Review Report

Neurologic dysfunction in newborn calves: understanding neonatal encephalopathy in clinical practice

Bailey Bailey, Ramanathan Kasimanickam

College of Veterinary Medicine, Washington State University, Pullman, WA, USA

Abstract

Neonatal encephalopathy (NE), a clinically important syndrome causing neurologic dysfunction in newborn calves, contributes to early-life morbidity and mortality. Affected calves exhibit impaired adaptation to extrauterine life, including delayed or absent respiration, difficulty standing, and ineffective nursing, compromising colostrum intake, passive immunity transfer, and overall viability. NE reflects a clinical presentation rather than a specific etiologic diagnosis and may result from hypoxic-ischemic injury, metabolic disturbances, trauma, infection, or intoxication. Historical terms such as ‘dummy calf’ and weak calf syndrome lack diagnostic precision and should be interpreted cautiously. Neonatal maladjustment syndrome, derived largely from equine and human literature, represents a proposed mechanistic subset of NE, potentially involving persistent neurosteroid activity but remains speculative in calves. Emerging hypotheses, including neurosteroid persistence and maternal gut microbiome influences, may contribute to neonatal maladaptation but require further validation. Management is primarily supportive whereas prevention should focus on dystocia reduction, timely obstetric intervention, and optimized periparturient and early neonatal care. Clarifying terminology and understanding underlying mechanisms is essential to improve clinical decision-making and research interpretation.

Keywords: Cattle, calf, neonatal encephalopathy, maladjustment syndrome, perinatal hypoxia, progesterone, gut microbiome

 

Citation: Clinical Theriogenology 2026, 18, 13247, http://dx.doi.org/10.58292/CT.v18.13247

Copyright: © 2026 The Author(s). This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/), permitting all noncommercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Published: 07 April 2026

CONTACT: Ramanathan Kasimanickam ramkasi@wsu.edu

Competing interests and funding: None to report.

 

Introduction

Newborn calves must achieve several critical physiologic and behavioral milestones within hours after birth to ensure survival and long-term health. One of the most immediate is initiation of respiration that ideally occurs within 30 seconds after umbilical cord separation.1–3 This is followed by the ability to assume a sternal position within minutes and to attempt standing within 15-30 minutes postpartum.2 Effective nursing is equally essential, with the first successful intake of colostrum ideally occurring within the 2 hours after birth.1–5 This period represents the window of maximal absorption of immunoglobulin (Ig) G and IgA across the small intestine and is critical for establishing passive and mucosal immunity.6,7 Failure to achieve these early milestones is associated with increased neonatal morbidity and mortality and may reflect underlying systemic or neurologic dysfunction. Such failures are frequently linked to events occurring during late pregnancy, parturition, or the immediate postpartum period, underscoring the importance of periparturient management in determining neonatal neurologic outcomes.

One important cause of impaired neonatal adaptation is neonatal encephalopathy (NE), a clinical syndrome describing neurologic dysfunction occurring within the first days of life.8–10 NE is characterized by altered mentation, abnormal reflexes, impaired motor function, seizures, abnormal respiratory patterns, or failure to perform expected neonatal behaviors such as standing and nursing. Importantly, NE is a clinical descriptor rather than an etiologic diagnosis. When a specific cause, such as trauma, infection, intoxication, metabolic disease, or hypoxic-ischemic injury (HII) is identified, the diagnosis should reflect that underlying etiology rather than NE itself. The clinical manifestations and severity of NE vary widely depending on the underlying cause and extent of neurologic injury.

The term neonatal maladjustment syndrome (NMS) has been proposed as a mechanistic subset of NE, based largely on work in foals and extrapolated to calves in limited experimental studies.8–10 In this context, NMS refers to impaired neurologic transition to extrauterine life, hypothesized to involve persistent neurosteroid activity rather than overt structural brain injury.10–12 However, peer-reviewed evidence supporting NMS as a distinct and clinically defined syndrome in calves remains limited, and the term should therefore be applied cautiously in bovine practice and research.

In clinical settings, the colloquial term ‘dummy calf’ is often used to describe neonates with abnormal mentation or behavior. However, this label lacks diagnostic specificity and should not be considered synonymous with NMS or NE.8–12 Similarly, calves with hypoxic-ischemic encephalopathy (HIE) represent a distinct and clinically significant subset of NE with differing pathophysiology, prognosis, and therapeutic implications. Conflating HIE with maladjustment terminology risks obscuring meaningful distinctions relevant to clinical management and outcome prediction.

Calves affected by NE commonly exhibit central nervous system (CNS) dysfunction that interferes with early postnatal behaviors essential for survival. Clinical features may include disorientation or lethargy, impaired maternal bonding, absence or weakness of the suckle reflex, abnormal responses to sensory stimuli, incoordination, seizures, and failure to thrive. These abnormalities may be evident at birth or may develop within the first hours to days of life, depending on the underlying cause and timing of injury.

The historical term weak calf syndrome (WCS) has also been used to describe neonatal calves that are unable to stand, nurse, or thrive. However, WCS represents a broad and nonspecific umbrella encompassing infectious, nutritional, congenital, environmental, and neurologic causes of neonatal weakness.8,10 Continued use of this term risks obscuring clinically relevant distinctions among disease processes and complicating diagnostic, therapeutic, and preventive decision-making.

Accordingly, this review focuses on NE in calves, emphasizing clinical recognition, differential diagnosis, and established etiologies such as HII, metabolic disturbances, and traumatic birth-related insults. Proposed maladaptive mechanisms are discussed where relevant. In addition, the review considers management and prevention strategies with particular emphasis on periparturient factors, including dystocia, obstetric intervention, and early neonatal care. Clarifying terminology and disease mechanisms is essential to improving clinical decision-making, accurately interpreting the existing literature, and optimizing outcomes for neonatal calves.

Clinical signs

As outlined above, NE encompasses a spectrum of clinical signs reflecting CNS dysfunction occurring within the first days of life and is therefore considered a clinical syndrome rather than a single disease entity.8–10 Affected calves fail to achieve normal postnatal milestones, including timely initiation of respiration, standing, and nursing, behaviors essential for survival and early neonatal health.

Clinically, calves with NE may appear alert but exhibit abnormal behavior and impaired neurologic function.11–13

Common clinical signs include:

Additional clinical signs may include:

These neurologic deficits are consistent with NE across species and may be observed in calves with a variety of underlying etiologies, including HII, metabolic derangements, trauma, or other perinatal insults. The presence, severity, or combination of clinical signs does not reliably distinguish among etiologies and must be interpreted in the context of periparturient history, calving events, and concurrent systemic disease. There are 2 general temporal patterns:

  1. Immediate onset with neurologic abnormalities evident at birth
  2. Delayed onset with clinical signs developing within the first several hours postpartum

In severe cases, NE may result in perinatal mortality, including stillbirth or death within the first 48 hours of life.14

Diagnosis

Diagnosis of NE is clinical and presumptive, based on the identification of neurologic dysfunction in the early neonatal period following initial evaluation for infectious, metabolic, or traumatic causes.10 Definitive etiologic diagnosis is often not possible antemortem, particularly in field settings.

When necropsy is performed, gross and histologic findings may support identification of a specific underlying etiology rather than NE itself. Lesions such as cerebral edema, neuronal necrosis, and malacia are consistent with HIE and indicate hypoxic brain injury as the cause of neurologic dysfunction.15–23 In some cases, however, no gross or histologic abnormalities are identified, particularly when neurologic dysfunction reflects functional rather than structural disturbances of the CNS.

Prevalence and economic impact

Estimates of the prevalence of NE in calves are limited, in part because of inconsistent terminology and variable case definitions within the literature. Reports describing weak or nonviable calves have suggested overrepresentation in certain beef breeds; however, dairy calves may also be affected, potentially reflecting differences in calving management and periparturient care.14 These associations are often weak or statistically insignificant, and clear breed predisposition has not been established.12,13

At the herd level, NE is typically sporadic, with prevalence influenced by herd size, calving supervision, nutritional status of the dam, and environmental conditions.12,13 Periodic increases in the number of weak or neurologically abnormal calves attributable to NE are often initially attributed to infectious causes; however, noninfectious contributors such as dystocia, prolonged parturition, nutritional deficiencies, and weather-related stressors should also be considered.13–17

Management of calves affected by NE frequently requires intensive supportive care, including assisted feeding,20–22 thermoregulation,18,19 monitoring, and environmental support.5,10,13,17–19 These interventions are labor-intensive and may be particularly challenging during peak calving periods. As a result, producers must balance the likelihood of survival and long-term productivity against the availability of labor and resources. Decisions regarding continued treatment versus culling are influenced by operation size, staffing, economic considerations, and prior experience with neonatal morbidity.

From a production standpoint, an annual calf crop loss of ~ 2% or less is generally considered acceptable for most operations. When losses exceed this threshold, herd-level investigation and modification of management practices, particularly those related to dystocia prevention, obstetric intervention, periparturient monitoring, and environmental protection18,19 may be warranted to reduce economic loss and improve animal welfare.

Etiology

Although the pathophysiology of NE in calves is not fully defined, a substantial body of evidence, particularly from human and equine medicine, has informed current understanding of established etiologies, most notably HIE. Comparative studies across species have identified several periparturient risk factors relevant to calves, including perinatal hypoxia, dystocia, placental insufficiency, umbilical cord compromise, and excessive traction during assisted parturition.24 Although species-specific differences exist, the fundamental mechanisms underlying hypoxic-ischemic brain injury are broadly conserved across mammals, supporting cautious extrapolation of these models to bovine neonates.

One well-characterized pathogenic mechanism underlying NE involves disruption of cerebral blood flow and oxygen delivery to the neonatal CNS. Causes of hypoxia-ischemia include dystocia, excessive force during assisted parturition, umbilical cord compression, in utero infection, premature placental separation, and placental insufficiency.5,16,25–30 Oxygen and glucose deprivation within the brain results in adenosine triphosphate depletion, lactate accumulation, cellular swelling, mitochondrial dysfunction, and injury to neuronal and glial cells.31–35 Secondary injury cascades include cytokine production, protease activation, generation of reactive oxygen species and nitric oxide, dysregulation of sodium and calcium fluxes, and excessive excitatory neurotransmitter release.34,35 Collectively, these processes predispose affected calves to reperfusion injury, cerebral edema, neuronal necrosis, excitotoxic damage, and blood-brain barrier disruption.36,37 These changes are characteristic of HIE and may result in permanent neurologic dysfunction.

A second proposed mechanism involves persistent neurosteroid activity and impaired neonatal neurologic transition, a hypothesis derived primarily from equine and human literature and extrapolated to calves.37,38 Neurosteroids are synthesized within the CNS from peripheral steroid precursors and include several compounds, most notably progestogens.38–42 These substances modulate γ-aminobutyric acid (GABA) and other receptor systems, promoting neuronal hyperpolarization and sedation.39–42 Allopregnanolone and pregnanolone are among the most potent sedative progestogens.41–44 Although such effects are physiologically beneficial in utero and during parturition, persistence of elevated progestogen concentrations after birth has been hypothesized to interfere with normal neonatal behavioral adaptation.44

Calves delivered by cesarian section may be predisposed to prolonged neurosteroid exposure due to altered parturition signaling and incomplete activation of fetal-to-neonatal transition pathways.44–52 However, elevated progesterone concentrations have also been documented following vaginal delivery, particularly in cases of dystocia.49,50 Importantly, neurosteroids may exert context-dependent neuroprotective effects, potentially mitigating ischemic injury or supporting recovery following traumatic brain injury.5,44–52 At present, persistent neurosteroid activity in calves should be regarded as a proposed contributory mechanism affecting a subset of NE cases, rather than an established or primary cause of hypoxic-ischemic brain injury.

Respiratory acidosis may further contribute to neurologic depression in affected neonates.53 Initiation of effective respiration represents the calf’s first critical postnatal physiologic challenge, and failure to establish ventilation is incompatible with life.54–57 All calves experience some degree of acidosis during parturition, even following uncomplicated deliveries, due to transient hypoxia and carbon dioxide accumulation.53,58,59 Most neonates compensate through increased respiratory effort, facilitating carbon dioxide elimination and correction of acid-base imbalance.53–61 However, prolonged or severe hypercapnia may impair this compensatory response, resulting in CNS depression and delayed initiation of respiration.54–61

In such cases, reduced neonatal vigor and survival may occur secondary to hypoxemia and metabolic disturbances rather than primary structural neurologic injury. This mechanism represents a functional rather than structural contributor to NE. Further research is needed to clarify the contribution of respiratory and metabolic derangements to the development and severity of NE in calves.

Risk factors

Many factors described in the literature relate broadly to neonatal morbidity, calf vigor, and survival rather than specifically to neonatal encephalopathy (Figure 1). Where applicable, these factors are discussed here in the context of their potential to contribute to perinatal hypoxia, impaired physiologic transition, or increased susceptibility to neurologic injury, rather than as direct causes of encephalopathy.

Figure 1.
Figure 1. Risk factors for neonatal calf morbidity

Several maternal, fetal, and periparturient factors have been associated with abnormal neonatal behavior or weakness and may influence the development or severity of NE, particularly when they predispose calves to HII. Although NMS has been proposed to describe a subset of calves with impaired postnatal neurologic transition, evidence supporting this entity as a distinct diagnosis in calves remains limited. Accordingly, the factors discussed below should be interpreted primarily as contributors to neonatal morbidity with potential relevance to NE in specific clinical contexts. The historical designation WCS is used in the literature to describe heterogeneous causes of neonatal weakness and is avoided here as a diagnostic category.

Maternal nutrition

Maternal nutrition, particularly during late pregnancy, has a critical role in fetal growth and neonatal viability. Dams with inadequate protein intake are more likely to produce weak or poorly viable calves.62–64 Approximately ⅔ of fetal growth occurs during the final 90 days of pregnancy, during which the fetus gains approximately 1 pound per day.62–64 Diets containing less than 10% crude protein during this period are associated with reduced offspring performance and increased neonatal morbidity.62–64 Although these studies do not specifically evaluate NE, inadequate maternal nutrition may indirectly increase susceptibility to neurologic dysfunction by contributing to low birth weight, reduced vigor, impaired thermoregulation, or increased dystocia risk. Protein intake is also essential for immunoglobulin synthesis, and undernourished dams may produce calves at greater risk for failed passive transfer.65

Thermoregulation and hypothermia

Impaired thermoregulation increases the risk of hypothermia and neonatal morbidity. Severe hypothermia is defined as a body temperature below 95°F (35°C).66,67 Inadequate thermoregulation is often related to insufficient brown adipose tissue, limiting neonatal heat production.60 Hypothermic calves may exhibit weakness, delayed standing, reduced suckle reflexes, impaired colostrum absorption, and increased mortality.66–71 Although hypothyroidism is not considered a common primary cause of neonatal weakness, thyroid hormones have a critical role in thermoregulation, and altered neonatal thyroid hormone concentrations may reflect impaired physiologic adaptation.69 These factors may exacerbate weakness or delay neonatal transition but should not be interpreted as direct causes of NE.

Damage and parity

Dam age and parity influence neonatal outcomes primarily through their association with dystocia and maternal nutritional demands. Heifers are at increased risk for dystocia and cesarian delivery, and calves born under these conditions may demonstrate reduced vigor or abnormal neonatal behavior.72–74 These associations likely reflect increased risk of perinatal hypoxia rather than a specific maladaptive neurologic syndrome. Older cows may also produce weaker calves if declining dentition or body condition limits nutrient intake despite acceptable forage quality.

Dystocia

Dystocia is among the most consistently documented and clinically relevant risk factors associated with neonatal mortality and neurologic dysfunction.5,10,71 Calves born following dystocia are more likely to experience perinatal hypoxia and metabolic acidosis, central mechanisms underlying hypoxic-ischemic encephalopathy, a well-established cause of NE.5,10,53 Factors contributing to dystocia include malpresentation, fetopelvic disproportion, prolonged labor, parity, fetal sex, pregnancy length, and twinning. Persistent acidosis may impair suckle reflexes and reduce immunoglobulin absorption even in calves that initially appear viable.5,53 When maternal nutrition is adequate, dystocia remains the most important modifiable risk factor associated with neonatal neurologic injury.

Environmental conditions

Environmental stressors such as cold, moisture, and wind increase heat loss and exacerbate cold stress in neonatal calves, particularly in the absence of adequate shelter.75,76 Severe weather conditions are associated with reduced dam productivity and increased neonatal mortality.75,76 Cold exposure increases metabolic demand and glucose utilization, which can be especially problematic for calves unable to nurse effectively. Although these factors contribute to neonatal morbidity and mortality, their role in NE is likely indirect and mediated through hypothermia,18,19 hypoglycemia,20–22 or delayed neonatal transition rather than primary neurologic injury.

Micronutrient deficiencies

Micronutrient deficiencies have been associated with neonatal weakness and mortality and may indirectly increase susceptibility to hypoxia or impaired neonatal adaptation. Selenium and vitamin E deficiencies are associated with white muscle disease, placental dysfunction, and increased risk of perinatal hypoxia.77,78 Severe selenium deficiency may result in fatal cardiac lesions. Iodine deficiency may lead to goiter and hypothyroidism, impairing thermoregulation and neonatal viability.68 Vitamin A deficiency has been associated with increased calf mortality and a range of clinical signs, including neurologic abnormalities, although these findings reflect systemic developmental effects rather than primary encephalopathy.77,78 These deficiencies should be considered contributors to generalized neonatal morbidity rather than direct causes of NE.

Infectious causes

During periods of increased neonatal morbidity, infectious diseases must be considered as important differential diagnoses rather than causes of neonatal encephalopathy.29,79,80 Bovine viral diarrhea virus infection may result in abortion, congenital abnormalities, or persistently infected calves, depending on the timing of fetal exposure.79 Leptospirosis, particularly infection with Leptospira hardjo, may cause abortion, stillbirth, or placental insufficiency.29 These conditions may produce weak or nonviable calves but represent distinct disease processes with different diagnostic, therapeutic, and preventive implications and should be differentiated from NE.

Major maternal, pregnancy, calving, environmental, early neonatal management risk factors contributing the syndrome. The condition is multifactorial and arises from interactions among prenatal nutrition, gut microbiome, placental and fetal development, parturition stress and environmental exposure at birth and impaired colostrum acquisition. These risk factors predispose to NE or general neonatal weakness, but only some directly contribute to neurologic injury (e.g. dystocia-related hypoxia).

Emerging pathophysiological theories

The following sections describe emerging hypotheses that may contribute to impaired neonatal neurologic adaptation or generalized neonatal morbidity in calves. These concepts are derived largely from human, rodent, and equine literature and should be interpreted as biologically plausible mechanisms requiring further validation in bovine populations. Where relevant, potential links to NE, neonatal maladjustment, or weak calf syndrome are discussed, with emphasis on distinguishing contributory factors from established etiologies.

Theory 1. Neurosteroid activity and the role of progesterone in neonatal brain function

Progesterone is widely recognized as a reproductive hormone essential for estrous cycle regulation and maintenance of pregnancy. Increasing evidence, however, demonstrates that progesterone also has important roles in CNS development, modulation, and protection.81 As a neurosteroid, progesterone is synthesized locally within the CNS and influences neural excitability, neurodevelopment, and adaptive responses to injury. This section reviews established and emerging roles of progesterone in brain physiology, with emphasis on mechanisms potentially relevant to neonatal neurologic transition rather than as primary causes of neonatal encephalopathy.

Progesterone as a neurosteroid

Although progesterone is primarily produced by the ovaries, adrenal glands, and placenta, it is also synthesized within the CNS by neurons and glial cells. This endogenous production classifies progesterone as a neurosteroid, enabling paracrine and autocrine effects within neural tissue. Neurosteroids exert many of their effects through modulation of neurotransmitter systems, particularly GABA system. Progesterone metabolites, most notably 3α, 5α-tetrahydroprogesterone (allopregnanolone), act as positive allosteric modulators of the γ-aminobutyric acid type A (GABAA) receptor and exhibit barbiturate-like pharmacologic activity.81,82

Through enhancement of GABAergic inhibition, progesterone and its metabolites exert sedative, anxiolytic, and anticonvulsant effects and contribute to regulation of arousal states and sleep architecture.81,82 These properties are particularly relevant during the perinatal period, when rapid neuroendocrine transitions are required to facilitate postnatal behavioral adaptation.

Neuroprotective effects of progesterone

Progesterone has well-documented neuroprotective effects in experimental models, including reduction of neuroinflammation, limitation of excitotoxicity, and inhibition of apoptotic pathways following neural injury. In animal models of traumatic brain injury, progesterone treatment has been associated with improved neurologic outcomes, including reductions in cerebral edema, oxidative stress, and neuronal loss.83,84 Progesterone also supports oligodendrocyte function and myelin synthesis, contributing to axonal conduction and neural network integrity.85

Progesterone further modulates expression of neurotrophic factors such as brain-derived neurotrophic factor that has a critical role in neuronal survival, synaptic plasticity, and adaptive learning processes.85–87 Collectively, these findings support a biologically plausible neuroprotective role for progesterone but do not establish it as a primary driver of neonatal neurologic disease.

Cognitive, behavioral, and affective effects

Progesterone influences multiple domains of cognitive and behavioral function, including learning, attention, mood regulation, and stress responsiveness.88 Fluctuations in progesterone concentrations have been associated with variable effects on cognition and behavior across species and life stages.89,90 Dysregulation of progesterone signaling has been implicated in affective disorders such as premenstrual dysphoric disorder, postpartum depression, and perimenopausal mood instability, largely mediated through neuroactive metabolites such as allopregnanolone acting on GABAA receptors.91,92

These observations have prompted investigation of progesterone-based therapies for mood and neurologic disorders, including traumatic brain injury, epilepsy, and neurodegenerative disease.83,84,93–97 However, results from large clinical trials have been mixed, underscoring the complexity of progesterone signaling and the importance of timing, dosage, and physiologic context.

Progesterone in domestic animals and relevance to neonatal calves

In veterinary medicine, progesterone has been evaluated primarily in the context of seizure disorders and behavior modulation in small animals.98–102 In dogs, progesterone and its metabolites may exert anticonvulsant effects through enhancement of GABAergic inhibition, paralleling mechanisms described in humans.99–101 In large animal species, fluctuations in progesterone concentrations have been associated with behavioral changes and altered stress responsiveness, suggesting broader neuroendocrine effects.103

In ruminants, progesterone is essential for establishment and maintenance of pregnancy and for supporting fetal development.103–105 It promotes uterine quiescence, endometrial receptivity, and secretion of histotroph necessary for early embryonic and fetal development prior to placental maturation.106 Throughout pregnancy, progesterone contributes to regulation of uterine blood flow, immune tolerance, and placental function, thereby supporting fetal growth and organ development.107

Disruptions in progesterone signaling during pregnancy have been proposed as contributors to syndromes such as WCS, characterized by calves born alive but weak, unresponsive, or unable to stand and nurse.5,13,17 Inadequate placental development or function, potentially influenced by suboptimal maternal progesterone concentrations during critical pregnancy windows, may impair fetal muscle and neurologic maturation. Conversely, persistence of elevated neurosteroid concentrations in the neonate has been hypothesized to interfere with postnatal arousal and behavioral adaptation, particularly in calves delivered by cesarean section or following dystocia.

At present, altered progesterone or neurosteroid dynamics should be regarded as proposed contributory mechanisms affecting neonatal vigor or behavioral adaptation, rather than established causes of neonatal encephalopathy.

Theory 2. Maternal gut microbiota and fetal gut-brain axis development as a contributor to weak calf syndrome

The maternal gut microbiota is increasingly recognized as an important regulator of fetal development through its influence on gut-brain axis (GBA). Although this concept has been extensively studied in human and rodent models, its relevance to bovine neonatal health remains largely unexplored. Dysbiosis-associated alterations in fetal neurodevelopment, enteric nervous system maturation, immune programming, and stress-response pathways represent a biologically plausible but unproven mechanism contributing to WCS rather than NE per se.

The WCS is characterized by calves born alive but weak, unable to stand or nurse, and exhibiting poor muscle tone, failure to thrive, and increased susceptibility to disease. The etiology of WCS is multifactorial and includes genetic, nutritional, environmental, metabolic, and infectious contributors. Emerging evidence suggests that maternal influences on fetal development, including maternal gut microbiota composition, may represent an underrecognized risk modifier.

Gut-brain axis development and neonatal function

Although the fetal GBA is not functionally active in utero, its structural and regulatory components develop during pregnancy under the influence of maternal microbial signaling.108 A balanced maternal microbiome produces metabolites such as short-chain fatty acids,109 neurotransmitter precursors (e.g. serotonin, GABA), and immune-modulating molecules that may cross the placenta and influence fetal CNS and enteric nervous system development, immune priming, and hypothalamic-pituitary-adrenal axis maturation.110–112

Disruption of these developmental processes may plausibly contribute to impaired neuromuscular coordination, delayed suckling behavior, gastrointestinal dysfunction, and increased disease susceptibility observed in weak calves.

These mechanisms are consistent with clinical observations in calves born to dams with suboptimal health, body condition, or dietary management but direct causal relationships have not been established.

Comparative evidence and research gaps

Most mechanistic evidence regarding fetal GBA development originates from human and rodent studies.46,47,109,119–124 Nevertheless, core biologic principles appear conserved across mammalian species. In precocial species such as cattle, late pregnancy represents a critical period for neural myelination, enteric nervous system maturation, and cortisol-mediated physiologic preparation for birth. Disruption of maternal microbiota signaling during this window could plausibly result in calves with reduced neuromotor tone, impaired thermoregulation, ineffective suckling, and delayed gastrointestinal and immune function.118

At present, maternal gut dysbiosis should be regarded as a theoretical and investigational contributor to WCS rather than a demonstrated cause of NE. Further controlled studies in cattle are required before management recommendations can be made.

Therapeutic options

Neonatal encephalopathy

Currently, the management remains primarily supportive, focusing on stabilization of vital functions, prevention of secondary injury, and optimization of neonatal adaptation.52,120,125,126 Therapeutic interventions are largely symptom-directed and must be tailored to the severity of neurologic dysfunction, systemic compromise, and concurrent metabolic disturbances.

Respiratory support

Respiratory dysfunction is a prominent feature of NE, often resulting from HII, perinatal asphyxia, or delayed postnatal adaptation.58,124 The HII is the primary driver of respiratory compromise in NE. Initial management involves ensuring airway patency, including manual removal of mucus or debris from the nasal and oral cavities. Historical practices such as suspension by the hind limbs to drain fluid are discouraged because of the potential for diaphragmatic compression and impaired ventilation; if used, suspension should not exceed 90 seconds.122

Supportive measures include stimulating the nostrils with a finger or straw, mimicking maternal licking through vigorous rubbing, or brief application of cool water to the head to initiate reflexive respiration.58,123 Positioning in sternal recumbency is critical for optimal lung expansion, whereas lateral recumbency may compromise ventilation in the dependent lung. Supplemental oxygen therapy may be indicated in calves failing to establish spontaneous respiration, delivered via flow-by, resuscitation bag, or endotracheal intubation with mechanical ventilation.58,124 Manual ventilation (mouth-to-mouth or mouth-to-nose) is less effective and carries zoonotic risk. Pharmacologic respiratory stimulants, including doxapram, caffeine, and epinephrine, have been utilized in emergency scenarios to enhance ventilation, improve arterial oxygenation, and promote bronchodilation, though these remain extra-label interventions in cattle and require adherence to food animal residue avoidance databank (FARAD) withdrawal guidelines.58,127,128

Metabolic and acid-base management

Calves with NE frequently exhibit mixed respiratory and metabolic acidosis due to hypoxia, impaired perfusion, and lactate accumulation.58 Management focuses on restoring adequate oxygenation and ventilation rather than solely correcting acid-base imbalance chemically, as indiscriminate use of sodium bicarbonate may exacerbate hypercapnia in hypoxemic calves. Intravenous fluids and glucose supplementation are indicated when hypoglycemia or poor energy reserves are present, supporting cellular metabolism and promoting early neonatal activity. In NE, lactate-driven metabolic acidosis may persist despite restoration of ventilation and perfusion.

Analgesia and pain management

Parturition-associated trauma may result in musculoskeletal injury, spinal cord compromise, or visceral trauma, necessitating analgesic intervention. Nonsteroidal antiinflammatory drugs (NSAIDs), including meloxicam, flunixin meglumine, or ketoprofen, have been employed to reduce pain, shorten recumbency periods, and facilitate earlier initiation of colostrum intake.58,129 Pain management may indirectly support neurologic recovery by improving mobility and systemic oxygen delivery.

Thermoregulation

Hypothermia is a common secondary complication in calves with NE and may exacerbate neurologic and systemic dysfunction. Supportive strategies include drying the neonate, removal from environmental stressors, and the use of external heat sources such as heated pads, lamps, or warm towels. Warm water baths (~ 37.5°C) may be considered if followed by immediate drying.53 Rapid rewarming, however, may not confer benefit in calves with primary hypoxic–ischemic brain injury, highlighting the importance of differentiating environmental hypothermia from neurologically mediated thermoregulatory impairment. Therapeutic hypothermia (33.5°C for 72 hours) has demonstrated neuroprotection in human neonates with HIE,130 but its efficacy and safety in calves remain untested. It is important to distinguish environmental hypothermia from neurologically mediated thermoregulatory dysfunction.

Nutritional support

Giving colostrum early in life is essential to support passive immunity, energy metabolism, and neonatal adaptation. Calves with NE often demonstrate weak suckle reflexes, necessitating assisted feeding via bottle, orogastric tube, or direct dam nursing.131 In severe cases, intravenous dextrose may be provided to meet immediate energy requirements. Extended absorption windows and impaired immunoglobulin uptake are common, and failure of passive transfer is indicated by serum total protein < 5.0 mg/dl.132 Plasma transfusion serves as an alternative when colostrum intake is insufficient, or absorption is inadequate.

Considerations for neurosteroid-associated syndromes

Therapies such as the Madigan squeeze technique (MST), described below, is designed to address persistent neurosteroid activity in maladaptive neonates, are not appropriate for NE resulting from HII, metabolic derangements, or infectious etiologies.48 In these contexts, interventions must target stabilization of organ function, correction of metabolic disturbances, and mitigation of secondary injury rather than manipulation of neurobehavioral states. Mechanistic rationale is extrapolated from equine studies; controlled trials in calves are lacking.

Neonatal maladjustment syndrome

At present, there is no definitive or disease-specific treatment for NMS in calves, particularly when the underlying etiology is unclear. Management is therefore primarily supportive and directed toward stabilization of vital functions, facilitation of neonatal physiologic transition, and prevention of secondary complications.52,120,125,126 Therapeutic interventions should be individualized based on clinical presentation, severity of neurologic depression, and the presence of concurrent metabolic, respiratory, or traumatic conditions (Table 1).

Table 1. Therapeutic considerations for neonatal encephalopathy (NE) versus neonatal maladjustment (NMS)
Therapeutic domain NE NMS Similarities
Respiratory support Focus on hypoxia and perfusion; oxygenation, mechanical ventilation Focus on maladaptive neurobehavior; oxygenation plus adjuncts like GV-26 acupuncture Airway clearance, positioning, supplemental O2, emergency stimulants
Metabolic/acid-base Lactate-driven metabolic acidosis; intravenous glucose, restore perfusion Respiratory acidosis from hypoventilation; resolves with improved ventilation Prioritize ventilation over chemical correction
Thermoregulation May reflect brain injury; aggressive rewarming less effective; experimental hypothermia untested Often secondary to weakness; controlled rewarming effective Drying, environmental control, external heat sources
Nutritional support Weak suckle reflex due to neurologic depression; colostrum, intravenous glucose, plasma as needed Weak suckle due to maladaptive behavior; colostrum, intravenous glucose, MST may assist feeding Assisted feeding, plasma transfusion if passive transfer fails
Pain management Supports mobility and systemic recovery Reduces trauma-related discomfort; facilitates behavioral normalization NSAIDs as adjunct, shorten recumbency
Condition-specific therapy MST not indicated; focus on stabilization and metabolic correction MST may improve neurobehavioral adaptation Supportive care remains cornerstone

Respiratory support

Establishment and maintenance of effective ventilation is the initial priority in calves with suspected NMS. Immediate interventions include clearing the nasal passages and oral cavity of mucus or fluids, which may be performed manually or using a bulb syringe.58 Historical practices such as suspending calves by the hind limbs to facilitate fluid drainage are discouraged, as gravitational displacement of abdominal viscera may restrict diaphragmatic excursion and impair ventilation.122 If attempted, suspension should be brief and not exceed 90 seconds.

Additional stimulation techniques aimed at initiating respiration include tactile stimulation of the nostrils with a finger or straw, vigorous rubbing with towels to mimic maternal licking, or pouring a small amount of cold water over the head.58,123 Proper positioning is critical; sternal recumbency promotes bilateral lung expansion, whereas lateral recumbency compromises ventilation of the dependent lung.

Supplemental oxygen may be indicated for calves that fail to establish spontaneous breathing or remain hypoxemic. Delivery methods include flow-by oxygen, resuscitation bags, or endotracheal intubation with mechanical ventilation.58,124 Manual ventilation using mouth-to-mouth or mouth-to-nose techniques is less effective and poses zoonotic risk.

Acupuncture at the Governing Vessel 26 (GV-26) point has been described as an adjunctive method to stimulate endogenous catecholamine release and support respiratory drive, particularly in cases of apnea.58 Although widely used in equine neonatology, evidence supporting its efficacy in calves remains limited.

Pharmacologic respiratory stimulants such as doxapram, caffeine, and epinephrine may be considered in emergency settings.58,127,128 Doxapram acts as a central respiratory stimulant and may transiently improve ventilation and arterial blood gases. Caffeine and epinephrine promote bronchodilation and cardiovascular support. These agents are used extra-label in cattle, and appropriate withdrawal intervals should be determined using FARAD guidance.

Pain management

Calves experiencing dystocia or traumatic delivery may suffer musculoskeletal injury, soft tissue trauma, or less commonly fractures or spinal cord injury. Appropriate analgesia is therefore an important component of supportive care; NSAIDs, including flunixin meglumine, ketoprofen, or meloxicam (extra-label in the United States), may reduce pain, inflammation, and recumbency time, potentially improving mobility and the likelihood of successful colostrum intake.58,129 Analgesic use should be balanced against hydration status and renal function.

Management of respiratory and metabolic acidosis

Calves with NMS frequently exhibit respiratory acidosis secondary to hypoventilation.58 Management should focus on improving ventilation and oxygen delivery rather than chemical correction. Sodium bicarbonate treatment is generally discouraged in hypoventilating calves, as it may worsen hypercapnia and intracellular acidosis if carbon dioxide elimination remains impaired.

In cases of perinatal asphyxia, a mixed respiratory-metabolic acidosis may be present. Although respiratory components often improve rapidly with effective ventilation, lactate-driven metabolic acidosis may persist longer and typically resolves with restoration of tissue perfusion and oxygenation rather than direct buffering.

Thermoregulation

Hypothermia is common in compromised neonates and contributes to weakness, hypoglycemia, and impaired immune function. Initial management includes drying the calf, removing environmental stressors, and providing external heat using warm towels, heat lamps, or warming pads. Warm water immersion (~ 37.5°C) may be considered if followed by thorough drying to prevent evaporative heat loss.

It is important to distinguish environmental hypothermia from neurologic depression due to hypoxic–ischemic injury, as calves with true brain injury may demonstrate limited response to aggressive rewarming.53 Therapeutic hypothermia has demonstrated neuroprotective benefits in human neonates with hypoxic-ischemic encephalopathy,130 but this approach has not been validated in calves. Current veterinary management prioritizes controlled rewarming, particularly when hypothermia is associated with hypoglycemia, inadequate colostrum intake, or environmental exposure.

Colostrum management

Early assessment and support of colostrum intake are essential components of care. Calves with NMS often exhibit weak or absent suckle reflexes, necessitating assisted feeding via bottle, orogastric tube, or supervised nursing from the dam.131 Supplemental intravenous dextrose may be indicated to address hypoglycemia and support energy requirements.

Impaired intestinal motility and delayed gut closure may alter immunoglobulin absorption in affected calves. Serum total protein concentrations below 5.0 g/dl are indicative of failure of passive transfer.132 When enteral absorption is inadequate or delayed beyond the effective window, plasma transfusion provides an alternative means of passive immunity.

Madigan squeeze technique

A technique that has been proposed as a therapeutic intervention for calves with suspected persistent neurosteroid exposure but is unlikely to benefit calves with hypoxic-ischemic brain injury, infectious disease, nutritional deficiencies, or structural trauma.48 Originally developed for equine neonates, MST involves application of sustained thoracic pressure intended to simulate birth canal compression and transiently induce a controlled, sleep-like state (Figure 2).

Figure 2.
Figure 2. Simulating birth canal pressure: Madigan squeeze technique in calves

Procedure overview:

Calves most likely to benefit include those delivered by cesarian, rapidly delivered calves, or calves born following prolonged but nonasphyxiating parturition. In calves with cardiopulmonary compromise (e.g. rib fractures or suspected thoracic injury) MST is contraindicated. Although the technique is low-cost and minimally invasive, controlled studies in calves are limited, and MST should be considered an adjunct rather than a replacement for standard supportive medical care.

Therapeutic options: Comparison of neonatal encephalopathy and neonatal maladjustment syndrome

Neonatal encephalopathy and neonatal maladjustment syndrome in calves share overlapping clinical features, including neurologic depression, impaired respiration, weak suckle reflex, and metabolic disturbances.52,120,125,126 Both conditions require prompt stabilization and supportive care, but the underlying pathophysiology dictates differences in therapeutic priorities and expected responses.

Keypoints

Prevention

Given the absence of definitive curative therapies for NE, prevention remains the most effective strategy. Management of maternal nutrition, minimization of perinatal stressors, and environmental optimization during late pregnancy are central to reducing the risk of NE and supporting fetal growth, neurological maturation, and neonatal vitality.52,85 Last 60 days of pregnancy are particularly critical, as maternal nutrient requirements escalate and fetal growth accelerates.

Nutritional management

Optimal maternal nutrition is essential for supporting fetal development and reducing the incidence of NE. Feed quality should be assessed through forage analysis, and intake must be carefully monitored, as physical constraints (e.g. reduced rumen volume in late pregnancy) may limit consumption. Provision of low-protein forage alone is insufficient; forages with ≥ 12% crude protein (CP) are recommended. When this target cannot be achieved, supplemental protein should be provided, though adequate intake monitoring is necessary to ensure efficacy. For example, providing hay with > 10% CP in combination with at least 2 lb of supplemental protein per cow per day has been associated with improved neonatal outcomes.52,85

Energy requirements vary according to stage of pregnancy, dam parity, environmental conditions, and whether the dam is a growing heifer that may require additional protein and energy to support concurrent maternal growth and fetal development.52,85

Micronutrient and vitamin supplementation is equally critical. Herd mineral status may be assessed through liver biopsy or serum sampling, ensuring representative sampling for accuracy. Selenium deficiency, commonly observed in many regions in USA, predisposes neonates to conditions such as white muscle disease (WMD), often accompanied by vitamin E deficiency.85 Oral supplementation of selenium and vitamin E supports both maternal and fetal health, and whole-blood testing (e.g. 6 weeks later) after supplementation can assess efficacy. Iodine and manganese are also essential during late pregnancy whereas vitamin A supplementation may be required during periods of poor-quality forage, such as drought years.17 Important nutrient and micronutrient recommendations for late pregnancy are summarized (Table 2).

Table 2. Important nutrient and micronutrient recommendations for late pregnancy
Nutrient/ micronutrient Typical requirement Notes/recommendations
Protein 10% CP Increase to ≥ 12% CP
Iodine 0.5 mg/kg Recommended supplementation
Manganese 50 mg/kg Supports neonatal development; may not fully meet dam requirements
Selenium 0.3 mg/kg Maximum safe dosage; oral supplementation preferred

Minimizing dystocia

Dystocia is a well-established risk factor for NE due to perinatal hypoxia and trauma.52,85,131 Preventive measures include culling dams with a history of calving difficulties, selecting sires with demonstrated calving ease, and performing pelvimetry in replacement heifers. Farm personnel should be trained in timely recognition and intervention during dystocia, and established protocols for veterinary consultation are recommended. Proactive management reduces neonatal hypoxia, stress, and trauma, all of which are critical in preventing NE.

Environmental management

Environmental stressors can exacerbate NE risk, particularly in preterm or weak neonates. Providing additional feed energy during periods of severe weather, along with shelter, windbreaks, and straw bedding, supports thermoregulation. A warm, dry environment reduces the energy expenditure required for maintaining body temperature, allowing neonates to prioritize standing, nursing, and establishing early postnatal adaptation.52,131

Herd-level infectious disease management

Maternal vaccination and herd biosecurity are essential components of NE prevention. Bovine viral diarrhea virus (BVDV) is managed through vaccination, maintenance of closed herds, screening and isolation of new additions, identification of persistently infected animals, and culling carriers.18 Preventing viral introduction is generally more effective than attempting eradication after establishment. Leptospirosis control is similarly achieved through vaccination, though vaccines do not cover all serovars, and immunity typically persists for approximately 6 months. Unlike BVDV, complete eradication of Leptospira from a herd is often impractical.18

Conclusion

Neonatal encephalopathy in calves is a multifactorial condition arising from a complex interaction of maternal, perinatal, and neonatal factors. Recognized risk factors include inadequate maternal nutrition, micronutrient deficiencies, dystocia, periparturient stress, hypoxic-ischemic events, environmental challenges, and exposure to infectious agents such as BVDV or Leptospira. These contributors may work alone or in combination, producing a spectrum of clinical presentations ranging from mild neurobehavioral depression to severe neurologic dysfunction. Persistent neurosteroid activity has been proposed as an emerging mechanistic theory, particularly in calves with NMS, highlighting the heterogeneity of NE and underscoring the need for precise terminology to guide diagnosis, management, and research.

Therapeutic interventions for NE are primarily supportive and symptom-directed. Supportive care remains the cornerstone; disease-specific interventions should be applied only when etiology is clearly identified. Respiratory support, thermoregulation, correction of metabolic disturbances, giving colostrum early, and analgesia form the cornerstone of care. Adjunctive therapies (e.g. pharmacologic respiratory stimulants or the Madigan squeeze technique) may benefit select calves, although evidence in cattle remains limited. Individualized assessment is essential, as therapies effective for NMS associated with neurosteroid persistence may not benefit calves with hypoxic-ischemic or metabolic etiologies.

Preventive strategies remain the most reliable means of improving neonatal survival and long-term productivity. These include optimizing maternal nutrition and micronutrient status during late pregnancy, minimizing dystocia through sire selection and heifer management, ensuring supportive environmental conditions, and implementing herd-level infectious disease control. Vigilant neonatal monitoring allows early recognition and timely intervention, reducing morbidity and improving outcomes.

Future research priorities include validation of emerging therapies, detailed characterization of NE subtypes, and elucidation of maternal and fetal determinants of neonatal susceptibility. A holistic approach integrating both maternal and neonatal care is essential for reducing NE incidence, enhancing welfare, and supporting sustainable herd productivity.

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