Brain Injury Biomarkers Associated with Outcomes of Premature Infants

High levels of neurofilament light (NfL), a brain injury biomarker, during the first weeks of postnatal life are associated with retinopathy of prematurity (ROP) and Bayley Scales of Infant Development (BSID) II and III scores at 2 years of age, according to new research from Sweden published in JAMA Network Open.

Researchers sought to describe the long-term effects of preterm birth on NfL and glial fibrillary acidic protein (GFAP) and any association with morbidities in the neurovascular unit, the eye, and the brain.

They included 3 cohorts of infants who were born before 32 weeks’ gestational age (GA): 84 infants admitted to neonatal intensive care units (NICUs) at Queen Silvia Children’s Hospital (n=70) and Uppsala University Hospital (n=14); 64 infants born before 31 weeks GA admitted to the NICU at Lund University Hospital; and 90 infants born before 28 weeks GA in the NICU at Queen Silvia Children’s Hospital. The infants were all born between 1999 and 2015.

The researchers measured the NfL and GFAP in all individuals, and the longitudinal data of those measures were categorized into subgroups based on the postnatal day (PND) they were collected. They reviewed individuals’ medical history to discover diagnoses of intraventricular hemorrhage (IVH) and ROP. The investigators assessed the neurodevelopmental outcomes of the second (n=48) cohort of participants using the BSID II and the third (n=72) cohort using the BSID III when the participants were a corrected age of 2 years[BL1] .

NfL cord blood levels at birth were negatively correlated with GA (n=32; Spearman correlation coefficient, -0.48; 95% CI, -0.72 to -0.14; P =.009). The median NfL concentration was 21.6 ng/L. Among 57 infants, NfL significantly increased at PND 1 (44.7 [11.5-438.0]; P <.001). NfL levels significantly increased during the first day of life among 23 infants who had a record of both cord blood and PND 1 samples (median [range] NfL levels at birth: 21.3 [11.6-57.4] ng/L; PND 1: 39.6 [17.4-87.8] ng/L; P <.001).

Infants born before 27 weeks GA showed significantly higher NfL between postnatal week 1 and 10 than those who were born after 27 weeks GA.

NfL levels increased after birth, were high during the first 4 weeks of life, and declined to steadily low levels by postnatal age 12 weeks (median [range] NfL level at birth: 58.8 [11.5-1371.3] ng/L; 1 wk: 83.5 [14.1-952.2] ng/L; 4 wk: 24.4 [7.0-306.0] ng/L; 12 wk: 9.1 [3.7-57.0] ng/L).

The strongest associations with NfL area under the curve (AUC) were GA at birth, followed by birth weight, ventilator support for more than 7 days, and ROP. Adjusting for GA at birth, birth weight standard deviation (SD) score, Apgar status at 5 minutes, and mode of delivery, NfL AUC at weeks 2 to 4 was independently associated with any ROP (odds ratio (OR), 4.79; 95% CI, 2.17-10.56; P <.001).

Limitations of the study include its retrospective design, the prolonged recruitment period during which new clinical practices may have emerged, and the unknown effect of storage time on the samples.

Among 81 infants with available NfL AUC, the NfL AUC at weeks 2 to 4 was independently associated with moderate to severe neurodevelopmental impairment at 2 years, adjusted for GA at birth and sex (OR per 10-unit increase, 1.07; 95% CI, 1.02-1.13; P =.01).