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Investigation of the impact of birth by cesarean section on fetal and maternal metabolism

  • Maternal-Fetal Medicine
  • Published:
Archives of Gynecology and Obstetrics Aims and scope Submit manuscript

Abstract

Purpose

Elective cesarean section (CS) was related to long-term adverse health effects in the offspring, but little is known about underlying mechanisms. Our study investigates the metabolic changes in both maternal and cord blood associated with CS in comparison to vaginal delivery (VD) to explore potential causal pathways.

Methods

Samples obtained from PREOBE study participants were subjected to LC–MS/MS-targeted metabolomics comprising > 200 metabolites.

Results

Elective CS showed an impact on both maternal and cord blood metabolomes. In maternal blood, the CS group showed lower levels of phospholipids (PL), principally ether-linked phosphatidylcholines (aaPC), pyruvic acid, branched chain keto-acids (BCKA), and other gluconeogenic substrates, but since the CS group showed different HDL levels in comparison to the VD group, we could not exclude contribution of the latter in the findings. In cord blood, the most remarkable finding in the CS group was the high levels of Cys; conversely, the lower levels of non-esterified fatty acids (NEFA), some tricarboxylic acid (TCA) cycle metabolites, gluconeogenic substrates, markers of β-oxidation, and the sum of hexoses were lower in CS-born babies in addition to tendentially lower levels of PL.

Conclusions

We speculate that lower levels of maternal and fetal corticosteroids in CS, due to less stressful condition, cause metabolic perturbations at birth initiating future negative health outcomes. This further supports the early programming hypothesis.

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References

  1. Strauss RS (1997) Effects of the intrauterine environment on childhood growth. Br Med Bull 33(1):81–89

    Article  Google Scholar 

  2. Dabelea D, Crume T (2011) Maternal environment and the transgenerational cycle of obesity and diabetes. Diabetes 60:1849–1855

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Childbirth Connection (2012) Vaginal or cesarean birth: What is at stake for women and babies? A best evidence review. New York: Childbirth Connection. https://www.nationalpartnership.org/research-library/maternal-health/vaginal-or-cesarean-birth-what-is-at-stake.pdf. Accessed 15 June 2018.

  4. Jacob L, Taskan S, Macharey G, Sechet I, Ziller V, Kostev K (2016) Impact of caesarean section on mode of delivery, pregnancy-induced and pregnancy-associated disorders, and complications in the subsequent pregnancy in Germany. GMS Ger Med Sci 14:Doc06

  5. Cardwell CR, Stene LC, Joner G, Cinek O, Svensson J, Goldacre MJ et al (2008) Caesarean section is associated with an increased risk of childhood-onset type 1 diabetes mellitus: a meta-analysis of observational studies. Diabetologia 51(5):726–735

    Article  CAS  PubMed  Google Scholar 

  6. Thavagnanam S, Fleming J, Bromley A, Shields MD, Cardwell CR (2008) A meta-analysis of the association between Caesarean section and childhood asthma. Clin Exp Allergy 38:629–633

    Article  CAS  PubMed  Google Scholar 

  7. Miller NM, Fisk NM, Modi N, Glover V (2005) Stress responses at birth: determinants of cord arterial cortisol and links with cortisol response in infancy. BJOG 112:921–926

    Article  CAS  PubMed  Google Scholar 

  8. Reinhardt C, Reigstad CS, Bäckhed F (2009) Intestinal microbiota during infancy and its implications for obesity. J Pediatr Gastroenterol Nutr 48(3):249–256

    Article  PubMed  Google Scholar 

  9. Dewey KG, Nommsen-Rivers LA, Heinig MJ, Cohen RJ (2003) Risk factors for suboptimal infant breastfeeding behavior, delayed onset of lactation, and excess neonatal weight loss. Pediatrics 112:607–619

    Article  PubMed  Google Scholar 

  10. Evans KC, Evans RG, Royal R, Esterman AJ, James SL (2003) Effect of caesarean section on breast milk transfer to the normal term newborn over the first week of life. Arch Dis Child Fetal Neonatal Ed 88:F380–F382

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Hyde MJ, Griffin JL, Herrera E, Byrne CD, Clarke L, Kemp PR (2010) Delivery by caesarean section, rather than vaginal delivery, promotes hepatic steatosis in piglets. Clin Sci 118:47–59

    Article  Google Scholar 

  12. Dixon L, Skinner J, Foureur M (2013) The emotional and hormonal pathways of labour and birth: integrating mind, body and behaviour. NZ Coll Midwives J 48:15–23

    Article  Google Scholar 

  13. Ward Platt M, Deshpande S (2005) Metabolic adaptation at birth. Semin Fetal Neonatal Med 10:341–350

    Article  PubMed  Google Scholar 

  14. Burcelin R, Mrejen C, Decaux JF, De Mouzon SH, Girard J, Charron MJ (1998) In vivo and in vitro regulation of hepatic glucagon receptor mRNA concentration by glucose metabolism. J Biol Chem 273:8088–8089

    Article  CAS  PubMed  Google Scholar 

  15. Mitanchez D (2007) Glucose regulation in preterm newborn infants. Horm Res 68:265–271

    CAS  PubMed  Google Scholar 

  16. US National Library of Medicine (2012) The role of nutrition and maternal genetics on the programming of development of fetal adipose tissue. search for markers of the obesity risk in early stages of life. ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT01634464. Accessed 14 Feb 2019

  17. Berglund SK, García-Valdés L, Torres-Espinola FJ, Segura MT, Martínez-Zaldívar C, Aguilar MJ et al (2016) Maternal, fetal and perinatal alterations associated with obesity, overweight and gestational diabetes: an observational cohort study (PREOBE). BMC Public Health 16:207

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Reference values during pregnancy (2018) In: West Covina: focus information technology. https://perinatology.com/Reference/Reference%20Ranges/Glucose,%20fasting.html.8.Referencevaluesduringpregnancy. Accessed 2 May 2018

  19. Harder U, Koletzko B, Peissner W (2011) Quantification of 22 plasma amino acids combining derivatization and ion-pair LC-MS/MS. J Chromatogr B Analyt Technol Biomed Life Sci 879:495–504

    Article  CAS  PubMed  Google Scholar 

  20. Hellmuth C, Weber M, Koletzko B, Peissner W (2012) Nonesterified fatty acid determination for functional lipidomics: comprehensive ultrahigh performance liquid chromatography-tandem mass spectrometry quantitation, qualification, and parameter prediction. Anal Chem 84:1483–1490

    Article  CAS  PubMed  Google Scholar 

  21. Rauschert S, Uhl O, Koletzko B, Kirchberg F, Mori TA, Huang RC et al (2016) Lipidomics reveals associations of phospholipids with obesity and insulin resistance in young adults. J Clin Endocrinol Metab 101:871–879

    Article  CAS  PubMed  Google Scholar 

  22. Kirchberg FF, Brandt S, Moß A, Peissner W, Koenig W, Rothenbacher D et al (2017) Metabolomics reveals an entanglement of fasting leptin concentrations with fatty acid oxidation and gluconeogenesis in healthy children. PLoS One 12(8):e0183185

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Sampath H, Ntambi JM (2008) Role of stearoyl-CoA desaturase in human metabolic disease. Future Lipidol 3:163–173

    Article  CAS  Google Scholar 

  24. Angelini R, Vortmeier G, Corcelli A, Fuchs B (2014) A fast method for the determination of the PC/LPC ratio in intact serum by MALDI-TOF MS: an easy-to-follow lipid biomarker of inflammation. Chem Phys Lipids 183:169–175

    Article  CAS  PubMed  Google Scholar 

  25. Zhang W, Sun G, Aitken D, Likhodii S, Liu M, Martin G et al (2016) Lysophosphatidylcholines to phosphatidylcholines ratio predicts advanced knee osteoarthritis. Rheumatology 55(9):1566–1567

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Pickens CA, Vazquez AI, Daniel Jones A, Fenton JI (2017) Obesity, adipokines, and C-peptide are associated with distinct plasma and phospholipid profiles in adult males, an untargeted lipidomic approach. Sci Rep 7:6335

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Wallner S, Schmitz G (2011) Plasmalogens the neglected regulatory and scavenging lipid species. Chem Phys Lipids 164:573–589

    Article  CAS  PubMed  Google Scholar 

  28. Maeba R, Hara H (2012) Serum choline plasmalogen is a reliable biomarker for atherogenic status. In: Squeri A (ed) Coronary artery disease—new Insights and Novel Approaches. InTech, Rijeka

  29. Fox J, Weisberg S (2011) An R companion to applied regression, 2nd edn. Sage, Thousand Oaks

    Google Scholar 

  30. Mastorakos G, Ilias I (2003) Maternal and fetal hypothalamic–pituitary–adrenal axes during pregnancy and postpartum. Ann N Y Acad Sci 997:136–139

    Article  CAS  PubMed  Google Scholar 

  31. Cheng YH, Nicholson RC, King B, Chan EC, Fitter JT, Smith R (2000) Glucocorticoid stimulation of corticotropin-releasing hormone gene expression requires a cyclic adenosine 3ʹ,5ʹ-monophosphate regulatory element in human primary placental cytotrophoblast cells. J Clin Endocrinol Metab 85(5):1937–1945

    CAS  PubMed  Google Scholar 

  32. Goldkrand JW, Schulte RL, Messer RH (1976) Maternal and fetal plasma cortisol levels at parturition. Obstet Gynecol 47(1):41–45

    CAS  PubMed  Google Scholar 

  33. Stjernholm YV, Nyberg A, Cardell M, Höybye C (2016) Circulating maternal cortisol levels during vaginal delivery and elective cesarean section. Arch Gynecol Obstet 294:267–271

    Article  CAS  PubMed  Google Scholar 

  34. Hyde MJ, Mostyn A, Modi N, Kemp PR (2012) The health implications of birth by caesarean section. Biol Rev Camb Philos Soc 87(1):229–243

    Article  PubMed  Google Scholar 

  35. Stjernholm YV, Nyberg A, Cardell M, Höybye C (2016) Circulating maternal cortisol levels during vaginal delivery and elective cesarean section. Arch Gynecol Obstet 294(2):267–271

    Article  CAS  PubMed  Google Scholar 

  36. Thristle QA (2013) Hypercortisolism. Thristle QA SANAS accredited organization. https://www.thistle.co.za/pdf_files/education/chemistry/chemistry_legends/2013/July%202013%20-%20Hypercortisolism.pdf. Accessed 25 Feb 2019

  37. Wynne-Edwards KE, Edwards HE, Hancock TM (2013) The human fetus preferentially secretes corticosterone, rather than cortisol. Response to intra-partum stressors. PLoS One 8(6):e63684

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Hundertmark S, Ragosch V, Schein B, Bühler H, Lorenz U, Fromm M et al (1994) Gestational age dependence of 11 beta-hydroxysteroid dehydrogenase and its relationship to the enzymes of phosphatidylcholine synthesis in lung and liver of fetal rat. Biochim Biophys Acta 1210(3):348–354

    Article  CAS  PubMed  Google Scholar 

  39. Sorenson DK, Kelly TM, Murray DK, Nelson DH (1988) Corticosteroids stimulate an increase in phospholipase A2 inhibitor in human serum. J Steroid Biochem 29(2):271–273

    Article  CAS  PubMed  Google Scholar 

  40. Goppelt-Struebe M, Wolter D, Resch K (1989) Glucocorticoids inhibit prostaglandin synthesis not only at the level of phospholipase A2 but also at the level of cyclo-oxygenase/PGE isomerse. Br J Pharmacol 98:1287–1295

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Ortsäter H, Sjöholm Å, Rafacho A (2012) Regulation of glucocorticoid receptor signaling and the diabetogenic effects of glucocorticoid excess. In: Magdeldin S (ed) State of the art of therapeutic endocrinology. IntechOpen. https://doi.org/10.5772/51759

  42. Anderson AJ, Sobocinski KA, Freedman DS, Barboriak JJ, Rimm AA, Gruchow HW (1988) Body fat distribution, plasma lipids and lipoproteins. Arteriosclerosis 8:88–94

    Article  CAS  PubMed  Google Scholar 

  43. Ginsberg HN (1991) Lipoprotein physiology in non diabetic and diabetic state. Relationship to atherosclerosis. Diabetes Care 14:839–855

    Article  CAS  PubMed  Google Scholar 

  44. Lewis GF (2006) Determinants of plasma HDL concentrations and reverse cholesterol transport. Curr Opin Cardiol 21(4):345–352

    Article  PubMed  Google Scholar 

  45. Scholler M, Wadsack C, Lang I, Etschmaier K, Schweinzer C, Marsche G et al (2012) Phospholipid transfer protein in the placental endothelium is affected by gestational diabetes mellitus. J Clin Endocrinol Metab 97(2):437–445

    Article  CAS  PubMed  Google Scholar 

  46. Boysen SR, Bozzetti M, Rose L, Dunn M, Pang DSJ (2009) Effects of prednisone on blood lactate concentrations in healthy dogs. J Vet Intern Med 23:1123–1125

    Article  CAS  PubMed  Google Scholar 

  47. Exton JH (1979) Regulation of gluconeogenesis by glucocorticoids. Monogr Endocrinol 12:535–546

    Article  CAS  PubMed  Google Scholar 

  48. Van Aerde JE, Wilke MS, Feldman M, Clandinin MT (2003) Accretion of lipid in the fetus and newborn. In: Polin RA, Fox WW, Abman SH (ed) Fetal and Neonatal Physiology, vol. 1. Saunders, London

  49. Duee PH, Pegorier JP, Quant PA, Herbin C, Kohl C, Girard J (1994) Hepatic ketogenesis in newborn pigs is limited by low mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase activity. Biochem J 298:207–212

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. You X-J, Xu C, Lu J-Q, Zhu X-Y, Gao L, Cui X-R et al (2011) Expression of Cystathionine β-synthase and cystathionine γ-lyase in human pregnant myometrium and their roles in the control of uterine contractility. PLoS ONE 6(8):e23788

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Postle AD, Henderson NG, Koster G, Clark HW, Hunt AN (2011) Analysis of lung surfactant phosphatidylcholine metabolism in transgenic mice using stable isotopes. Chem Phys Lipids 164:549–555

    Article  CAS  PubMed  Google Scholar 

  52. Goss V, Hunt AN, Postle AD (2013) Regulation of lung surfactant phospholipid synthesis and metabolism. Biochim Biophys Acta 1831:448–458

    Article  CAS  PubMed  Google Scholar 

  53. Beaconsfield P, Villee C (1979) Placenta—A neglected experimental animal, 1st edn. Pergamon press, Oxford

    Google Scholar 

  54. Vitale SG, Marilli I, Rapisarda AM, Rossetti D, Belluomo G, Iapichino V et al (2014) Cellular and biochemical mechanisms, risk factors and management of preterm birth: state of the art. Minerva Ginecol 66(6):589–595

    CAS  PubMed  Google Scholar 

  55. Barbara G, Pifarotti P, Facchin F, Cortinovis I, Dridi D, Ronchetti C et al (2016) Impact of mode of delivery on female postpartum sexual functioning: spontaneous vaginal delivery and operative vaginal delivery vs cesarean section. J Sex Med 13(3):393–401

    Article  PubMed  Google Scholar 

  56. El Sayed HA, Ramadan SA, Moursi HA, Ibrahim HA (2017) The effect of mode of delivery on postpartum sexual function and sexual quality of life in primiparous women. Am J Nurs Sci 6(4):347–357

    Article  Google Scholar 

  57. Keag OE, Norman JE, Stock SJ (2018) Long-term risks and benefits associated with cesarean delivery for mother, baby, and subsequent pregnancies: Systematic review and meta-analysis. PLoS Med 15(1):e1002494

    Article  PubMed  PubMed Central  Google Scholar 

  58. Nordlie RC, Foster JD, Lange AJ (1999) Regulation of glucose production by the liver. Ann Rev Nutr 19:379–406

    Article  CAS  Google Scholar 

  59. Rafiq N, Younossi ZM (2008) Interaction of metabolic syndrome, nonalcoholic fatty liver disease and chronic hepatitis C. Expert Rev Gastroenterol Hepatol 2:207–215

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

The authors thank the study participants, the obstetricians, pediatricians and technicians of the EURISTIKOS team, and the PREOBE team at the University of Granada, Spain, for their support of the study. We are grateful to Stephanie Winterstetter, Alexander Haag and Tina Honsowitz (Division of Metabolic and Nutritional Medicine, Dr von Hauner Children’s Hospital, University of Munich, Munich, Germany) for their support in the analysis of the blood plasma samples. We would also like to thank Dr. Stefan Hutter (Department of Obstetrics and Gynecology, University of Munich, Munich, Germany) for his consultation.

Funding

This work was supported by Supported by the Andalusian Ministry of Economy, Science and Innovation, PREOBE Excellence Project (Ref. P06-CTS-02341), Spanish Ministry of Economy and Competitiveness (Ref. BFU2012-40254-C03-01 and Ref. SAF2015-69265-C2-2-R), the European Research Council Advanced Grant META-GROWTH (ERC-2012-AdG 322605), and the European Commission research projects EarlyNutrition, FP7-FP7 KBBE-2011-1 (289346 y), and DynaHEALTH (63359). The funders had no role in study design, data collection, and analysis, decision to publish, or preparation of the manuscript.

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Author notes

  1. Engy Shokry and Linda Marchioro contributed equally to this work.

Authors and Affiliations

  1. Division of Metabolic and Nutritional Medicine, Dr. von Hauner Children’s Hospital, LMU Medical Center, LMU-Ludwig-Maximilians-Universität Munich, Campus Innenstadt, Lindwurmstr. 4, 80337, Munich, Germany

    Engy Shokry, Linda Marchioro, Olaf Uhl & Berthold Koletzko

  2. Department of Paediatrics, School of Medicine, EURISTIKOS Excellence Centre for Paediatric Research, University of Granada, Avenida de la Investigación 11, 18016, Granada, Spain

    Mercedes G. Bermúdez, Jose Antonio García-Santos, Mª Teresa Segura & Cristina Campoy

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  1. Engy Shokry
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  2. Linda Marchioro
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Contributions

MGB, JAG, and MTS coordinated and conducted the data and sample collection. OU performed the metabolic analysis. LM conducted the statistical analyses. ES discussed the results and wrote the paper. CC and BK are the principal investigators, responsible for the design and coordination of the research. BK and CC are also the guarantors of this work and, as such, had full access to all the data in the study and take responsibility for the integrity of the data, accuracy of the data analysis, and the final content of the manuscript. All the authors reviewed, edited and approved the manuscript.

Corresponding author

Correspondence to Berthold Koletzko.

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Conflict of interest

None of the authors report conflicts of interest.

Ethical approval

The study was approved by the Bioethical Committees for Clinical Research of the Clinical University Hospital San Cecilio, the Mother-Infant University Hospital of Granada, Spain.

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The authors declare compliance with the EQUATOR (Enhancing the QUAlity and Transparency of Research) network guidelines available at: https://equator-network.org.

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Participation was voluntary and written informed consent was obtained from participants at study entry.

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Shokry, E., Marchioro, L., Uhl, O. et al. Investigation of the impact of birth by cesarean section on fetal and maternal metabolism. Arch Gynecol Obstet 300, 589–600 (2019). https://doi.org/10.1007/s00404-019-05213-w

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