Effect of mode of delivery and woman’s obstetric history on cytokine and immunoglobulins content in cord blood and breast milk

Objective. To establish the effect of mode of delivery, aspects of obstetric history (parity, miscarriages), and gestational weight gain on cytokines and immunoglobulins content in cord blood (CB) and breast milk (BM).

Materials and methods. 379 pregnant women were included in the study. Study materials: CB; BM expressed in 1 (BM1) and 3 months (BM2) after childbirth. L-4, IL-5, IL-6, IL-10, IL-25, TSLP, IFN-γ, TGFβ1, TGFβ2, CCL17, CCL22, CXCL10 were typed in body fluids by the method of enzyme immunoassay (ELISA).

Results. Caesarean deliveries are associated with essential higher concentrations of CCL17 in CB (p=0.0006), IgE in BM1 (p=0.02), IL-5 in BM2 (p=0.048) and lower sIgA level in BM2 (p=0.05), more significant decrease in TGFβ1 concentration in BM within first three months (p=0.004). Significantly higher levels of ССL17 (p=0,04) and IgE (p=0,019) in CB, IL-5 (p=0,037) and IFN-γ (p=0,031) in BM2 were in a group of women having miscarriages in their medical history. Primiparous women had higher levels of CCL22 (p=0.0006) and IL-4 (p=0.032) in CB, as well as IL-4 (p=0.047) and IL-5 (p=0.047) in BM1, and IL-6 in BM2 (p=0.035).

Conclusion. Women delivered by caesarean section, primiparous women, and women with miscarriages in obstetric history were associated with higher BM and CB IgE levels and T2-associated cytokine concentration (IL-4, IL-5, CCL17, CCL22), as well IL-6 and IFN-γ, but lower sIgA and TGFβ1 concentrations. Effect of such cytokine patterns during the period of immune tolerance development may lead to infant immune maturing trajectory changing towards T2 predominance.

1. Prüss-Ustün A, van Deventer E, Mudu P, Campbell-Lendrum D, Vickers C, Ivanov I, et al. Environmental risks and non-communicable diseases. BMJ. 2019;364:l265. DOI: https://doi.org/10.1136/bmj.l265

2. Mohamad Zainal NH, Mohd Nor NH, Saat A, Clifton VL. Childhood allergy susceptibility: The role of the immune system development in the in-utero period. Hum Immunol. 2022;83(5):437-446. DOI: https://doi.org/10.1016/j.humimm.2022.02.002

3. Wopereis H, Oozeer R, Knipping K, Belzer C, Knol J. The first thousand days - intestinal microbiology of early life: establishing a symbiosis. Pediatr Allergy Immunol. 2014;25(5):428-438. DOI: https://doi.org/10.1111/pai.12232

4. Grijincu M, Buzan MR, Zbîrcea LE, Păunescu V, Panaitescu C. Prenatal Factors in the Development of Allergic Diseases. Int J Mol Sci. 2024;25(12):6359. DOI: https://doi.org/10.3390/ijms25126359

5. Ptaschinski C, Gibbs BF. Early-life risk factors which govern pro-allergic immunity. Semin Immunopathol. 2024;46(3-4):9. DOI: https://doi.org/10.1007/s00281-024-01020-x

6. Dutta S, Sengupta P, Liew FF. Cytokine landscapes of pregnancy: mapping gestational immune phases. Gynecologyand Obstetrics Clinical Medicine. 2024;4:e000011. DOI: https://doi.org/10.1136/gocm-2024-000011

7. Karmaus W, Arshad SH, Sadeghnejad A, Twiselton R. Does maternal immunoglobulin E decrease with increasing order of live offspring? Investigation into maternal immune tolerance. Clin Exp Allergy. 2004;34(6):853-859. DOI: https://doi.org/10.1111/j.1365-2222.2004.01959.x

8. Dawod B, Marshall JS. Cytokines and Soluble Receptors in Breast Milk as Enhancers of Oral Tolerance Development. Front Immunol. 2019;10:16. DOI: https://doi.org/10.3389/fimmu.2019.00016

9. Kiełbasa A, Gadzała-Kopciuch R, Buszewski B. Cytokines-Biogenesis and Their Role in Human Breast Milk and Determination. Int J Mol Sci. 2021;22(12):6238. DOI: https://doi.org/10.3390/ijms22126238

10. Gay MCL, Koleva PT, Slupsky CM, Toit ED, Eggesbo M, Johnson CC, et al. Worldwide Variation in Human Milk Metabolome: Indicators of Breast Physiology and Maternal Lifestyle? Nutrients. 2018;10(9):1151. DOI: https://doi.org/10.3390/nu10091151

11. Ramiro-Cortijo D, Herranz Carrillo G, Singh P, RebolloHernanz M, Rodríguez-Rodríguez P, Ruvira S, et al. Maternal and Neonatal Factors Modulating Breast Milk Cytokines in the First Month of Lactation. Antioxidants (Basel). 2023;12(5):996. DOI: https://doi.org/10.3390/antiox12050996

12. Tsikhan NM, Lialikau SA, Belevtsev MV, Kupchynskaya AN, Dubovik VS, Hayeuskaya EA, et al. Effect of Cord Blood and Breast Milk Immune Factors on Urine Eosinophil-Derived Neurotoxin Concentration in Infants. Pediatrics. Eastern Europe. 2023;11(3):362-373. (In Russ.). DOI: https://doi.org/10.34883/PI.2023.11.3.006

13. Amyx M, Philibert M, Farr A, Donati S, Smárason AK, Tica V, et al. Trends in caesarean section rates in Europe from 2015 to 2019 using Robson’s Ten Group Classification System: A Euro-Peristat study. BJOG. 2024;131(4):444-454. DOI: https://doi.org/10.1111/1471-0528.17670

14. Filippov OS, Pavlov KD. Results of the analysis of the frequency and causes of caesarean section based on Robson’s classification in obstetric hospitals of the Federal Medical and Biological Agency of Russia. Russian Bulletin of Obstetrician-Gynecologist = Rossiiskii vestnik akushera-ginekologa. 2023;23(5):7-12. (In Russ.). DOI: https://doi.org/10.17116/rosakush2023230517

15. Keag OE, Norman JE, Stock SJ. Long-term risks and benefits associated with cesarean delivery for mother, baby, and subsequent pregnancies: Systematic review and meta-analysis. PLoS Med. 2018;15(1):e1002494. DOI: https://doi.org/10.1371/journal.pmed.1002494

16. Mitselou N, Hallberg J, Stephansson O, Almqvist C, Melén E, Ludvigsson JF. Cesarean delivery, preterm birth, and risk of food allergy: Nationwide Swedish cohort study of more than 1 million children. J Allergy Clin Immunol. 2018;142(5):1510-1514.e2. DOI: https://doi.org/10.1016/j.jaci.2018.06.044

17. Tamai K, Matsumoto N, Mitsui T, Masuyama H, Yorifuji T. Association between cesarean delivery and childhood allergic diseases in a longitudinal population-based birth cohort from Japan. Sci Rep. 2025;15(1):19206. DOI: https://doi.org/10.1038/s41598-025-03703-3

18. Li N, Liang S, Chen Q, Zhao L, Li B, Huo G. Distinct gut microbiota and metabolite profiles induced by delivery mode in healthy Chinese infants. J Proteomics. 2021;232:104071. DOI: https://doi.org/10.1016/j.jprot.2020.104071

19. Strachan DP, Aït-Khaled N, Foliaki S, Mallol J, Odhiambo J, Pearce N, et al. Siblings, asthma, rhinoconjunctivitis and eczema: a worldwide perspective from the International Study of Asthma and Allergies in Childhood. Clin Exp Allergy. 2015;45(1):126-136. DOI: https://doi.org/10.1111/cea.12349

20. Fiocchi A, Dahdah L, Fierro V, Artesani MC, Valluzzi R. Food allergy trends at the crossing among socio-economics, history and geography. Curr Opin Allergy Clin Immunol. 2018;18(3):271-276. DOI: https://doi.org/10.1097/ACI.0000000000000437

21. Magnus MC, Karlstad Ø, Parr CL, Page CM, Nafstad P, Magnus P, et al. Maternal history of miscarriages and measures of fertility in relation to childhood asthma. Thorax. 2019;74(2):106-113. DOI: https://doi.org/10.1136/thoraxjnl-2018-211886

22. Gurram RK, Zhu J. Orchestration between ILC2s and Th2 cells in shaping type 2 immune responses. Cell Mol Immunol. 2019;16(3):225-235. DOI: https://doi.org/10.1038/s41423-019-0210-8

23. Lebold KM, Drake MG, Hales-Beck LB, Fryer AD, Jacoby DB. IL-5 Exposure in Utero Increases Lung Nerve Density and Airway Reactivity in Adult Offspring. Am J Respir Cell Mol Biol. 2020;62(4):493-502. DOI: https://doi.org/10.1165/rcmb.2019-0214OC

24. Yeh KW, Chiu CY, Su KW, Tsai MH, Hua MC, Liao SL, et al. High cord blood CCL22/CXCL10 chemokine ratios precede allergic sensitization in early childhood. Oncotarget. 2017;8(5):7384-7390. DOI: https://doi.org/10.18632/oncotarget.13374

25. Chiu CY, Su KW, Tsai MH, Hua MC, Liao SL, Lai SH, et al. Low Mother-to-Child CCL22 Chemokine Levels Are Inversely Related to Mite Sensitization and Asthma in Early Childhood. Sci Rep. 2018;8(1):6043. DOI: https://doi.org/10.1038/s41598-018-24523-8

26. Balla J, Rathore APS, St John AL. Maternal IgE Influence on Fetal and Infant Health. Immunol Rev. 2025;331(1):e70029. DOI: https://doi.org/10.1111/imr.70029

27. Sitarik AR, Bobbitt KR, Havstad SL, Fujimura KE, Levin AM, Zoratti EM, et al. Breast Milk Transforming Growth Factor β Is Associated With Neonatal Gut Microbial Composition. J Pediatr Gastroenterol Nutr. 2017;65(3):e60-e67. DOI: https://doi.org/10.1097/MPG.0000000000001585

28. Scheurer S, Junker AC, He C, Schülke S, Toda M. The Role of IgA in the Manifestation and Prevention of Allergic Immune Responses. Curr Allergy Asthma Rep. 2023;23(10):589-600. DOI: https://doi.org/10.1007/s11882-023-01105-x

29. Orivuori L, Loss G, Roduit C, Dalphin JC, Depner M, Genuneit J, et al. Soluble immunoglobulin A in breast milk is inversely associated with atopic dermatitis at early age: the PASTURE cohort study. Clin Exp Allergy. 2014;44(1):102-112. DOI: https://doi.org/10.1111/cea.12199

30. Morita Y, Campos-Alberto E, Yamaide F, Nakano T, Ohnisi H, Kawamoto M, et al. TGF-β Concentration in Breast Milk is Associated with the Development of Eczema in Infants. Front. Pediatr. 2018;6:162. DOI: https://doi.org/10.3389/fped.2018.00162

31. Mizutani Y, Takagi N, Nagata H, Inoue S. Interferon-γ downregulates tight junction function, which is rescued by interleukin-17A. Exp Dermatol. 2021;30(12):1754-1763. DOI: https://doi.org/10.1111/exd.14425