PCSK9 and Lp(a) levels of children born after assisted reproduction technologies

  • Charalambos VlachopoulosEmail author
  • Ioanna Kosteria
  • Sophia Sakka
  • Alexandra Gkourogianni
  • Dimitrios Terentes-Printzios
  • Iosif Koutagiar
  • Ioannis Skoumas
  • Antigoni Miliou
  • Ioannis Papassotiriou
  • Vasiliki Gardikioti
  • Dimitrios Loutradis
  • George Chrousos
  • Christina Kanaka-Gantenbein
  • Dimitrios Tousoulis
Assisted Reproduction Technologies



Proprotein convertase subtilisin/kexin type 9 (PCSK9) and lipoprotein (a) (Lp[a]) levels are associated with cardiovascular risk. To investigate PCSK9 and Lp(a) levels of children born after assisted reproduction technologies (ART) compared with naturally conceived (NC) controls.


In this exposure-matched cohort study, 73 racial-, sex-, and age-matched children (mean age 98 ± 35 months) of ART (intracytoplasmic sperm injection [ICSI] n = 33, classic in vitro fertilization [IVF] n = 40) and 73 NC children were assessed. Blood lipid profile, including PCSK9 and Lp(a) levels, was measured. Children were grouped according to age (< 8 years, 8–10 years, ≥ 10 years).


In the overall population, PCSK9 levels were related to total cholesterol, low-density lipoprotein, and systolic blood pressure, while Lp(a) levels were related to age, apolipoprotein-B, birth weight, height, waist-to-hip ratio, insulin resistance, insulin, and high-sensitivity C-reactive protein. No significant differences were observed regarding lipid biomarkers between ART and NC children. However, a significant interaction was found between age groups and conception method (p < 0.001) showing that PCSK9 levels increase with age in ART children, while they decline with age in NC offspring. IVF children showed higher levels of adjusted mean Lp(a) than ICSI (13.5 vs. 6.8 mg/dl, p = 0.010) and NC children (12.3 vs. 8.3 mg/dl, p = 0.048).


We show that PCSK9 levels increase with age in ART children, indicating a gradual deterioration of lipidemic profile that could lead to increased cardiovascular risk. Moreover, our results indicate that ART method may be of importance given that classic IVF is associated with higher levels of Lp(a).


PCSK9 In vitro fertilization Assisted reproduction technologies Lipoprotein (a) Cardiovascular risk Age 


Compliance with ethical standards

All children were included only after informed written consent was obtained from their parents or guardians. The study protocol was approved by the Institutional Research Ethics Committee and the Ethics Committee of the “Aghia Sophia” Children’s Hospital. The procedures followed were according to institutional guidelines and the Declaration of Helsinki.

Conflict of interest

The authors declare that they have no conflict interest.

Supplementary material

10815_2019_1474_MOESM1_ESM.pdf (338 kb)
ESM 1 (PDF 337 kb)


  1. 1.
    Guo XY, Liu XM, Jin L, Wang TT, Ullah K, Sheng JZ, et al. Cardiovascular and metabolic profiles of offspring conceived by assisted reproductive technologies: a systematic review and meta-analysis. Fertil Steril. 2017;107(3):622–31.CrossRefGoogle Scholar
  2. 2.
    Scherrer U, Rexhaj E, Allemann Y, Sartori C, Rimoldi SF. Cardiovascular dysfunction in children conceived by assisted reproductive technologies. Eur Heart J. 2015;36(25):1583–9.CrossRefGoogle Scholar
  3. 3.
    Yeung EH, Druschel C. Cardiometabolic health of children conceived by assisted reproductive technologies. Fertil Steril. 2013;99(2):318–26.CrossRefGoogle Scholar
  4. 4.
    Sakka SD, Loutradis D, Kanaka-Gantenbein C, Margeli A, Papastamataki M, Papassotiriou I, et al. Absence of insulin resistance and low-grade inflammation despite early metabolic syndrome manifestations in children born after in vitro fertilization. Fertil Steril. 2010;94(5):1693–9.CrossRefGoogle Scholar
  5. 5.
    Gkourogianni A, Kosteria I, Telonis AG, Margeli A, Mantzou E, Konsta M, et al. Plasma metabolomic profiling suggests early indications for predisposition to latent insulin resistance in children conceived by ICSI. PLoS One. 2014;9(4):e94001.CrossRefGoogle Scholar
  6. 6.
    Lambert G, Sjouke B, Choque B, Kastelein JJ, Hovingh GK. The PCSK9 decade. J Lipid Res. 2012;53(12):2515–24.CrossRefGoogle Scholar
  7. 7.
    Baass A, Dubuc G, Tremblay M, Delvin EE, O’Loughlin J, Levy E, et al. Plasma PCSK9 is associated with age, sex, and multiple metabolic markers in a population-based sample of children and adolescents. Clin Chem. 2009;55(9):1637–45.CrossRefGoogle Scholar
  8. 8.
    Filippatos TD, Liberopoulos E, Georgoula M, Tellis CC, Tselepis AD, Elisaf M. Effects of increased body weight and short-term weight loss on serum PCSK9 levels - a prospective pilot study. Arch Med Sci Atheroscler Dis. 2017;5(2):e46–51.CrossRefGoogle Scholar
  9. 9.
    Vlachopoulos C, Terentes-Printzios D, Georgiopoulos G, Skoumas I, Koutagiar I, Ioakeimidis N, et al. Prediction of cardiovascular events with levels of proprotein convertase subtilisin/kexin type 9: a systematic review and meta-analysis. Atherosclerosis. 2016;252:50–60.CrossRefGoogle Scholar
  10. 10.
    Ridker PM, Rifai N, Bradwin G, Rose L. Plasma proprotein convertase subtilisin/kexin type 9 levels and the risk of first cardiovascular events. Eur Heart J. 2016;37(6):554–60.CrossRefGoogle Scholar
  11. 11.
    Tsimikas S. A Test in Context: Lipoprotein (a): diagnosis, prognosis, controversies, and emerging therapies. J Am Coll Cardiol. 2017;69(6):692–711.CrossRefGoogle Scholar
  12. 12.
    Obisesan TO, Aliyu MH, Adediran AS, Bond V, Maxwell CJ, Rotimi CN. Correlates of serum lipoprotein (A) in children and adolescents in the United States. The third National Health Nutrition and Examination Survey (NHANES-III). Lipids Health Dis. 2004;16(3):29.CrossRefGoogle Scholar
  13. 13.
    Wang XL, Wang J. Lipoprotein (a) in children and adolescence. Pediatr Endocrinol Rev. 2003;1(2):109–19.Google Scholar
  14. 14.
    Kwiterovich PO Jr, Virgil DG, Garrett ES, Otvos J, Driggers R, Blakemore K, et al. Lipoprotein heterogeneity at birth: influence of gestational age and race on lipoprotein subclasses and Lp (a) lipoprotein. Ethn Dis. 2004 Summer;14(3):351–9.Google Scholar
  15. 15.
    Pecks U, Rath W, Maass N, Berger B, Lueg I, Farrokh A, et al. Fetal gender and gestational age differentially affect PCSK9 levels in intrauterine growth restriction. Lipids Health Dis. 2016;15(1):193.CrossRefGoogle Scholar
  16. 16.
    Kosteria I, Tsangaris GT, Gkourogianni A, Anagnostopoulos A, Papadopoulou A, Papassotiriou I, et al. Proteomics of children born after intracytoplasmic sperm injection reveal indices of an adverse cardiometabolic profile. J Endocr Soc. 2017;1(4):288–301.Google Scholar
  17. 17.
    Shimomura I, Matsuda M, Hammer RE, Bashmakov Y, Brown MS, Goldstein JL. Decreased IRS-2 and increased SREBP-1c lead to mixed insulin resistance and sensitivity in livers of lipodystrophic and ob/ob mice. Mol Cell. 2000;6(1):77–86.CrossRefGoogle Scholar
  18. 18.
    Cui Q, Ju X, Yang T, Zhang M, Tang W, Chen Q, et al. Serum PCSK9 is associated with multiple metabolic factors in a large Han Chinese population. Atherosclerosis. 2010;213(2):632–6.CrossRefGoogle Scholar
  19. 19.
    Whitelaw N, Bhattacharya S, Hoad G, Horgan GW, Hamilton M, Haggarty P. Epigenetic status in the offspring of spontaneous and assisted conception. Hum Reprod. 2014;29(7):1452–8.CrossRefGoogle Scholar
  20. 20.
    Ingelfinger JR. Pathogenesis of perinatal programming. Curr Opin Nephrol Hypertens. 2004;13(4):459–64.CrossRefGoogle Scholar
  21. 21.
    Lewandowski AJ, Leeson P. Preeclampsia, prematurity and cardiovascular health in adult life. Early Hum Dev. 2014;90(11):725–9.CrossRefGoogle Scholar
  22. 22.
    Ceelen M, van Weissenbruch MM, Vermeiden JP, van Leeuwen FE, Delemarre-van de Waal HA. Pubertal development in children and adolescents born after IVF and spontaneous conception. Hum Reprod. 2008;23(12):2791–8.CrossRefGoogle Scholar
  23. 23.
    Persson L, Cao G, Ståhle L, Sjöberg BG, Troutt JS, Konrad RJ, et al. Circulating proprotein convertase subtilisin kexin type 9 has a diurnal rhythm synchronous with cholesterol synthesis and is reduced by fasting in humans. Arterioscler Thromb Vasc Biol. 2010;30(12):2666–72.CrossRefGoogle Scholar
  24. 24.
    Ghosh M, Gälman C, Rudling M, Angelin B. Influence of physiological changes in endogenous estrogen on circulating PCSK9 and LDL cholesterol. J Lipid Res. 2015;56(2):463–9.CrossRefGoogle Scholar
  25. 25.
    Kronenberg F. Human genetics and the causal role of lipoprotein(a) for various diseases. Cardiovasc Drugs Ther. 2016;30(1):87–100.CrossRefGoogle Scholar
  26. 26.
    Zlatohlávek L, Zídková K, Vrablík M, Haas T, Prusíková M, Svobodová H, et al. Lipoprotein(a) and its position among other risk factors of atherosclerosis. Physiol Res. 2008;57(5):777–83.Google Scholar
  27. 27.
    Srinivasan SR, Dahlen GH, Jarpa RA, Webber LS, Berenson GS. Racial (black-white) differences in serum lipoprotein (a) distribution and its relation to parental myocardial infarction in children. Bogalusa Heart Study. Circulation. 1991;84(1):160–7.CrossRefGoogle Scholar
  28. 28.
    Bridges PJ, Jeoung M, Kim H, Kim JH, Lee DR, Ko C, et al. Methodology matters: IVF versus ICSI and embryonic gene expression. Reprod BioMed Online. 2011;23(2):234–44.CrossRefGoogle Scholar
  29. 29.
    Rodríguez-Moran M, Guerrero-Romero F. Low birthweight and elevated levels of lipoprotein(a) in prepubertal children. J Paediatr Child Health. 2014;50(8):610–4.CrossRefGoogle Scholar
  30. 30.
    Miles HL, Hofman PL, Peek J, Harris M, Wilson D, Robinson EM, et al. In vitro fertilization improves childhood growth and metabolism. J Clin Endocrinol Metab. 2007;92(9):3441–5.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Charalambos Vlachopoulos
    • 1
    Email author
  • Ioanna Kosteria
  • Sophia Sakka
  • Alexandra Gkourogianni
  • Dimitrios Terentes-Printzios
    • 1
  • Iosif Koutagiar
    • 1
  • Ioannis Skoumas
    • 1
  • Antigoni Miliou
    • 1
  • Ioannis Papassotiriou
    • 3
  • Vasiliki Gardikioti
    • 1
  • Dimitrios Loutradis
    • 4
  • George Chrousos
    • 2
  • Christina Kanaka-Gantenbein
    • 2
  • Dimitrios Tousoulis
    • 1
  1. 1.1st Department of Cardiology, Hypertension and Cardiometabolic Syndrome UnitNational and Kapodistrian University of Athens, Hippokrateion HospitalAthensGreece
  2. 2.1st Department of Pediatrics, Division of Endocrinology, Diabetes and MetabolismNational and Kapodistrian University of Athens, “Agia Sophia” Children’s HospitalAthensGreece
  3. 3.Department of Clinical Biochemistry“Aghia Sophia” Children’s HospitalAthensGreece
  4. 4.1st Department of Gynecology and ObstetricsNational and Kapodistrian University of Athens, Alexandra Sophia Children’s HospitalAthensGreece

Personalised recommendations