KEY POINTS
- 1.
Neonatal intensive care unit graduates are at risk of neurodevelopmental impairment (NDI).
- 2.
NDI can occur in cognitive, motor, vision, hearing, or language domains and can seriously impair the child’s social, academic, and behavioral functioning.
- 3.
Periventricular white matter injury is the leading cause of long-term NDI, especially motor impairment in preterm infants.
- 4.
Infants with hypoxic-ischemic encephalopathy, bronchopulmonary dysplasia, necrotizing enterocolitis, intraventricular hemorrhage, and sepsis are at high risk of NDI.
Introduction
Neurodevelopmental impairment (NDI) is an important long-term complication for neonatal intensive care unit (NICU) graduates. Neonates admitted to the NICU are undergoing a critical period of neurologic development, and any insult to the brain could lead to detrimental neurodevelopmental outcomes. The improvement in high-risk neonates’ survival rates due to neonatal care advancements has highlighted the importance of studying long-term neurologic prognosis. NDI can occur in cognitive, motor, vision, hearing, or language domains and can seriously impair the child’s social, academic, and behavioral functioning. To optimize outcomes, there should be a obligation to follow-up and ameliorate the neurodevelopmental outcomes of the NICU survivors.
This chapter discusses the epidemiology and pathophysiology of NDI in the context of five conditions frequently seen in the NICU. These are hypoxic-ischemic encephalopathy (HIE), bronchopulmonary dysplasia (BPD), necrotizing enterocolitis (NEC), intraventricular hemorrhage (IVH), and sepsis. This review includes evidence from our own quality-improvement studies and an extensive literature review of the PubMed, Embase, and Scopus databases. To avoid bias in identifying studies, keywords were short-listed a priori from anecdotal experience and PubMed’s Medical Subject Heading thesaurus. In this review, considerable overlap is demonstrated in the neurodevelopmental manifestations and neurologic abnormalities among neonatal conditions, which indicates multifactorial pathogenesis of NDI.
Pathophysiology
The underlying mechanism of NDI in preterm NICU infants could be related to anatomic and physiologic vascular abnormalities associated with the relative immaturity of the brain ( Fig. 96.1 ). Cerebral white matter is especially susceptible to prematurity-related vascular insults. Periventricular white matter injury (PWMI) such as that seen in the lesions in Figs. 96.2 and 96.3 is a leading cause of long-term NDI. , These lesions frequently lead to motor impairment. PWMI is attributed to cerebral white matter blood flow interference because of the immature vasculature; ischemic white matter is vulnerable to free radical–mediated injury to the oligodendrocyte progenitors. The severity of white matter abnormality in neonatal sepsis depends on the timing (postmenstrual age) of diagnosis, with more severe pathology in infants developing sepsis before 28 weeks. Figs. 96.4 and 96.5 show the evolution of white matter lesions over longer periods of time.
Oligodendrocyte progenitors are particularly susceptible to ischemia and inflammation in the process of preterm encephalopathy. The loss of lineage-specific progenitors and the consequent reduction in the number of mature oligodendrocytes can impair cerebral myelination. In animal models, cerebral hypoperfusion and hypoxia-ischemia have shown abnormalities in oligodendrocyte progenitor cells, periventricular white matter, and cortical gray matter. Along similar lines, excessive glutamate release during neonatal stress in the NICU could lead to excitotoxic damage to the oligodendrocyte progenitors and cause PWMI. In addition, cerebral maturation is impeded in NEC, as evidenced by a lower rate of increase of the N-acetyl cysteine–choline ratio in affected infants than in unaffected controls. Periventricular injuries could also be a consequence of moderate-severe IVH.
Intestinal inflammation could directly affect the severity of neuroinflammation ( Fig. 96.6 ). Immunogenic systemic inflammatory reaction with an increase in cytokines such as tumor necrosis factor might contribute to the pathogenesis of PWMI. Elevated plasma and cerebrospinal fluid interleukin-1 beta and tumor necrosis factor-alpha increase the risk for white matter injury in preterm neonates with early-onset sepsis. Biouss et al. reported that neonatal mice with NEC had reduced cortical girth, abnormal cell apoptosis, a decreased population of mature neurons and oligodendrocytes, and defective development of neural progenitor cells. Two other experimental models showed that animal neonates with NEC develop neuroinflammation associated with altered hippocampal gene expression, abnormal myelination, and cognitive deficits due to activation of microglial cells. ,
Furthermore, Niño et al. explained that inflamed intestinal tissue in NEC releases toll-like receptor 4 activators such as lipopolysaccharides that propagate neuroinflammation and promote oxidative stress; this, as a result, leads to reduced myelination in the hippocampus, midbrain, and corpus callosum. Haynes et al. hypothesized that free-radical oxidative and nitrative (due to nitric oxide) damage to oligodendrocyte progenitor cells contributes to PWMI. The studies described above indicate that early surgical removal of necrotic intestinal tissue in NEC could lower the severity of neuroinflammatory response in the brain, supporting a dose-related effect.
Other potential pathogenic mechanisms contribute to NDI development in NICU infants; poor nutrition and decreased growth associated with a prolonged stay in a NICU and exposure to surgery and anesthetics could contribute to abnormal neurologic development. Ehrenkranz et al. demonstrated that growth velocity during NICU admission was inversely associated with cerebral palsy (CP) and NDI incidence in extremely low birth weight (ELBW) infants. Besides, poor nutrition and inadequate caloric intake in preterm infants can lead to poor head growth, representing poor neurologic development. It is important to note that antenatal steroids reduce the risk of NDI in extremely preterm infants partially by reducing the incidence of IVH and cystic periventricular leukomalacia. A summary of the most frequently seen magnetic resonance imaging (MRI) prognostic biomarkers is shown in Tables 96.1 and 96.2 .
| Most common cerebral quantitative measurements | (1) Regional brain diameter or volume on structural MRI; (2) fractional anisotropy and/or mean diffusivity on dMRI; (3) brain metabolites, most commonly N-acetylaspartate (NAA)/choline ratio on MRS |
| Brain regions most predictive of neurodevelopmental impairment (identified in three or more studies) | Corpus callosum; centrum semiovale; sensorimotor cortex; subcortical gray matter; posterior limb of the internal capsule; cerebellum |
| Predicted outcomes examined | Cerebral palsy; minor motor abnormalities; permanent hearing loss; cognitive deficits; working memory; executive function; psychological/behavioral abnormalities |
| Condition | Structural Abnormalities | Clinical Outcomes | References |
|---|---|---|---|
| Hypoxic-ischemic encephalopathy |
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| Intraventricular hemorrhage |
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| Bronchopulmonary dysplasia |
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| Necrotizing enterocolitis |
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| Neonatal sepsis |
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Hypoxic-Ischemic Encephalopathy
Structural Abnormalities on Neuroimaging
MRI is better than cranial ultrasound at assessing cerebral parenchymal abnormalities. Cerebral MRI proves valuable in predicting neurodevelopmental outcomes (in motor, language, and cognition domains) in HIE infants; it had 95% sensitivity and 94% specificity in predicting neurodevelopment. There are 6.23 times higher odds for NDI in the form of delayed development if MRI and magnetic resonance spectroscopy findings suggest HIE in the first week of life. Cerebral MRI and magnetic resonance spectroscopy are validated biomarkers for predicting neurodevelopmental outcomes and evaluating the neurologic response to therapeutic hypothermia.
Doppler ultrasound of the anterior or middle cerebral artery can be helpful; increased diastolic blood flow is correlated with NDI. Annink et al. studied 10-year-old children with HIE and showed mammillary bodies and hippocampi structural defects on MRI and diffusion tensor imaging (DTI) scans associated with memory problems and cognitive deficits. An alteration or reversal of the white matter signal in the posterior limb of the internal capsule during the first week of life has a high sensitivity (92%) and a high positive predictive value (88%) for severe motor impairment at 2 years of age. Besides, basal ganglia-thalamic lesions in HIE have an 89% predictive accuracy for severe motor impairment. Other prominent injury sites are the cortical gray matter, brainstem, and cerebellar white matter, which are also associated with motor or cognitive NDI. Diffusion-weighted imaging can detect basal ganglia–thalami lesions in the first week of life, and a low apparent diffusion coefficient and high lactate/N-acetyl aspartate ratio can prognosticate poor neurologic outcomes. ,
Clinical Outcomes
HIE continues to be a major cause of NDI despite advancements in therapeutic hypothermia. HIE is one of the most common causes of CP; the other manifestations include epilepsy, global developmental delay, motor impairment, language delay, and cognitive impairment. , Neurologic prognosis depends on the severity of HIE; neonates with an initial cord blood pH <6.7 have a 90% risk for death or severe NDI at 18 months of age. In addition, Apgar scores of 0 to 3 at 5 minutes, a base deficit >20 mmol/L, decerebrate posture, lack of spontaneous activity, apnea, absence of oculocephalic reflexes, and refractory seizures increase the risk and severity of NDI. HIE is also associated with defects in visual function.
The hypothermia protocol in HIE states that therapeutic hypothermia should be initiated in neonates who are born at >36 weeks’ gestation and have evidence of HIE or moderate to severe encephalopathy. However, a systematic review by Conway et al. showed that 25% of infants with mild HIE had poor neurodevelopmental outcomes at 8 months or older. Therapeutic hypothermia can decrease the incidence of CP and developmental delay. Edmonds et al. showed that therapeutic hypothermia prevented NDI in 75.5% of neonates in their study sample; 12.1% of children developed minor neurologic signs and were at a higher risk for cognitive and behavioral defects.
Intraventricular Hemorrhage
Structural Abnormalities on Neuroimaging
Data on long-term neurologic and developmental follow-up of neonates with IVH are primarily based on cranial ultrasonography. However, cerebral MRI is more sensitive than ultrasound at identifying subtle parenchymal abnormalities associated with IVH—for instance, periventricular leukomalacia. IVH damages the germinal matrix and glial precursor cells and can thereby adversely affect cortical development. Vasileiadis et al. used three-dimensional volumetric imaging in preterm neonates to document a 16% reduction in cortical gray matter volume at near-term age. Tract-based spatial statistics analysis of DTI results showed lower fractional anisotropy and higher radial and mean diffusivity of the corpus callosum, limbic pathway, and cerebellar white matter in neonates with IVH, which indicates white matter microstructural defects. White matter microstructural defects can lead to NDI at 24 months of age. Generally, ventriculomegaly present at term can heighten the risk of a poor neurodevelopmental outcome, because it is associated with periventricular parenchymal damage.
Clinical Outcomes
IVH is an independent risk factor for poor neurodevelopmental outcomes among high-risk NICU survivors. Both low-grade (grade I-II) and severe IVH (grade III-IV) predispose to NDI. , Bolisetty et al., in their cohort study of 1472 preterm NICU survivors, showed that preterm infants with severe IVH had increased rates of CP (30%), developmental delay (17.5%), deafness (8.6%), and blindness (2.2%). Preterm infants with low-grade IVH had higher rates of CP (10.4% vs. 6.5%), developmental delay (7.8% vs. 3.4%), and deafness (6.0% vs. 2.3%) than the group without IVH.
ELBW infants with low-grade IVH had significantly higher rates of NDI (47% versus 28%), low Bayley Mental Development Index scores (<70) (45% versus 25%), and major neurologic defects (13% versus 5%) compared with infants with normal cranial ultrasound at 20 months’ corrected age. However, Payne et al. found that low-grade periventricular IVH in infants does not increase the risk of NDI significantly compared with infants without hemorrhage. The laterality of severe IVH determines the extent of NDI in ELBW infants; infants with bilateral grade IV IVH had more severe NDI than those with unilateral grade IV IVH, whereas NDI associated with grades I-III IVH did not differ based on laterality. The severity of NDI related to IVH does not depend on gender differences.
Bronchopulmonary Dysplasia
Structural Abnormalities on Neuroimaging
Cerebral MRI has provided a way to describe the anatomic abnormalities and predict neurodevelopmental outcomes in specific neonatal disorders. BPD is associated with defects in cortical maturation in preterm infants; it increases the risk for reduced cerebral surface and abnormal gyrification index on neuroimaging. Neubauer et al. demonstrated that BPD is a significant predictor for abnormal cortical maturation and increases the probability of neurodevelopmental delay four-fold. On DTI, the anisotropy score was lower, and the apparent diffusion coefficient was higher in the white matter of the internal capsule, corpus callosum, and cerebellum, suggesting abnormal white matter development. The cerebral white matter volume in the corpus callosum, superior cerebellar peduncle, and corpus callosum were lower in BPD survivors than in infants without BPD.
Clinical Outcomes
BPD is strongly linked with poor neurodevelopmental outcomes, especially in preterm children. The incidence of CP is higher in neonatal BPD survivors than in gestational age–matched controls; the odds ratio for CP in BPD survivors was 1.66 (95% confidence interval, 1.01–2.74) in a retrospective study on preterm neonates by Hintz et al. Natarajan et al. evaluated BPD survivors at 18 to 22 months’ corrected age using the Bayley III assessment and concluded that cognitive impairment was more prevalent in those with BPD. They also demonstrated that moderate to severe CP (Gross Motor Function Classification System level 2 or higher) (7.0% versus 2.1%), spastic diplegia (7.8% versus 4.1%), and quadriplegia (3.9% versus 0.9%) were more common in the BPD group than the non-BPD group. ,
Majnemer et al. showed a 71% prevalence of neurodevelopmental defects, including microcephaly, gross and fine motor deficits, and behavioral difficulties, in the BPD group. , Gross and fine motor deficits, blindness, deafness, language delay, and learning disabilities are more prevalent in BPD survivors than non-BPD children. , BPD children exhibited poorer speech and language outcomes at 8 years of age, with poorer articulation, intelligence quotient (IQ), and receptive language skills. BPD survivors have lower full-scale IQ, performance IQ, verbal IQ, and reading and math grades than non-BPD students. , These findings highlight the importance of prevention and rehabilitation efforts for BPD survivors.
Neonates with BPD have recurrent episodes of hypoxia that can precipitate hypoxic brain injury. Increased severity of BPD, with a longer duration of hospitalization and home oxygen treatment, is associated with poorer neurodevelopmental outcomes. One such report is summarized in Table 96.3 . Short et al. found that children with more severe BPD had worse neurodevelopmental outcomes, with lower IQ, poorer Bayley mental and psychomotor development index scores, and less developed language abilities at 3 years. The presence of pulmonary hypertension in BPD neonates aggravated NDI and growth parameters.
| Severity Groups of BPD | Non-BPD | |||
|---|---|---|---|---|
| Mild | Moderate | Severe | ||
| Infants, No. | 47 | 19 | 13 | 79 |
| Normal cognitive development, No. (%) | 32 (68.1) | 7 a (36.8) | 4 a (30.8) | 66 (83.5) |
| Borderline cognitive development, No. (%) | 8 (17.0) | 6 a (31.6) | 6 a (46.2) | 7 (8.9) |
| Cognitive impairment, No. (%) | 7 (15.0) | 6 a (31.6) | 3 (23.1) | 6 (7.6) |
| OR [95% CI] | 2.38 a [1.0–5.6] | 8.70 a [2.9–26.3] | 11.42 a [3.1–42.7] | |
| Corrected OR [95% CI] | 1.85 [0.7–4.8] | 7.88 a [2.4–26.4] | 8.53 a [1.9–37.7] | |
| Normal motor development, No. (%) | 36 (76.6) | 13 (68.4) | 7 a (53.8) | 65 (82.3) |
| MND, No. (%) | 6 (12.8) | 5 a (26.3) | 5 a (38.5) | 6 (7.6) |
| CP, No. (%) | 5 (10.6) | 1 (5.3) | 1 (7.7) | 7 (8.9) |
| OR [95% CI] | 1.53 [0.6–3.7] | 2.31 [0.7–7.2] | 5.83 a [1.7–20.2] | |
| Corrected OR [95% CI] | 0.70 [0.2–2.5] | 2.20 [0.5–9.7] | 3.30 [0.5–20.9] | |
| Normal hearing, No. (%) | 42 (89.4) | 14 a (73.7) | 10 (76.9) | 75 (94.9) |
| Hearing loss, No. (%) | 5 (10.6) | 5 a (26.3) | 3 (23.1) | 4 (5.1) |
| Severe hearing loss, No. (%) | 2 (4.3) | 1 (5.3) | 1 (7.7) | 1 (1.3) |
| OR [95% CI] | 2.74 [0.7–10.3] | 5.0 a [1.7–20.2] | 8.30 a [1.8–39.2] | |
| Corrected OR [95% CI] | 2.16 [0.5–9.0] | 4.05 [0.8–21.1] | 5.08 [0.8–30.7] | |
| Normal sight, No. (%) | 18 a (38.3) | 8 a (42.1) | 2 a (15.4) | 58 (73.4) |
| Refraction defects/strabismus, No. (%) | 17 a (36.2) | 3 (15.8) | 5 (38.5) | 13 (16.5) |
| Blindness/residual vision, No. (%) | 12 a (25.5) | 8 a (42.1) | 6 a (46.2) | 8 (10.1) |
| OR [95% CI] | 4.45 a [2.1–9.6] | 3.80 a [1.3–10.7] | 15.20 a [3.1–74.3] | |
| Corrected OR [95% CI] | 2.51 [0.97–6.5] | 1.83 [0.5–6.4] | 11.52 a [1.2–109.7] | |
| No disability, No. (%) | 25 (53.2) | 8 (42.1) | 5 (38.5) | 52 (65.8) |
| Mild disability, No. (%) | 9 (19.1) | 2 (10.5) | 2 (15.4) | 13 (16.5) |
| Moderate/severe disability, No. (%) | 13 (27.7) | 9 a (47.4) | 5 a (38.5) | 15 (19.0) |
| OR [95% CI] | 1.70 [0.8–3.5] | 2.65 [0.95–7.4] | 3.08 [0.9–10.3] | |
| Corrected OR [95% CI] | 0.71 [0.3–1.9] | 1.30 [0.4–4.4] | 2.88 [0.16–4.8] | |
Necrotizing Enterocolitis
Structural Abnormalities on Neuroimaging
Neuroimaging is helpful to establish a link between neurodevelopmental outcomes and cerebral injury patterns. A randomized controlled trial by Hintz et al. found the importance of near-term cranial ultrasound and MRI in prognosticating the neurodevelopmental outcomes in extremely preterm infants. Woodward et al. also established the predictive value of term MRI in very preterm infants for NDI at 2 years of age. Merhar et al. used MRI of the brain to demonstrate more severe brain injury in infants with surgical NEC than in those with medical NEC; brain injury was graded using a white matter injury scoring system, which was modified to include IVH and cerebellar hemorrhage.
Various studies have used cranial ultrasound and MRI to evaluate and grade brain parenchymal abnormalities. An MRI brain scan can quantitatively assess the degree of brain maturation in preterm neonates. Cranial ultrasound is more easily accessible and is used more than MRI in preterm infants. Cranial ultrasound can accurately detect germinal layer hemorrhage, IVH, hemorrhagic parenchymal infarction, and periventricular leukomalacia; however, its accuracy diminishes when identifying white matter injury patterns. MRI is a better imaging modality than ultrasound to define the extent of cerebral and cerebellar white matter and gray matter abnormalities. , Neuroimaging needs to be further studied in the context of long-term neurodevelopmental follow-up of NEC survivors to advance its utility in predicting poor outcomes.
Clinical Outcomes
About 50% of NEC survivors have significant long-term morbidity, including gastrointestinal complications, growth impairment, and disrupted neurologic development. , NDI primarily occurs as CP, cognitive defects, visual impairment, and deafness. , NEC survivors are twice as likely to develop NDI than are infants without NEC, according to three systematic reviews. According to a systematic review and meta-analysis by Matei et al., the overall NDI incidence in preterm infants with NEC is 40%, and the risk of NDI is significantly higher in NEC infants than in age-matched controls without NEC. Pike et al. followed NEC survivors until 7 years and reported long-term functional impairment using the Health Utilities Index 3.
NDI is a broad term that encompasses entities such as CP, blindness, deafness, and cognitive defects. CP is the most common NDI in preterm infants with NEC, with an incidence of approximately 17%. In addition, blindness and deafness, both having an incidence of approximately 3%, were also more common in infants with NEC than in age-matched controls. Preterm very low birth weight (VLBW) infants with NEC also have a higher probability of developing attention deficit hyperactivity disorder, especially parent-reported, during the early and middle childhood periods. , , In a study of NEC infants by Stanford et al., 28% needed special education provision in school, and 21% required speech therapy. In addition, NEC infants also have a higher likelihood of developing a poor cognitive index, language and speech impairment, behavioral disorders, memory and attention deficits, and overall poor educational results. Table 96.4 shows the details of another such study that showed adverse neurodevelopmental outcomes in infants with surgical NEC.
