ESPE Yearbook of Paediatric Endocrinology

Brief Summary: This prospective singleton birth cohort (N=288, 43.4% male) from Flanders, Belgium, was a subset of a larger longitudinal cohort (ENVIRONAGE). The authors used a targeted proteomic panel to measure 386 inflammatory-related proteins in cord blood and examined their associations with birth weight (BW), birth weight ratio (BWR - BW divided by the median BW for gestational age for sex and parity), and rapid infant weight gain (defined as [weight z score at 12 m minus BW z score] > 0.67). Other outcomes at 4-6 y were weight, body mass index (BMI), waist circumference and overweight. Multiple logistic regression models were adjusted for several maternal and offspring factors and Bonferroni correction was used to correct for multiple testing.

Mother’s pre-pregnancy BMI was (mean ± SD) 24.1±4.1, 52.4% were primiparous, 66.3% had a college or university diploma, gestational age was 39.6±1.7 weeks, birth weight 3389±493 g (10% > 4000 g; 2.4% < 2500 g) and 95% had at least 2 European grandparents. 31% showed rapid infant weight gain, and 11.8% were overweight or obese at 4-6 y.

Seven proteins were of significant interest; these were involved in GH pathway, metabolism and metabolic disorders, neurological pathways and placental vascularization. Positive associations with BWR and/or BW were seen with afamin and SFRP4. Both proteins are linked to the Wnt signaling pathway, which is involved in cell proliferation, survival migration and polarity in pre- and postnatal life. Afamin overexpression in transgenic mice leads to increased birth weight, and elevated afamin and SFRP4 concentrations in the first trimester in humans are associated with gestation diabetes.

Lower cord blood levels of 5 proteins showed negative associations with growth. EPHA4 (which has a positive role in IGF-1R signalling and postnatal body growth in mice), TCN1 (which binds vitamin B12, and B12 deficiency is associated with lower BW), CELSR2, SLITRK1, and UNC5D (these latter 3 are involved in neurological pathways but yet unknown roles in growth). For rapid infant weight gain and overweight at age 4-6 y, odds ratios (and 95% CI) were well below 1.0 for afamin, and a trend was noted for SFRP4: OR 0.49; 0.29-1.01 for rapid infant weight gain). In contrast, an elevated OR (2.44; 95% CI 1.26-4.8) was seen for TCN1 and rapid infant weight gain. Forest plots per doubling of protein levels were also calculated for weight, BMI and waist circumference at age 4-6 y and again pointed to negative associations of EPHA4, SLITRK1, CELSR2 and UNC50.

This study presents many novel findings. None of the associations appeared to be sex-specific. Further studies should explore how stress during pregnancy can influence the fetal proteome and contribute to newborn growth as well as to future disease risks.