Skip to main content
Log in

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

  • Assisted Reproduction Technologies
  • Published:
Journal of Assisted Reproduction and Genetics Aims and scope Submit manuscript

Abstract

Purpose

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.

Methods

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).

Results

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).

Conclusions

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).

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  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.

    Article  Google Scholar 

  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.

    Article  Google Scholar 

  3. Yeung EH, Druschel C. Cardiometabolic health of children conceived by assisted reproductive technologies. Fertil Steril. 2013;99(2):318–26.

    Article  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  Google Scholar 

  6. Lambert G, Sjouke B, Choque B, Kastelein JJ, Hovingh GK. The PCSK9 decade. J Lipid Res. 2012;53(12):2515–24.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  11. Tsimikas S. A Test in Context: Lipoprotein (a): diagnosis, prognosis, controversies, and emerging therapies. J Am Coll Cardiol. 2017;69(6):692–711.

    Article  CAS  Google Scholar 

  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.

    Article  Google Scholar 

  13. Wang XL, Wang J. Lipoprotein (a) in children and adolescence. Pediatr Endocrinol Rev. 2003;1(2):109–19.

    PubMed  Google Scholar 

  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.

    PubMed  Google Scholar 

  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.

    Article  Google Scholar 

  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.

    CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  20. Ingelfinger JR. Pathogenesis of perinatal programming. Curr Opin Nephrol Hypertens. 2004;13(4):459–64.

    Article  CAS  Google Scholar 

  21. Lewandowski AJ, Leeson P. Preeclampsia, prematurity and cardiovascular health in adult life. Early Hum Dev. 2014;90(11):725–9.

    Article  Google Scholar 

  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.

    Article  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  25. Kronenberg F. Human genetics and the causal role of lipoprotein(a) for various diseases. Cardiovasc Drugs Ther. 2016;30(1):87–100.

    Article  CAS  Google Scholar 

  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.

    PubMed  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  Google Scholar 

  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.

    Article  Google Scholar 

  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.

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Charalambos Vlachopoulos.

Ethics declarations

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.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Electronic supplementary material

ESM 1

(PDF 337 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Vlachopoulos, C., Kosteria, I., Sakka, S. et al. PCSK9 and Lp(a) levels of children born after assisted reproduction technologies. J Assist Reprod Genet 36, 1091–1099 (2019). https://doi.org/10.1007/s10815-019-01474-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10815-019-01474-1

Keywords

Navigation