Encephalopathy of prematurity reflects white and gray matter injury combined with neuronal-axonal abnormalities impacting preterm infants.
Key risk factors include hypotension and the need for inotropes, hypoxia, and inflammation.
Evaluation of high-risk infants in the neonatal intensive care unit (NICU) includes use of neuroimaging and neurobehavioral assessments such as the General Movements Assessment.
Management starts prior to birth and continues throughout the NICU stay and is geared toward prevention and treatment of risk factors.
After NICU discharge, management is geared toward use of developmental surveillance, parental support, and physical and occupational therapy.
Encephalopathy of prematurity is the result of altered brain development and brain injury after preterm birth. The term “encephalopathy of prematurity” describes a phenomenon that results from a variety of different pathophysiologic factors that occur either alone or in combination. These affect the development and maturation of white and gray matter, both of which undergo crucial development during the third trimester. Infants at highest risk are very low birth weight infants (<1500 g) and to a greater extent extremely low birth weight infants (<1000 g). Periventricular leukomalacia (PVL) combined with neuronal-axonal injury is the hallmark of encephalopathy of prematurity. , These findings can be seen either in isolation or in conjunction with other forms of preterm brain injury, such as periventricular-intraventricular hemorrhage, intraparenchymal hemorrhage, or cerebellar injury.
White matter involvement can be focal or diffuse, both involving damage to the preoligodendrocytes and disruption of developmental myelination. Consequences of this white matter injury include motor deficits such as cerebral palsy, affecting about 5% to 10% of very low birth weight infants and much more commonly visual, cognitive, and neurobehavioral abnormalities including autism, which can be seen in up to 25% to 50% of patients. Although white matter injury most commonly affects infants born prior to 32 weeks’ gestation, similar injury patterns have been associated with intrauterine chronic hypoxic states including placental insufficiency and cyanotic heart disease.
As implied by the name, encephalopathy of prematurity affects mainly preterm infants. The overall rate of prematurity, defined as birth before 37 weeks of gestation, is 10.6% worldwide; of those, 15.4% are born before 32 weeks’ gestation. In the United States, the rate of preterm birth decreased from 12.5% in 2004 to a low of 9.57% in 2014 but has since increased to 10.0% in 2018, with a stable rate of birth before 32 weeks of 2.75%.
The incidence of cystic PVL has decreased overtime, but diffuse white matter injury remains prevalent and is now the most common manifestation of encephalopathy of prematurity. The incidence of any degree of white matter injury has been reported in some studies to be as high as 72%. Abnormal neurodevelopmental outcome is strongly correlated to the degree of white matter injury, in particular moderate to severe white matter injury.
White Matter Injury
Periventricular leukomalacia is the hallmark of encephalopathy of prematurity, defined by the pathologic characteristics of focal necrosis in the periventricular area combined with diffuse reactive gliosis and activation of microglia cells in the surrounding white matter. Large areas of necrosis (>1 mm) may evolve over weeks into macroscopic cysts, termed cystic PVL. This occurs in less than 5% of preterm infants in the current era. Diffuse PVL is characterized by small focal necrotic areas measuring ≤1mm, surrounded by reactive astrocytosis and microgliosis. These smaller or microscopic areas of necrosis, caused by injury to immature oligodendrocytes, evolve into glial scars. Punctate white matter lesions and diffuse white matter injury represent the most common imaging manifestations of white matter injury. Both patterns result in damage to the preoligodendrocytes and thus result in impaired maturation of preoligodendrocytes and dysfunctional oligodendrocytes. Oligodendrocytes derive from neuroglial stem cells, which differentiate sequentially into oligodendrocyte precursors and premyelinating oligodendrocytes before becoming mature myelinating oligodendrocytes. As a result, hypomyelination can be observed. Myelin surrounds the axons and facilitates signal transmission and developmental migration. Abnormal myelination can result in axonal damage and modification of the white matter tracts. Oligodendrocytes also play an important role in axonal development, and impaired function of the mature oligodendrocyte has been associated with abnormal axonal development. ,
White matter injury has historically been described as an appearance of cysts alongside the ventricles, termed cystic PVL, occurring approximately 10 days to 2 weeks after an insult. These cysts may disappear over the following weeks, replaced with glial tissue, which can be detected on later brain magnetic resonance imaging (MRI) as diffuse white matter lesions, now the most common form of preterm brain injury ( Fig. 48.1 ). Several risk factors have been associated with a higher risk of PVL, including hypoxia-ischemia, prolonged hypercapnia, inflammatory states, and transient impairment of cerebrovascular autoregulation.
A combination of neuronal and axonal injury is commonly found in conjunction with PVL. White matter injury can generate abnormalities in the gray matter as a result of terminal axonal injury. Axonal guidance is required for developing and migrating neurons to reach their target destination. Interruption of such guides results in abnormal migration, most commonly seen as reduction of neurons and pyramidal cells in cortical layer V.
One of the underlying pathophysiologic mechanisms of preterm brain injury is related to impaired cerebrovascular autoregulation and the resulting pressure passive state. Cerebrovascular autoregulation refers to the ability to maintain a stable cerebral blood flow independent of systemic blood pressure. This mechanism, however, is not fully developed in preterm infants and may result in a pressure-passive state where systemic blood flow correlates linearly with cerebral blood flow ( Fig. 48.2 ). This is particularly common in the most critically ill patients. The pressure-passive state can be observed in nearly all preterm neonates for some period of time, and the duration of time spent in a pressure-passive state correlates with an increased risk for brain injury. Near infrared spectroscopy in combination with blood pressure monitoring can be used to evaluate cerebral blood flow and thereby identify the infants at highest risk. Predisposing factors for a pressure passive state include extreme prematurity, hypocarbia (P co 2 <30 mm Hg), and hypercarbia (P co 2 >55 mm Hg). Three injury types have been described in the setting of impaired cerebral autoregulation: focal cystic necrosis, incidence ≤5%; focal microscopic necrosis, incidence 15% to 20%; and diffuse nonnecrotic injury, incidence ≥50%.
Gray Matter Injury
The gray matter component of encephalopathy of prematurity is characterized by neuronal loss combined with reactive gliosis. Synaptic connections formed during brain development are also altered by preterm birth, resulting in altered functional connectivity that persists through adolescence and is a significant risk factor of neurodevelopmental impairment.
The patterns of injury are heterogeneous and reflect different types of injury. The disruption of normal cortical development can result in a delay in cortical folding of >2 weeks and volume loss. , Gray matter lesions are most commonly found in the subcortical area and cerebellum. Fig. 48.2 illustrates the interactions that result in encephalopathy of prematurity. A summary of the mechanisms implicated in the pathogenesis of encephalopathy of prematurity is shown in Fig. 48.3 .
Clinical Features and Evaluation
The early clinical features of preterm infants with encephalopathy of prematurity and related white and gray matter abnormalities are often challenging to detect clinically. Thus knowledge of the risk factors associated with encephalopathy of prematurity and routine surveillance methods should be employed to aid in early identification and subsequent management.
Neonates at greatest risk for encephalopathy of prematurity are those exposed to a combination of prenatal and postnatal inflammatory insults, difficult resuscitation, and ongoing hypoxic events as shown in Table 48.1 . The risk is inversely related to gestational age. The presence of prolonged premature rupture of membranes or chorioamnionitis and associated inflammatory states is associated with higher risk for PVL. , Infections, intraventricular hemorrhage (IVH), and seizures during the neonatal intensive care unit (NICU) stay have been associated with impaired motor outcome and higher incidence of PVL. , Furthermore, infants with periventricular white matter injury are more commonly found to have IVH and seizures. Clinically, routine examination may not clearly detect those neonates who will develop symptomatic encephalopathy of prematurity, and thus heightened awareness of the diagnosis and involvement of ancillary services such as physical, occupational, and feeding therapists is necessary to detect those with subtle features requiring longer-term evaluation.
|Magnesium sulfate||Delayed cord clamping||Euglycemia|
|Minimize prolonged hypocarbia|
|Avoid prolonged hypercarbia|
Clinical and Imaging Evaluation
Examination with the General Movements Assessment (GMA) by a trained professional within the NICU can aid in identifying infants at risk for sequelae of encephalopathy of prematurity. GMA utilizes observation of the spontaneous movements of the newborn at key time points, with the theory that these spontaneous movements provide insight into the integrity of the neurologic system at key points of early development. , Work by the Prechtl group suggests that the spontaneous movements of preterm infants are reflective of the cortical subplate and its projections to central pattern generators. Thus, injury to these areas by encephalopathy of prematurity affect the spontaneous movements observed. As the brain matures, the spontaneous movements noted evolve from “writhing movements” that occur until 45 weeks’ postmenstrual age to “fidgety movements”; these are typically noted up to 60 weeks’ postmenstrual age, theorized to reflect the maturation of projections from the subplate neurons. Absence of fidgety movements on the GMA has been strongly correlated with later development of cerebral palsy, minor neurologic dysfunction, , attentional disorders, and cognitive disabilities.
Utilization of the GMA in the NICU is increasing because abnormal cramped synchronous movements in the writhing period are associated with abnormal neurodevelopmental outcomes but are less specific compared with abnormalities later with absent fidgety movements in the postneonatal period (48–60 weeks’ postmenstrual age), which can be highly predictive for later neurodevelopmental sequelae. , , Use of this early diagnostic tool can allow for earlier identification and therapeutic intervention for symptomatic infants.
Neuroimaging plays a role in the evaluation of the preterm infant at risk for neurodisability. Although ultrasonography is excellent for detecting IVH and historically was used for detection of cystic periventricular leukomalacia, it is not optimal for detecting noncystic white matter disease or cerebellar injury. There is therefore an increasing role for the use of term-equivalent MRI (TE-MRI) in the evaluation of preterm infants to help stratify risk of neurodevelopmental impairment beyond cerebral palsy and cognitive sequelae ( Fig. 48.4 ). White matter injury noted on TE-MRI is predictive of neurodevelopmental impairment in the first years of life. , , TE-MRI obtained at or after 36 weeks’ postmenstrual age can detect white matter injury including white matter lesions, reduced white matter volumes, reduced gray matter volume, and ventriculomegaly. , In addition, MRI can detect cerebellar hypoplasia or microhemorrhages typically not well appreciated by ultrasound.
Advanced MRI techniques of diffusion tractography have been studied to look specifically at white matter tracts and the effects of signal changes in long-term development. The corticospinal tracts, corpus callosum, thalamic connections, and optic radiations among other pathways have been evaluated. Changes in diffusivity with lower fractional anisotropy values in the corticospinal tracts and corpus callosum have been associated with lower psychomotor scores on developmental testing.
Diffuse excessive high signal intensity (DEHSI) can be detected on TE-MRI and is reported in up to 75% of preterm infants imaged at term. Because increased white matter signal can be subjective, studies have demonstrated poor inter- and intraobserver reliability ; thus researchers have attempted to better grade the extent of high signal abnormality. The significance of DEHSI remains debated, with uncertainty as to whether it represents a developmental state versus a biomarker of later neurocognitive sequelae.
Given the frequency with which DEHSI is identified, there has been interest in determining its relevance for developmental outcome. Several studies have looked at presence or absence of DEHSI, whereas others have looked at DEHSI grading and outcome. Although initial studies demonstrated a correlation between the presence of DEHSI and later neurodevelopmental outcome at 18 to 36 months, multiple studies subsequently did not find that neurodevelopmental outcomes correlated with DEHSI. , Newer studies have raised the suggestion that abnormal signal in the posterior crossroads (the posterior periventricular white matter representing commissural white matter pathways and projection associations) may correlate with outcome; however, this remains uncertain. ,
Utilization of TE-MRIs for all preterm neonates remains controversial, , with some families of former preterm infants noting the adverse psychological impact of this knowledge on the family , and others questioning the added value of such a study over ultrasound. Although white matter injury on TE-MRI correlates with adverse neurodevelopmental outcome, a significant cohort of patients with white matter injury do not manifest significant developmental impacts. , , Concomitant use of a neurologic exam marginally increases both the positive and negative predictive values for neurodevelopmental outcome. A TE-MRI with normal or minor abnormalities in conjunction with a normal neurologic exam can marginally increase the negative predictive value for a later reassuring standardized neurologic exam (from 99% to 100%), suggesting that a reassuring MRI and exam together would portend a favorable outcome. In contrast, a TE-MRI with moderate or severe abnormalities alone has a positive predictive value for neurologic impairment at 2 years of age of 27%. With an abnormal neurologic exam at discharge, the positive predictive value for neurologic impairment at 2 years of age increases to 35%. Ultimately, TE-MRI can provide insight into those patients at risk for developing cerebral palsy and neurocognitive sequelae and, if obtained, should be used to advocate for early introduction of physical and occupational therapy through early intervention services and close neurodevelopmental surveillance while acknowledging the uncertainty that remains regarding outcome. Discussion with both clinicians and caregivers regarding MRI should acknowledge the limitations of imaging in prognostication. A combination of MRI findings and GMA may further refine prediction, and if abnormal, heighten concern for sequelae from prematurity such as cerebral palsy, , , promoting early referral to therapy services.
Management of the neonate at risk for encephalopathy of prematurity is multipronged and includes neuroprotective measures prenatally and in the NICU and long-term follow-up with developmental therapies.
Prenatal Treatments: Antenatal Corticosteroids and Magnesium Sulfate
Two doses of antenatal corticosteroids within a week of preterm birth can reduce the incidence of PVL and IVH by up to 50%, even in neonates as young as 23 weeks’ gestation. A single dose is not as effective. The mechanism of action is direct, by stabilizing the vasculature of the germinal matrix, and indirect, mediated by a reduction in severity of respiratory distress syndrome and improved cardiovascular stability, particularly in the first 24 hours of life. Multiple studies have shown that repeating a two-dose course of prenatal steroids after 14 days if preterm delivery is still a concern confers additional benefit. The American College of Obstetricians and Gynecologists (ACOG) currently recommends repeat administration of prenatal steroids every 7 to 14 days as a rescue treatment if delivery prior to 34 weeks is impending. Caution must be used, however, because a large randomized controlled trial examining the effect of repeat courses of antenatal steroids found four or more courses to be associated with a higher rate of cerebral palsy or death at the 2- to 3-year follow-up (5.6% versus 1.4%). No difference in Bayley scores or head circumference was detected.
Magnesium sulfate has been given to pregnant women for a variety of indications, most commonly to prevent preeclampsia, and early observational data suggested exposure to magnesium sulfate might have a neuroprotective effect on the preterm brain. , Several randomized controlled trials and meta-analyses have now been conducted, including over 4000 neonates. Although none of the studies showed a difference in PVL, a reduction in the combined outcome of death and severe gross motor dysfunction was reproduced in the trials. When combining the trials in meta-analyses, magnesium sulfate also appears to decrease risk of cerebral palsy. In 2009, antenatal magnesium sulfate was recommended with a number to treat (NNT) of 63 to prevent 1 preterm baby from developing cerebral palsy. In 2017, a meta-analysis including over 4000 neonates showed a decrease in the NNT of 46 to prevent cerebral palsy and an NNT of 42 to prevent impaired neurodevelopmental outcome. The ACOG affirmed the findings of these studies and supports the short-term use of magnesium sulfate for neuroprotective measures in fetuses at risk for delivery prior to 32 weeks’ gestation. In 2013, the Food and Drug Administration recommended against the use of magnesium sulfate for more than 5 days due to concerns for osteopenic changes in bone mineralization. The mechanisms of action are not completely understood, but amelioration of free radicals or reduction of hypoxic-ischemic events through the stabilization of cerebral blood flow have been proposed. Modulation of N-methyl-D-aspartate (NMDA) glutamate channels has also been proposed as a mechanism of reducing NMDA receptor-mediated injury.
Intrapartum Management—Delayed Cord Clamping
Delayed cord clamping has been investigated as a potential protective mechanism for several decades. In a small randomized controlled trial in the 1980s, a reduction in IVH was demonstrated that inspired further investigations. Since then, delayed cord clamping has been shown in multiple studies to improve and stabilize blood pressure, blood glucose, and temperature and decrease the rate of late onset sepsis, all factors associated with an increased risk for encephalopathy of prematurity. A reduction in red blood cell transfusion has also been shown in some trials, further reducing exposure to an inflammatory state and various cytokines, which could possibly contribute to the decreased rate of brain injury seen in this population. , , ,
Improved hemodynamic status and thus fewer fluctuations in blood pressure and cerebral blood flow in the first 24 hours after delivery is of particular interest, because this is the highest risk period for the occurrence of an IVH. Delayed cord clamping is also associated with improved cerebral oxygenation during the first 24 hours of life. In a randomized controlled trial of 200 neonates between 27 and 34 weeks of gestation, no difference was demonstrated in the rate of IVH or PVL. This study was originally designed to include less mature neonates; however, the mean gestational age of participants was >30.5 weeks, so the study was likely underpowered to identify decreased incidence of IVH and PVL. In a larger Australian study, delayed cord clamping was associated with a trend toward decreased death, but major morbidities including significant brain injury were comparable between groups. The overall analysis and assessment of the studies resulted in a 2012 ACOG recommendation to delay cord clamping by a minimum of 30 seconds in infants born at <32 weeks, with the prospect of potentially reducing IVH by as much as 50%, endorsed in 2017 by the American Academy of Pediatrics and the Neonatal Resuscitation Program and reindorsed by ACOG in 2020. A meta-analysis published in 2018 confirmed the findings of the Cochrane Review from 2012 that delayed cord-clamping was associated with decreased mortality but not with a significant decrease in IVH or PVL, and a more recent randomized controlled trial showed a significant risk reduction of severe IVH by more than 50% with delayed cord clamping versus cord milking. , ,
Targeted euglycemia is recommended because both absolute levels of blood glucose and glucose variability contribute to preterm brain injury. Hypoglycemia stresses energy metabolism, and in the resultant state of deprivation, oligodendrocytes and neurons become injured, sometimes severely enough to result in necrosis. Hyperglycemia during the first 24 hours of life has also been associated with an increased risk of death and white matter injury on MRI. These findings likely reflect an underlying event that results in a significant stress response, displayed as hyperglycemia. Stress-associated hyperglycemia results in an overall improvement of the infants’ energy state but has detrimental effects on astrocytes, leading to intracellular acidosis and targeted damage. In a small study conducting continuous glucose monitoring during the first week of life, no difference in outcome in regard to IVH and PVL could be demonstrated.
Hypercarbia and Hypocarbia
Both hypo- and hypercarbia are detrimental to the developing brain and can potentiate white matter injury. Hypocarbia decreases cerebral blood flow and therefore increases the risk of ischemic white matter injury. Although no definite cutoff values have been identified, persistent Pa co 2 <25 mm Hg has been shown in several studies to decrease cerebral blood flow with concomitant decreased oxygen delivery. In a large sample of preterm infants, Shankaran et al. described a dose response relationship between time spent in a hypocarbic state (Pa co 2 <35 mm Hg) during the first 7 days of life and periventricular leukomalacia, with those experiencing the most exposure to hypercarbia having a more than fivefold increase in incidence of PVL.
Hypercarbia has vasodilatory effects that in turn cause alterations in cerebral blood flow, placing the infant at risk for hemorrhagic injury. Ventilated preterm infants who have a Pa co 2 >45 mm Hg demonstrate a dose dependent increase in cerebral blood flow and subsequently have progressive loss of autoregulation.
The neuroprotective effects of methylxanthines are mediated through inhibition of adenosine receptors, resulting in protection from energy failure and subsequent cell death. , Caffeine has neuroprotective effects and improves long-term neurodevelopmental outcomes of preterm infants, in particular motor outcome. Furthermore, chronic caffeine exposure appears to preserve the maturation and development of the microstructural white matter. In a large randomized controlled trial, caffeine exposure was associated with improved motor outcome and decreased cognitive impairment. The NNT to prevent 1 preterm baby from having an adverse outcome was 16 based on this study. However, these benefits did not consistently persist with age. At the 5-year follow-up visit, the incidence of cerebral palsy was not different between groups, but there was a significant improvement in developmental coordination disorders in the caffeine group. Brain structural differences were no longer evident at 11 years, yet the caffeine group continued to show improved motor development compared with placebo-treated infants. ,
Caffeine has a wide toxicity margin; however, safety of dosing must still be considered: in a randomized pilot study of 74 preterm infants comparing the standard loading dose of caffeine to a dose four times higher, increased cerebellar injury and motor abnormalities including hypertonicity were observed. A higher loading dose has also raised concern for an increased incidence of seizures and a threefold increase in seizure burden.
Seizures and Role of Electroencephalography
Recognition of seizures in preterm infants requires a high degree of suspicion because they may be clinically silent (“subclinical” or “electrographic-only”), and the use of electroencephalography (EEG) to appropriately recognize seizure is needed. Risk factors for seizures in preterm neonates include sepsis, meningitis, IVH, and encephalopathy. This forms the basis of the recommendation to monitor patients with high-grade IVH, meningitis, or encephalopathy for development of seizures. Reports of seizure rates in preterm populations vary from 4% to 48%. Neonatal seizures are a risk factor for subsequent epilepsy, cognitive impairment, and mortality. A recent publication from the extremely low gestational age newborns (ELGANs) study demonstrated a 12% risk of at least one seizure and a 7% risk of epilepsy; infants more likely to develop epilepsy included those with more cerebral white matter injury, initial instability, severe bronchopulmonary dysplasia, and postnatal hydrocortisone. EEG background is also associated with cognitive outcomes, particularly when combined with findings from term-equivalent MRI.
Early Developmental Therapy
After addressing neuroprotective measures, the introduction of developmental assessments while neonates are in the NICU is imperative. This not only aids in detection of patients at risk for neurodisability but also provides the opportunity to begin early introduction of therapies geared toward improving outcome. The beneficial effects of early intervention therapies and programs on motor outcomes persist through infancy, and systematic reviews suggest that the cognitive benefits remain through preschool.
The home environment and parental interaction play an important role in neurodevelopment and are impacted by stressors related to the NICU. Teaching of parenting skills and involvement of parents in developmental care, starting in the NICU and continuing through early intervention, can help through 36 months’ age.
Preterm infants require long-term developmental follow-up for assessment of motor, cognitive, and behavioral development, thus allowing appropriate interventions to be instituted in a timely manner to improve outcome.