Analysis of genetic causes and related factors of spontaneous abortion in the first trimester of pregnancy

doi:10.3969/j.issn.1673-8640.2025.04.012

Abstract

Abstract:

Objective To investigate the genetic causes and related factors of spontaneous abortion in the first trimester of pregnancy.Methods The 765 cases of spontaneous abortion in the first trimester of pregnancy were enrolled from January 2020 to May 2024 in Zhengzhou Central Hospital of Zhengzhou University. The occurrence of chromosomal abnormalities and copy number variation（CNV） was analyzed by microsatellite short tandem repeat（STR） and copy number variation sequencing（CNV-seq），and the factors that may affect early spontaneous abortion were analyzed，including the age of pregnant women and the number of spontaneous abortion.Results Among the 765 cases of spontaneous abortion in the first trimester of pregnancy，there were 320 cases of aneuploidy（41.83%），60 cases of pathogenic/possibly pathogenic CNV（7.84%），42 cases of uncertain significance CNV（5.49%），28 cases of triploidy（3.66%） and 9 cases of homologous uniparental diploidy（1.18%）. Two recurrent CNV of uncertain significance（≥2 cases） were identified，including 4q32.3（164718249-164867678）×3 with a frequency of 1.18%（9/765） and 16q22.1（70045096-70166731）×3 with a frequency of 1.70%（13/765）. The determination rate of chromosomal numerical abnormalities and pathogenic/possibly pathogenic CNV was higher in the advanced maternal age group（≥35 years old） compared to the younger group（<35 years old）（P<0.001）. There was no statistical significance in the determination rates of chromosomal numerical abnormalities，pathogenic/possibly pathogenic CNV and CNV of uncertain significance among women with different numbers of spontaneous abortion（P>0.05）.Conclusions The 60% of the cases of spontaneous abortion in the first trimester of pregnancy are due to chromosomal abnormalities. The age of pregnant women is related to chromosomal abnormalities in spontaneous abortion in the first trimester of pregnancy.

Key words: Microsatellite short tandem repeat, Copy number variation sequencing, Spontaneous abortion

CLC Number:

R446.1

GUO Tingting, LOU Huan, HU Hangzhan, YANG Xiaofeng. Analysis of genetic causes and related factors of spontaneous abortion in the first trimester of pregnancy[J]. Laboratory Medicine, 2025, 40(4): 383-387.

Figures/Tables 3

References 25

[1]	Practice Committee of the American Society for Reproductive Medicine. Evaluation and treatment of recurrent pregnancy loss:a committee opinion[J]. Fertil Steril, 2012, 98(5):1103-1111.
[2]	谢幸, 苟文丽. 妇产科学[M]. 8版. 北京: 人民卫生出版社, 2013.
[3]	周冉, 王艳, 孟露露, 等. 高通量连接探针扩增联合染色体微阵列分析技术在早期自然流产遗传学诊断中的应用[J]. 中华妇产科杂志, 2022, 57(3):219-223.
[4]	GONG G, YIN C, HUANG Y, et al. A survey of influencing factors of missed abortion during the two-child peak period[J]. J Obstet Gynaecol, 2021, 41(6):977-980.
[5]	ZHANG T, SUN Y, CHEN Z, et al. Traditional and molecular chromosomal abnormality analysis of products of conception in spontaneous and recurrent miscarriage[J]. BJOG, 2018, 125(4):414-420.
[6]	QU S, SHI P, ZHANG T, et al. Application of CNV-seq and chromosomal karyotyping in the prenatal diagnosis for carriers of balanced translocations[J]. Zhonghua Yi Xue Yi Chuan Xue Za Zhi, 2022, 39(4):366-369.
[7]	刘颖迪, 邬玲仟. 高通量测序技术在产前筛查和产前诊断中的应用[J]. 中华预防医学杂志, 2021, 55(9):1037-1042.
[8]	RIGGS E R, ANDERSEN E F, CHERRY A M, et al. Technical standards for the interpretation and reporting of constitutional copy-number variants:a joint consensus recommendation of the American College of Medical Genetics and Genomics(ACMG)and the Clinical Genome Resource(ClinGen)[J]. Genet Med, 2020, 22(2):245-257.
[9]	PYLYP L Y, SPYNENKO L O, VERHOGLYAD N V, et al. Chromosomal abnormalities in products of conception of first-trimester miscarriages detected by conventional cytogenetic analysis:a review of 1 000 cases[J]. J Assist Reprod Genet, 2018, 35(2):265-271.
[10]	FAN L, WU J, WU Y, et al. Analysis of chromosomal copy number in first-trimester pregnancy loss using next-generation sequencing[J]. Front Genet, 2020, 11:545856.
[11]	WANG Y, LI Y, CHEN Y, et al. Systematic analysis of copy-number variations associated with early pregnancy loss[J]. Ultrasound Obstet Gynecol, 2020, 55(1):96-104. DOI PMID
[12]	郭芳芳, 侯亚萍, 胡听听, 等. CNV-seq结合QF-PCR在孕早期流产物检测中的临床应用价值[J]. 现代妇产科进展, 2023, 32(3):166-170.
[13]	HASSOLD T, MERRILL M, ADKINS K, et al. Recombination and maternal age-dependent nondisjunction:molecular studies of trisomy 16[J]. Am J Hum Genet, 1995, 57(4):867-874.
[14]	彭小芳, 林少宾, 萧晓琴, 等. 16号染色体三体、嵌合体、单亲二体——更新的认识[J]. 中国产前诊断杂志(电子版), 2021, 13(1):12-16.
[15]	GOMEZ R, HAFEZI N, AMRANI M, et al. Genetic findings in miscarriages and their relation to the number of previous miscarriages[J]. Arch Gynecol Obstet, 2021, 303(6):1425-1432. DOI PMID
[16]	雷彩霞, 张月萍, 伍俊萍, 等. 1 437例早孕期自然流产胚胎核型分析[J]. 生殖与避孕, 2014, 34(4):6.
[17]	魏友华, 王志俊, 王蕊, 等. 低深度高通量基因测序在早期自然流产胚胎检测中的应用[J]. 国际遗传学杂志, 2020, 43(4):202-208.
[18]	许海霞, 李清平. 妊娠合并部分性葡萄胎1例报告及文献复习[J]. 世界最新医学信息文摘(连续型电子期刊), 2020, 20(77):231-236.
[19]	LIU S, HUA T, XIN X, et al. Altered expression of hormone receptor,integrin β3 and pinopode in the endometrium of luteal phase defect women[J]. Gynecol Endocrinol, 2017, 33(4):315-319.
[20]	PAUTA M, GRANDE M, RODRIGUEZ-REVENGA L, et al. Added value of chromosomal microarray analysis over karyotyping in early pregnancy loss:systematic review and meta-analysis[J]. Ultrasound Obstet Gynecol, 2018, 51(4):453-462.
[21]	WANG Y, LI Y, CHEN Y, et al. Systematic analysis of copy-number variations associated with early pregnancy loss[J]. Ultrasound Obstet Gynecol, 2020, 55(1):96-104. DOI PMID
[22]	SHENG Y R, HOU S Y, HU W T, et al. Characterization of copy-number variations and possible candidate genes in recurrent pregnancy losses[J]. Genes(Basel), 2021, 12(2):141.
[23]	LIU A, ZHOU L, HUANG Y, et al. Analysis of copy number variants detected by sequencing in spontaneous abortion[J]. Mol Cytogenet, 2024, 17(1):13. DOI PMID
[24]	SATO T, MIGITA O, HATA H, et al. Analysis of chromosome microstructures in products of conception associated with recurrent miscarriage[J]. Reprod Biomed Online, 2019, 38(5):787-795. DOI PMID
[25]	中华预防医学会出生缺陷预防与控制专业委员会遗传病防控学组,中华医学会医学遗传学分会临床遗传学组,中国医师协会医学遗传医师分会遗传病产前诊断专业委员会, 等. 流产物基因组拷贝数变异检测应用及家庭再生育咨询的专家共识[J]. 中华医学遗传学杂志, 2023, 40(2):129-134.

组别	例数	染色体数目异常/[例（%）]	致病/可能致病CNV/ [例（%）]	意义不明CNV/ [例（%）]	未检出异常染色体/ [例（%）]
高龄组	167	102（61.1）	23（13.8）	14（8.4）	28（16.8）
低龄组	598	246（41.1）	37（6.2）	28（4.7）	278（46.5）
χ²值		20.933	10.391	3.446	48.050
P值		<0.001	<0.001	0.063	<0.001

组别	例数	染色体数目异常/[例（%）]	致病/可能致病CNV/ [例（%）]	意义不明CNV/ [例（%）]	未检出异常染色体/ [例（%）]
高龄组	167	102（61.1）	23（13.8）	14（8.4）	28（16.8）
低龄组	598	246（41.1）	37（6.2）	28（4.7）	278（46.5）
χ²值		20.933	10.391	3.446	48.050
P值		<0.001	<0.001	0.063	<0.001

流产次数	例数	染色体数目异常/ [例（%）]	致病/可能致病CNV/ [例（%）]	意义不明CNV/ [例（%）]	未检出异常染色体/[例（%）]
1次	463	213（46.0）	32（6.9）	29（6.3）	199（43.0）
2次	213	97（45.5）	19（8.9）	15（7.0）	85（39.9）
≥3次	89	38（42.7）	9（10.1）	8（9.0）	42（47.2）
χ²值		0.329	1.531	0.903	1.426
P值		0.850	0.460	0.640	0.490

流产次数	例数	染色体数目异常/ [例（%）]	致病/可能致病CNV/ [例（%）]	意义不明CNV/ [例（%）]	未检出异常染色体/[例（%）]
1次	463	213（46.0）	32（6.9）	29（6.3）	199（43.0）
2次	213	97（45.5）	19（8.9）	15（7.0）	85（39.9）
≥3次	89	38（42.7）	9（10.1）	8（9.0）	42（47.2）
χ²值		0.329	1.531	0.903	1.426
P值		0.850	0.460	0.640	0.490