Cord Blood Proteomic Profiles, Birth Weight, and Early Life Growth Trajectories

Abstract

Importance: The cord blood proteome, a repository of proteins derived from both mother and fetus, might offer valuable insights into the physiological and pathological state of the fetus. However, its association with birth weight and growth trajectories early in life remains unexplored.

Objective: To identify cord blood proteins associated with birth weight and the birth weight ratio (BWR) and to evaluate the associations of these cord blood proteins with early growth trajectories.

Design, setting, and participants: This cohort study included 288 mother-child pairs from the ongoing prospective Environmental Influence on Early Aging birth cohort study. Newborns were recruited from East-Limburg Hospital in Genk, Belgium, between February 2010 and November 2017 and followed up until ages 4 to 6 years. Data were analyzed from February 2022 to September 2023.

Main outcomes and measures: The outcome of interest was the associations of 368 inflammatory-related cord blood proteins with birth weight or BWR and with early life growth trajectories (ie, rapid growth at age 12 months and weight, body mass index [BMI] z score, waist circumference, and overweight at age 4-6 years) using multiple linear regression models. The BWR was calculated by dividing the birth weight by the median birth weight of the population-specific reference growth curve, considering parity, sex, and gestational age. Results are presented as estimates or odds ratios (ORs) for each doubling in proteins.

Results: The sample included 288 infants (125 [43.4%] male; mean [SD] gestation age, 277.2 [11.6] days). The mean (SD) age of the child at the follow-up examination was 4.6 (0.4) years old. After multiple testing correction, there were significant associations of birth weight and BWR with 7 proteins: 2 positive associations: afamin (birth weight: coefficient, 341.16 [95% CI, 192.76 to 489.50]) and secreted frizzled-related protein 4 (SFRP4; birth weight: coefficient, 242.60 [95% CI, 142.77 to 342.43]; BWR: coefficient, 0.07 [95% CI, 0.04 to 0.10]) and 5 negative associations: cadherin EGF LAG 7-pass G-type receptor 2 (CELSR2; birth weight: coefficient, -237.52 [95% CI, -343.15 to -131.89]), ephrin type-A receptor 4 (EPHA4; birth weight: coefficient, -342.78 [95% CI, -463.10 to -222.47]; BWR: coefficient, -0.11 [95% CI, -0.14 to -0.07]), SLIT and NTRK-like protein 1 (SLITRK1; birth weight: coefficient, -366.32 [95% CI, -476.66 to -255.97]; BWR: coefficient, -0.11 [95% CI, -0.15 to -0.08]), transcobalamin-1 (TCN1; birth weight: coefficient, -208.75 [95% CI, -305.23 to -112.26]), and unc-5 netrin receptor D (UNC5D; birth weight: coefficient, -209.27 [95% CI, -295.14 to -123.40]; BWR: coefficient, -0.07 [95% CI, -0.09 to -0.04]). Further evaluation showed that 2 proteins were still associated with rapid growth at age 12 months (afamin: OR, 0.32 [95% CI, 0.11-0.88]; TCN1: OR, 2.44 [95% CI, 1.26-4.80]). At age 4 to 6 years, CELSR2, EPHA4, SLITRK1, and UNC5D were negatively associated with weight (coefficients, -1.33 to -0.68 kg) and body mass index z score (coefficients, -0.41 to -0.23), and EPHA4, SLITRK1, and UNC5D were negatively associated with waist circumference (coefficients, -1.98 to -0.87 cm). At ages 4 to 6 years, afamin (OR, 0.19 [95% CI, 0.05-0.70]) and SLITRK1 (OR, 0.32 [95% CI, 0.10-0.99]) were associated with lower odds for overweight.

Conclusions and relevance: This cohort study found 7 cord blood proteins associated with birth weight and growth trajectories early in life. Overall, these findings suggest that stressors that could affect the cord blood proteome during pregnancy might have long-lasting associations with weight and body anthropometrics.

Figure 1.. Volcano Plot of the Proteomics Analysis for Birth Weight and Birth Weight Ratio (BWR)

Volcano plot of the results of the large proteomics analysis showing the difference in infant’s birth weight (grams) and BWR per doubling in cord blood protein levels (x-axis) vs multiple linear regression model P values (y-axis). Multiple linear regression models were adjusted for sex, gestational age, maternal prepregnancy body mass index, maternal age at delivery, month and year of delivery, ethnicity, parity, smoking during pregnancy, and maternal education. ADAM12 indicates ADAM metallopeptidase domain 12; AFM, afamin; APOA4, apolipoprotein A-IV; ASGR2, asialoglycoprotein receptor 2; C3, complement component 3; CELSR2, cadherin EGF LAG seven-pass G-type receptor 2; CFB, complement factor B; CFD, factor D; CFH, factor H; CFHR4, complement factor H-related protein 4; CFI, complement factor I; EPHA4, ephrin type-A receptor 4; F2, prothrombin; F10, factor X; F12, coagulation factor XII; FGF12, fibroblast growth factor 12; FOLH1, glutamate carboxypeptidase II; GC, human group-specific component; GSR, glutathione-disulfide reductase; HMCN2, hemicentin 2; IL-31, interleukin 31; INHBB, inhibin, beta B; INSR, insulin receptor; ITGA2, integrin alpha-2; LCAT, lecithin–cholesterol acyltransferase; MKI67, marker of proliferation Kiel 67; NXPH3, neurexophilin-3; PENK, proenkephalin; PGLYRP2, peptidoglycan recognition protein 2; PI16, peptidase inhibitor 16; PLCB1, phospholipase C beta 1; PPL, periplakin; PRR4, proline-rich protein 4; S100A13, S100 calcium-binding protein A13; SDK2, protein sidekick-2; SERPINA4, kallistatin; SERPINA5, serpina family A member 5; SERPINC1, serpin family C member 1; SERPINF2, serpin family F member 2; SFRP4, secreted frizzled-related protein 4; SHBG, sex hormone–binding globulin; SLITRK1, SLIT and NTRK-like protein 1; SUSD5, sushi domain-containing protein 5; TCN1, transcobalamin; TGFBR1, transforming growth factor-beta receptor 1; TPSG1, tryptase gamma 1; TTR, transthyretin; UNC5D, unc-5 netrin receptor D; and ZBP1, Z-DNA binding protein 1.

Figure 2.. Forest Plot of the Child’s Weight, Body Mass Index (BMI) z Score, and Waist Circumference With Cord Blood Proteins

Differences (with 95% CIs) were calculated at age 4 to 6 years per doubling in cord blood protein levels. Multiple linear regression models were adjusted for sex, gestational age, maternal prepregnancy BMI (calculated as weight in kilograms divided by height in meters squared), maternal age at delivery, month and year of delivery, race and ethnicity, parity, smoking during pregnancy, maternal education, and age of the child at the follow-up examination. Corresponding numeric data are provided in eTable 7 in Supplement 1. AFM indicates afamin; CELSR2, cadherin EGF LAG seven-pass G-type receptor 2; EPHA4, ephrin type-A receptor 4; SFRP4, secreted frizzled-related protein 4; SLITRK1, SLIT and NTRK-like protein 1; TCN1, transcobalamin-1; UNC5D, unc-5 netrin receptor D.