Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
BMC Pregnancy and Childbirth
Published in: BMC Pregnancy and Childbirth 1/2024

Open Access 01-12-2024 | Biomarkers | Research

Specific plasma microRNA profiles could be potential non-invasive biomarkers for biochemical pregnancy loss following embryo transfer

Authors: Lang Shen, Hong Zeng, Yu Fu, Wenmin Ma, Xiaoling Guo, Guoqun Luo, Rui Hua, Xiaocong Wang, Xiao Shi, Biao Wu, Chen Luo, Song Quan

Published in: BMC Pregnancy and Childbirth | Issue 1/2024

Login to get access

Abstract

Background

Plasma microRNAs act as biomarkers for predicting and diagnosing diseases. Reliable non-invasive biomarkers for biochemical pregnancy loss have not been established. We aim to analyze the dynamic microRNA profiles during the peri-implantation period and investigate if plasma microRNAs could be non-invasive biomarkers predicting BPL.

Methods

In this study, we collected plasma samples from patients undergoing embryo transfer (ET) on ET day (ET0), 11 days after ET (ET11), and 14 days after ET (ET14). Patients were divided into the NP (negative pregnancy), BPL (biochemical pregnancy loss), and CP (clinical pregnancy) groups according to serum hCG levels at day11~14 and ultrasound at day28~35 following ET. MicroRNA profiles at different time-points were detected by miRNA-sequencing. We analyzed plasma microRNA signatures for BPL at the peri-implantation stage, we characterized the dynamic microRNA changes during the implantation period, constructed a microRNA co-expression network, and established predictive models for BPL. Finally, the sequencing results were confirmed by Taqman RT-qPCR.

Results

BPL patients have distinct plasma microRNA profiles compared to CP patients at multiple time-points during the peri-implantation period. Machine learning models revealed that plasma microRNAs could predict BPL. RT-qPCR confirmed that miR-181a-2-3p, miR-9-5p, miR-150-3p, miR-150-5p, and miR-98-5p, miR-363-3p were significantly differentially expressed between patients with different reproductive outcomes.

Conclusion

Our study highlights the non-invasive value of plasma microRNAs in predicting BPL.
Appendix
Available only for authorised users
Literature
1.
Dickey RP, Olar TT, Taylor SN, Curole DN, Harrigill K. Relationship of biochemical pregnancy to pre-ovulatory endometrial thickness and pattern in patients undergoing ovulation induction. Hum Reprod. 1993;8(2):327–30.PubMedCrossRef
2.
3.
Troncoso C, Bosch E, Rubio C, Remohí J, Simón C, Pellicer A. The origin of biochemical pregnancies: lessons learned from preimplantation genetic diagnosis. Fertil Steril. 2003;79(2):449–50.PubMedCrossRef
4.
Vaiarelli A, Cimadomo D, Patrizio P, Venturella R, Orlando G, Soscia D, et al. Biochemical pregnancy loss after frozen embryo transfer seems independent of embryo developmental stage and chromosomal status. Reprod Biomed Online. 2018;37(3):349–57.PubMedCrossRef
5.
Dahan MH, Zeadna A, Dahan D, Son WY, Steiner N. The biochemical pregnancy loss rate remains stable up irrespective of age and differs in pattern from clinical miscarriages. Gynecol Endocrinol. 2021;37(1):61–4.PubMedCrossRef
6.
Zhang X, Guo F, Wang Q, Bai W, Zhao A. Low-dose aspirin improves blood perfusion of endometrium of unexplained recurrent biochemical pregnancy loss. Int J Gynaecol Obstet. 2022;157(2):418–23.PubMedCrossRef
7.
Hou Y, Li J, Liu Q, Zhang L, Chen B, Li Y, et al. The optimal timing of immunotherapy may improve pregnancy outcome in women with unexplained recurrent pregnancy loss: A perspective follow-up study in northeastern China. Am J Reprod Immunol. 2020;83(4): e13225.PubMedCrossRef
8.
Annan JJ, Gudi A, Bhide P, Shah A, Homburg R. Biochemical pregnancy during assisted conception: a little bit pregnant. J Clin Med Res. 2013;5(4):269–74.PubMedPubMedCentral
9.
Díaz-Gimeno P, Ruiz-Alonso M, Sebastian-Leon P, Pellicer A, Valbuena D, Simón C. Window of implantation transcriptomic stratification reveals different endometrial subsignatures associated with live birth and biochemical pregnancy. Fertil Steril. 2017;108(4):703–710.e703.PubMedCrossRef
10.
Macklon NS, Geraedts JP, Fauser BC. Conception to ongoing pregnancy: the “black box” of early pregnancy loss. Hum Reprod Update. 2002;8(4):333–43.PubMedCrossRef
11.
Zinaman MJ, Clegg ED, Brown CC, O’Connor J, Selevan SG. Estimates of human fertility and pregnancy loss. Fertil Steril. 1996;65(3):503–9.PubMedCrossRef
12.
Lenton EA, Hooper M, King H, Kumar A, Monks N, Verma S, et al. Normal and abnormal implantation in spontaneous in-vivo and in-vitro human pregnancies. J Reprod Fertil. 1991;92(2):555–65.PubMedCrossRef
13.
Kolte AM, van Oppenraaij RH, Quenby S, Farquharson RG, Stephenson M, Goddijn M, et al. Non-visualized pregnancy losses are prognostically important for unexplained recurrent miscarriage. Hum Reprod. 2014;29(5):931–7.PubMedCrossRef
14.
Eslamizadeh S, Akbari A. Serum or plasma; which is a more competent molecular source for investigating the blood-based tumor-specific miRNA biomarkers? J Cell Physiol. 2020;235(7–8):5858–9.PubMedCrossRef
15.
16.
Chen CH, Lu F, Yang WJ, Yang PE, Chen WM, Kang ST, et al. A novel platform for discovery of differentially expressed microRNAs in patients with repeated implantation failure. Fertil Steril. 2021;116(1):181–8.PubMedCrossRef
17.
Capalbo, A., F.M. Ubaldi, D. Cimadomo, L. Noli, Y. Khalaf, A. Farcomeni, et al., MicroRNAs in spent blastocyst culture medium are derived from trophectoderm cells and can be explored for human embryo reproductive competence assessment. Fertil Steril, 2016. 105(1):225-235.e221-223.
18.
Timofeeva AV, Chagovets VV, Drapkina YS, Makarova NP, Kalinina EA, Sukhikh GT. Cell-Free, Embryo-Specific sncRNA as a Molecular Biological Bridge between Patient Fertility and IVF Efficiency. Int J Mol Sci. 2019;20(12):2912.PubMedPubMedCentralCrossRef
19.
Freis A, Keller A, Ludwig N, Meese E, Jauckus J, Rehnitz J, et al. Altered miRNA-profile dependent on ART outcome in early pregnancy targets Wnt-pathway. Reproduction. 2017;154(6):799–805.PubMedCrossRef
20.
Zeng H, Fu Y, Shen L, Quan S. MicroRNA signatures in plasma and plasma exosome during window of implantation for implantation failure following in-vitro fertilization and embryo transfer. Reprod Biol Endocrinol. 2021;19(1):180.PubMedPubMedCentralCrossRef
21.
Smith MD, Pillman K, Jankovic-Karasoulos T, McAninch D, Wan Q, Bogias KJ, et al. Large-scale transcriptome-wide profiling of microRNAs in human placenta and maternal plasma at early to mid gestation. RNA Biol. 2021;18(sup1):507–20.PubMedPubMedCentralCrossRef
22.
Fang F, Li Z, Yu J, Long Y, Zhao Q, Ding X, et al. MicroRNAs secreted by human embryos could be potential biomarkers for clinical outcomes of assisted reproductive technology. J Adv Res. 2021;31:25–34.PubMedPubMedCentralCrossRef
23.
Alpha Scientists in Reproductive Medicine and ESHRE Special Interest Group of Embryology. The Istanbul consensus workshop on embryo assessment: proceedings of an expert meeting. Hum Reprod, 2011. 26(6);1270-1283.
24.
Heitmann RJ, Hill MJ, Richter KS, DeCherney AH, Widra EA. The simplified SART embryo scoring system is highly correlated to implantation and live birth in single blastocyst transfers. J Assist Reprod Genet. 2013;30(4):563–7.PubMedPubMedCentralCrossRef
25.
Racca A, Santos-Ribeiro S, De Munck N, Mackens S, Drakopoulos P, Camus M, et al. Impact of late-follicular phase elevated serum progesterone on cumulative live birth rates: is there a deleterious effect on embryo quality? Hum Reprod. 2018;33(5):860–8.PubMedCrossRef
26.
Gardner DK, Lane M, Stevens J, Schlenker T, Schoolcraft WB. Blastocyst score affects implantation and pregnancy outcome: towards a single blastocyst transfer. Fertil Steril. 2000;73(6):1155–8.PubMedCrossRef
27.
28.
29.
30.
31.
Liaw A, Wiener M. Classification and regression by randomForest. R news. 2002;2(3):18–22.
32.
Kuhn, M., Caret: classification and regression training. Astrophysics Source Code Library, 2015: p. ascl: 1505.1003.
33.
34.
Jairajpuri DS, Malalla ZH, Mahmood N, Khan F, Almawi WY. Differentially expressed circulating microRNAs associated with idiopathic recurrent pregnancy loss. Gene. 2021;768: 145334.PubMedCrossRef
35.
Wander PL, Boyko EJ, Hevner K, Parikh VJ, Tadesse MG, Sorensen TK, et al. Circulating early- and mid-pregnancy microRNAs and risk of gestational diabetes. Diabetes Res Clin Pract. 2017;132:1–9.PubMedPubMedCentralCrossRef
36.
Hromadnikova I, Kotlabova K, Hympanova L, Krofta L. Gestational hypertension, preeclampsia and intrauterine growth restriction induce dysregulation of cardiovascular and cerebrovascular disease associated microRNAs in maternal whole peripheral blood. Thromb Res. 2016;137:126–40.PubMedCrossRef
37.
Kim S, Park M, Kim JY, Kim T, Hwang JY, Ha KS, et al. Circulating miRNAs Associated with Dysregulated Vascular and Trophoblast Function as Target-Based Diagnostic Biomarkers for Preeclampsia. Cells. 2020;9(9):2003.PubMedPubMedCentralCrossRef
38.
Kim SH, MacIntyre DA, Binkhamis R, Cook J, Sykes L, Bennett PR, et al. Maternal plasma miRNAs as potential biomarkers for detecting risk of small-for-gestational-age births. EBioMedicine. 2020;62: 103145.PubMedPubMedCentralCrossRef
39.
Zhou W, Dimitriadis E. Secreted MicroRNA to Predict Embryo Implantation Outcome: From Research to Clinical Diagnostic Application. Front Cell Dev Biol. 2020;8: 586510.PubMedPubMedCentralCrossRef
40.
Zeng Y, Wei L, Lali MS, Chen Y, Yu J, Feng L. miR-150-5p mediates extravillous trophoblast cell migration and angiogenesis functions by regulating VEGF and MMP9. Placenta. 2020;93:94–100.PubMedCrossRef
41.
Revel A, Achache H, Stevens J, Smith Y, Reich R. MicroRNAs are associated with human embryo implantation defects. Hum Reprod. 2011;26(10):2830–40.PubMedCrossRef
42.
Da Broi MG, Meola J, Plaça JR, Peronni KC, Rocha CV, Silva WA, et al. Is the profile of transcripts altered in the eutopic endometrium of infertile women with endometriosis during the implantation window? Hum Reprod. 2019;34(12):2381–90.PubMedCrossRef
43.
Thamotharan S, Chu A, Kempf K, Janzen C, Grogan T, Elashoff DA, et al. Differential microRNA expression in human placentas of term intra-uterine growth restriction that regulates target genes mediating angiogenesis and amino acid transport. PLoS One. 2017;12(5): e0176493.PubMedPubMedCentralCrossRef
44.
von Grothusen C, Frisendahl C, Modhukur V, Lalitkumar PG, Peters M, Faridani OR, et al. Uterine fluid microRNAs are dysregulated in women with recurrent implantation failure. Hum Reprod. 2022;37(4):734–46.CrossRef
45.
Smith MD, Leemaqz SY, Jankovic-Karasoulos T, McAninch D, McCullough D, Breen J, et al. Haemolysis Detection in MicroRNA-Seq from Clinical Plasma Samples. Genes (Basel). 2022;13(7):1288.PubMedCrossRef
46.
Xia HF, Jin XH, Cao ZF, Shi T, Ma X. MiR-98 is involved in rat embryo implantation by targeting Bcl-xl. FEBS Lett. 2014;588(4):574–83.PubMedCrossRef
47.
Nakamura K, Kusama K, Hori M, Imakawa K. The effect of bta-miR-26b in intrauterine extracellular vesicles on maternal immune system during the implantation period. Biochem Biophys Res Commun. 2021;573:100–6.PubMedCrossRef
48.
Wang Y, Lv Y, Wang L, Gong C, Sun J, Chen X, et al. MicroRNAome in decidua: a new approach to assess the maintenance of pregnancy. Fertil Steril. 2015;103(4):980–989.e986.PubMedCrossRef
49.
Cui L, Chen S, Wang D, Yang Q. LINC01116 promotes proliferation and migration of endometrial stromal cells by targeting FOXP1 via sponging miR-9-5p in endometriosis. J Cell Mol Med. 2021;25(4):2000–12.PubMedCrossRef
50.
Huang J, Yang Y, Tian M, Deng D, Yu M. Spatial Transcriptomic and miRNA Analyses Revealed Genes Involved in the Mesometrial-Biased Implantation in Pigs. Genes (Basel). 2019;10(10):808.PubMedCrossRef
51.
Tan Q, Shi S, Liang J, Cao D, Wang S, Wang Z. Endometrial cell-derived small extracellular vesicle miR-100-5p promotes functions of trophoblast during embryo implantation. Mol Ther Nucleic Acids. 2021;23:217–31.PubMedCrossRef
52.
Yang Q, Gu WW, Gu Y, Yan NN, Mao YY, Zhen XX, et al. Association of the peripheral blood levels of circulating microRNAs with both recurrent miscarriage and the outcomes of embryo transfer in an in vitro fertilization process. J Transl Med. 2018;16(1):186.PubMedPubMedCentralCrossRef
53.
Xu H, Wang X, Wang Z, Li J, Xu Z, Miao M, et al. MicroRNA expression profile analysis in sperm reveals hsa-mir-191 as an auspicious omen of in vitro fertilization. BMC Genomics. 2020;21(1):165.PubMedPubMedCentralCrossRef
54.
Acuña-González RJ, Olvera-Valencia M, López-Canales JS, Lozano-Cuenca J, Osorio-Caballero M, Flores-Herrera H. MiR-191-5p is upregulated in culture media of implanted human embryo on day fifth of development. Reprod Biol Endocrinol. 2021;19(1):109.PubMedPubMedCentralCrossRef
55.
Li K, Lv C, Zhang W, Fang J. CircFN1 upregulation initiated oxidative stress-induced apoptosis and inhibition of proliferation and migration in trophoblasts via circFN1-miR-19a/b-3p-ATF2 ceRNA network. Reprod Biol. 2022;22(2): 100631.PubMedCrossRef
56.
Yang Y, Li H, Ma Y, Zhu X, Zhang S, Li J. MiR-221-3p is down-regulated in preeclampsia and affects trophoblast growth, invasion and migration partly via targeting thrombospondin 2. Biomed Pharmacother. 2019;109:127–34.PubMedCrossRef
57.
Noli L, Capalbo A, Dajani Y, Cimadomo D, Bvumbe J, Rienzi L, et al. Human Embryos Created by Embryo Splitting Secrete Significantly Lower Levels of miRNA-30c. Stem Cells Dev. 2016;25(24):1853–62.PubMedPubMedCentralCrossRef
58.
Shih JC, Lin HH, Hsiao AC, Su YT, Tsai S, Chien CL, et al. Unveiling the role of microRNA-7 in linking TGF-β-Smad-mediated epithelial-mesenchymal transition with negative regulation of trophoblast invasion. Faseb j. 2019;33(5):6281–95.PubMedCrossRef
59.
Bahramy A, Zafari N, Izadi P, Soleymani F, Kavousi S, Noruzinia M. The Role of miRNAs 340–5p, 92a–3p, and 381–3p in Patients with Endometriosis: A Plasma and Mesenchymal Stem-Like Cell Study. Biomed Res Int. 2021;2021:5298006.PubMedPubMedCentralCrossRef
60.
Nikolova M, Naydenov M, Glogovitis I, Apostolov A, Saare M, Boggavarapu N, et al. Coupling miR/isomiR and mRNA Expression Signatures Unveils New Molecular Layers of Endometrial Receptivity. Life (Basel). 2021;11(12):1391.PubMed
61.
Timofeeva AV, Fedorov IS, Pirogova MM, Vasilchenko ON, Chagovets VV, Ezhova LS, et al. Clusterin and Its Potential Regulatory microRNAs as a Part of Secretome for the Diagnosis of Abnormally Invasive Placenta: Accreta, Increta, and Percreta Cases. Life (Basel). 2021;11(4):270.PubMed
Metadata
Title
Specific plasma microRNA profiles could be potential non-invasive biomarkers for biochemical pregnancy loss following embryo transfer
Authors
Lang Shen
Hong Zeng
Yu Fu
Wenmin Ma
Xiaoling Guo
Guoqun Luo
Rui Hua
Xiaocong Wang
Xiao Shi
Biao Wu
Chen Luo
Song Quan
Publication date
01-12-2024
Publisher
BioMed Central
Published in
BMC Pregnancy and Childbirth / Issue 1/2024
Electronic ISSN: 1471-2393
DOI
https://doi.org/10.1186/s12884-024-06488-x

Other articles of this Issue 1/2024

BMC Pregnancy and Childbirth 1/2024 Go to the issue

Research

The value of intraovarian autologous platelet rich plasma in women with poor ovarian reserve or ovarian insufficiency: a systematic review and meta-analysis

Research

The effect of paternal anxiety on mother-infant bonding in neonatal intensive care

Research

Adverse birth outcome among women who gave birth at the University of Gondar comprehensive specialized hospital, Northwest Ethiopia

Research

Exploring the association between unintended pregnancies and unmet contraceptive needs among Ugandan women of reproductive age: an analysis of the 2016 Uganda demographic and health survey

Research

Low-dose aspirin for the prevention of preterm birth in nulliparous women: systematic review and meta-analysis

Research

Predicting fluid responsiveness in spontaneously breathing parturients undergoing caesarean section via carotid artery blood flow and velocity time integral measured by carotid ultrasound: a prospective cohort study