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Cytokine production by newborns: influence of sex and season of birth



Immune signatures at birth could be associated with clinical outcomes and will improve our understanding of immunity prenatal programming.


Data come from 235 newborns from the cohort study NELA. Production of cytokines was determined using Luminex technology. Associations between cytokine concentrations with sex and season of birth were examined by multivariate regression models.


Umbilical cord blood cells produced high levels of inflammatory cytokines, moderate levels of Th1/Th2/Tr-related cytokines, and low levels of Th17 cytokines. Compared to females, male newborn cells secreted higher levels of Th2 (peptidoglycan-stimulated IL-13, odds ratio [OR] = 2.26; 95% CI 1.18, 4.31, p value = 0.013) and Th17 (polyinosinic:polycytidylic acid-stimulated IL-23, OR = 1.82, 95% CI 1.01, 3.27, p value = 0.046) and lower levels of Th1 (olive-stimulated IL-2, OR = 0.56, 95% CI 0.31, 0.99, p value = 0.047) cytokines. Also, children born during warm seasons showed decreased innate cytokine response to peptidoglycan (IL-6, OR = 0.28, 95% CI 0.15, 0.52, p value < 0.001) compared to those born in cold seasons; meanwhile, adaptive immunity cytokines were more frequently secreted by children born during warm seasons in response to allergen extracts (IL-10, OR = 2.11, 95% CI 1.12, 3.96, p value = 0.020; IL-17F, OR = 3.31, 95% CI 1.83, 5.99, p value < 0.001).


Newborns showed specific cytokines signatures influenced by sex and season of birth.


  • There is a limited number of population-based studies on the immune status at birth and the influence of prenatal and perinatal factors on it.

  • Characterization of cytokine signatures at birth related to the prenatal environment could improve our understanding of immunity prenatal programming.

  • Newborns exhibit specific unstimulated and stimulated cytokine signatures influenced by sex and season of birth.

  • Unstimulated and stimulated cytokine signatures in newborns may be associated with the development of related clinical outcomes later in life.

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Fig. 1: Cytokine concentrations and patterns of response in cord blood cells.
Fig. 2: Correlation matrix based on Spearman coefficients for cytokine concentrations in unstimulated and stimulated cord blood cells.
Fig. 3: Cytokine response in unstimulated and stimulated cord blood cells according to sex.
Fig. 4: Cytokine response in unstimulated and stimulated cord blood cells according to season.

Data availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.


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We are extremely grateful to all the families who participate in this study, the hospital technicians, midwives, and gynecologists for recruitment and following them up, and the whole NELA team for their commitment and their role in the success of the study. We want to particularly acknowledge the BioBank “Biobanco en Red de la Región de Murcia” (PT17/0015/0038 and PT20/00109) integrated with the Spanish National Biobanks Network (B.000859) for its collaboration. We acknowledge Dr José Joaquín Cerón and Dr Luis Pardo Marín for their support with the cytokine determination and Dr Manuel Sanchez Angulo for the critical reading of the manuscript and helpful suggestions. Finally, we thank Francisco Arques for his excellent technical support.


This work has been supported by grants from Instituto de Salud Carlos III, Spanish Ministry of Science, Innovation and Universities, and Fondos FEDER (grant numbers CP14/00046, PIE15/00051, PI16/00422, and ARADyAL network RD160006). A.M.G.-S. was funded by a predoctoral Fellowship (FI17/00086) and E.M. was funded by Miguel Servet Fellowships (MS14/00046 and CPII19/00019) awarded by the Instituto de Salud Carlos III (ISCIII), Spanish Ministry of Science, Innovation and Universities, and Fondos FEDER. The funders had no role in the study design, data collection, and analysis, decision to publish, or preparation of the manuscript.

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Conception and design of the study: A.M.G.-S., E.M., L.G.-M., and E.M.-O. Acquisition and analysis of data: A.M.G.-S., E.M., E.C.-C., M.N.-M., M.A.G.-B., J.V.-M., T.H.-C., V.P.-F., A.E.M.-T., and E.M.-O. Drafting of the manuscript: E.M. and E.M.-O. Critical revision and final approval of the version to be published: A.M.G.-S., E.M., E.C.-C., M.N.-M., M.A.G.-B., J.V.-M., T.H.-C., V.P.-F., A.E.M.-T., L.G.-M., and E.M.-O.

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Correspondence to Eva Morales or Elena Martin-Orozco.

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Garcia-Serna, A.M., Morales, E., Cantero-Cano, E. et al. Cytokine production by newborns: influence of sex and season of birth. Pediatr Res (2022).

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