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

William Hellström, Lisa M Hortensius, Chatarina Löfqvist, Gunnel Hellgren, Maria Luisa Tataranno, David Ley, Manon J N L Benders, Ann Hellström, Isabella M Björkman-Burtscher, Rolf A Heckemann, Karin Sävman, William Hellström, Lisa M Hortensius, Chatarina Löfqvist, Gunnel Hellgren, Maria Luisa Tataranno, David Ley, Manon J N L Benders, Ann Hellström, Isabella M Björkman-Burtscher, Rolf A Heckemann, Karin Sävman

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).

Conflict of interest statement

A.H. and C.L. hold stock/stock options in Premalux AB. In addition, A.H. and D.L. have received consulting fees from Shire, a Takeda company. The rest of the authors declare no competing interests.

© 2022. The Author(s).

Figures

Fig. 1. Consort study flowchart.
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…
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…
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.

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