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Published in final edited form as: Pediatr Neurol. 2013 Feb;48(2):123–129.e1. doi: 10.1016/j.pediatrneurol.2012.10.016

SNAP-II Predicts Corticospinal Tract Development in Premature Newborns

Jill G Zwicker *,†, Ruth E Grunau *,†, Elysia Adams *, Vann Chau *,‡, Rollin Brant †,§, Kenneth J Poskitt *,†,‡, Anne Synnes *,†,||, Steven P Miller *,†,‡
PMCID: PMC4489879  CAMSID: CAMS4780  PMID: 23337005

Abstract

Premature infants are at risk for adverse motor outcomes, including cerebral palsy and developmental coordination disorder. The purpose of this study was to examine the relationship of ante-, peri-, and postnatal risk factors for abnormal development of the corticospinal tract, the major voluntary motor pathway, during the neonatal period. In a prospective cohort study, 126 premature neonates (24–32 weeks gestational age) underwent serial brain imaging near birth and at term-equivalent age. Using diffusion tensor tractography, mean diffusivity and fractional anisotropy of the corticospinal tract were measured to reflect microstructural development. Generalized estimating equation models examined associations of risk factors on corticospinal tract development.

The perinatal risk factor of greater early illness severity [as measured by the Score for Neonatal Acute Physiology-II (SNAP-II)] was associated with a slower rise in fractional anisotropy of the corticospinal tract (p=0.02), even after correcting for gestational age at birth and postnatal risk factors (p=0.009). Consistent with previous findings, neonatal pain adjusted for morphine and postnatal infection were also associated with a slower rise in fractional anisotropy of the corticospinal tract (p=0.03 and 0.02 respectively). Lessening illness severity in the first hours of life might offer potential to improve motor pathway development in premature newborns.

INTRODUCTION

Despite the decreasing incidence of cerebral palsy in children born prematurely [1], motor impairments, such as developmental coordination disorder, remain a considerable problem in this population [2]. In a prospective cohort of 55 premature newborns (24–32 weeks gestational age), we used serial diffusion tensor tractography to identify that altered development during the neonatal period of the major voluntary motor pathway, the corticospinal tract, was related to moderate-severe brain injuries and postnatal infection [3]. The ability to comprehensively examine risk factors for abnormal corticospinal tract development was limited by the sample size of the cohort. Given this, with an expanded cohort of premature newborns studied serially with diffusion tensor tractography, we sought to more comprehensively examine a number of ante-, peri-, and postnatal factors hypothesized to be associated with altered corticospinal tract development.

While low birth weight and early gestational age have been identified as important risk factors for motor impairment [2, 3], recent diffusion tensor imaging results suggest that neonatal comorbidities, rather than prematurity per se, are associated with adverse brain microstructural development [5]. Thus, neonatal comorbidities may be important risk factors for altered corticospinal tract development. Our aim was to explore in a prospective cohort of premature newborns serially studied with diffusion tensor imaging, the associations of established risk factors for motor impairment with development of the major motor pathway measured with diffusion tensor tractography. These risk factors include antenatal exposures, such as pregnancy-induced hypertension [6], gestational diabetes [7], and intrauterine inflammation [8–10], as well as male sex [11–13]. Putative perinatal and post-natal risk factors include early illness severity as measured by the Score of Neonatal Acute Physiology-Version II (SNAP-II) [14,15], infection [9, 16, 17], necrotizing enterocolitis [16, 17], patent ductus arteriosus [18], chronic lung disease [18–21], and neonatal procedural pain [22]. We hypothesized that these ante-, peri- and postnatal comorbidities, rather than gestational age at birth, would predict poorer microstructural development in the corticospinal tract, as evidenced by higher mean diffusivity and lower fractional anisotropy in this motor pathway [23, 24].

STUDY DESIGN AND METHODS

Participants

Our study sample comprised a prospective cohort of preterm infants born at Children’s and Women’s Health Centre of British Columbia from April 2006 to September 2010, participating in an ongoing study of early brain development (e.g. Chau et al. [25, 26], Adams et al. [3], Brummelte et al. [27]). Neonates born between 24 and 32 weeks gestation were eligible to participate. Age at birth was calculated based on the last menstrual period or early ultrasound scan (< 24 weeks), with the latter being used if age differed by more than 7 days. Infants with a major congenital abnormality, antenatal infection, or a large parenchymal hemorrhagic infarction (>2cm) on ultrasound were not enrolled [3, 25–27]. Parents of 188 newborns provided informed consent for the study, with serial diffusion tensor imaging obtained for 126 infants (6 infants died, 34 not scanned serially, 22 inadequate diffusion tensor imaging quality for tractography due to patient motion or incomplete scans). This study was approved by the UBC/Children’s and Women’s Health Centre of BC Research Ethics Board.

Clinical Data Collection

Data regarding ante-, peri-, and post-natal risk factors for motor impairment were obtained through detailed chart review. Pregnancy-induced hypertension was defined as the development of new arterial hypertension (blood pressure over 140/90 mmHg) during pregnancy, after 20 weeks gestation and without proteinuria. Given the association of PROM with poor motor outcome [8–10], we examined the role of chorioamnionitis as measured by placental histopathology, a more sensitive measure of intrauterine infection [25]. To measure early illness severity, we used SNAP-II during the first 24 hours of life; SNAP-II quantifies six physiological variables (blood pressure, temperature, PO2/fraction of inspired oxygen, serum pH, seizures, and urine output), with higher scores reflecting more disturbances in neonatal physiology [14]. SNAP-II was available for 116/126 (92%) of the newborns. In order to characterize potential effect-modification (interaction) of SNAP-II scores on the change in corticospinal tract DTT parameters over time, we categorized SNAP-II scores into three groups, based on cut-off points established in the literature: (1) scores below 10 (most favourable outcomes [14]); (2) scores from 10–29 (higher mortality and morbidity than lower scores [14]); and (3) scores 30 and above (poorer motor outcomes [15]). Post-natal infection was defined as any clinical or culture-positive infection before the time of the first brain scan. Chronic lung disease was diagnosed if the infant required oxygen after 36 weeks postmenstrual age. Similar to our previous work [22, 27], we operationalized neonatal procedural pain as the total number of skin-breaking procedures (e.g., heel lance, intramuscular injection, chest tube insertion, central line insertion) from birth to hospital discharge or term-equivalent age, adjusted for cumulative morphine exposure. Cumulative morphine exposure was calculated from the average daily dose of intravenous and oral morphine (equivalence calculated), adjusted for daily weight, and multiplied by the number of days on morphine from birth to term-equivalent age.

Magnetic Resonance and Diffusion Tensor Imaging

As our MRI and diffusion tensor imaging protocols have been previously described [3, 25–27], we present a synopsis of our neuroimaging methods. Newborns had an MRI scan within the first weeks of life and again at term-equivalent age. An experienced pediatric neuroradiologist (KJP) blinded to clinical history reviewed the MRIs and used a validated system to determine the severity of white matter injury [28]. Diffusion tensor images were acquired with a multi-repetition, single-shot echo planar sequence with 12 gradient directions (for details, see Chau et al. [23]). To map the corticospinal tract, we conducted diffusion tensor tractography using DTIStudio software and the Fiber Assignment by Continuous Tracking method [29, 30]. Consistent with our previous work [3], we initiated fiber tracking of the corticospinal tract with a seeding region of interest in the posterior limb of the internal capsule at the level of the Foramen Munro. Given the low fractional anisotropy of the white matter of the brain at the ages at which these newborns were studied, we used a fractional anisotropy threshold of 0.15, and terminated tracts if fractional anisotropy dropped below 0.03 or if the angle between the primary eigenvectors of consecutive voxels exceeded 50 degrees or if they did not pass through two limiting regions of interest at the precentral gyrus and cerebral peduncle (Figure 1A–D) [3, 31, 32].

FIGURE 1. Diffusion Tensor Tractography of the Corticospinal Tract.

FIGURE 1

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A. Limiting region-of-interest in the white matter underlying the motor cortex;

B. Seeding region-of-interest in the posterior limb of the internal capsule;

C. Limiting region-of-interest in the cerebral peduncle;

D. Corticospinal tract.

We calculated two primary diffusion statistics for the corticospinal tract: (1) mean diffusivity, which is the average amount of water diffusion in three orthogonal directions (λ1, λ2, λ3); and (2) fractional anisotropy, which reflects the variance of these three eigenvalues and represents the directionality of water diffusion. When changes in fractional anisotropy were noted, we determined whether this difference was primarily associated with changes in axial diffusivity (λ1; the diffusion of water parallel to the primary direction of the tracts) or radial diffusivity (water diffusion perpendicular to the tracts [(λ2 + λ3)/2]). As brain white matter matures, mean diffusivity decreases and fractional anisotropy increases due to a decrease in radial diffusivity reflecting the maturation of the oligodendrocyte lineage and early myelination [23, 33]. Inter-rater and intra-rater reliability of DTT were very high as assessed on 20 randomly selected scans, using intraclass correlation and Bland-Altman limits of agreement [34](see Supplemental Table 1).

Data Analysis

Statistical analyses were performed using Stata 11.1 for Mac (Stata Corporation, College Station, Texas). Differences between risk factors for motor impairment across SNAP-II groups were compared using the Fisher exact test for categorical variables and the Kruskal-Wallis one-way analysis of variance for continuous data. To account for serial MR studies and adjust for gestational age at birth and postmenstrual age at scan, we used generalized estimating equations to examine the effects of ante-, peri-, and postnatal factors on diffusion parameters of the corticospinal tract. We tested for interactions by multiplying the variable of interest by gestational age at birth, and entering this value into the peri- and postnatal models.

RESULTS

Infant Characteristics

Our sample comprised 126 newborns born at a median age of 27.7 weeks post-menstrual age (range 24–32; inter-quartile range [IQR] 25.9–29.9). Infants underwent serial imaging at a median post-menstrual age of 32.1 weeks (IQR 30.5–33.9) and again at 40.3 weeks post-menstrual age (IQR 38.7–42.6). Table 1 outlines the number of infants exposed to the putative ante-, peri-, and postnatal risk factors for abnormal corticospinal tract development.

TABLE 1.

Presence of Putative Risk Factors for Abnormal Corticospinal Tract Development in Cohort (n=126)

Risk Factors for Motor Impairment N (%) or Median (IQR)
ANTENATAL FACTORS
 Male 64 (51)
 Pregnancy-induced hypertension (n=117) 27 (23)
 Maternal diabetes 11 (9)
 Histological chorioamnionitis (n=112) 45 (40)
PERINATAL FACTORS
 Gestational age at birth (weeks) 27.7 (25.9–29.9)
 Birth weight (grams) 1030 (805–1290)
 SNAP-II 11 (7–22)
POSTNATAL FACTORS
 Postnatal infection 47 (37)
 Necrotizing enterocolitis 29 (23)
 Patent ductus arteriosus 55 (44)
 Chronic lung disease (n=123) 41 (33)
 Pain (# skin breaking procedures) 104 (67–189)
 White matter injury 36 (29)
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Antenatal Models

Maternal diabetes (n=11) was associated with a slower decrease in mean diffusivity of the corticospinal tract over time (p=0.03) and a trend for slower increase in fractional anisotropy (p=0.054). Male sex, pregnancy-induced hypertension, and histological chorioamnionitis were not significantly associated with mean diffusivity or fractional anisotropy of the corticospinal tract (Table 2), nor with the rate of change of mean diffusivity (p=0.20–0.87) and fractional anisotropy (p=0.28–0.96) from the early to the term-equivalent scans.

TABLE 2.

Association of Antenatal and Postnatal Predictors of Motor Impairment on Development of the Corticospinal Tract

Mean Diffusivity Fractional Anisotropy
Co-efficient p Co-efficient p
ANTENATAL PREDICTORS OF MOTOR IMPAIRMENT*
 Male sex 4.86 × 10−5 0.30 1.91 × 10−3 0.82
 Pregnancy-induced hypertension −1.04 × 10−5 0.88 4.99 × 10−3 0.67
 Maternal diabetes See Text for description of interaction
 Histological chorioamnionitis 6.22 × 10−5 0.28 −3.44 × 10−3 0.73
POSTNATAL PREDICTORS OF MOTOR IMPAIRMENT†
 Postnatal infection See Text for description of interaction
 Necrotizing enterocolitis −5.13 × 10−5 0.39 −1.31 × 10−2 0.22
 Patent ductus arteriosus −9.51 × 10−5 0.10 −4.22 × 10−3 0.68
 Chronic lung disease 1.93 × 10−4 0.006 −2.91 × 10−2 0.006
 Pain adjusted for morphine See Text for description of interaction
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*

Adjusting for gestational age at birth and age at MRI

†

Adjusting for gestational age at birth and the interaction of SNAP-II and age at MRI on diffusion parameters over time

Perinatal Models

We noted an apparent interaction of SNAP-II scores with the rate of change in fractional anisotropy from the early to the term-equivalent diffusion tensor imaging scan (p=0.1). To better characterize this interaction, we used the three-group categorization of the SNAP-II scores; Table 3 shows the clinical features of the cohort by SNAP-II score groupings. We found a significant interaction of SNAP-II scores over time on fractional anisotropy of the corticospinal tract (p=0.02), which remained after correcting for gestational age at birth (p=0.02). Increasing SNAP-II scores were associated with a slower rise in fractional anisotropy (Figure 2), which is primarily being driven by a slower decline in radial diffusivity (p=0.14) compared to axial diffusivity (p=0.79). SNAP-II was not significantly associated with mean diffusivity of the corticospinal tract (p=0.42).

TABLE 3.

Clinical features of premature newborns by severity of early illness (n=116)*

SNAP-II Day 1
Number (%) or Median (IQR) <10 10–29 >30 p
Number 57 41 18
ANTENATAL FACTORS
 Male sex 25 (44) 24 (59) 11 (61) 0.27
 Pregnancy-induced hypertension 11 (20)† 9 (23)† 5 (29)† 0.71
 Maternal diabetes 4 (7) 5 (12) 2 (11) 0.62
 Histological chorioamnionitis 22 (42)† 15 (41)† 7 (41)† >0.99
PERINATAL FACTORS
 Gestational age at birth (weeks) 29.3 (27.3–31.4) 26.1 (25.4–27.6) 26.3 (25.3–28.6) 0.0001
 Birth weight (grams) 1145 (1000–1400) 895 (755–1095) 783 (595–1125) 0.0001
 Apgar (5 minutes) 8 (7–9) 7 (5–8) 7 (6–8) 0.001
POSTNATAL FACTORS
 Postnatal infection 13 (23) 21 (51) 11 (61) 0.002
 Necrotizing enterocolitis 11 (19) 14 (34) 4 (22) 0.22
 Patent ductus arteriosus 16 (28) 23 (56) 11 (61) 0.005
 Chronic lung disease 11 (20)† 21 (54)† 8 (44) 0.002
 Pain (# skin breaking procedures) 69 (51–113) 160 (100–202) 153 (83–243) 0.0001
 White matter injury 16 (28) 12 (29) 4 (22) 0.92
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*

SNAP-II scores not available for n=10

†

Missing 1–5 values

FIGURE 2. Corticospinal Tract Fractional Anisotropy by SNAP-II Scores.

FIGURE 2

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SNAP-II, Score for Acute Neonatal Physiology-II

Postnatal Models

Postnatal infection was associated with a slower increase in fractional anisotropy of the corticospinal tract from scan 1 to scan 2 (p=0.02). We also noted a significant interaction of neonatal pain adjusted for morphine with corticospinal tract development over time (p=0.03). The other postnatal risk factors examined were not associated with a difference in the change of mean diffusivity or fractional anisotropy over time; chronic lung disease was associated with higher mean diffusivity and lower fractional anisotropy of the corticospinal tract (p=0.006; Table 2).

In a multivariate model adjusting for gestational age at birth, postnatal infection, necrotizing enterocolitis, patent ductus ateriosus, chronic lung disease, and neonatal pain adjusted for morphine exposure, the interaction of SNAP-II and fractional anisotropy values over time remained significant (p=0.006). Given that white matter injury may be an additional confounder, we added white matter injury to the model, and SNAP-II continued to be robustly associated with fractional anisotropy of the corticospinal tract (p=0.009).

DISCUSSION

SNAP-II predicts microstructural development of the corticospinal tract

In our cohort of premature newborns, our primary result showed that higher illness severity in the first 24 hours of life was associated with impaired microstructural development of this motor pathway, independent of gestational age at birth as hypothesized. Higher SNAP-II was associated with lower fractional anisotropy of the corticospinal tract over time, even after adjusting postnatal adversities. Lower fractional anisotropy was related to lesser changes in radial diffusivity, which suggests that very early illness severity may interfere with maturation of the oligodendrocyte lineage or early events of myelination of the corticospinal tract [23, 33].

SNAP-II was initially developed to predict mortality of infants admitted to neonatal intensive care units [14]. Several studies have reported that SNAP-II is predictive of infant mortality for various conditions, including prematurity [15, 35, 36], congenital diaphragmatic hernia [37–39], gastroschisis [40], respiratory distress [41], and persistent pulmonary hypertension [42]. However, SNAP-II has also been shown to be predictive of brain abnormalities in the preterm population, specifically suppressed amplitude-integrated electroencephalographic activity [43], intraventricular hemorrhage [15, 44], moderate to severe ventriculomegaly, and echodense lesions in white matter [15]. Our findings build on this literature, showing that SNAP-II also predicts slower microstructural development of the corticospinal tract. Dammann et al. [15] postulate that SNAP-II might be in the causal chain leading to brain damage, or that early illness severity is a marker for other aspects of developmental vulnerability. While we cannot establish causation, our results suggest that early illness severity is associated with slower brain development over time, even after accounting for other postnatal complications. Consistent with our findings, Kaukola et al. [45] reported that the severity of perinatal illness predicted reduced growth of the cortical surface area in premature newborns. Although co-morbid adverse events that occur during neonatal intensive care (i.e., days on ventilation, PDA, and necrotizing enterocolitis) play a significant role in early brain development [5], our results show that postnatal illness as early as the first 24 hours of life itself predicts slower development of the major motor pathway. Thus, the first day of life is an important window in which to protect the developing brain.

SNAP-II has also been shown to predict neurodevelopmental outcomes in extremely premature newborns. Dammann et al. [15] reported that higher SNAP-II scores were associated with poorer cognitive and motor outcomes at 24 months, and showed some promise in predicting positive screening for autism at the same age. Our future work will determine if SNAP-II, via microstructural development of the corticospinal tract, is predictive of motor impairment in premature newborns.

Other risk factors for abnormal corticospinal tract development

Antenatal factors of male sex, pregnancy-induced hypertension, and histological chorioamnionitis were not significantly associated with diffusion parameters of the corticospinal tract. Although male preterm babies tend to have poorer neurodevelopmental outcomes compared to girls [46, 47], male sex did not have a significant relationship with corticospinal tract development. Sex differences in development of the corticospinal tract have been reported in different parts of the corticospinal tract in school-age children [48]; our contrasting results may reflect our quantification of the tract from the cerebral cortex to cerebral peduncles or because developmental differences are manifest at a later age.

Maternal diabetes appears to have an association with microstructural development of the corticospinal tract over time. As we only had 11 infants in our study exposed to maternal diabetes, this finding will need to be replicated in a larger sample of exposed infants.

Consistent with our previous work, in this expanded cohort, we confirmed that postnatal infection is an important risk factor for altered corticospinal development over time [3]. We also extended previous findings of the relationship of neonatal pain with altered brain development measured in white and gray matter regions of interest [27] by showing that neonatal pain is also associated with corticospinal tract development in the neonatal period. However, the relationship of SNAP-II with motor pathway development persisted even after adjusting for these factors, suggesting that illness severity in the first 24 hours of life is a significant predictor of corticospinal tract development.

Limitations

As we only included maternal and neonatal factors established as risks for motor impairment, we may have overlooked other clinical variables that may affect corticospinal tract development. However, our work was hypothesis driven to examine the most likely ante-, peri-, and postnatal risk factors for adverse corticospinal tract development. Our study design of serial diffusion tensor imaging in a prospective cohort of premature newborns allowed us to characterize development of the corticospinal tract in the neonatal period. Based on the imaging acquired in this cohort, our study is limited to microstructural development of the major motor pathway. Future work is needed to examine the relationship of risk factors for motor impairment with connectivity of motor brain regions using novel imaging tools, such as functional connectivity MRI.

CONCLUSION

Early illness severity (as measured by SNAP-II) is predictive of corticospinal development in very premature infants, a population at high risk of adverse motor outcomes, such as cerebral palsy and developmental coordination disorder [2, 49, 50]. Although early illness severity is related to subsequent clinical conditions that may affect brain development, these results suggest that illness on the first day of life is significantly associated with altered development of the corticospinal tract, even after controlling for gestational age and postnatal adversities. Lessening illness severity in the first hours of life, by means such as temperature regulation and ventilation strategies, might offer potential to improve motor pathway development in premature newborns. As previous research has shown that altered development of the corticospinal tract in childhood has been associated with poor motor outcomes [51, 52], longitudinal follow-up of this cohort will determine if corticospinal tract development in the neonatal period is related to motor outcomes of premature newborns.

Supplementary Material

Acknowledgments

This study was funded by Canadian Institutes of Health Research (CIHR) grants (MOP 79262 PI Miller and MOP 86489 PI Grunau). JGZ is supported by the Canadian Child Health Clinician Scientist Program, Child & Family Research Institute (CFRI), Michael Smith Foundation for Health Research (MSFHR), and NeuroDevNet. REG is a Senior Scientist with CFRI. SPM is a Canada Research Chair (Tier 2) and MSFHR Scholar.

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