JAMA Network Open | April 2, 2021

Sjöbom U, Hellström W, Löfqvist C, Nilsson AK, Holmström G, Pupp IH, Ley D, Blennow K, Zetterberg H, Sävman K and Hellström A

JAMA network open. 2021;4:e214138

DOI: 10.1001/jamanetworkopen.2021.4138

Abstract

Importance  Circulating levels of neurofilament light (NfL) and glial fibrillary acidic protein (GFAP) are important in the course of brain injury in adults, but longitudinal postnatal circulating levels in preterm infants have not been investigated.

Objectives  To examine postnatal longitudinal serum levels of NfL and GFAP in preterm infants during the first 15 weeks of life and to explore possible associations between these biomarkers, neonatal morbidities, and neurodevelopmental outcomes at 2 years.

Design, Setting, and Participants  This cohort study used data from 3 clinical studies, including 221 infants born before 32 weeks gestational age (GA) from 1999 to 2015; neurodevelopmental outcomes were evaluated in 120 infants. Data were collected at tertiary-level neonatal intensive care units in Gothenburg, Lund, and Uppsala, Sweden. Data analysis was conducted from January to October 2020.

Exposure  Preterm birth.

Main Outcomes and Measures  Serum NfL and GFAP levels, retinopathy of prematurity (ROP), intraventricular hemorrhage, and Bayley Scales of Infant Development II and III at 2 years of age, analyzed by multivariate logistic regression measured by odds ratio (OR), and receiver operating characteristic curve (ROC) analysis. Area under the curve (AUC) was also measured.

Results  The 221 included infants (108 [48.9%] girls) had a mean (SD) GA at birth of 26.5 (2.1) weeks and a mean (SD) birth weight of 896 (301) grams. NfL levels increased after birth, remaining high during the first 4 weeks of life before declining to continuously 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). In a binary logistic regression model adjusted for GA at birth, birth weight SD score, Apgar status at 5 minutes, and mode of delivery, the NfL AUC at weeks 2 to 4 was independently associated with any ROP (OR, 4.79; 95% CI, 2.17-10.56; P < .001). In an exploratory analysis adjusted for GA at birth and sex, NfL AUC at weeks 2 to 4 was independently associated with unfavorable neurodevelopmental outcomes at 2 years corrected age (OR per 10-unit NfL increase, 1.07; 95% CI, 1.02-1.13; P = .01). Longitudinal GFAP levels were not significantly associated with neonatal morbidity or neurodevelopmental outcome.

Conclusions and Relevance  In this study, high NfL levels during the first weeks of life were associated with ROP and poor neurodevelopmental outcomes at 2 years of age. Associations between NfL and later neurovascular development in infants born prematurely should be investigated further.