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Published in: European Journal of Medical Research 1/2023

Open Access 01-12-2023 | Hypercholesterolemia | Research

Maternal hypercholesterolemia would increase the incidence of embryo aneuploidy in couples with recurrent implantation failure

Authors: Yang Liu, Tianxiang Ni, Qing Zhao, Weiran Cui, Xiangxin Lan, Tingting Zhou, Qian Zhang, Junhao Yan

Published in: European Journal of Medical Research | Issue 1/2023

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Abstract

Background

The association of dyslipidemia with embryo development and pregnancy outcomes is largely unknown, especially in unexplained recurrent implantation failure (uRIF) patients. Here, this study aimed to explore the impact of abnormal blood lipid levels on embryo genetic status and pregnancy outcomes after preimplantation genetic testing for aneuploidy (PGT-A) from a clinical perspective.

Methods

This study retrospectively analyzed 502 patients diagnosed as uRIF. They were divided into four groups according to the levels of cholesterol and triglyceride: nonhyperlipidemia group (NonH group), simple hypercholesterolemia group (SHC group), simple hypertriglyceridemia group (SHC group) and mixed hyperlipidemia group (MixH group). At the same time, patients were divided into non-low HDL-C group and low HDL-C group according to their HDL-C level. The outcomes of embryos genetic testing and pregnancy outcomes after PGT-A was analyzed between groups. Binary logistic regression and/or generalized estimating equation (GEE) model were conducted to investigate the association of different types of dyslipidemia with embryonic aneuploidy rate and cumulative live-birth rate.

Results

474 women who met the inclusion criteria were divided into four groups: NonH group (N = 349), SHC group (N = 55), SHT group (N = 52) and MixH group (N = 18). Compared with the NonH group, SHC group had a significantly increased rate of embryo aneuploidy [48.3% vs. 36.7%, P = 0.006; adjusted OR (95% confidence interval) = 1.52(1.04–2.22), P = 0.029], as well as a reduced number of good-quality embryos on day 5 or 6 [3.00 ± 2.29 vs. 3.74 ± 2.77, P = 0.033]. The SHC group showed a tendency of a lower cumulative live birth rate (47.0% vs. 40.0%), a lower incidence of good birth outcome (37.2% vs. 34.5%) and a higher risk of clinical pregnancy loss (11.1% vs. 17.9%), but did not reach statistical significance (P > 0.05). The incidences of obstetric or neonatal complications and other adverse events were similar in the four groups. Whether patients have low HDL-C did not differ in pregnancy outcomes.

Conclusions

We found that uRIF women with hypercholesterolemia had an increased proportion of aneuploid embryos and a reduced proportion of high-quality embryos, while different types of hyperlipidemia had no correlation with cumulative live birth rate as well as pregnancy and neonatal outcomes.
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Literature
1.
go back to reference Arias A, Quiroz A, Santander N, Morselli E, Busso D. Implications of high-density cholesterol metabolism for oocyte biology and female fertility. Front Cell Dev Biol. 2022;10:941539.CrossRefPubMedPubMedCentral Arias A, Quiroz A, Santander N, Morselli E, Busso D. Implications of high-density cholesterol metabolism for oocyte biology and female fertility. Front Cell Dev Biol. 2022;10:941539.CrossRefPubMedPubMedCentral
2.
go back to reference Arora H, Collazo I, Eisermann J, Hendon N, Kuchakulla M, Khodamoradi K, Bidhan J, Dullea A, Zucker I, Khosravizadeh Z, et al. Association between mitoscore, BMI, and body fat percentage as a predictive marker for the outcome of in-vitro fertilization (IVF). Cureus. 2022;14:e27367.PubMedPubMedCentral Arora H, Collazo I, Eisermann J, Hendon N, Kuchakulla M, Khodamoradi K, Bidhan J, Dullea A, Zucker I, Khosravizadeh Z, et al. Association between mitoscore, BMI, and body fat percentage as a predictive marker for the outcome of in-vitro fertilization (IVF). Cureus. 2022;14:e27367.PubMedPubMedCentral
3.
go back to reference Buschiazzo J, Ialy-Radio C, Auer J, Wolf JP, Serres C, Lefevre B, Ziyyat A. Cholesterol depletion disorganizes oocyte membrane rafts altering mouse fertilization. PLoS ONE. 2013;8:e62919.CrossRefPubMedPubMedCentral Buschiazzo J, Ialy-Radio C, Auer J, Wolf JP, Serres C, Lefevre B, Ziyyat A. Cholesterol depletion disorganizes oocyte membrane rafts altering mouse fertilization. PLoS ONE. 2013;8:e62919.CrossRefPubMedPubMedCentral
4.
go back to reference Bellver J, Marín C, Lathi RB, Murugappan G, Labarta E, Vidal C. Obesity affects endometrial receptivity by displacing the window of implantation. Reprod Sci. 2021;28:3171–80.CrossRefPubMed Bellver J, Marín C, Lathi RB, Murugappan G, Labarta E, Vidal C. Obesity affects endometrial receptivity by displacing the window of implantation. Reprod Sci. 2021;28:3171–80.CrossRefPubMed
6.
go back to reference Cao H, You D, Yuan M, Xi M. Hysteroscopy after repeated implantation failure of assisted reproductive technology: a meta-analysis. J Obstet Gynaecol Res. 2018;44:365–73.CrossRefPubMed Cao H, You D, Yuan M, Xi M. Hysteroscopy after repeated implantation failure of assisted reproductive technology: a meta-analysis. J Obstet Gynaecol Res. 2018;44:365–73.CrossRefPubMed
7.
go back to reference Cabunac P, Karadzov Orlic N, Ardalic D, Banjac G, Ivanisevic J, Janac J, Vekic J, Zeljkovic A, Mihajlovic M, Rajovic N, et al. Unraveling the role of oxidative stress and lipid status parameters in the onset of preeclampsia. Hypertens Pregnancy. 2021;40:162–70.CrossRefPubMed Cabunac P, Karadzov Orlic N, Ardalic D, Banjac G, Ivanisevic J, Janac J, Vekic J, Zeljkovic A, Mihajlovic M, Rajovic N, et al. Unraveling the role of oxidative stress and lipid status parameters in the onset of preeclampsia. Hypertens Pregnancy. 2021;40:162–70.CrossRefPubMed
8.
9.
go back to reference Duffy JMN, Bhattacharya S, Bhattacharya S, Bofill M, Collura B, Curtis C, Evera JLH, Giudice LC, Farquharson RG, Franik S, et al. Standardizing definitions and reporting guidelines for the infertility core outcome set: an international consensus development study. Fertil Steril. 2021;115:201–12.CrossRefPubMed Duffy JMN, Bhattacharya S, Bhattacharya S, Bofill M, Collura B, Curtis C, Evera JLH, Giudice LC, Farquharson RG, Franik S, et al. Standardizing definitions and reporting guidelines for the infertility core outcome set: an international consensus development study. Fertil Steril. 2021;115:201–12.CrossRefPubMed
10.
go back to reference ESHRE, Calhaz-Jorge C, de Geyter C, Kupka MS, de Mouzon J, Erb K, Mocanu E, Motrenko T, Scaravelli G, et al. Assisted reproductive technology in Europe, 2012: results generated from European registers by ESHRE. Hum Reprod. 2016;31:1638–52.CrossRef ESHRE, Calhaz-Jorge C, de Geyter C, Kupka MS, de Mouzon J, Erb K, Mocanu E, Motrenko T, Scaravelli G, et al. Assisted reproductive technology in Europe, 2012: results generated from European registers by ESHRE. Hum Reprod. 2016;31:1638–52.CrossRef
11.
go back to reference ESHRE Working Group on Recurrent Implantation Failure, Cimadomo D, de Los Santos MJ, Griesinger G, Lainas G, Clef NL, McLernon DJ, Montjean D, Toth B, Vermeulen N, Macklon N. ESHRE good practice recommendations on recurrent implantation failure. Hum Reprod Open. 2023;2023(3):hoad023.CrossRefPubMedCentral ESHRE Working Group on Recurrent Implantation Failure, Cimadomo D, de Los Santos MJ, Griesinger G, Lainas G, Clef NL, McLernon DJ, Montjean D, Toth B, Vermeulen N, Macklon N. ESHRE good practice recommendations on recurrent implantation failure. Hum Reprod Open. 2023;2023(3):hoad023.CrossRefPubMedCentral
12.
go back to reference Gardner DK. In vitro culture of human blastocyst. In: Jansen R, Mortimer D, editors. Toward reproductive certainty: infertility and genetics beyond 1999. Carnforth: Parthenon Press; 1999. p. 378–88. Gardner DK. In vitro culture of human blastocyst. In: Jansen R, Mortimer D, editors. Toward reproductive certainty: infertility and genetics beyond 1999. Carnforth: Parthenon Press; 1999. p. 378–88.
13.
go back to reference Ghobara T, Gelbaya TA, Ayeleke RO. Cycle regimens for frozen-thawed embryo transfer. Cochrane Database Syst Rev. 2017;7:CD003414.PubMed Ghobara T, Gelbaya TA, Ayeleke RO. Cycle regimens for frozen-thawed embryo transfer. Cochrane Database Syst Rev. 2017;7:CD003414.PubMed
15.
go back to reference Horn J, Tanz LJ, Stuart JJ, Markovitz AR, Skurnik G, Rimm EB, Missmer SA, Rich-Edwards JW. Early or late pregnancy loss and development of clinical cardiovascular disease risk factors: a prospective cohort study. BJOG. 2019;126:33–42.CrossRefPubMed Horn J, Tanz LJ, Stuart JJ, Markovitz AR, Skurnik G, Rimm EB, Missmer SA, Rich-Edwards JW. Early or late pregnancy loss and development of clinical cardiovascular disease risk factors: a prospective cohort study. BJOG. 2019;126:33–42.CrossRefPubMed
16.
go back to reference Joshi N, Kissin D, Anderson JE, Session D, Macaluso M, Jamieson DJ. Trends and correlates of good perinatal outcomes in assisted reproductive technology. Obstet Gynecol. 2012;120:843–51.CrossRefPubMedPubMedCentral Joshi N, Kissin D, Anderson JE, Session D, Macaluso M, Jamieson DJ. Trends and correlates of good perinatal outcomes in assisted reproductive technology. Obstet Gynecol. 2012;120:843–51.CrossRefPubMedPubMedCentral
17.
18.
go back to reference Kohn TP, Kohn JR, Darilek S, Ramasamy R, Lipshultz L. Genetic counseling for men with recurrent pregnancy loss or recurrent implantation failure due to abnormal sperm chromosomal aneuploidy. J Assist Reprod Genet. 2016;33:571–6.CrossRefPubMedPubMedCentral Kohn TP, Kohn JR, Darilek S, Ramasamy R, Lipshultz L. Genetic counseling for men with recurrent pregnancy loss or recurrent implantation failure due to abnormal sperm chromosomal aneuploidy. J Assist Reprod Genet. 2016;33:571–6.CrossRefPubMedPubMedCentral
19.
go back to reference Lee E, Illingworth P, Wilton L, Chambers GM. The clinical effectiveness of preimplantation genetic diagnosis for aneuploidy in all 24 chromosomes (PGD-A): systematic review. Hum Reprod. 2015;30:473–83.CrossRefPubMed Lee E, Illingworth P, Wilton L, Chambers GM. The clinical effectiveness of preimplantation genetic diagnosis for aneuploidy in all 24 chromosomes (PGD-A): systematic review. Hum Reprod. 2015;30:473–83.CrossRefPubMed
20.
go back to reference Lisovskaya TV, Perepletina TA, Sevost’ Yanova OY, Mayasina EN, Salimov DF, Osipenko AA. Clinical and laboratory parameters and morphological characteristics of the endometrium in women with impaired fat metabolism and failed IVF attempts. Gynecol Endocrinol. 2019;35:41–4.CrossRefPubMed Lisovskaya TV, Perepletina TA, Sevost’ Yanova OY, Mayasina EN, Salimov DF, Osipenko AA. Clinical and laboratory parameters and morphological characteristics of the endometrium in women with impaired fat metabolism and failed IVF attempts. Gynecol Endocrinol. 2019;35:41–4.CrossRefPubMed
21.
go back to reference Liu Y, Yao Y, Sun H, Zhao J, Li H, Wang S, Zhang T, Meng M, Zhou S. Lipid metabolism-related genes as biomarkers and therapeutic targets reveal endometrial receptivity and immune microenvironment in women with reproductive dysfunction. J Assist Reprod Genet. 2022;39:2179–90.CrossRefPubMedPubMedCentral Liu Y, Yao Y, Sun H, Zhao J, Li H, Wang S, Zhang T, Meng M, Zhou S. Lipid metabolism-related genes as biomarkers and therapeutic targets reveal endometrial receptivity and immune microenvironment in women with reproductive dysfunction. J Assist Reprod Genet. 2022;39:2179–90.CrossRefPubMedPubMedCentral
22.
go back to reference Miller WL, Auchus RJ. The molecular biology, biochemistry, and physiology of human steroidogenesis and its disorders. Endocr Rev. 2011;32:81–151.CrossRefPubMed Miller WL, Auchus RJ. The molecular biology, biochemistry, and physiology of human steroidogenesis and its disorders. Endocr Rev. 2011;32:81–151.CrossRefPubMed
23.
go back to reference Practice Committees of the American Society for Reproductive Medicine and the Society for Assisted Reproductive Technology. The use of preimplantation genetic testing for aneuploidy (PGT-A): a committee opinion. Fertil Steril. 2018;109:429–36.CrossRef Practice Committees of the American Society for Reproductive Medicine and the Society for Assisted Reproductive Technology. The use of preimplantation genetic testing for aneuploidy (PGT-A): a committee opinion. Fertil Steril. 2018;109:429–36.CrossRef
24.
go back to reference Pinola P, Lashen H, Bloigu A, Puukka K, Ulmanen M, Ruokonen A, Martikainen H, Pouta A, Franks S, Hartikainen A-L, et al. Menstrual disorders in adolescence: a marker for hyperandrogenaemia and increased metabolic risks in later life? Finnish general population-based birth cohort study. Hum Reprod. 2012;27:3279–86.CrossRefPubMed Pinola P, Lashen H, Bloigu A, Puukka K, Ulmanen M, Ruokonen A, Martikainen H, Pouta A, Franks S, Hartikainen A-L, et al. Menstrual disorders in adolescence: a marker for hyperandrogenaemia and increased metabolic risks in later life? Finnish general population-based birth cohort study. Hum Reprod. 2012;27:3279–86.CrossRefPubMed
25.
go back to reference Papler TB, Bokal EV, Zmrzljak UP, Stimpfel M, Laganà AS, Ghezzi F, et al. PGR and PTX3 gene expression in cumulus cells from obese and normal weighting women after administration of long-acting recombinant follicle-stimulating hormone for controlled ovarian stimulation. Arch Gynecol Obstet. 2019;299:863–71.CrossRef Papler TB, Bokal EV, Zmrzljak UP, Stimpfel M, Laganà AS, Ghezzi F, et al. PGR and PTX3 gene expression in cumulus cells from obese and normal weighting women after administration of long-acting recombinant follicle-stimulating hormone for controlled ovarian stimulation. Arch Gynecol Obstet. 2019;299:863–71.CrossRef
26.
go back to reference Roeca C, Johnson R, Carlson N, Polotsky AJ. Preimplantation genetic testing and chances of a healthy live birth amongst recipients of fresh donor oocytes in the United States. J Assist Reprod Genet. 2020;37:2283–92.CrossRefPubMedPubMedCentral Roeca C, Johnson R, Carlson N, Polotsky AJ. Preimplantation genetic testing and chances of a healthy live birth amongst recipients of fresh donor oocytes in the United States. J Assist Reprod Genet. 2020;37:2283–92.CrossRefPubMedPubMedCentral
27.
go back to reference Rosenwaks Z, Adashi EY. Introduction. Fertility in the face of genetically determined steroidogenic dysfunction. Fertil Steril. 2014;101:299–300.CrossRefPubMed Rosenwaks Z, Adashi EY. Introduction. Fertility in the face of genetically determined steroidogenic dysfunction. Fertil Steril. 2014;101:299–300.CrossRefPubMed
28.
go back to reference Schisterman EF, Mumford SL, Browne RW, Barr DB, Chen Z, Louis GM. Lipid concentrations and couple fecundity: the LIFE study. J Clin Endocrinol Metab. 2014;99:2786–94.CrossRefPubMedPubMedCentral Schisterman EF, Mumford SL, Browne RW, Barr DB, Chen Z, Louis GM. Lipid concentrations and couple fecundity: the LIFE study. J Clin Endocrinol Metab. 2014;99:2786–94.CrossRefPubMedPubMedCentral
29.
go back to reference Stouffer RL, Xu F, Duffy DM. Molecular control of ovulation and luteinization in the primate follicle. Front Biosci. 2007;12:297–307.CrossRefPubMed Stouffer RL, Xu F, Duffy DM. Molecular control of ovulation and luteinization in the primate follicle. Front Biosci. 2007;12:297–307.CrossRefPubMed
30.
go back to reference Valdes CT, Schutt A, Simon C. Implantation failure of endometrial origin: it is not pathology, but our failure to synchronize the developing embryo with a receptive endometrium. Fertil Steril. 2017;108:15–8.CrossRefPubMed Valdes CT, Schutt A, Simon C. Implantation failure of endometrial origin: it is not pathology, but our failure to synchronize the developing embryo with a receptive endometrium. Fertil Steril. 2017;108:15–8.CrossRefPubMed
31.
go back to reference van Montfoort AP, Plosch T, Hoek A, Tietge UJ. Impact of maternal cholesterol metabolism on ovarian follicle development and fertility. J Reprod Immunol. 2014;104–105:32–6.CrossRefPubMed van Montfoort AP, Plosch T, Hoek A, Tietge UJ. Impact of maternal cholesterol metabolism on ovarian follicle development and fertility. J Reprod Immunol. 2014;104–105:32–6.CrossRefPubMed
32.
go back to reference Wei D, Liu JY, Sun Y, Shi Y, Zhang B, Liu JQ, Tan J, Liang X, Cao Y, Wang Z, et al. Frozen versus fresh single blastocyst transfer in ovulatory women: a multicentre, randomised controlled trial. Lancet. 2019;393:1310–8.CrossRefPubMed Wei D, Liu JY, Sun Y, Shi Y, Zhang B, Liu JQ, Tan J, Liang X, Cao Y, Wang Z, et al. Frozen versus fresh single blastocyst transfer in ovulatory women: a multicentre, randomised controlled trial. Lancet. 2019;393:1310–8.CrossRefPubMed
33.
go back to reference Woollett LA. Where does fetal and embryonic cholesterol originate and what does it do? Annu Rev Nutr. 2008;28:97–114.CrossRefPubMed Woollett LA. Where does fetal and embryonic cholesterol originate and what does it do? Annu Rev Nutr. 2008;28:97–114.CrossRefPubMed
34.
go back to reference Willnow TE, Hammes A, Eaton S. Lipoproteins and their receptors in embryonic development: more than cholesterol clearance. Development. 2007;134:3239–49.CrossRefPubMed Willnow TE, Hammes A, Eaton S. Lipoproteins and their receptors in embryonic development: more than cholesterol clearance. Development. 2007;134:3239–49.CrossRefPubMed
35.
go back to reference Yesilaltay A, Dokshin GA, Busso D, Wang L, Galiani D, Chavarria T, Vasile E, Quilaqueo L, Orellana J, Walzer D, et al. Excess cholesterol induces mouse egg activation and may cause female infertility. Proc Natl Acad Sci U S A. 2014;111:E4972-4980.CrossRefPubMedPubMedCentral Yesilaltay A, Dokshin GA, Busso D, Wang L, Galiani D, Chavarria T, Vasile E, Quilaqueo L, Orellana J, Walzer D, et al. Excess cholesterol induces mouse egg activation and may cause female infertility. Proc Natl Acad Sci U S A. 2014;111:E4972-4980.CrossRefPubMedPubMedCentral
36.
go back to reference Yan J, Qin Y, Zhao H, Sun Y, Gong F, Li R, Sun X, Ling X, Li H, Hao C, et al. Live birth with or without preimplantation genetic testing for aneuploidy. N Engl J Med. 2021;385:2047–58.CrossRefPubMed Yan J, Qin Y, Zhao H, Sun Y, Gong F, Li R, Sun X, Ling X, Li H, Hao C, et al. Live birth with or without preimplantation genetic testing for aneuploidy. N Engl J Med. 2021;385:2047–58.CrossRefPubMed
37.
go back to reference Yang T, Zhao J, Liu F, Li Y. Lipid metabolism and endometrial receptivity. Hum Reprod Update. 2022;28:858–89.CrossRefPubMed Yang T, Zhao J, Liu F, Li Y. Lipid metabolism and endometrial receptivity. Hum Reprod Update. 2022;28:858–89.CrossRefPubMed
38.
go back to reference Yang X, Wu LL, Chura LR, Liang X, Lane M, Norman RJ, Rebecca LR. Exposure to lipid-rich follicular fluid is associated with endoplasmic reticulum stress and impaired oocyte maturation in cumulus-oocyte complexes. Fertil Steril. 2012;97:1438–43.CrossRefPubMed Yang X, Wu LL, Chura LR, Liang X, Lane M, Norman RJ, Rebecca LR. Exposure to lipid-rich follicular fluid is associated with endoplasmic reticulum stress and impaired oocyte maturation in cumulus-oocyte complexes. Fertil Steril. 2012;97:1438–43.CrossRefPubMed
39.
go back to reference Yu X, Gao J, Huang Y, Zou Y, Huang Y, Du T, Zhang J. Effect of the increase rate of blood lipid concentration during pregnancy on the adverse pregnancy outcomes: a cohort study of 1051 singleton pregnancy. Gynecol Endocrinol. 2022;38:1125–8.CrossRefPubMed Yu X, Gao J, Huang Y, Zou Y, Huang Y, Du T, Zhang J. Effect of the increase rate of blood lipid concentration during pregnancy on the adverse pregnancy outcomes: a cohort study of 1051 singleton pregnancy. Gynecol Endocrinol. 2022;38:1125–8.CrossRefPubMed
Metadata
Title
Maternal hypercholesterolemia would increase the incidence of embryo aneuploidy in couples with recurrent implantation failure
Authors
Yang Liu
Tianxiang Ni
Qing Zhao
Weiran Cui
Xiangxin Lan
Tingting Zhou
Qian Zhang
Junhao Yan
Publication date
01-12-2023
Publisher
BioMed Central
Published in
European Journal of Medical Research / Issue 1/2023
Electronic ISSN: 2047-783X
DOI
https://doi.org/10.1186/s40001-023-01492-x

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