1. Introduction
Neonatal encephalopathy (NE) syndrome refers to neonates with non-infectious neurologic signs or uncharacteristic behavior in the immediate postpartum period [
1]. Although the etiology is not fully understood, it is supposed to be a consequence of several antepartum and intrapartum events that lead to cerebral hypoxia and ischemia. Furthermore, based on current comparative research, some studies showed increased progestogen and neuroactive steroid concentrations in these foals so it is reasonable to assume that they may play a role in NE [
2,
3,
4]. Another possible theory regarding the pathophysiology of this disease has emerged from human medicine, as some cases of NE do not show evidence of a hypoxic–ischemic event. This theory suggests that a fetal systemic inflammatory response to an intrauterine infection could lead to the release of pro-inflammatory cytokines, which may cause neonatal brain injury. Since placentitis in mares is relatively common and is considered a risk factor for acute neurological dysfunction in foals, this theory seems plausible but requires further corroboration [
3,
5,
6]. NE is considered the most prevalent neurological disease of newborn foals being a life-threatening condition [
7,
8,
9]. No consensus exists regarding nomenclature, with other terminologies being used to describe this disease, including neonatal maladjustment syndrome, neonatal multisystemic syndrome, hypoxic–ischemic encephalopathy (HIE), perinatal asphyxia syndrome (PAS), dummy foal syndrome, wanderer, and barker foal [
3,
10,
11,
12,
13].
NE is recognized across different species; however, the knowledge that exists specifically about horses is somewhat scarce, being mostly extrapolated from humans and other animals [
14].
Clinically, newborn foals with NE may appear normal at birth and may develop behavioral and neurological signs hours later. Behavioral abnormalities include a lack of affinity for the mare, abnormal udder seeking and suckling, tongue incoordination, and abnormal vocalization [
1,
15]. Neurological disturbances can include alterations in muscle tone, changes in responsiveness, seizures, autonomic disturbances, and vestibular signs. Due to behavioral and neurological disturbances at birth, affected foals may have a decreased capability to meet their nutritional needs and antibody-rich colostrum intake, which impairs immunity, and is called failure of passive transfer immunity (FPTI) [
1,
9,
11,
12]. Under such circumstances, many of these foals begin to develop organic disturbances that can culminate in non-specific laboratory findings such as acid–base and electrolyte disturbances, failure of body temperature regulation, poor glucose control (hyperglycemia or hypoglycemia), azotemia, and high levels of blood creatinine [
1,
9,
12,
16,
17]. NE may lead to compromised gastrointestinal and respiratory physiologic functions which can be complicated with systemic disease characterized by varying degrees of multiorgan dysfunction. These foals can also present concomitant sepsis as a consequence of the failure of passive transfer immunity (FPTI) [
1,
2,
3].
Considering the high propensity for sudden deterioration of the clinical state, these foals should be closely monitored [
1,
18,
19]. The treatment is mainly supportive, directed to control neurological disturbances and concomitant metabolic dysfunctions, with some authors defending the Madigan’s squeeze procedure for some cases [
1,
20,
21]. Although the prognosis for foals with primary diagnosis of NE without complications is generally good (70% to 80% of survival rates), this scenario can change in the presence of clinical and laboratorial disturbances presented above or comorbidities [
1]. Treatment and recovery become more difficult with guarded prognosis. However, there is a great lack of prognostic studies in foals with NE aimed at helping clinicians understand which clinical and laboratory findings most negatively influence prognosis, and which should be used to advertise owners and aid decision-making. Since these foals can carry high medical costs, a prognostic outcome is valuable, reinforcing the need for such studies.
The aim of this study was to evaluate the impact that clinical and laboratory factors assessed during admission, as well as comorbidities developed during hospitalization, have on foals with NE, and thus determine which can be used as prognostic factors.
4. Discussion
Even though NE is commonly reported, information regarding prognostic indicators in the scientific literature is scarce. The present work provides an insight into the value that some simple and accessible clinical and laboratory parameters can help predict the outcome of foals with NE upon admission. It also evaluates the impact that comorbidities developing during hospitalization may have on these foals.
The overall survival rate of the foals with NE and associated comorbidities presented in our sample (57.4%) is lower than the 70 to 80% reported in recent literature regarding foals with NE [
3,
16,
24,
25]. However, some authors mention that these high survival percentages refer to foals with NE but without the presence of complications [
1], and in fact, in our sample, all the foals that did not develop comorbidities survived. Our study included 72.1% of foals that developed comorbidities which likely contributed to the lower survival rate. Furthermore, this study relied on medical records within a large time frame (2000 to 2022), presenting a tendency for older cases to have higher mortality than more recent ones. Several factors may be related to this event, such as an increase in knowledge about equine neonatology over the last few decades and an increase in the experience of clinical staff in this field. Nevertheless, most of the foals that did not develop any kind of comorbidity during hospitalization survived.
Regarding the medical history of the foals and mares, none of the evaluated factors showed an association with the outcome, which agrees with some studies and disagrees with others. The fact that we had a small number of premature foals and mares with placental problems and diseases during gestation may have contributed to this since Gold et al. 2016 [
10] found an association between these variables and non-survival. Regarding the sex of the foals, Lyle-Dugas et al. 2017 [
9] did not find any association with survival rate either. Prematurity is a condition that can predispose foals to acquire some clinicopathological signs that may be similar to NE, such as impairment of temperature and glucose regulation as well as renal, gastrointestinal, and respiratory dysfunction. However, some of the etiological factors related to prematurity are the same that cause NE, namely diseases during pregnancy and placental abnormalities. This may explain why some premature foals have concomitantly NE. Furthermore, some authors consider prematurity as a risk factor for the development of NE since it leads to a state of decreased tissue oxygenation and blood flow [
3,
12,
21]. Regardless, the inclusion of premature foals with NE in this study may have created a bias in the interpretation of clinical and laboratory parameters, as these alterations could be related to the condition of prematurity rather than NE, being a limitation of the study.
Regarding clinical parameters, rectal temperature upon admission seems to have an important role in the outcome of these foals, since hypothermic foals presented greater odds of non-surviving. This was an expected finding since the presence of hypothermia in neonatal foals has been previously associated with non-survival in several studies [
26,
27]. Nevertheless, these studies included critically ill foals that presented with a wide range of diseases upon admission being non-specific for neonatal encephalopathy. Giguère et al., 2017 [
27] also reported significant differences in the means of rectal temperature between survivors (higher mean) and non-survivors (lower mean), in accordance with our results. The same author also demonstrated that hypothermic neonatal foals had 6.24 greater odds of dying than the normothermic ones, which is higher than the 4.85 odds of non-surviving found in our sample. A possible justification is that Giguère et al., 2017 [
27] evaluated neonatal foals that presented a wide range of diseases upon admission, being unspecific for NE, and evaluated clinical and laboratory parameters during hospitalization, which together may have influenced the results since these foals presented a more compromised clinical stage. In contrast, the clinicopathological features assessed in our study were recorded solely at the time of admission, when these foals had not yet exhibited significant changes beyond NE. Any additional comorbidities emerged afterward, during their hospitalization. Body temperature was also associated with survival in Dembek et al., 2014 [
28] with the survivors group presenting a significantly higher temperature mean compared with non-survivors group, once more corroborating our results.
Upon admission, most foals (83.3%) presented recumbency. This clinical feature can have a role in the development of some comorbidities as stated by Perina et al., 2024 that reported a statistically significant association between recumbency and the development of umbilical diseases [
29]. Our findings are similar to the results reported by Lyle-Dugas et al., 2017 [
9] which found that recumbency was associated with non-survival and that foals with recumbency had 9.18 greater odds of dying, being higher than the likelihood reported in the present work (6.84 greater odds to die).
Regarding seizures, our results are in line with those of other studies such as Gold et al., 2016 [
8], which found a significant association between the presence of seizures and the death of foals with NE. However, this study reported that foals with NE and seizures were 24 times more likely to die, which is much higher than the probability we found (4.14 times more likely to die). In humans, seizures are also associated with a worse prognosis [
30]. Seizures increase oxygen and glucose consumption which can culminate in a more severe or even irreversible cerebral injury [
1].
Blood glucose is a common parameter evaluated in several studies regarding newborn foals [
9,
22,
27,
28]. However, most of these studies are performed in critically ill foals, with various concomitant diseases. Hypoglycemia is common in neonatal foals given their low glycogen stores, particularly if they suffered significant stress at birth or if they have difficulties nursing. If prolonged, severe hypoglycemia can be life-threatening [
12]. Hollis et al., 2008 [
22] reported that, upon admission, 29.1% of the critically ill foals had blood glucose concentrations within the normal range, 36.5% had hyperglycemia, and 34.4% had hypoglycemia. Although our work presented a similar percentage of foals within the normal range (32.7%), we had more foals with hypoglycemia (51%) and just a few foals with hyperglycemia (16.3%). Nevertheless, Hollis et al., 2008 [
22] reported a significant association between hypoglycemia at admission and death, in accordance with our findings. Foals that did not survive also had lower mean blood glucose concentrations at admission, which once more is in accordance with our results. Dembek et al., 2014 [
28] also reported a significant difference in the blood glucose medians between survivors and non-survivors, in a sample of critically ill foals, somewhat corroborating our results. A feature reported by Hollis et al., 2008 [
22], but not found in our study, was an association between hypoglycemia and septicemia. Perhaps the fact that Hollis included foals with different disorders may have contributed to this difference. Although the prevalence of hyperglycemia and its association with outcomes in foals is not well documented, there is a general acceptance that it is common and that it could be associated with poor outcomes [
31]. Once more, Hollis et al., 2008 [
22] did not find any association between low or moderate hyperglycemia and survival. However, extreme hyperglycemia was associated with a poorer prognosis. In our sample, the low number of foals presenting hyperglycemia did not allow us to perform any kind of interpretation. In our work, besides association tests, a multivariate test was carried out to assess the influence that multiple variables in conjunction could have on the survival of these foals. Blood glucose concentration was the only variable that stood out and reached statistical significance, underlining the importance of measuring this parameter during admission, giving it potential as a prognostic factor.
Transient high creatinine concentrations are frequently found in newborn foals that underwent hypoxic episodes during parturition, or in cases where maternal or placental abnormal conditions are reported [
32]. Creatinine concentrations tend to decrease more than 50% in 24 h, however, this may not happen in some cases. An increase in creatinine concentrations on these foals may also be a consequence of hypovolemia with subsequently decreased renal perfusion or a result of nephrotoxic drugs, which, if not solved promptly, may lead to death [
32]. A previously retrospective study that included 78 foals with NE reported that hypercreatinemia was one of the most common (32%) laboratory abnormalities found [
7]. Even so, this percentage is lower than in our sample (61.8%). Although the same abnormality was common in Lyle-Dugas et al., 2017 [
9]’s work, no association with survival was found. Similarly, Chaney et al., 2010 [
32] did not find any significant difference in the creatinine means between survival and non-survival foals admitted at the hospital. As such, both articles presented contrasting results when compared with our work. Nevertheless, Dembek et al., 2014 [
28] found significant differences in the creatinine median between survival and non-survival foals (2.3 and 4.3 mg/dL, respectively) being in line with our results, although we found slightly lower medians (1.95 and 3 mg/dL respectively).
According to McKenzie 2018 [
12], anemia is a common finding in premature foals as well as hypoglycemia. Although in this study there was no association between these mentioned variables, anemic foals presented greater odds of dying. Similarly, Giguère et al., 2017 [
27] reported that low red blood cell count was associated with non-survival.
Regarding FPTI, there is still some controversy, with some studies finding that foals presenting FPTI were less likely to survive [
14], while others did not find any association [
26]. In our study, no association was found either. One possible reason for this discrepancy between studies may be related to the IgG levels of the foals included in these studies. In our study, all the foals had IgG levels between 400 mg/dL and 800 mg/dL, which is considered a partial failure of the transfer of immunity and not a total failure. This condition, unlike total failure, is easily reversible in most cases and may not have any major consequences for the foal [
12], which may have contributed to the lack of statistical association between the presence of this condition and death.
The other clinical and laboratory parameters evaluated during admission, like heart rate, respiratory rate, total protein, and BUN, did not show an association with survival. This is consistent with some previous reports [
9,
26,
27,
33].
Most of the foals included in this study developed at least one comorbidity during hospitalization. This finding is in line with the literature which mentions that, given the debilitated state of many of these foals, worsening of their clinical condition is common [
1].
Pneumonia is a well-known cause of morbidity and mortality in foals since it increases the risk of sepsis. Depending on the severity, the respiratory distress also makes it difficult for the foal to feed and contributes to hypoxia [
12]. Therefore, the association found in our study between the development of this comorbidity and mortality was expected and it is in line with several previous studies [
9,
12,
27,
34]
Regarding septicemia, the present study stands out from others by presenting a few cases of foals that developed septicemia (13.4%). Despite septicemia being one of the most common comorbidities in foals and undoubtedly the leading cause of mortality, the fact that the foals included in this study were admitted early and did not have a complete failure of passive transfer of immunity (FPTI) (<400 mg/dL), may have been factors that significantly impacted the low prevalence of this comorbidity. These foals had the opportunity to receive immediate therapy at all levels, with a rapid normalization of IgG levels and, consequently, of their immunity. Furthermore, the fact that the presence of sepsis on admission was considered an exclusion criterion in this study may have contributed to the low number of foals with this comorbidity. Nevertheless, all the foals that developed sepsis died, underlying the results of other studies, which also found an association between septicemia and non-survival [
9,
10,
27].
The retrospective nature of the study led to some limitations. Not all the medical records were completed and the time frame between clinical cases could have some impact on the outcome of the foals given the differences in the diagnostic and therapeutical skills.