Perinatal asphyxia
Perinatal asphyxia, also known as birth asphyxia or neonatal asphyxia, is a medical condition characterized by the deprivation of oxygen and blood flow to a newborn infant before, during, or immediately after birth, leading to hypoxemia (low blood oxygen levels) and acidosis (buildup of acid in the blood).[1] This oxygen deprivation can result in hypoxic-ischemic encephalopathy (HIE), a type of brain injury, and affects multiple organ systems if not addressed promptly.[2]Historical Background
The condition has been recognized since antiquity, but the term "birth asphyxia" emerged in the 18th century, replacing "apparent death of the newborn" amid fears of premature burial.[3] Modern understanding advanced with 20th-century developments in fetal monitoring and neonatal resuscitation, and the World Health Organization formalized aspects of the definition in 1997 to encompass failure to establish breathing at birth.[4] Globally, perinatal asphyxia accounts for approximately 900,000 neonatal deaths annually (as of recent WHO estimates), representing a leading cause of early neonatal mortality, particularly in low-resource settings where incidence rates can reach 20 per 1,000 live births compared to 2 per 1,000 in high-resource countries.[5] It primarily arises from complications interrupting fetal oxygen supply, such as placental issues or labor dystocia, with antepartum factors contributing in about 20% of cases and intrapartum events in the majority.[1] Prompt resuscitation and interventions like therapeutic hypothermia can mitigate brain damage, though survivors may face long-term neurologic deficits, with 15-20% mortality in the neonatal period.[1] Prevention focuses on antenatal care, skilled delivery, and access to emergency services.[5]Introduction
Definition
Perinatal asphyxia refers to the deprivation of oxygen (hypoxia or anoxia) and/or reduced blood flow (ischemia) to the fetus or newborn in the immediate period surrounding birth, which can result in systemic and neurological injury.[1] This condition arises from an interruption in gas exchange or fetal oxygenation during the perinatal phase, potentially leading to metabolic acidosis and organ dysfunction if severe.[6] Common synonyms for perinatal asphyxia include birth asphyxia and neonatal asphyxia, while the term hypoxic-ischemic encephalopathy (HIE) is specifically used when there is prominent neurological involvement due to brain injury from the hypoxic-ischemic event.[1] The scope of perinatal asphyxia encompasses the antepartum (before labor), intrapartum (during labor and delivery), and postpartum (immediately after birth) periods, focusing on acute events rather than chronic fetal hypoxia, such as that seen in prolonged intrauterine growth restriction.[7] Diagnosis of perinatal asphyxia is often associated with low Apgar scores, such as a score of less than 5 at 5 minutes of age, indicating poor adaptation to extrauterine life, though Apgar scores alone are not sufficient for definitive diagnosis and must be considered alongside other clinical evidence.[8] This criterion helps identify newborns at risk but underscores the need for a multifaceted assessment to confirm the presence and severity of asphyxia.[9]Historical Background
The concept of perinatal asphyxia originated in the 18th century as "apparent death of the newborn," a term arising amid widespread European fears of premature burial, which prompted early efforts in neonatal resuscitation to distinguish stillborn infants from those merely appearing lifeless.[10] This diagnosis was initially linked to impaired placental respiration, even before the discovery of oxygen in the late 18th century, and reflected a growing medical interest in distinguishing recoverable newborns from the truly deceased.[10] By the late 1700s, the term evolved into "birth asphyxia," recognizing oxygen deprivation as the underlying cause, with classifications like "blue" (cyanotic) and "white" (pale) asphyxia emerging to describe clinical presentations.[10] In the 19th and early 20th centuries, understanding advanced with the identification of oxygen deprivation's role in neonatal distress, shifting focus from supernatural or accidental causes to physiological ones, though blame often fell on midwives and obstetricians for perceived mishandling of deliveries.[10] A pivotal development came in 1953 when anesthesiologist Virginia Apgar introduced the Apgar score, a standardized 10-point assessment of newborn vitality at one and five minutes post-birth, evaluating appearance, pulse, grimace, activity, and respiration to guide immediate interventions and quantify asphyxia severity. This tool marked a transition toward objective evaluation, reducing subjective blame and enabling better resuscitation practices.[11] By the late 20th century, the terminology and perspective shifted further from broad "birth asphyxia" to evidence-based recognition of hypoxic-ischemic encephalopathy (HIE) as a specific brain injury pattern resulting from perinatal oxygen and blood flow deprivation, diminishing earlier tendencies to attribute outcomes solely to practitioner error.[10] In the post-2000 era, this understanding spurred the adoption of neuroprotective therapies, notably therapeutic hypothermia, following landmark randomized trials in the mid-2000s that demonstrated its efficacy in reducing mortality and neurodevelopmental disability in moderate to severe HIE cases when initiated within six hours of birth. The World Health Organization highlighted perinatal asphyxia as a major global neonatal killer in early 2000s reports, estimating around 900,000 annual deaths and underscoring the need for improved prevention and intervention strategies.[5]Etiology
Causes
Perinatal asphyxia arises from events that disrupt oxygen delivery to the fetus or newborn, primarily through impaired blood flow or gas exchange across the placenta or in the immediate postnatal period. These causes are categorized by timing relative to delivery: antepartum (before labor), intrapartum (during labor), and postpartum (after birth). Intrapartum events account for the majority of cases (estimates vary, with antepartum causes representing about 20% in some sources), while postpartum issues are less common (around 10%) but critical in the early neonatal period.[1][12] Intrapartum causes, occurring during labor and delivery, are the most frequent precipitants of oxygen deprivation and often coincide with the second stage of labor when fetal expulsion occurs. Key examples include uterine rupture, which leads to acute hemorrhage and reduced uteroplacental perfusion; placental abruption, causing separation of the placenta from the uterine wall and interrupting blood flow; umbilical cord prolapse or compression, which obstructs venous return and arterial supply to the fetus; and shoulder dystocia, where delayed delivery compresses the cord against the maternal pelvis. These sentinel events can result in near-total asphyxia if not rapidly addressed.[13][14][15] Antepartum causes involve chronic or acute insults prior to the onset of labor, leading to progressive fetal hypoxia. Maternal hypotension, such as from sepsis or hypovolemic shock, reduces placental perfusion and oxygen transfer. Placental insufficiency, often due to vascular abnormalities or preeclampsia, impairs nutrient and oxygen exchange across the placenta. Fetal-maternal hemorrhage, where fetal blood enters the maternal circulation, causes acute fetal anemia and hypovolemia, severely limiting oxygen-carrying capacity.[16][17][18] Postpartum causes emerge immediately after birth and can exacerbate or independently cause asphyxia through respiratory or circulatory failure. Airway obstruction, such as from congenital malformations or retained amniotic debris, prevents effective ventilation. Severe anemia, often from unresolved antepartum hemorrhage or birth trauma, diminishes the newborn's ability to transport oxygen to tissues. Additionally, meconium aspiration, where the newborn inhales meconium-stained amniotic fluid during or just after delivery, leads to airway blockage, chemical pneumonitis, and respiratory compromise, particularly in stressed fetuses during prolonged labor.[19][20][21][22]Risk Factors
Risk factors for perinatal asphyxia encompass a range of maternal, fetal, obstetric, and preconceptional conditions that increase the likelihood of oxygen deprivation to the fetus during the perinatal period. These predispositions highlight the importance of antenatal screening and monitoring to mitigate potential complications. Maternal factors include advanced maternal age greater than 35 years, which is associated with higher rates of placental insufficiency and fetal distress leading to asphyxia.[23] Anemia in the mother reduces oxygen-carrying capacity to the fetus, elevating asphyxia risk.[24] Hypertensive disorders such as preeclampsia impair uteroplacental blood flow, contributing to hypoxia.[25] Maternal infections, including chorioamnionitis, trigger inflammatory responses that compromise fetal oxygenation.[26] Substance use, particularly cocaine, induces vasoconstriction and abruptio placentae, further predisposing to asphyxial events.[27] Fetal factors involve intrauterine growth restriction (IUGR), where placental insufficiency limits nutrient and oxygen supply, heightening vulnerability to asphyxia during labor.[28] Post-term pregnancy beyond 42 weeks increases risks due to placental aging and reduced efficiency.[29] Multiple gestations, such as twins, are linked to higher asphyxia incidence owing to shared placental resources and preterm delivery complications.[26] Congenital anomalies, including cardiac defects, can exacerbate intrapartum stress and oxygen demand mismatches.[1] Obstetric factors encompass prolonged labor exceeding 24 hours, which exhausts fetal reserves and promotes acidosis.[30] Abnormal presentations like breech position complicate delivery and elevate cord compression risks.[31] Meconium-stained amniotic fluid signals fetal distress and is correlated with higher asphyxia rates, often necessitating urgent intervention.[32] Preconceptional elements such as low socioeconomic status and inadequate prenatal care amplify overall vulnerability, with higher asphyxia prevalence in low-resource settings due to delayed access to monitoring and interventions.[33][34][5]Pathophysiology
Mechanisms
Perinatal asphyxia initiates a hypoxic-ischemic insult characterized by reduced oxygen delivery to tissues, prompting a shift to anaerobic metabolism, accumulation of lactic acid, and depletion of adenosine triphosphate (ATP).[35] This energy failure disrupts cellular homeostasis, as oxidative phosphorylation halts in mitochondria, leading to impaired ion pumps and membrane potential collapse.[36] In the brain, this insult particularly targets vulnerable regions such as the hippocampus and basal ganglia, where high metabolic demands exacerbate the effects.[35] The primary phase of injury involves immediate neuronal cell death due to profound energy failure, manifesting as necrosis in severely affected areas or apoptosis in less intense zones.[36] Necrotic cells swell and rupture, releasing contents that amplify damage, while apoptotic pathways activate through caspase cascades in structures like the hippocampal dentate gyrus.[35] This phase occurs during the acute hypoxic event, with selective vulnerability in neurons reliant on aerobic metabolism.[35] Upon reoxygenation, reperfusion injury exacerbates damage through reactive oxygen species (ROS) production from mitochondrial electron transport chains, causing lipid peroxidation, protein oxidation, and DNA fragmentation.[35] Excitotoxicity arises from excessive glutamate release, overstimulating NMDA receptors and triggering calcium influx that propagates cell death.[35] Concurrently, inflammation intensifies with microglial activation, neutrophil infiltration, and cytokine release shortly after the insult.[35] Beyond the brain, the hypoxic-ischemic cascade induces multi-organ dysfunction, including cardiac stunning from reperfusion-mediated myocardial injury that reduces output.[37] Renal tubular necrosis results from ischemic hypoperfusion, leading to acute kidney injury in up to 44% of cases.[37] Hepatic involvement manifests as enzyme elevation due to hypoperfusion-induced hepatocyte damage, affecting 57% of neonates with encephalopathy.[37]Stages and Injury Patterns
Perinatal asphyxia progresses through distinct temporal phases of brain injury, primarily characterized by energy failure and cellular damage in the context of hypoxic-ischemic encephalopathy (HIE). The primary phase occurs within minutes of the acute hypoxic-ischemic insult, involving immediate deprivation of oxygen and glucose, leading to anaerobic metabolism, ATP depletion, and failure of the Na+/K+ ATPase pump. This results in neuronal depolarization, cytotoxic edema, and initial cell death through necrosis and early apoptosis.[36][38] Following the primary phase, a latent phase ensues, typically lasting 1 to 6 hours after partial restoration of cerebral blood flow, during which there is an apparent clinical recovery with normalization of cerebral energy metabolism. However, subclinical processes such as ongoing inflammation and initiation of apoptotic cascades continue, representing a potential therapeutic window before further deterioration.[36][38][39] The secondary phase develops 6 to 48 hours post-insult, peaking between 24 and 72 hours, and is marked by delayed secondary energy failure driven by reperfusion injury, including oxidative stress, excitotoxicity from excessive glutamate release, and inflammatory responses. These mechanisms culminate in cerebral edema, further apoptosis, and infarction, exacerbating neuronal loss independent of the initial acidosis.[36][38][39] A tertiary phase extends from days to months or even years after the insult, involving persistent neuroinflammation, impaired neurogenesis and oligodendrogenesis, blood-brain barrier disruption, and epigenetic modifications that contribute to long-term neurodegeneration and neurodevelopmental impairments.[38] Injury patterns in perinatal asphyxia vary by gestational age and insult severity, reflecting selective vulnerability of brain regions. In term infants (≥36 weeks), partial prolonged hypoxia commonly produces watershed injuries affecting the parasagittal cortex and subcortical white matter, visible on MRI as diffusion restriction and later atrophy or ulegyria in vulnerable border zones between major arterial territories. In contrast, preterm infants exhibit predominant periventricular white matter injury, such as periventricular leukomalacia, due to the immaturity of oligodendrocytes and vascular supply in this region, leading to cystic changes and ventriculomegaly on imaging.[40][41] The severity of HIE resulting from perinatal asphyxia is often classified using the Sarnat staging system, which integrates clinical and electroencephalographic features across three stages. Stage I (mild) involves hyperalertness, normal EEG, and hypertonia lasting less than 24 hours, with full recovery expected. Stage II (moderate) features lethargy, hypotonia, seizures, and periodic EEG patterns, typically resolving within days but associated with potential neurodevelopmental risks. Stage III (severe) presents with stupor, flaccidity, suppressed reflexes, and suppressed or isoelectric EEG, correlating with high mortality or profound impairment.[42][43]Diagnosis
Clinical Signs
Perinatal asphyxia in newborns is characterized by immediate clinical signs reflecting acute oxygen deprivation and metabolic derangement at birth. These include low Apgar scores at 5 minutes (0-3 for more than 5 minutes), indicating poor heart rate, respiratory effort, muscle tone, reflex irritability, and color.[1] Affected infants often present with a weak or absent cry, hypotonia (floppy appearance), bradycardia (heart rate below 100 beats per minute), and central cyanosis due to inadequate oxygenation.[2] These signs arise from the pathophysiological interruption of fetal oxygenation, leading to rapid decompensation in the immediate postnatal period.[1] Neurological manifestations are prominent and may evolve over the first hours to days. Common findings include altered levels of consciousness, ranging from lethargy to stupor, and seizures, which can be overt (clonic or tonic) or subtle (e.g., lip smacking or pedaling movements).[44] In the recovery phase, some infants develop hypertonia or exaggerated reflexes as cerebral edema subsides.[1] These neurological signs reflect hypoxic-ischemic injury to the brain, often culminating in encephalopathy if severe.[44] Systemic signs indicate multi-organ involvement beyond the central nervous system. Respiratory distress is frequent, featuring grunting respirations, apnea, or irregular gasping due to pulmonary immaturity or aspiration.[2] Metabolic acidosis with arterial pH below 7.0 is a hallmark, often accompanied by signs of renal dysfunction such as oliguria (urine output less than 1 mL/kg/hour).[1] Other systemic features may include hepatic enzyme elevation or myocardial dysfunction, manifesting as poor perfusion or hypotension.[44] The severity of encephalopathy is commonly graded using the Sarnat clinical staging system, which categorizes findings into three levels based on neurological examination within the first 24 hours.[44]| Stage | Level of Consciousness | Muscle Tone | Posture | Stretch Reflexes | Complex Reflexes | Seizures |
|---|---|---|---|---|---|---|
| I (Mild) | Hyperalert to irritable | Normal | Normal | Normal or increased | Weak suck; strong Moro; mild tonic neck | None |
| II (Moderate) | Lethargic or obtunded | Hypotonia | Distal flexion (decorticate) | Decreased or increased | Weak or absent suck and Moro; strong tonic neck | Frequent, focal or multifocal |
| III (Severe) | Stupor | Flaccid | Decerebrate | Hypoactive or absent | Absent suck, Moro, and tonic neck | Uncommon or delayed |