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Background <p>Umbilical cord blood IL-6 is implicated in preterm brain injury, but prior studies often assumed linearity, potentially masking complex relationships. We aim to investigate the relationship and threshold effects between umbilical cord blood IL-6 and cerebral injury risk in preterm infants.</p> Methods <p>This prospective cohort study enrolled 1028 very preterm infants (VPIs) below 32 weeks. Severe Brain Injury (SBI) or death was the primary outcome. IL-6 was measured in umbilical cord serum. Restricted cubic spline (RCS) regression assessed linearity and identified inflection points, with adjustments for key confounders.</p> Results <p>The risk of cerebral injury started to increase significantly at 7.27 pg/mL (adjusted odds ratio [aOR] = 1.512). RCS revealed a significant nonlinear relationship (P&lt;sub&gt;nonlinear&lt; or sub &gt; &lt; 0.05) with the threshold at 49.09 pg/mL. Below this threshold, each 1-unit increase in IL-6 may raise the risk odd of cerebral injury by 2.6% (aOR = 1.026). Above 49.09 pg/mL, the risk curve plateaued.</p> Conclusions <p>Umbilical cord blood IL-6 shows a sigmoidal, threshold-dependent relationship with SBI risk. IL-6 &gt; 49.09 pg/ml identify infants at substantially elevated risk, supporting its potential use as a biomarker for early risk stratification. Clinical validation in larger studies is warranted.</p> Impact <p><UnorderedList Mark="Bullet"> <ItemContent> <p>The IL-6 level in the umbilical cord blood shows a nonlinear, threshold-dependent association with cerebral injury in preterm infants, with the risk ratio plateauing above 49.09 pg/mL.</p> </ItemContent> <ItemContent> <p>This is the first large cohort study using RCS to depict a sigmoidal IL-6-injury relationship, overcoming limitations of linear/dichotomous models in prior works.</p> </ItemContent> <ItemContent> <p>IL-6 &gt; 49.09 pg/mL may serve as a clinically applicable biomarker for early identification of high-risk preterm infants, which may guide neuroprotective strategies.</p> </ItemContent> </UnorderedList></p>

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Nonlinear dose-response of umbilical cord blood IL-6 to severe brain injury in preterm infants: a prospective cohort study

  • 期刊论文

  • 发表日期：

    2026年5月11日

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  • Ling Li,
  • Yuqiao Li,
  • Xuewei Cui,
  • Yongyan Shi

摘要

Background

Umbilical cord blood IL-6 is implicated in preterm brain injury, but prior studies often assumed linearity, potentially masking complex relationships. We aim to investigate the relationship and threshold effects between umbilical cord blood IL-6 and cerebral injury risk in preterm infants.

Methods

This prospective cohort study enrolled 1028 very preterm infants (VPIs) below 32 weeks. Severe Brain Injury (SBI) or death was the primary outcome. IL-6 was measured in umbilical cord serum. Restricted cubic spline (RCS) regression assessed linearity and identified inflection points, with adjustments for key confounders.

Results

The risk of cerebral injury started to increase significantly at 7.27 pg/mL (adjusted odds ratio [aOR] = 1.512). RCS revealed a significant nonlinear relationship (P<sub>nonlinear< or sub > < 0.05) with the threshold at 49.09 pg/mL. Below this threshold, each 1-unit increase in IL-6 may raise the risk odd of cerebral injury by 2.6% (aOR = 1.026). Above 49.09 pg/mL, the risk curve plateaued.

Conclusions

Umbilical cord blood IL-6 shows a sigmoidal, threshold-dependent relationship with SBI risk. IL-6 > 49.09 pg/ml identify infants at substantially elevated risk, supporting its potential use as a biomarker for early risk stratification. Clinical validation in larger studies is warranted.

Impact

The IL-6 level in the umbilical cord blood shows a nonlinear, threshold-dependent association with cerebral injury in preterm infants, with the risk ratio plateauing above 49.09 pg/mL.

This is the first large cohort study using RCS to depict a sigmoidal IL-6-injury relationship, overcoming limitations of linear/dichotomous models in prior works.

IL-6 > 49.09 pg/mL may serve as a clinically applicable biomarker for early identification of high-risk preterm infants, which may guide neuroprotective strategies.