Postnatal serum IGF-1 levels associate with brain volumes at term in extremely preterm infants

Abstract

Background: Growth factors important for normal brain development are low in preterm infants. This study investigated the link between growth factors and preterm brain volumes at term.

Material/methods: Infants born <28 weeks gestational age (GA) were included. Endogenous levels of insulin-like growth factor (IGF)-1, brain-derived growth factor, vascular endothelial growth factor, and platelet-derived growth factor (expressed as area under the curve [AUC] for serum samples from postnatal days 1, 7, 14, and 28) were utilized in a multivariable linear regression model. Brain volumes were determined by magnetic resonance imaging (MRI) at term equivalent age.

Results: In total, 49 infants (median [range] GA 25.4 [22.9-27.9] weeks) were included following MRI segmentation quality assessment and AUC calculation. IGF-1 levels were independently positively associated with the total brain (p < 0.001, β = 0.90), white matter (p = 0.007, β = 0.33), cortical gray matter (p = 0.002, β = 0.43), deep gray matter (p = 0.008, β = 0.05), and cerebellar (p = 0.006, β = 0.08) volume adjusted for GA at birth and postmenstrual age at MRI. No associations were seen for other growth factors.

Conclusions: Endogenous exposure to IGF-1 during the first 4 weeks of life was associated with total and regional brain volumes at term. Optimizing levels of IGF-1 might improve brain growth in extremely preterm infants.

Impact: High serum levels of insulin-like growth factor (IGF)-1 during the first month of life were independently associated with increased total brain volume, white matter, gray matter, and cerebellar volume at term equivalent age in extremely preterm infants. IGF-1 is a critical regulator of neurodevelopment and postnatal levels are low in preterm infants. The effects of IGF-1 levels on brain development in extremely preterm infants are not fully understood. Optimizing levels of IGF-1 may benefit early brain growth in extremely preterm infants. The effects of systemically administered IGF-1/IGFBP3 in extremely preterm infants are now being investigated in a randomized controlled trial (Clinicaltrials.gov: NCT03253263).

Fig. 1. Consort study flowchart.

In total, 49 infants were eligible for analysis with complete MRI volume segmentation and growth factor AUC. *In two infants, IGF-1 AUC was available, but not BDNF, VEGF, and PDGF. RCT randomized controlled trial, n number, TEA term equivalent age, IGF Insulin-like growth factor, BDNF brain-derived neurotrophic factor, AUC area under the curve, MRI magnetic resonance imaging.

Fig. 2. Serum levels of IGF-1 AUC (PND 1–28) and regional brain volumes at TEA.

Higher IGF-1 levels were associated with total brain volume; r = 0.49, p < 0.001 (a), white matter volume; r = 0.55, p < 0.001 (b), cortical gray matter volume; r = 0.40, p = 0.004 (c), deep gray matter volume r = 0.45, p = 0.001 (d), and cerebellar volume; r = 0.47, p < 0.001 (e). IGF insulin-like growth factor, AUC area under the curve, PND postnatal day, TEA term equivalent age.

Fig. 3. The impact of gestational age at birth on brain volume and serum IGF-1 levels.

a Estimated unstandardized probabilities of total brain volume, retrieved from the full statistical model, illustrated per gestational week. Error bars indicate 95% CI. Colored area: interpolated. b Distribution of serum levels of IGF-1 during postnatal days 1, 7, 14, and 28 in relation to gestational age at birth (below or over 25 weeks). More immature infants show less increase in endogenous IGF-1 levels. Dotted line shows 30 ng/ml. A prolonged period with serum IGF-1 levels below this threshold has been related to morbidities in the neurovascular unit. Boxes illustrate interquartile range, whiskers show full range. IGF-1 insulin-like growth factor 1, CI confidence interval, PND postnatal day, GA gestational age.