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Neonatal maladjustment syndrome (NMS), also known as hypoxic-ischaemic encephalopathy, perinatal asphyxia syndrome and neonatal encephalopathy [1, 2], is reportedly the most common problem observed in neonatal foals during the first 72 h after birth . Neurological signs of NMS can range from subtle to severe and may include convulsions/seizures, weakness and behavioural abnormalities . While in severe cases an early death is likely, recovery is possible with human intervention, especially in less severe cases [1, 4].
Neonatal maladjustment syndrome is mainly attributed to cerebral hypoxia and ischaemia leading to neuronal cell death shortly before, during or after birth [1, 2, 4]. Signs of central nervous system (CNS) disease in equine neonatal patients have been attributed to hypoxic encephalopathy in 92% of cases, of which 59% experienced dystocia or premature placental separation . Other possible causes may include post natal persistence of or reversion to an inhibited fetal state of cerebral cortical function  and meningitis, congenital lesions, CNS haemorrhage or oedema, metabolic insults, sepsis, endotoxins, and in utero infections . Thus, NMS appears to represent a number of different but related conditions that reflect untoward responses to the exceptional physiological challenges that precede, accompany and follow expulsion from the uterus at birth.
In line with the distinction made by Aleman et al. , the focus of this editorial will be the impact of variations in the oxygen status of the foal  and their suggestion that a fetal state of inhibited cerebral cortical function may be retained or return after birth . Although the latter area is of more contemporary interest [2, 8], both merit consideration because their effects may interact. The first area relates to established pathophysiological causes of impaired perinatal oxygen status and its various impacts on metabolic and other processes that support neonatal heat production . The second area concerns less well-recognised changes in the physiological environment of the brain during the transition of the young from the intrauterine to the extrauterine environment, in particular the impact of that on post natal levels of arousal and the onset of consciousness [9-11]. Hindrances to the successful completion of this transition in brain function would jeopardise the newborn's capacity to interact with its physical environment and mother in ways that otherwise promote its survival and well-being. Finally, in addition to emphasising the above 2 areas, consideration will be limited to mild cases of NMS where brain function is only temporarily affected and is therefore reversibly inhibited.
Pathophysiology of the perinatal period
The well demonstrated prenatal increase in fetal hypothalamic–pituitary–adrenocortical (HPA) activity is important for integrating 4 key processes. They are the onset of labour, an acceleration of fetal tissue maturation just before birth, the timely onset of colostrum/milk production by the mother, and a physiologically generated impetus to engage in mother–young bonding . All of these processes are crucial for neonatal survival, which is jeopardised if one or more of them is impaired. Moreover, superimposed on these processes may be negative impacts of pathophysiological and related conditions that arise as a result of placental insufficiency, intrapartum hypoxia, dystocia, premature birth, starvation of the newborn and maternal underfeeding. Each one of these has been discussed in detail elsewhere [7, 12, 13] and has been identified as relevant to some manifestations of NMS [1-4].
Hypothermia is often observed shortly after outdoor births of ungulate young, is a common outcome of perinatal pathophysiology, may often be severe and predisposes the newborn to death or debility (Table 1). Importantly, in the context of managing impaired newborns, hypothermia of as little as 2–3°C is anticipated to result in some dulling of consciousness, and this in its turn may contribute to the reduced behavioural responsiveness of chilled newborns to their mothers . Hypothermia occurs in healthy vigorous newborns that mount full heat production responses to ambient cold that is so severe that heat loss still exceeds heat production. In contrast, hypoxia associated with placental insufficiency or dystocia can inhibit heat production sufficiently to cause hypothermia even at mild ambient temperatures. This inhibition is associated with various consequences of anaerobic metabolism as indicated by elevated concentrations of plasma lactate and hydrogen ions and evidence of metabolic and respiratory acidosis [14-16], and it is rarely associated with cerebral lesions [17, 18]. The newborn may also be predisposed to hypothermia by immature shivering and nonshivering thermogenic mechanisms and/or by reduced energy reserves available to fuel heat production [13, 17, 19]. Moreover, such immature newborns may be further disadvantaged by high rates of heat loss due to a high surface area to body weight ratio. Immaturity of other organ systems may also adversely affect their survival. Practically, however, normothermia can usually be restored and maintained by initially keeping most such newborns at air temperatures near the upper limit of their species-specific thermoneutral range [7, 12].
Table 1. Pathophysiological states and their effects on the newborn animal [7, 12]
Effects of pathophysiological state
Chronic fetal hypoxia
Fetal growth retardation
Inhibition of heat production
Acute fetal hypoxia
Inhibition of heat production
Failure to suck due to weakness, competition, inadequate mothering
Deficient production of colostrum/milk
Inhibited heat production
Hypothermia in cold conditions
Cerebral compromise in warm environments
Immaturity at birth
Immature thermogenic mechanisms
Reduced thyroidal and adrenocortical support of post natal metabolic activity
Excessive heat loss and/or impaired heat production
Restricted placental size
Fetal growth retardation
Reduced deposition of fetal fat reserves
Inadequate maternal udder development and colostrum/milk production
Inhibition of or impaired heat production
Excessive heat loss
Energy-rich nutrients are required to fuel heat production and these are derived from body energy reserves deposited before birth and from colostrum/milk drunk after birth [19-21]. Starvation or inadequate colostrum/milk intakes lead to hypoglycaemia as body energy reserves become depleted, and the onset of hypoglycaemia in such newborns may be more rapid in intensive care units because the warm conditions would usually inhibit shivering and its glucose-sparing effects . Severe hypoglycaemia in warm conditions will eventually lead to cerebral compromise as indicated by seizure activity, while in cold conditions it will inhibit heat production and usually lead to hypothermia [7, 19]. In addition, it is well known that starvation deprives newborns of immunoglobulins and thus predisposes them to infections that can result in a variety of debilitating, often fatal, conditions . The routine intensive management of NMS foals is obviously directed at specifically minimising such problems. Interestingly, the volumes of colostrum required to meet the newborn's energy needs  will substantially exceed the minimum necessary to provide sufficient immunoglobulins for reasonable protection against many neonatal infections.
Onset of consciousness after birth
As already mentioned, NMS is commonly associated with encephalopathy due to cerebral hypoxia and ischaemia shortly before, during or after birth. However, it has been suggested that in some mild cases of NMS, where a normal birth has apparently occurred and the NMS newborns have recovered quickly and fully from the condition, other factors may be at play . In particular these may include a post natal persistence of fetal physiological conditions linked to aberrant activity of the fetal HPA axis and/or elevated pregnane concentrations . This intriguing suggestion raises the possibility that factors other than hypoxia may impair or delay the onset of consciousness after birth of some NMS foals. If so, this would reduce their capacity to engage in survival-critical volitional behaviour, and this would be the case whether they were kept outdoors or indoors in a stall or a neonatal care unit. It also emphasises the value of developing interventions that would help caregivers to more effectively manage this transitional period in such foals.
Integrated analyses of the literature suggest that ungulate fetuses, which are neurologically mature at birth, are actively maintained in sleep-like, unconscious states despite the fact that their brains have attained the capacity for conscious perception before birth [9-11, 22]. Maintenance of such unconscious states is apparently due to the combined neuroinhibitory effects of high circulating and cerebral concentrations of adenosine, allopregnanolone, pregnanolone and prostaglandin D2 acting together with a placental neuroinhibitory peptide, warmth, buoyancy and cushioned tactile stimulation [9-11] (Table 2). Therefore, conscious perception is not anticipated to occur until shortly after birth in these species.
Table 2. Summary of neuroinhibitory factors involved in maintaining late-term fetuses in unconscious sleep-like states and activators involved in arousal and onset of consciousness after birth. Details of published primary investigations may be accessed via previous reviews [10, 11]
Potent neuroinhibitor promoting sleep and unconsciousness
Responds rapidly due to very short biological half-life
Demonstrated inhibition of cerebral cortical electrical activity
Placental and fetal tissues including the brain
High circulating levels in fetus
Production varies with fetal oxygen status – elevated in hypoxia, reduced in normoxia
Neuroactive steroidal metabolites of progesterone
Act via GABAA receptors to bring about sedative/hypnotic and anaesthetic effects
Produced by the fetal brain and the placenta from progesterone and cholesterol
High circulating levels in fetus
Elevated during stress and hypoxia
Produced by the fetal brain
Present in cerebrospinal fluid in fetal sheep during late pregnancy
Placental peptide extract inhibits fetal arousal observed upon in utero ventilation and umbilical cord occlusion
Somnogenic effects of heat
The fetus is exposed to a fluid environment at ∼37–39°C
Cushioned tactile stimulation and buoyancy
Low tactile sensory stimulation
Due to immersion in amniotic fluid and surrounding soft tissues
Withdrawal of inhibition
Onset of breathing
Increased oxygenation leads to decreases in brain adenosine concentrations
Severance from the placenta
Loss of placental supply of adenosine, neuroactive steroids and some precursors, and the placental peptide inhibitor
Neuroactive steroid with rapid-acting excitatory effects within the brain
Progressive switch in placental steroidogenesis from progesterone to oestrogen leading up to birth.
Stimulates arousal and alert vigilance
Locus coeruleus–noradrenaline system and associated connections to other brain areas
Barrage of sensory impulses
Stimulation of locus coeruleus–noradrenergic system
Hypoxic and tactile stimulation during birth and exposure to air, gravity, hard surfaces, unlimited space and cold after birth
These observations raise the question of how the post natal onset of consciousness is achieved in healthy newborns. Key factors are considered to include a reduction in cerebral cortical inhibition by factors that are unique to life in utero, as well as to an increase in cerebral cortical activation associated with birth [9, 10]. Thus, a marked elevation of tissue oxygen concentrations in response to the onset of successful breathing after birth and the loss of the placenta as a source of circulating adenosine are both considered to lead to a rapid decrease in circulating and cerebral adenosine concentrations and to a decrease in an overriding adenosine inhibition of cerebral cortical function . Loss of the placenta at birth would also contribute by removing a significant source of allopregnanolone, pregnanolone and their precursors, and the only source of the placental peptide neuroinhibitor. The rapid post natal removal of this neuroinhibition, especially that due to adenosine, is presumed to allow a suite of activators of cerebral cortical function to operate. The combined effect of these activators is presumed to be sufficient to overcome residual but declining inhibitory effects of the neuroactive steroids which persist for some time after the rapid decline in the overriding adenosine inhibition has occurred [9, 23].
Activators of arousal observed in newborns include high circulating levels of 17β-oestradiol, which is mostly of placental origin, and stimulation of the locus coeruleus–noradrenaline system by strong intrapartum tactile stimulation and hypoxia and by post partum exposure to cold ambient conditions [24, 25]. The neuroactive steroid 17β-oestradiol has rapid-onset excitatory effects in a variety of brain areas [26, 27]. The locus coeruleus–noradrenaline system extends noradrenergic nerves widely throughout the brain and has major roles in stimulating arousal and alert vigilance . In addition, neurons of the locus coeruleus project to the olfactory bulb so that activation of this nucleus may facilitate teat-seeking and bonding in neonatal animals [29, 30]. With the successful onset of breathing after birth, 17β-oestradiol and noradrenaline presumably act together with cold stimulation of cutaneous thermoreceptors, and with tactile stimulation through contact with hard surfaces and maternal licking, to promote the first appearance of consciousness [9, 10].
Arousal is observed in the normal healthy newborn within minutes of birth and accompanies the onset of breathing . This is followed by volitional behaviours suggestive of some level of conscious perception, such as interactions with the dam, standing successfully and then teat seeking. Arousal and the associated onset of breathing are essential for survival; in their absence the newborn will rapidly become hypoxic/hypercapnic and die . In addition, behaviours of the newborn that contribute to mother–young bonding and help to secure adequate colostrum/milk intake are equally important when human intervention is not possible [7, 19].
Intersection between pathophysiology and the onset of consciousness at birth: implications for NMS foals
Behaviours associated with survival become possible by the time of birth in precocial young because their neurological apparatus has developed sufficiently to process sensory inputs from the environment, allowing them to find the dam and a teat, or even to seek shelter in cold conditions . Such behaviours, which may initially reflect innate drives, are indicative of arousal and the onset of consciousness. Factors associated with hypothermia that adversely affect this process and thereby threaten newborn survival include the pathophysiological states listed in Table 1. Relationships between these factors and associated key features of NMS foals have been summarised in Figure 1. Clearly, NMS foals are usually managed clinically in ways designed to minimise these problems . The point here, of course, is to clarify whether or not a possible delay in the progression from prenatal unconsciousness to post natal consciousness occurs independently of hypoxia in some NMS foals, a condition that would manifest functionally as retention of an inhibited state of fetal cerebral cortical activity as suggested by Aleman et al. . Such a demonstration is made somewhat more complex because persistent hypoxia also delays the usually rapid post natal reduction in adenosine inhibition of cerebral cortical activity [9, 11].
For example, many of the foals showing clinical signs of CNS impairment are likely to have experienced one or both of 2 forms of hypoxic insult. They are chronic hypoxia caused by placental insufficiency associated with a small placental size or other placental impairments that reduce its oxygen transfer capacity over an extended period, and acute hypoxia during birth resulting from dystocia and/or premature separation of the placenta. Interestingly, 12 of the 32 NMS foals observed by Aleman et al.  were reported to have had a clinical history of acute hypoxia of these types.
Nevertheless, the aetiology of hypoxic influences on the state of consciousness and on commonly observed behaviour in NMS foals, such as lack of affinity for the mare, absence of sucking and weakness , is likely to be quite complex. This is because such influences probably involve at least 2 factors acting separately or together. First, where neonatal breathing is not compromised, persistent inhibitory effects of prepartum or intrapartum hypoxia on heat-producing mechanisms would often lead to hypothermia which has the capacity to dull consciousness due to its specific thermal effects on cerebral metabolic rate . Of course, providing sufficient thermal support to maintain normothermia would rule out this possibility. The second factor is a subtle involvement of hypoxia in some mild cases of NMS which appear to manifest as a post partum continuation of an inhibited fetal cerebral cortical status, or a reversion to such a state after apparently normal post natal arousal and activity have occurred . This might arise if respiratory function remained suboptimal from birth or if such suboptimal function appeared after a successful post partum onset of optimal function. In either case, the potent neuroinhibitory effects of adenosine and/or the pregnane steroid metabolites allopregnanolone and pregnanolone might be anticipated to persist straight after birth or return later, because their concentrations are reported to increase during hypoxia and other stressful situations [11, 32]. If this did occur, such inhibition might override activation of cerebral cortical activity resulting from 17β-oestradiol, noradrenaline, strong tactile stimulation and, if thermal support is not provided, by cold exposure. This possibility could be ruled out and/or managed by continuous monitoring of oxygen status and, if required, by providing respiratory support.
A third possibility, which accords with the proposal of Aleman et al. , is that a post natal persistence or return of a fetal state of cerebral cortical inhibition may occur in normoxic NMS foals. Of the 32 NMS foals in their study, there was no clinical history of hypoxia in 12. However, clarifying the aetiology of NMS in 6 of these was somewhat complicated by other clinically significant factors, whereas the remaining 6 foals apparently exhibited none . It is understood of course that heterogeneity of study groups is usual when they are made up of clinical cases acquired serendipitously.
Nevertheless, taken as a whole, the group of 32 NMS foals provides interesting information . First, the plasma neuroactive steroid concentrations exhibited far greater ranges in the NMS foals than in healthy ones. This presumably reflected their heterogeneity and raises the possibility that some of the subgroups considered above might be found to have significantly different hormone profiles once they have been identified and studied in sufficient numbers. Second, progesterone, as a precursor of allopregnanolone and pregnanolone, has neuroinhibitory actions [8, 9, 11] and is therefore of particular interest here because, to the present authors' knowledge, none of the other steroids reported to be significantly elevated in NMS foals  have documented neuroinhibitory actions. The elevated plasma concentrations of progesterone are consistent with dulled consciousness [33-35], but the exceptionally low, and therefore unreported  concentrations of allopregnanolone are not. Third, although the mechanisms remain elusive at present , the significantly higher mean plasma concentrations of pregnenolone, androstenedione, dehydroepiandrosterone and epitestosterone, as well as progesterone, do indicate different patterns of steroidogenesis and/or clearance, and support the view of Aleman et al.  that after further investigation and validation such hormone profiles might become useful aids to diagnosing some types of NMS. Fourth, the behavioural evidence of cerebral cortical inhibition in NMS foals , considered in the context of an apparent requirement for the withdrawal of neuroinhibition to be accompanied by increasing neuroactivation if birth is to be followed by the timely onset of consciousness [9-11], raises the prospect of testing the therapeutic efficacy of potent neuroactivators in some NMS foals. One candidate is 17β-oestradiol because of evidence that it could promote behavioural arousal, breathing and subsequent survival in lambs that were initially ‘flat’ or inactive after delivery by hysterectomy close to the time of normal birth . Another candidate is the use of strong tactile stimulation to elicit locus coeruleus–noradrenaline mediated neuroactivation. A suggested way to achieve such tactile stimulation (J.E. Madigan, personal communication) is to use a modified soft rope ‘squeeze’ technique to simulate compression of the young by the cervix and vagina during birth , a natural process that is known to strongly stimulate the locus coeruleus [9, 11].
It is apparent from these observations that the fresh perspectives provided by the notion that inhibited fetal states of cerebral cortical function may persist or return after birth in some NMS foals, as outlined by Aleman et al. , lays open several fruitful lines of investigation. In building on earlier insights into the onset of consciousness in other neurologically mature young shortly after an uneventful birth [9-11, 31], such investigations, as is usual in their early stages, are likely to constructively generate more interesting questions than they provide answers, but answers do eventually become clear. So, watch this space!