Cortisol intermediates and hydrocortisone responsiveness in critical neonatal disease

<p><i>Objective</i>: Therapy-resistant hypotension complicates diseases in neonates. Our objective was to investigate whether lack of therapeutic response to plasma expanders and inotropes associates with serum levels of cortisol and its precursors.</p> <p><i>Methods</i>: We investigated 96 infants with hypotension and critical neonatal disease for cortisol metabolism and are divided into responders and non-responders to plasma expanders and inotropes. Serum concentrations of steroids were analysed soon after the onset of volume expansion and inotrope treatment for shock. The 48 non-responders were treated with intravenous hydrocortisone (HC) and serum cortisol concentrations were monitored a week later.</p> <p><i>Results</i>: The mean cortisol concentrations did not differ between the responders and non-responders: 13.6 ± 2.5 and 12.5 ± 4.5 μg/dL, respectively. Dehydroepiandrosterone (37.3 ± 19.5 versus 324.0 ± 106.3; <i>p </i>< 0.0001) and 17-hydroxy-pregnenolone concentrations were lower in responders than in non-responders. Dehydroepiandrosterone levels in non-responders were inversely associated with postnatal age (<i>r</i> = 0.50, <i>p </i>< 0.0001). There were no differences in 17-hydroxy-progesterone, 11-deoxy-cortisol and cortisone between the responders and non-responders. Hydrocortisone administration acutely increased blood pressure. Six non-responders who died despite HC administration had low levels of cortisol. The responders had normal serum cortisol after HC treatment.</p> <p><i>Conclusion</i>: Precursors of cortisol, proximal to the 3β-hydroxysteroid dehydrogenase activity, accumulated in neonates with hypotension, responding to HC treatment.</p

Association between <i>TLR4</i> genotypes and BPD in preterm cohort B.

<p>GA: Gestational age; BW: Birth weight;</p>*<p>Combining heterozygous/rare homozygous genotypes.</p>†<p>Chi-square or Fisher exact as indicated.</p

Clinical characteristics of infants in preterm cohort A.

&<p>Up to transfer to peripheral centre or discharge home.</p>*<p>Based on neonates alive at 36 weeks PMA.</p>†<p>Differences considered statistically significant are underlined.</p>£<p>Differences were not statistically significant (p>0.05) based on non-parametric Mann-Whitney U testing. NC = Not calculated.</p

Association between <i>TLR4</i> genotypes and BPD in preterm cohort A.

<p>GA: Gestational age; BW: Birth weight; 95%CI: 95% confidence interval.</p>*<p>Combining heterozygous/rare homozygous genotypes.</p>†<p>Statistically significant differences are underlined;</p>§<p>Comparing the Moderate/Severe with the No BPD group.</p

Ethnicity of infants in preterm cohort A and matched control term infants.

†<p>Differences considered statistically significant are underlined.</p>*<p>Combined heterogenous/rare homozygous genotype includes both preterm and infants born at term. NF  =  none found. The term “First Nations” refers to Canadian Indigenous Nations as defined by the Government of Canada.</p

Multiple regression analysis between clinical co-variables and <i>TLR4-299</i> genotype^* (dependent variable).

*<p>Results are shown for combined heterozygous/rare homozygous genotypes in binary regression. Significance was also comparable using all three genotypes (Asp/Asp, Asp/Gly and Gly/Gly) in regression models using BPD (p = 0.016) as the dependent variable.</p

Pairwise correlation among genetic scores.

<p>* M, maternal genotype score (M1 + M2); M1 (C1), maternal transmitted haplotype score; M2, maternal nontransmitted haplotype score; C, fetal genotype score (C1 + C2); C2, paternal transmitted haplotype score.</p><p>Pairwise correlation among genetic scores.</p

Schematic representation of various causal mechanisms that can lead to the observational associations between maternal height and pregnancy outcomes.

<p>(A) Direct causal effect of maternal height on pregnancy outcomes. (B) Associations of social and nutritional confounders that have impacts on both maternal height and pregnancy outcomes. (C) Fetal genetics that directly influences pregnancy outcomes.</p

Maternal transmission of alleles and haplotype scores.

<p>We inferred maternal transmission of alleles (M1 → C1) and constructed haplotype scores: M1 and C1, maternal transmitted haplotype score; M2, maternal nontransmitted haplotype score; and C2, paternal transmitted haplotype score.</p

Association between haplotype genetic scores and pregnancy outcomes.

<p>* M1 (C1), maternal transmitted haplotype score; M2, maternal nontransmitted haplotype score; C2, paternal transmitted haplotype score.</p><p>Association between haplotype genetic scores and pregnancy outcomes.</p