and risk of death. The clinical goal at the present time for obstetric management of these risk pregnancies is to distinguish between these two periods. Key words: Nervous system, fetus, hypertension, growth retardation, placental inSUfficiency. Amie/-Tison C, PettigrewAG. Adaptive changes in the developing brain during intrauterine stress. Brain Dev 1991 .. 13:67-76

Intra-uterine growth retardation (IUGR) is a complication of pregnancy that is most commonly associated with placental insufficiency and is often associated with poor outcome. Recent advances in the technology and practice of Doppler velocimetry arid cordocentesis have shed new light on this condition [1]. The Doppler technique, for example, has been refmed clinically to the extent that a classification of placental function, which is based on umbilical artery velocimetry and which has high positive and negative predictive values, is now available [2,3]. These techniques have also been used in laboratory investigations on pregnant sheep where placental vascular resistance has been increased by umbilical placental embolization [4]. This type of chronic preparation has

From the Group Hospitalier Co chin, Clinique Baudelocque, Paris (CA-T); Department of Physiology, University of Sydney, and Department of Perinatal Medicine, King George V Hospital, Camperdown, New South Wales (AGP). Received for publication: September 21, 1990. Accepted for pUblication: January 14, 1991. Correspondence address: Associate Professor C. Amiel-Tison, Group Hospitalier Cochin, Clinique Baudelocque, 123 Boulevard de Port-Royal, 75014 Paris, France.

been used to investigate the circulatory responses of the fetus to acute hypoxemic stress in "early" IUGR, "late" lUG R and controls animals [5] . The results of these studies have suggested that fetuses have a considerable capacity to adapt to chronic oxygen deficiency that is secondary to decreased placental blood flow. This fetal adaptation is characterized by decreased growth rate and, therefore, reduced oxygen requirement. However, at later stages of placental insufficiency, when the decrease in total placental blood flow exceeds 50%, the placental circulatory reserve capacity and the capacity of the fetus to produce an adequate circulatory response to an hypoxic stress is exceeded [5]. Biochemical data obtained by cordocentesis suggest that the major cause of hypoglycemia and low levels of amino acids in IUGR fetuses is reduced supply secondary to placental insufficiency [6, 7]. All of these new data are consistent with the view expressed in 1985 by Warshaw [8] that IUGR, when secondary to placental insufficiency, can be viewed as an adaptive response of the fetus rather than pathology. In other words, the early response of the fetus faced with placental insufficiency includes reduced growth in order to increase the likelihood of intact survival. The reduced incidence of respiratory distress syndrome associated with early maturation of the

lungs in IUGR preterm neonates compared to appropriately grown preterm infants of the same gestation [9, 10] is also consistent with this view. It is to be expected, however, that with continued severe malnutrition and asphyxia, the adaptive capacity of the fetus might be exceeded and fetuses surviving in this condition might be expected to have a poor outcome. IUGR has often been associated with later disturbances in central nervous system performance (see, for example, 11-13). Recent studies have, however, drawn attention to observations which indicate that these phenomena are not consistently related [14 -16] and causative factors for poor central nervous system performance in IUGR have been difficult to identify [15]. In this paper we present and discuss evidence which supports the hypothesis that early fetal adaptation to adverse intrauterine conditions associated with placental insufficiency includes accelerated maturation of parts of the central nervous system. A corollary to this hypothesis is the proposal that the variability in neurological outcome between neonates with IUGR may be related to the extent to which adverse intrauterine conditions of this type have stimulated or, if allowed to continue, have overwhelmed the adaptive capacity of the fetus. Data will be presented concerning the accelerated maturation of clinical neurological performance and neurophysiological measures in healthy newborn IUGR infants [9, 17, 18]. Data from experimental models of IUGR and from other experiments which indicate possible mechanisms that may underly the phenomenon are also presented. CLINICAL STUDIES

Methodology When clinical assessment of neurological maturation of premature infants was first developed it appeared that in most cases neurological maturation was strictly linked to the duration of gestation and was not influenced by complications of pregnancy. However, with more precision in the dating of pregnancies, using early ultrasound, and the increased number of pregnancies with strictly accurate dates, the dogma of non-dependence of maturational phenomena whatever the gestational circumstances appeared to be oversimplistic and erroneous. There is now evidence which clearly suggests that the functional maturation of the fetus does not always correspond to its gestational age. The method of assessing neurological maturation in premature infants that has been used in several studies relies on the very rapid changes that occur in motor activity during the last trimester of gestation. The maturation of passive tone, active tone and primary reflexes proceeds so quickly, and individual variations are so small, that it has been possible to schematize development in

68 Brain & Development, Vol 13, No 2,1991

the preterm period into successive stages with a resolution of two weeks [19, 20]. The determination of these stages is made possible by two main observations, namely, a) the caudocephalic progression of active tone in the axis and of flexor tone in the limbs, and b) the lag observed between active flexion in the axis (cortical function) compared with extension (sub-cortical function). Thus, the ascending wave of reinforcement of tone does not reach the whole body at the same time and, therefore, there are precise markers of neurological maturation between 28 and 37 weeks gestation. It is rarely possible to examine newborn infants before 28 weeks and the precision of assessment in infants older than 37 weeks is poorer because maturation at these older ages is slower. Other methods of neonatal neurological assessment have been proposed and one of these, the Dubowitz score [21], will be discussed later. There are, however, undeniable limitations with whatever clinical assessment or score is used. Finnstrom [22], for example, has stressed that the natural Variability of maturation is such that the confidence interval in the determination of gestational age is ± 3 weeks. Furthermore, the assessment is likely to lead to erroneous conclusions when it is applied to cases where severe cerebral dysfunction is present at the time of birth. Findings The first demonstration of advanced neurological maturation in some newborn premature infants was published by Gluck and colleagues in 1977 [9] as a continuation of their important work on lung maturation in risk pregnancies [10]. The first of two studies presented by these authors was designed to screen a variety of unselected high risk pregnancies in order to determine the conditions with intrauterine stress in which there was an association between accelerated pulmonary maturity and accelerated neurological development. Using the Dubowitz score [21], Gluck et al found 8 infants in a cohort of 51 from high risk pregnancies with neurological maturation that was 3 or more weeks in advance of that predicted from the gestational age [9]. In their second study, Gluck and colleagues studied 25 infants with documented early development of pulmonary surfactant (lecithin/sphingomyelin or L/S ratio ;;;. 2 at gestational age ~32 weeks) [9]. All of these infants also had accelerated neurological maturation of between 3 and 8 weeks. The complications of pregnancy amongst these cases included retroplacental bleeding, prolonged rupture of membranes, placental infarction, severe toxemia, hypertensive disease, circumvallation and amnionitis. Those infants from pregnancies involving chronic retroplacental bleeding had the most dramatically accelerated pUlmonary and neurological maturation [9]. In the study from the Port-Royal Maternity Hospital in Paris [17], 16 infants that were studied between 1972 and 1978 had neurological development more than 4 weeks

ahead of their gestational age as detennined using the Arnie1-Tison assessment described above [19, 20]. (The LIS ratio in the amniotic fluid was not routinely perfonned in these cases). All of the infants were examined by the same observer (C.A-T.) thereby ruling out the problem of inter-observer variability which has been reported [22] to be the main cause of poor reproducibility in neonatal assessment. The gestational circumstances of these infants (Table 1) included maternal hypertension (7 cases), uterine malfonnation and or multiple pregnancy (4 cases) or uterine hypercontractility throughout the third trimester (2 cases). None of the 13 pregnancies was considered to be nonnal. According to the Leroy and Lefort French growth curves, 5 of the 16 infants had birthweights below the 10th centile, 12 of the 16 were on or below the 25th centile and 15 of the 16 were below the 50th centile. Nine of the 16 infants had no neonatal problems, 4 had a transient tachypnea and only one child was ventilated for severe idiopathic respiratory distress (IRDS) (30 weeks gestational age; 1,500 g). One child had signs of moderate cerebral dysfunction, with subarachnoid hemorrhage and recurrent apnoeic spells. Necrotizing enterocolitis was observed in 2 cases. It was not possible to detect any further advanced levels of maturation in these infants over the months following discharge from hospital because the rate of development of infants at these ages is slower and the variation between individuals becomes more prominent. However, 12 of the infants were followed to one year (the other 4 infants were lost to followup) and 11 of the infants were considered nonnal at this age. The child with severe IRDS, however, showed peristent hyperexcitability. (The child with apneic spells and the 2 cases with enterocolitis were in the nonnal cohort.) Incidence and recognition of the phenomenon Gluck and colleagues [9] made no attempt in their original studies to detennine the incidence of advanced neurological maturation amongst growth-retarded infants. The studies in Paris [17] were also hampered by the lack

Table I Gestational history of infants with clinical advanced maturation (from 17) Number of pregnancies

Gestational history Hypertension

Chronic Gravidic

Uterine malformation and/or multiple pregnancy Uterine hypercon tractili ty throughout 3rd trimester Total

4

3

Number of infants 7

4

7

2

2

13

16

of precision in detennination of gestational age in most of the available pregnancies because ultrasonography was not systematically perfonned on the general maternity ward during the period of the study (1972-1978). There are three comments, however, that emerge from the continuing study of newborn infants at the Baudelocque Maternity Hospital. First, the advanced maturation of neurological perfonnance in growth-retarded pretenn infants is not an "all-or-nothing" phenomenon. Rather, it is a progressive response of variable degree. Even during the years of the original study 16 additional cases were observed where the neurological maturation was 2 to 3 weeks in advance of the gestational age. Second, it is common that the smallest infant in sets of twins or triplets is more advanced than its sibling(s), and the siblings may also be advanced with respect to most nonnally grown infants. Finally, some appropriately grown infants from stressed pregnancies show advanced neurological maturation. This observation suggests that the effects on nervous system maturation in these pregnancies may preceed a degree of growth-retardation severe enough to label the fetus as small-for-gestational-age (SGA). In other words, an advanced level of nervous system maturation can often be detected in newborn infants whose birth weight following an at-risk pregnancy has not yet fallen below the 10th centile. Recent technological advances in obstetric monitoring are now freely available and will be used in a new prospective study to confinn the observations described above. The aim of the study will be to define precisely the conditions associated with both a) the early phase of stressed pregnancies that appear to lead to advanced maturation of neurological development of the fetus and b) the late phase when development of the fetal nervous system is compromised. Placental insufficiency will be quantified using Doppler velocimetry of the uterine and umbilical vessels [23] and measurement of fetal blood gases [24]. The question arises as to why the phenomenon of advanced maturation in SGA infants has not been more widely recognised by pediatric neurologists, particularly since detennination of gestational age has become more accurate. One possible explanation may lie in the fact that the Dubowitz assessment is a popular method to assign gestational age. Spinnato et al [25] have shown, however, that the Dubowitz score overestimates the neurological age of premature newborn infants by 1 to 2 weeks and by even more in very low-birth-weight infants. Thus, the phenomenon of advanced maturation may be obscured or considered as an error of methodology in the Dubowitz assessment. The error in the Dubowitz assessment appears to lie more in the neurological criteria than in the external criteria, probably because the score relies mainly on the estimation of passive tone and is applied very early in life (in the delivery room or before 24 hours) [25]. Spinnato et al [25] have shown in their study that an

Amiel-Tison & Pettigrew: Adaptive changes in developing brain 69

advance in maturation is statistically significant only in infants born to hypertensive mothers. These data on the subgroup of infants from hypertensive pregnancies, as well as similar data of Perkins [26] confirm, nevertheless, the reality of advanced neurological maturation in stressed pregnancies. Finally, it is tempting to try to fmd differences in the in utero motor behaviour of SGA fetuses compared to that of AGA fetuses. This question has recently been examined by Bekedam et al [27]. These authors used realtime ultrasound recordings to assess the movements of 10 SGA fetuses (9 of the 10 had hypertensive disease of pregnancy) between 28 and 35 weeks of gestation. Brief· ly, it was shown that the SGA fetuses moved less, there was a reduction in both the number and duration of general movements, and there were fewer startles, twitches and isolated limb movements. Moreover, the movement patterns were slower and more monotonous and the variability within each movement pattern was less. These results are apparently contrary to the possibility of advanced neurological maturation in SGA fetuses. However, 7 of the 10 studies were performed in the 24 hours before delivery by Caesarian section, the decision for which was made on the basis of abnormalities in fetal heart rate. Thus, it is very likely that most of these fetuses were studied in the second period of fetal distress and not in the preceding first period of adaptation. These alterations in motor behaviour when fetal distress is present or threatening are not surprising and probably do not give an accurate reflection of the stage of neurological maturation. In fact, a later publication [28] from the same group indicates that the reduction of fetal movements correlates with the presence of late decelerations of the heart rate, thus confirming our interpretation. ELECTROPHYSIOLOGICAL OBSERVATIONS Evoked potentials The clinical observations of advanced maturation of the nervous system in some preterm infants who are small-for· gestational-age (SGA) has found support in recent studies of nervous system development using sensory evoked potentials. In their study of "normal" and SGA preterm infants, Pettigrew et al [18] recorded brainstem auditory evoked responses (BAERs). These responses ocCUr in the first 10 ms following an auditory stimulus and the deflections of the averaged waveform are believed to be associated with activity at different levels of the brainstem auditory pathway. For example, Wave I of the response is generated in the peripheral auditory nerve and wave V is generated in the region of the lateral lemniscus and inferior colliculus [29-31]. The interval between waves I and V provides therefore a convenient, objective measure of neural performance in the auditory pathway of the

70 Brain & Development, Vol 13, No 2,1991

brainstem. It is well known that the I -V interval decreases during maturation of the nervous system and that this decrease is most rapid during the period 27 weeks gestation (when the BAER can first be reliably recorded) to about term age [18,32-35]. Pettigrew et al [18] compared BAER data for SGA and appropriately grown (AGA) preterm infants and showed that the mean I-V and IIn-V intervals in SGA infants were significantly shorter than those for AGA infants up to about term age (Fig 1). Furthermore, the decreases in the I-V and IIn-V intervals over this period were less in the SGA infants (Fig 2). The same was true for individual infants from multiple deliveries. The I-V interval for the SGA infants was always less than that for their AGA sibling. All of the infants in this study were healthy. Data from infants who had clinical or ultrasound evidence of periventricular haemorrhage, birth asphyxia (umbilical cord pH <7.20 or clinical signs), fetal alcohol syndrome, maternal narcotic abuse, congenital abnormality of the central nervous system, intra-uterine infection or profound hearing loss were excluded from the analyses. The observations in this study are consistent with the hypothesis that the initiation and or progress of maturation of the brainstem auditory pathway occurs at an earlier stage in the development of many SGA infants. The suggestion by others [36] that the reduced I-V interval in SGA infants may be the result of a selective delay in wave I of the response is not substantiated because the mean latencies of wave I in the two groups of infants were not significantly different. Furthermore, the mean IIn-V and III-V intervals (Jiang et al, in preparation) in preterm SGA infants are also lower than those in preterm AGA infants.

A

·2oonY

B

200nY

4.6

·2oonY

Fig 1 BAERs in AGA & SGA siblings. Duplicate BAERs recorded in AGA (AJ and SGA (BJ siblings at 32 weeks post menstrual age. The I-Vand IIn- Vinterpeak intervals are indicated on each set of responses.

After their original study, Henderson-Smart et al [37] reported that significantly shorter I-V intervals were observed during most of the preterm period in SGA infants born to mothers with hypertensive disease of pregnancy (HDP) but not in AGA infants born to mothers with HDP (Fig 3). The conclusion drawn from this analysis has been that factors other than the drugs used to treat HDP during pregnancy are responsible for the advanced maturation of the brainstem auditory pathway. It is of interest however, that the mean I-V intervals in AGA infants of HDP mothers lay between the values for AGA infants without HDP and the SGA infants. Furthermore, the mean I-V interval at 30-31 weeks (post-menstrual age) for AGA infants with HDP was Significantly shorter than the value for AGA infants without HDP (p < 0.05). It is possible that these observations represent a continuum of effects on maturation of the nervous system associated with malfunction of the placenta during pregnancy. Thus, the maturation of the brainstem auditory pathway may be less noticeably advanced in cases where the abnormal stress during pregnancy associated with HDP has yet not reduce growth below the general standard used to defme SGA.

7.0

• A

AGA SGA

Accelerated maturation of synaptic transmission? The interval between waves I and V of the BAER is associated with the transmission of impulses from one neural generator to another via axons and synaptic contacts between neurones. It has been of interest to determine whether a more rapid maturation of either or both of these components is responsible for the shorter I-V interval in SGA infants. It has been known for some time that the conduction velocity in peripheral nerves improves during the last trimester of pregnancy and that this improvement is similar in AGA and SGA infants [38, 39] . In a combined study, using BAERs and measurements of peripheral nerve conduction velocity, Kesson et al [40] confirmed the previous observations and, furthermore, showed that the maturation of peripheral nerves occurs at the normal rate in SGA infants with advanced maturation of the BAER We have also shown that the reduction in the latency of wave I in the BAER during development is similar in AGA and SGA infants. Since wave I of the BAER is generated in the axons of the auditory nerve [29-31], it seems likely that the advanced maturation of the I-V interval in SGA infants may be associated with changes in synaptic mechanisms rather than changes in the development ofaxons. However, a defmitive conclusion regarding this possibility can only be gained by direct measurement of axon conduction velocity within the brainstem. Evidence in support of an alteration in the maturation of synaptic mechanisms has been presented by Edwards et

7.0

• AGA A SGA ---- NO HOP - - HOP

g

,......._-...~_-+__~

~,

"-l

I-V

~

1==

z

o

6.0

B :J

\

,,

'".

"

Cl

Z

o u ~

"-l

5.0

.......

"

.......

r--r--+------...

~

I-V

Z

::;:

IIn-V

0:: P'l

3.0

4.0 L-J

'--'

.......,

~

L.......J

30-31

32-33

34-35

36-37

38-42

.......,

30-31

POST MENSTRUAL AGE (WEEKS)

.....,

32·33

...........

34-35

.......

36-37

"-'

38-42

POST MENSTRUAL AGE (WEEKS)

Fig 2 Mean brain stem conduction time in AGA & SGA preterm infants. Mean (± SEM) interval between peaks / and Vand lIn and Vof BAERs recorded in appropriately grown (AGA) and growth retarded (SGA) preterm infants. Analysis of variance indicates that the data for A GA and SGA infants are different at the level p < 0.001. Data in part from Pettigrew et al [18].

Fig 3 Mean brainstem conduction time in 3 groups of preterm infants. Mean (± SEM) /- V interval in the BAERs of AGA infants bam to mothers without hypertensive disease of pregnancy (HDP) (filled circles and dashed lines), of AGA infants born to mothers with HDP (filled circles and solid line) and SGA infants (filled triangles). Data from Henderson-Smart et al [37].

Amiel-Tison & Pettigrew: Adaptive changes in developing brain

71

al [41]. This evidence is based on the prolongation of the intervals between waves of the BAER when the rate of stimulus presentation is increased. Several authors have reported that the amplitudes of some waves in the BAER of adults are reduced and that the latencies oflater waves of the response are increased more than those for earlier waves when the stimulus rate is increased from about 10 to 90 per second [42-44]. Such changes in stimulus presentation are unlikely to affect the conduction velocity of axons but can affect synaptic transmission such that the speed of neural transmission from one region of the auditory pathway in the lower brains tern to another at a more rostral level will be reduced [45, 46]. Edwards et al [41] have shown that in both AGA and SGA preterm infants, the prolongation of the interval between wave lin (generated in the intracranial portion of the auditory nerve, 31) and wave V produced by increasing the stimulus rate from 11 Hz to 41 Hz decreases during the preterm period. Of greater interest, however, is the observation that the prolongation of the IIn-V interval in preterm SGA infants was significantly less than that for preterm AGA infants studied between 30 and 34 post-menstrual weeks. Data for slightly older infants were consistent with this observation but did not reach statistical significance. The results suggest that the maturation of mechanisms associated with synaptic transmission in the brainstem can be advanced in healthy preterm SGA infants.

Development of respiratory control Further evidence in support of the hypothesis that the maturation of neural function in subcortical structures can be advanced in SGA infants can be found in the analysis of respiratory control in these infants. In the general popUlation of preterm infants, the incidence of recurrent apnoea is most frequent in those with low gestational age [47,48]. In their combined study of the incidence of clinical apnoea and the maturation of the BAER, Henderson-Smart et al [49] noted that the incidence of apnoea was high when the I-V interval of the BAER was relatively long, and that apnoea was rare when the I-V interval had decreased with maturation below an apparent cut-off level. Longitudinal studies on a group of infants included data from multiple births. In these cases, the incidence of apnoea was higher in the siblings with longer I-V intervals. The SGA siblings had shorter I-V intervals and no apnoea. All of these observations suggest that the incidence of apnoea may be related to the level of maturation of neural circuits in the brainstem. The reduced incidence of apnoea in some preterm SGA infants is consistent with the view that the maturation of neural function in their brainstem is advanced. ANIMAL EXPERIMENTAL OBSERVATIONS Comparison of data from animal experiments concerning

72 Brain & Development, Voll3, No 2,1991

growth-retardation and the rate of maturation of the central nervous system with evidence from clinical studies is complicated by differences in the timing of normal developmental events relative to any abnormal circumstances that might arise. Furthermore, most attention in this area has been directed toward the development of cortical structures.

Evoked potentials The development of BAERs in rats undernourished after birth has been studied by Plantz et al [50], Nakamura et al [51] and Kawai et al [52]. These studies report that the shortening of wave latency with maturation is delayed in the experimental animals. Pettigrew and Morey [53] have also reported that the onset of the BAER in a rabbit that was growth-retarded at birth was also delayed but the shortening of wave latency with maturation proceeded more rapidly than that for appropriately grown animals. Further experiments are required to establish whether the more rapid rate of maturation in this animal also occurs in normal animals in which the onset of hearing has been delayed. The difference in the results for the rabbit and undernourished rat pups may be related to the timing of the particular insult relative to the timing of various factors in the schedule of brain development. The maturation of both auditory and somatosensory evoked responses in fetal sheep has been investigated recently by Cook et al [54]. The studies from this laboratory have been carried out on normal fetuses as well as on fetuses which were growth-retarded following earlier carunclectomy of the ewe. The interpeak intervals in the evoked responses for both sensory modalities were shorter and the prolongation of the responses with higher rates of stimulation was less in the growth-retarded fetuses. These observations are very similar to those described above concerning the advanced maturation of BAERs in SGA infants. Neurochemistry Ugation of uterine blood vessels has been used as a technique to increase the frequency of growth-retarded fetuses in rats and rabbits [55-57]. In a series of experiments, Chanez and colleagues have examined the structural and biochemical development of various regions of the brain in rats whose growth after the 16th day in utero was restricted by this method. These authors have examined the increase in Na/K-ATPase activity that occurs during the postnatal development of different regions of the brain [58]. It is of interest that the Na/K-ATPase ac· tivity determined in the· brainstem of growth-retarded rats was significantly higher than that of normal rats at postnatal days 15 and 21. The activity in both groups of rats was similar at older ages, suggesting that the maturation of production of this enzyme in the brainstem is advanced in growth-retarded rats. The development of

enzyme activity in the forebrain, cerebellum and hippocampus of growth-retarded animals was delayed when compared to the data for normal animals. These observations highlight the differential sensitivity of different parts of the brain to adverse conditions which occur at particular stages of development. POSSIBLE MECHANISMS OF ADVANCED MATURATION The search for possible mechanisms which might underly the advanced maturation of certain regions of the nervous system in infants with intrauterine growth-retardation must rely on two other areas of research. The first area concerns observations of other physiological changes that occur in the fetus in response to abnormal placental function. The second area concerns independent observations concerning any possible influence these physiological changes may exert on the development of neuronal function. There are many areas of research which could be discussed here but most emphasis appears to be placed on the roles of corticosteroids and monoamines in the response to placental dysfunction. Steroids It has been reported that the levels of fetal corticosteroids and other steroid hormones can be elevated in pregnancies characterized by placental dysfunction that is likely to cause 'stress' on the fetus [59-61]. Recent evidence from clinical studies of preeclampsia with intrauterine growth retardation suggests that corticotropin-releasing hormone released by the placenta might initiate the rise in fetal corticosteroid levels in these stressed pregnancies [62]. The influence of steroids on brain development and function have been recently reviewed by Baethmann [63]. Briefly, it has been demonstrated, for example, that {3estradiol stimulates the formation of nerve growth factor by glial cells in tissue culture [64] and that glucocorticoids can potentiate enzyme induction in rat sympathetic ganglion cells which is mediated by nerve growth factor [65]. The other positive actions of nerve growth factor (NGF) are numerous but they include the stimulation of neurite outgrowth, an influence on the motility and direction of movement of growth cones, increased protein synthesis, incorporation of ion channels in cell membranes, and increased cell survival [66]. Although the actions of NGF mainly affect sympathetic neurones and sensory neurones, other growth factors which act on other types of neurones have been identified. It is likely that the genomic and non-genomic actions of these factors [66] may also be influenced by the levels of glucocorticoids. It has also been reported that glucocorticosteroids can accelerate the maturation of mechanisms of transmitter release [67] and that they exert a powerful influence on the levels of a wide variety of enzymes associated with

neurotransmitter synthesis and breakdown and control of electrolyte distribution across neuronal membranes [63]. It is perhaps not surprising then that a positive effect of steroids on the spontaneous and evoked release of neurotransmitters has been reported [68, 69]. Direct effects of glucocorticoid hormones on the activity of single neurones in the reticular formation has also been reported by Avanzino et al [70]. These authors found that the activity of some neurones was enhanced while others were supressed, or there was no effect. Feldman has also reported that the excitability of several regions of the brain, particularly in the brainstem, can be enhanced after direct infusion of cortisol [71, 72]. A positive effect of glucocorticoids on levels of serotonin in the brain has been reported [73, 74]. Moreover, Lauder and Krebs [75] have suggested that the differentiation of neurones in the fetal brain can be accelerated by glucocorticoid induced elevations in 5-hydroxytryptamine (5-HT) synthesis. Recent support for this suggestion has been provided by Chubakov et al [76]. These authors have shown that the addition of 5-HT in physiological concentrations to organotypic cultures of the developing visual cortex from newborn rats stimulated glial proliferation, neurone differentiation, neuropil formation, axon myelination and synaptogenesis. Furthermore, electrophysiological studies revealed that the expression of spontaneous activity in these neurones was advanced. Catecholamines Recent reports have also established that the levels of fetal catecholamines can be elevated by intrauterine stress [77] and in pregnancies characterized by intrauterine growthretardation [78,79]. The latter observations have been linked with the accelerated maturation of the pulmonary system of the SGA fetus. Apart from its role as a neurotransmitter, noradrenaline has been reported to have neuromodulatory functions which can influence the level of synaptic and neuronal activity. For example, several groups have shown that noradrenaline can produce both immediate [80] and longlasting modulation [81-84] of synaptic transmission in the hippocampus. Furthermore, application of low concentrations of noradrenaline to slices of the rat olfactory cortex facilitates the release of excitatory neurotransmitters [85]. It has been postulated that the modulation of transrnitter release by noradrenaline involves an alteration in the calcium current in the presynaptic membrane [86]. An increase in the responsiveness of postsynaptic cerebellar neurones to the excitatory neurotransmitter glutamate following application of noradrenaline has recently been shown to be associated with {3-adrenergic receptor activity and activation of cyclic-AMP synthesis. Supression effects of higher doses of noradrenaline on these responses appear to act via Cl:2-receptors [87] . The actions of noradrenaline on ionic channels, and

Arniel-Tison & Pettigrew: Adaptive changes in developing brain 73

therefore its direct effects on neuronal excitability, have also been reported. Gray and Johnston [88], for example, have shown that the activity of voltage-dependent (depolarizing) calcium channels in hippocampal neurones is increased with exposure of the cells to noradrenaline and other ti-adrenoceptor agonists. Foehring et al [89] have reported that noradrenaline selectively reduces the slow Ca2 +- and Na+-dependent K+ currents in cat neocortical neurones. This effect is mediated via til -receptors and is most pronounced during long de polarizations of the neurones. Consequently the excitability of these neurones remains higher than normal during periods of prolonged repetitive firing when noradrenaline levels are elevated. The possibility that noradrenaline may also playa role in the regulation of neuronal plasticity and the formation of neuronal circuits was proposed several years ago [90]. However the conclusions from recent work in other laboratories have created some controversy in this area [91]. Studies on younger animals have, on the other hand, clearly demonstrated that elevated levels of noradrenaline can influence the way in which retinal axons from segregated fields of synaptic connection in the lateral geniculate nucleus [92]. Neuronal activity The discussion above reveals that there are several possible mechanisms by which the maturation of some parts of the central nervous system in fetuses 'stressed' by suboptimal conditions of pregnancy could be directly stimulated. Furthermore, any effect which serves to directly influence the activity of neurones is likely to also exert an indirect effect on the maturation of neural circuits served by those neurones. There are many experiments which illustrate that the formation of normal neural circuits in the nervous system is dependent on the levels of activity in neurones [93, 94]. It follows that enhanced neuronal activity could itself exert a powerful indirect effect on the maturation of nerve pathways in different regions of the developing brain. While the exact mechanism for advanced maturation of subcortical structures in the nervous system in 'stressed' pregnancies has yet to be defmed, it remains that there are observations from different disciplines of research which are consistent with the clinical and experimental observations that the rate of maturation of some neural pathways can be influenced in a direction which is favourable for early extra-uterine survival. CONCLUSIONS The clinical and experimental data that has been summarised here suggests that neurological maturation is not always independent of gestational circumstances and can be accelerated in pregnancies characterized by intrauterine stress. The acceleration of maturation of the brainstem

74 Brain & Development, Vol 13, No 2,1991

and the lungs in SGA fetuses which is associated with maternal hypertension or other placental insufficiencies appears to be a favourable adaptation for possible early extrauterine life. An adaptive interPretation for moderate intrauterine growth-retardation and advanced maturation of the lungs and brainstem in some abnormal pregnancies can be proposed. By combining new methodology, and in particular Doppler velocimetry and appropriate biochemical assays of fetal blood it should be possible to better evaluate fetal well-being. We believe that the purpose of such improved methodology will be to indicate the extraction of SGA fetuses in which there has already been early adaptive maturation of the brainstem and lungs before later decompensatory changes associated with prolonged placental dysfunction occur. ACKNOWLEDGMENTS We wish to thank David Henderson-Smart, Joe Warshaw and Rowena Korobkin for their criticisms of an earlier version of the manuscript. This work was prepared when A.G.P. was on a special studies program (overseas) from the University of Sydney. REFERENCES 1. Toubas PL. Placental circulation in fetal growth. In: Senterre J, ed. Intrauterine growth retardation. Nestle Nutrition Workshop Series Vol 18. Nestec Ltd. New York: Vevey/ Raven Press, 1989:1-21. 2. Trudinger BJ, Giles WB, Cook LM. Flow velocity wave-forms in the maternal uteroplacental and fetal umbilical placental circulations. Am J Obstet Gynecol 1985; 152: 155-63. 3. Fleischer A, Schulman H, Farmakides G, et al. Uterine artery Doppler velocimetry in pregnant women with hypertension. Am J Obstet Gynecol 1986; 154:806-13. 4. Trudinger BJ, Stevens D, Connelly A, et al. Umbilical artery flow velocity waveforms and placental resistance: the effects of embolization of the umbilical circulation. Am J Obstet Gynecol 1987; 157:1443-8. 5. Block BS, Schlafer DH, Wentworth RA, et al. Intrauterine growth retardation and the circulatory responses to acute hypoxemia in fetal sheep. Am J Obstet Gynecol 1989; 161: 1576-9. 6. Economides DL, Nicolaides KH. Blood glucose and oxygen tension levels in small-for-gestational-age fetuses. Am J Obstet Gynecol 1989; 160:385-9. 7. Economides DL, Nicolaides KH, Gahl WA, et al. Plasma amino acids in appropriate and small-for-gestational-age fetuses. Am J Obstet Gynecol 1989; 161: 1219-27. 8. Warshaw JB. Intrauterine growth retardation: adaptation or pathology. Pediatrics 1985;76:998-9. 9. Gould JB, Gluck L, Kulovich MV. The relationship between accelerated pulmonary maturity and accelerated neurological maturity in certain chronically stressed pregnancies. Am J Obstet Gynecol 1971; 127:181-6. 10. Gluck L, Kulovich MV. Lecithin/sphingomyelin ratios in amniotic fluid in normal and abnormal pregnancy. Am J Obstet Gynecol 1973; 115:539-46. 11. Parkinson CE, Wallis S, Harvey D. School achievement and behavior of children who were small-for-dates at birth. Dev Med Child Neural 1981;23:41-50. 12. Harvey D, Prince J, Bunton J, Parkinson C, Campbell S. Abilities of children who were small for gestational age babies. Pediatrics 1982;69:296-300.

13. Calame A, Fawer CL, Claeys V, Arrozola L, Ducret S, Jaunin L. Neurodevelopmental outcome and school performance of very-Iow-birth-weight infants at 8 years of age. EurJ Pediatr 1986; 145:461-6. 14. Berg AT. Indices of fetal growth-retardation, perinatal hypoxia-related factors and childhood neurological morbidity. Early HumDev 1989; 19:271-83. 15. Blair E, Stanley F. Intrauterine growth and spastic cerebral palsy. I. Association with birth weight for gestational age. Am J Obstet Gynecol 1990; 162:229-37. 16. Burke G, Stuart B, Crowley P, Ni Scanaill S, Drumm J. Is intrauterine growth retardation with normal umbilical artery blood flow a benign condition? Br Med J 1990; 300: 1044-5. 17. Amiel-Tison C. Possible acceleration of neurological maturity following high risk pregnancy. Am J Obstet Gynecol 1980; 138:303-6. 18. Pettigrew AG, Edwards DA, Henderson-Smart DJ. The influence of intrauterine growth retardation on brainstem development of pre term infants. Dev Med Child Neurol 1985;27:467-72. 19. Amiel-Tison C. Neurological evaluation of the maturity of newborn infants. Arch Dis Child 1968;43:89-93. 20. Amiel-Tison C. Neurological evaluation of the small neonate: the importance of head straightening reactions. In: Gluck L, ed. Modern perinatal medicine. Chicago: Year Book Medical Publishers Inc, 1974:347-57. 21. Dubowitz LM, Dubowitz V, Goldberg C. Clinical assessment of gestational age in the newborn infant. J Pediatr 1970; 77: 1-10. 22. Finnstrom O. Studies on maturity in newborn infants. IV. Comparison between different methods for maturity estimation. Acta Paediatr Scand 1972;61 :33-41. 23. Schulman H, Winter D, Farmakides, G, et a1. Pregnancy surveillance with Doppler velocimetry of uterine and umbilical arteries. Am J Obstet Gynecol 1989; 160:192-6. 24. Cox WL, Daffos F, Forestier F, et a1. Physiology and management of intrauterine growth retardation: a biological approach with fetal blood sampling. Am J Obstet Gynecol 1988; 159: 36-41. 25. Spinnato JA, Sibac BM, Shaver DC, Anderson GD. Inaccuracy of Dubowitz gestational age in low birth weight infants. Obstet Gynecol 1984;63:491-5. 26. Perkins RP. The neonatal significance of selected perinatal events among infants of low birth weight. I. Overall results. Am J Obstet Gynecol 1981; 139:546-61. 27. Bekedam DJ, Visser GHA, de Vries 11, Prechtl HFR. Motor behaviour in the growth retarded fetus. Early Hum Dev 1985; 12: 155-66. 28. Bekedam DJ, Visser GHA, Mulder EJH, Poelmann Weesjes G. Heart rate variation and movement incidence in growthretarded fetuses: the significance of antenatal late heart rate decelerations. Am J Obstet Gynecol 1987; 157: 126-33. 29. M¢ller A, Janetta PJ. Evoked potentials from the inferior colliculus in man. Electroencephalogr Clin Neurophysiol 1982a; 53:612-20. 30. M¢ller A, Janetta PJ. Auditory evoked potentials recorded intracranially from the brainstem in man. Exp Neurol 1982b; 78: 144-57. 31. M¢ller A, Janetta PJ. Interpretation of brainstem auditory evoked potentials: results from intracranial recordings in humans. Scand Audiol 1983; 12: 125-33. 32. Starr A, Amlie RN, Martin WH, Sanders S. Development of auditory function in newborn infants revealed by auditory brainstem potentials. Pediatrics 1977;60:831-9. 33. Goldstein PJ, Krumholtz A, Felix JK, Shannon D, Carr RF. Brainstem evoked response in neonates. Am J Obste t Gynecol 1979; 135:622-8.

34. Despland PA, Galambos R. The auditory brainstem response (ABR) is a useful diagnostic tool in the intensive care nursery. PediatrRes 1980;14:154-8. 35. Pettigrew AG, Edwards DA, Henderson-Smart DJ. Screening for auditory dysfunction in high risk neonates. Early Hum Dev 1986; 14:109-20. 36. Soares I, Collet L, Morgon A, Salle B. Effect of brains tern auditory evoked potential stimulus intensity variations in neonate of small for gestational age. Brain Dev (Tokyo) 1988; 10: 174-7. 37. Henderson-Smart DJ, Pettigrew AG, Edwards, DA. Prenatal influences on the brainstem development of pre term infants. In: Jones CT, Mott JC, Nathanielsz PW, eds. Physiological development of the fetus and newborn. Oxford: Academic Press, 1985:627-31. 38. Moosa A. Further studies of motor nerve conduction velocity in newborn infants. Arch Dis Child 1969 ;44: 782-3. 39. Moosa A, Dubowitz V, Postnatal maturation of peripheral nerves in preterm and full-term infants. J Pediatr 1971;79: 915-22. 40. Kesson AM, Henderson-Smart DJ, Pettigrew AG, Edwards DA. Peripheral nerve conduction velocity and brainstem auditory evoked responses in small for gestational age preterm infants. Early HumDev 1985; 11:213-9. 41. Edwards DA, Pettigrew AG, Henderson-Smart DJ. Analysis of neural transmission in the brainstem of pre term infants. In: Tudehope D, Chenoweth J, eds. Perinatal medicine. Brisbane: Aust. Perinatal Society, 1986:207. 42. Pratt H, Sohmer H. Intensity and rate functions of cochlear and brainstem evoked responses to electrical stimuli in man. Arch Oto-Rhino·LaryngoI1976;212:85-92. 43. Chiappa KH, Gladstone KJ, Young RR. Brainstem auditory evoked responses: Studies of waveform variation in 50 normal human SUbjects. Arch NeuroI1979;36:81-7. 44. Suzuki T, Kobayashi K, Takagi N. Effects of stimulus repetition rate on slow and fast components of auditory brain-stem responses. Electroencephalogr Gin Neurophysiol 1986;65: 150-6. 45. Huang CM, Buchwald TS. Changes of acoustic nerve and cochlear nucleus evoked potentials due to repetitive stimulation. Electroencephalogr Gin Neurophysiol 1980;49: 15-22. 46. Debruyne F. Influence of age and hearing loss on the latency shifts of the auditory brainstem response as a result of increased stimulus rate. Audiol. 1986; 25: 101-6. 47. Avery ME, Fletcher BD, Williams RG. The lung and its disorders in newborn infants, 4th edition. Philadelphia: WB Saunders, 1981. 48. Henderson-Smart DJ. The effect of gestational age on the incidence and duration of recurrent apnoea in newborn babies. AustPaediatrJ 1981;17:273-6. 49. Henderson-Smart DJ, Pettigrew AG, Campbell DJ. Clinical apnea and brainstem neural function in pre term infants. N EngiJ Med 1983;308:353-7. 50. Plantz RG, Williston JS, Jewett DL. Effects of undernutrition on development of far-field auditory brain stem responses in rat pups. Brain Res 1981 ;213: 319-26. 51. Nakamura H, Kawai S, Nakazawa S, Matsuo T. Evolution of auditory brainstem responses (AER) in undernourished newborn rats. Pediatr Res 1987;21:371. 52. Kawai S, Nakamura H, Matsuo T. Effects of postnatal undernutrition on brainstem auditory evoked potentials in weanling rats. BiolNeonate 1989;55:268-74. 53. Pettigrew AG, Morey AL. Chariges in the brainstem auditory evoked response of the rabbit during the first postnatal month. Dev Brain Res 1987; 33:267-76. 54. Cook CJ, Gluckman PD, Williams C, Bennet L. Precocial

Amiel-Tison & Pettigrew: Adaptive changes in developing brain

75

55. 56. 57. 58.

59. 60. 61.

62.

63. 64. 65.

66.

67. 68. 69. 70.

71. 72. 73. 74. 75.

neural function in the growth-retarded fetal lamb. Pediatr Res 1988;24:600-4. Wigglesworth JS. Experimental growth retardation in the foetal rat. J Pathol BacterioI1964;88:1-13. Roux JM, Tordet-Caridroit C, Chanez C. Studies on experimental hypotrophy in the rat. Bioi Neonate 1970;15: 342-7. van Marthens E, Harel S, Zamenhof S. Experimental intrauterine growth retardation. Bioi Neonate 1975;26:22131. Chanez C, Flexor MA, Hamon M. Long lasting effects on intrauterine growth retardation on basal and 5-HT stimulated Na+K+ ATPase in the brain of developing rats. Neurochem Int 1985;2:319-29. Gewolb JM, Hobbins IC, Tan SY. Amniotic fluid cortisol in high-risk human pregnancies. Obstet Gynecol 1977;49: 466-70. Ward IL, Weisz J. Maternal stress alters plasma testosterone in fetal males. Science 1980;207:328-9. Challis JRG, Fraher L, Oosterhuis I, White SE, Bocking AD. Fetal and maternal endocrine responses to prolonged reductions in uterine blood flow in pregnant sheep. Am J Obstet GynecoI1989;160:926-32. Laatikainen TJ, Raisanen IJ, Salminen KR. Corticotropinreleasing hormone in amniotic fluid during gestation and labor and in relation to fetal lung maturation. Am J Obstet Gynecol1988; 159:891-5. Baethmann A. Steroids and brain function. In: James HE, Anas NG, Perkins RM, eds. Brain insults in infants and children. Orlando Florida: Grune & Stratton, 1985:3-17. Perez-Polo JR, Hall K, Livingston K, Westlund K. Steroid induction of nerve growth factor synthesis in cell culture. Life Sci 1977;21:1535-44. Otten U, Thoenen H. Effect of glucocorticoids on nerve growth factor-mediated enzyme induction in organ cultures of rat sympathetic ganglia: enhanced response and reduced time requirement to initiate enzyme induction. J Neurochem 1977;29:69-75. Greene LA, Bernd P, Black MM, et al. Genomic and nongenomic actions of nerve growth factor in development. In: Changeux JP, Glowinski J, Imbert M, Bloom FE, eds. Mo· lecular and cellular interactions underlying higher brain func· tions. London: Academic Press. Progress in Brain Research 1983;58:347-57. Puro DG. Glucocorticoid regulation of synaptic development. Dev Brain Res 1983;8:283-90. Wilson RW, Ward MD, Johns TR. Corticosteroids: a direct effect at the neuromuscular junction. Neurology 1974;24: 1091-5. Hall ED, Baker T, Riker WF. Glucocorticoid effects on spinal cord function. J Pharmacol Exp Ther 1978; 206:361-70. Avanzino GL, Celasco G, Cogo CE, Ermirio R, Ruggeri P. Actions of microelectrophoretically applied glucocorticoid hormones on reticular formation neurones in the rat. Neuroscience Letts 1983;38:45-9. Feidman S. Electrical activity of the brain following cerebral microfusion of cortisol. Epi/epsia 1971; 12:249-62. Feldman S, Dafny N. Effects of adrenocortical hormones on the electrical activity of the brain. Progr Brain Res 1970; 32:90-100. Telegdy G, Vermes I. Effect of adrenocortical hormones on activity of the serotonergic system in limbic structures in rats. Neuroendocrinology 1975; 18:16-26. Sze PY, Neckers L, Towle AC. Glucocorticoids as a regulatory factor for brain tryptophan hydroxylase. J Neurochem 1976;76:169-73. Lauder JM, Krebs H. Effects of p-chlorophenyl-alanine on

76 Brain & Development, Vol 13, No 2,1991

76.

77. 78.

79.

80. 81.

82. 83. 84. 85.

86. 87.

88.

89. 90.

91. 92. 93. 94.

time of neuronal ongm dUring embrYogenesis in the rat. Brain Res 1976; 107:638-44. Chubakov AR, Gromova EA, Konovalov GV, Sarkisova EF, Chumasov EI. The effects of serotonin on the morphofunctional development of rat cerebral neocortex in tissue culture. Brain Res 1986;294:211-23. Weiner CP, Robillard IE, Nakamura KT. Human fetal response to stress-plasma catecholamines, and renin in continuing pregnancies. Pediatr Res 1987;21:381. Divers WA, Babaknia A, Hopper BR, Wikes MM, Yen SS. Fetal lung maturation: amniotic fluid catecholamines, phospholipids, and cortisol. Am J Obstet Gynecol 1982; 142:440-4. Sagawa N, Okasaki T, Muneshige A, Morl T. Accelerated fetal lung maturation and fetal catecholamines. In: Jones CT, Nathanielsz PW, eds. The physiological deVelopment of the fetus and newborn. London: Academic Press, 1985:319-23. Lacaille J-C, Harley CWo The action of norepinephrine in the dentate gyrus: betamediated facilitation of evoked potentials in vitro. Brain Res 1985;358:210-20. Bliss TVP, Goddard GV, Robertson HA, Sutherland RI. Noradrenaline depletion reduces long-term potentiation in the rat hippocampus. In: Feher 0, Joo F, eds. Cellular analogues of conditioning and neural plasticity. London: Academic Press, 1981 :175-85. Neuman RS, Harley CWo Long-lasting potentiation of the dentate gyrus population spike by norepinephrine. Brain Res 1983;273: 162-6. Hopkins WF, Johnston D. Frequency-dependent noradrenergic modulation oflong-term potentiation in the hippocampus. Science 1984;226:350-1. Lynch MA, Bliss TVP. Noradrenaline modulates release of 14C glutamate from dentate but not from CA1/CA3 slices of rat hippocampus. Neuropharmacology 1986;25:493-8. Collins GGS, Probett GA, Anson J, McLauglin NJ. Excitatory and inhibitory effects of noradrenaline on synaptic transmission in the rat olfactory cortex slice. Brain Res 1984; 294:211-23. Dunlap K, Fischback GD. Neurotransmitters decrease the calcium conductance activated by depolarization of embryonic chick sensory neurones. J Physiol 1981; 317:519-35. Mori-Okamoto J, Tatsuno J. Participation of cyclic adenosine monophosphate and ~-adrenergic receptors in the facilitatory effect of noradrenaline on the response of cultured cerebellar neurons to glutamate. Brain Res 1989;490:64-72. Gray R, Johnston D. Noradrenaline and i3-adrenoreceptor agonists increase activity of voltage-dependent calcium channels in hippocampal neurons. Nature (Land) 1987; 327:620-2. Foehring RC, Schwindt PC, Crill WE. Norepinephrine selectively reduces slow Ca2 +- and Na+-mediated K+ currents in cat neocortical neurons. J Neurophysiol 1989;61:245-56. Kasamatsu T. The role of the central noradrenaline system in regulating neuronal plasticity in the developing neocortex. In: Marois M, ed. Prevention of physical and mental congenital defects. Part C. New York: Alan R Liss Inc, 1985:369-74. Adrien J, Blanc G, Buisseret P, et al. Noradrenaline and functional plasticity in kitten visual cortex: a re-examination. J PhysioI1985;367:73-98. Land PW, Rose LL. Exogenous monoamines affect the segregation of retinogeniculate fibers in developing rats. Dev Brain Res 1985; 22: 135-40. Changeux I, Danchin A. Selective stabilisation of developing synapses as a mechanism for the specification of neuronal networks. Nature (Land) 1976;264:705-12. Kennedy M, Dehay C. Le developpement du cerveau. La Recherche 1987; 18:26-34.