辅助生殖技术在葡萄胎治疗中的应用及研究进展

doi:10.12280/gjszjk.20200612

摘要/Abstract

摘要：

葡萄胎（hydatidiform mole）是一种临床上较常见的产科疾病,属于妊娠滋养细胞疾病,主要特征是绒毛水肿变性。现阶段葡萄胎的诊断和分类主要通过临床表现和组织学检查。但是,葡萄胎分类复杂且病因不清楚,且复发性葡萄胎再发风险较高,很难预防。随着测序技术的发展,辅助生殖技术,尤其是胚胎植入前遗传学检测,近年来得到了飞速发展,可以应用于体外获取胚胎并予以评估。然而,由于现阶段对葡萄胎这一疾病了解的局限性,辅助生殖技术在葡萄胎患者中的应用依旧较局限。对于有生育要求的葡萄胎患者,特别是复发性葡萄胎患者,建议给予再生育指导。综述葡萄胎的流行病学、临床表现、组织病理学以及遗传学特点,并探讨辅助生殖技术在复发性葡萄胎中的应用进展。

关键词: 葡萄胎, 妊娠滋养细胞疾病, NLR蛋白质类, 生殖技术,辅助, 突变

Abstract:

Hydatidiform mole (HM) is a common obstetric disease, which is classified as a gestational trophoblastic disease. HM is characterized by swollen villi. HM can be diagnosed and classified by clinical manifestations and histological examination. However, the complex classification and limitations of etiological knowledge of HM, in addition to the high risk of recurrence, make it difficult to prevent. With the development of sequencing technology, the assisted reproductive technology has been rapidly developed in recent years, especially the pre-implantation genetic testing. These technologies can be applied in the acquisition and evaluation of embryos in vitro. However, the application of assisted reproductive technology in HM patients is still confined due to the limitations of current understanding on HM. There are very limited knowledge on the prevention and reproductive guidance of HM, especially the recurrent HM. The epidemiology, clinical manifestations, histology and the genetic characteristics were reviewed in this article, while the application progress of assisted reproductive technology in HM was also discussed.

Key words: Hydatidiform mole, Gestational trophoblastic disease, NLR proteins, Reproductive techniques,assisted, Mutation

杨婧祎, 刘岩, 智旭. 辅助生殖技术在葡萄胎治疗中的应用及研究进展[J]. 国际生殖健康/计划生育, 2021, 40(3): 209-215.

YANG Jing-yi, LIU Yan, ZHI Xu. Application of Assisted Reproductive Technology in Hydatidiform Mole[J]. Journal of International Reproductive Health/Family Planning, 2021, 40(3): 209-215.

图/表 2

参考文献 38

[1]	Cavoretto P, Cioffi R, Mangili G, et al. A Pictorial Ultrasound Essay of Gestational Trophoblastic Disease[J]. J Ultrasound Med, 2020,39(3):597-613. doi: 10.1002/jum.15119. doi: 10.1002/jum.15119 URL pmid: 31468566
[2]	Kalogiannidis I, Kalinderi K, Kalinderis M, et al. Recurrent complete hydatidiform mole: where we are, is there a safe gestational horizon? Opinion and mini-review[J]. J Assist Reprod Genet, 2018,35(6):967-973. doi: 10.1007/s10815-018-1202-9. doi: 10.1007/s10815-018-1202-9 URL
[3]	Jauniaux E, Memtsa M, Johns J, et al. New insights in the pathophysiology of complete hydatidiform mole[J]. Placenta, 2018,62:28-33. doi: 10.1016/j.placenta.2017.12.008. doi: S0143-4004(17)31212-2 URL pmid: 29405964
[4]	Deveault C, Qian JH, Chebaro W, et al. NLRP7 mutations in women with diploid androgenetic and triploid moles: a proposed mechanism for mole formation[J]. Hum Mol Genet, 2009,18(5):888-897. doi: 10.1093/hmg/ddn418. doi: 10.1093/hmg/ddn418 URL
[5]	Akoury E, Gupta N, Bagga R, et al. Live births in women with recurrent hydatidiform mole and two NLRP7 mutations[J]. Reprod Biomed Online, 2015,31(1):120-124. doi: 10.1016/j.rbmo.2015.03.011. doi: 10.1016/j.rbmo.2015.03.011 URL
[6]	Qian J, Cheng Q, Murdoch S, et al. The genetics of recurrent hydatidiform moles in China: correlations between NLRP7 mutations, molar genotypes and reproductive outcomes[J]. Mol Hum Reprod, 2011,17(10):612-619. doi: 10.1093/molehr/gar027. doi: 10.1093/molehr/gar027 URL
[7]	Nguyen N, Khawajkie Y, Mechtouf N, et al. The genetics of recurrent hydatidiform moles: new insights and lessons from a comprehensive analysis of 113 patients[J]. Mod Pathol, 2018,31(7):1116-1130. doi: 10.1038/s41379-018-0031-9. doi: 10.1038/s41379-018-0031-9 URL
[8]	Moein-Vaziri N, Fallahi J, Namavar-Jahromi B, et al. Clinical and genetic-epignetic aspects of recurrent hydatidiform mole: A review of literature[J]. Taiwan J Obstet Gynecol, 2018,57(1):1-6. doi: 10.1016/j.tjog.2017.12.001. doi: S1028-4559(17)30295-4 URL pmid: 29458875
[9]	Khawajkie Y, Mechtouf N, Nguyen N, et al. Comprehensive analysis of 204 sporadic hydatidiform moles: revisiting risk factors and their correlations with the molar genotypes[J]. Mod Pathol, 2020,33(5):880-892. doi: 10.1038/s41379-019-0432-4. doi: 10.1038/s41379-019-0432-4 URL
[10]	沈梅, 郭俭, 吕蓓, 等. 完全性葡萄胎和部分性葡萄胎的临床分析[J]. 中国妇产科临床杂志, 2019,20(3):264-265. doi: 10.13390/j.issn.1672-1861.2019.03.028.
[11]	Heller DS. Update on the pathology of gestational trophoblastic disease[J]. APMIS, 2018,126(7):647-654. doi: 10.1111/apm.12786. doi: 10.1111/apm.12786 URL pmid: 30129126
[12]	Ronnett BM. Hydatidiform Moles: Ancillary Techniques to Refine Diagnosis[J]. Arch Pathol Lab Med, 2018,142(12):1485-1502. doi: 10.5858/arpa.2018-0226-RA. doi: 10.5858/arpa.2018-0226-RA URL
[13]	Baine I, Hui P. Practical applications of DNA genotyping in diagnostic pathology[J]. Expert Rev Mol Diagn, 2019,19(2):175-188. doi: 10.1080/14737159.2019.1568874. doi: 10.1080/14737159.2019.1568874 URL
[14]	Maisenbacher MK, Merrion K, Kutteh WH. Single-nucleotide polymorphism microarray detects molar pregnancies in 3% of miscarriages[J]. Fertil Steril, 2019,112(4):700-706. doi: 10.1016/j.fertnstert.2019.06.015. doi: 10.1016/j.fertnstert.2019.06.015 URL
[15]	李广栋, 崔炜, 田秀芝, 等. NLRP7基因在母源印记中的研究进展简[J]. 中国畜牧兽医, 2018,45(4):1002-1008. doi: 10.16431/j.cnki.1671-7236.2018.04.021.
[16]	Alici-Garipcan A, Özçimen B, Süder I, et al. NLRP7 plays a functional role in regulating BMP4 signaling during differentiation of patient-derived trophoblasts[J]. Cell Death Dis, 2020,11(8):658. doi: 10.1038/s41419-020-02884-1. doi: 10.1038/s41419-020-02884-1 URL pmid: 32814763
[17]	Demond H, Anvar Z, Jahromi BN, et al. A KHDC3L mutation resulting in recurrent hydatidiform mole causes genome-wide DNA methylation loss in oocytes and persistent imprinting defects post-fertilisation[J]. Genome Med, 2019,11(1):84. doi: 10.1186/s13073-019-0694-y. doi: 10.1186/s13073-019-0694-y URL
[18]	Zhang P, Zhu X, Yu X, et al. Abnormal processing of IL-1β in NLRP7-mutated monocytes in hydatidiform mole patients[J]. Clin Exp Immunol, 2020,202(1):72-79. doi: 10.1111/cei.13472. doi: 10.1111/cei.v202.1 URL
[19]	Gheldof A, Mackay D, Cheong Y, et al. Genetic diagnosis of subfertility: the impact of meiosis and maternal effects[J]. J Med Genet, 2019,56(5):271-282. doi: 10.1136/jmedgenet-2018-105513. doi: 10.1136/jmedgenet-2018-105513 URL
[20]	Hui P. Germline NLRP7 mutations: genomic imprinting and hydatidiform mole[J]. Virchows Arch, 2020,477(2):175-176. doi: 10.1007/s00428-020-02802-y. doi: 10.1007/s00428-020-02802-y URL
[21]	Amoushahi M, Sunde L, Lykke-Hartmann K. The pivotal roles of the NOD-like receptors with a PYD domain, NLRPs, in oocytes and early embryo development?[J]. Biol Reprod, 2019,101(2):284-296. doi: 10.1093/biolre/ioz098. doi: 10.1093/biolre/ioz098 URL
[22]	Zhang W, Chen Z, Zhang D, et al. KHDC3L mutation causes recurrent pregnancy loss by inducing genomic instability of human early embryonic cells[J]. PLoS Biol, 2019,17(10):e3000468. doi: 10.1371/journal.pbio.3000468. doi: 10.1371/journal.pbio.3000468 URL
[23]	Fallahi J, Anvar Z, Razban V, et al. Founder Effect of KHDC3L, p.M1V Mutation, on Iranian Patients with Recurrent Hydatidiform Moles[J]. Iran J Med Sci, 2020,45(2):118-124. doi: 10.30476/IJMS.2019.45335.
[24]	Wang X, Song D, Mykytenko D, et al. Novel mutations in genes encoding subcortical maternal complex proteins may cause human embryonic developmental arrest[J]. Reprod Biomed Online, 2018,36(6):698-704. doi: 10.1016/j.rbmo.2018.03.009. doi: 10.1016/j.rbmo.2018.03.009 URL
[25]	Ji M, Shi X, Xiang Y, et al. NLRP7 and KHDC3L variants in Chinese patients with recurrent hydatidiform moles[J]. Jpn J Clin Oncol, 2019,49(7):620-627. doi: 10.1093/jjco/hyz036. doi: 10.1093/jjco/hyz036 URL
[26]	Nguyen N, Ge ZJ, Reddy R, et al. Causative Mutations and Mechanism of Androgenetic Hydatidiform Moles[J]. Am J Hum Genet, 2018,103(5):740-751. doi: 10.1016/j.ajhg.2018.10.007. doi: 10.1016/j.ajhg.2018.10.007 URL
[27]	Krausz C, Riera-Escamilla A, Moreno-Mendoza D, et al. Genetic dissection of spermatogenic arrest through exome analysis: clinical implications for the management of azoospermic men[J]. Genet Med, 2020,22(12):1956-1966. doi: 10.1038/s41436-020-0907-1. doi: 10.1038/s41436-020-0907-1 URL
[28]	Qian J, Nguyen N, Rezaei M, et al. Biallelic PADI6 variants linking infertility, miscarriages, and hydatidiform moles[J]. Eur J Hum Genet, 2018,26(7):1007-1013. doi: 10.1038/s41431-018-0141-3. doi: 10.1038/s41431-018-0141-3 URL
[29]	Zhao JR, Cheng WW, Wang YX, et al. Identification of microRNA signature in the progression of gestational trophoblastic disease[J]. Cell Death Dis, 2018,9(2):94. doi: 10.1038/s41419-017-0108-2. doi: 10.1038/s41419-017-0108-2 URL
[30]	贾继晶. 葡萄胎患者的临床疗效分析[J]. 心理月刊, 2019,14(9):162.
[31]	Pal L, Toth TL, Leykin L, et al. High incidence of triploidy in in-vitro fertilized oocytes from a patient with a previous history of recurrent gestational trophoblastic disease[J]. Hum Reprod, 1996,11(7):1529-1532. doi: 10.1093/oxfordjournals.humrep.a019432. URL pmid: 8671499
[32]	Reubinoff BE, Lewin A, Verner M, et al. Intracytoplasmic sperm injection combined with preimplantation genetic diagnosis for the prevention of recurrent gestational trophoblastic disease[J]. Hum Reprod, 1997,12(4):805-808. doi: 10.1093/humrep/12.4.805. URL pmid: 9159446
[33]	Ogilvie CM, Renwick PJ, Khalaf Y, et al. First use of preimplantation genotyping in prevention of recurrent diandric complete hydatidiform mole[J]. Reprod Biomed Online, 2009,19(2):224-227. doi: 10.1016/s1472-6483(10)60077-6. doi: 10.1016/S1472-6483(10)60077-6 URL
[34]	Sills ES, Obregon-Tito AJ, Gao H, et al. Pathogenic variant in NLRP7 (19q13.42) associated with recurrent gestational trophoblastic disease: Data from early embryo development observed during in vitro fertilization[J]. Clin Exp Reprod Med, 2017,44(1):40-46. doi: 10.5653/cerm.2017.44.1.40. doi: 10.5653/cerm.2017.44.1.40 URL
[35]	沈曦, 陈秋菊, 匡延平. 妊娠滋养细胞疾病史的不孕患者体外受精/卵胞质内单精子显微注射结局分析[J]. 中华生殖与避孕杂志, 2018,38(8):671-676. doi: 10.3760/cma.j.issn.2096-2916.2018.08.017.
[36]	Hafezi M, Chekini Z, Zamanian M. Which One Is More Prominent in Recurrent Hydatidiform Mole, Ovum or Sperm?[J]. Int J Fertil Steril, 2020,14(2):154-158. doi: 10.22074/ijfs.2020.6017.
[37]	Cozette C, Scheffler F, Lombart M, et al. Pregnancy after oocyte donation in a patient with NLRP7 gene mutations and recurrent molar hydatidiform pregnancies[J]. J Assist Reprod Genet, 2020,37(9):2273-2277. doi: 10.1007/s10815-020-01861-z. doi: 10.1007/s10815-020-01861-z URL
[38]	Handyside AH, McCollin A, Summers MC , et al. Copy number analysis of meiotic and postzygotic mitotic aneuploidies in trophectoderm cells biopsied at the blastocyst stage and arrested embryos[J]. Prenat Diagn, 2021,41(5):525-535. doi: 10.1002/pd.5816. doi: 10.1002/pd.v41.5 URL

类型	MIM number （表型）	MIM number （基因）	遗传方式	基因名称	定位
Recurrent HM1	231090	609661	AR	NALP7	19q13.42
Recurrent HM2	614293	611687	AR	KHDC3L	6q13
Recurrent HM3	618431	608797	AR	MEI1	22q13.2
Recurrent HM4	618432	616109	-	C11orf80	11q13.2

类型	MIM number （表型）	MIM number （基因）	遗传方式	基因名称	定位
Recurrent HM1	231090	609661	AR	NALP7	19q13.42
Recurrent HM2	614293	611687	AR	KHDC3L	6q13
Recurrent HM3	618431	608797	AR	MEI1	22q13.2
Recurrent HM4	618432	616109	-	C11orf80	11q13.2

年份	内容	参考文献
1996年	该病例提示有复发性GTD病史的患者IVF更易形成三倍体受精卵。该病例中女方有2次复发GTD病史,其中1次组织病理学证实为CHM,1次临床诊断为宫角妊娠伴葡萄胎样改变。2次IVF-胚胎移植（ET）周期中形成三倍体胚胎的比例分别为21%和47%。	[31]
1997年	该病例是第一次将ICSI联合FISH技术应用到阻止复发性GTD发生的报道。该病例中女方因双侧输卵管堵塞行两次IVF,均因孕期β-hCG值异常人工终止妊娠。后经ICSI联合FISH技术,取卵MⅡ9枚,2PN 6枚,最终选取2枚男胚,移植后未孕。	[32]
2009年	该病例是第一次将ICSI和胚胎植入前的单倍型分析（preimplantation genetic haplotyping,PGH）应用到复发性父系来源CHM的报道,该病例中女方孕3产0（G3P0）,其中2次为葡萄胎病史,后经ICSI和STR技术,移植1枚胚胎后成功分娩出同卵双胎女婴。	[33]
2011年	该研究收集并分析了35例至少发生过1次葡萄胎的患者,其中7例携带NLRP7双等位基因变异,4例携带NLRP7杂合变异。该研究中3例携带NLRP7双等位基因变异的患者、2例携带NLRP7单基因变异的患者接受了辅助生殖技术治疗（PGT/PGH/FISH）。携带NLRP7双等位基因变异的患者未成功受孕,1例携带NLRP7单基因变异的患者接受了辅助生殖技术治疗后正常妊娠至24周（截止文章发表时）。	[6]
2017年	该研究是第一篇关于携带NLRP7基因变异患者早期体外胚胎发育的报道。该患者G5P0,5次葡萄胎病史,经筛查发现携带NLRP7纯合变异（c.2810+2T>G）。该病例中10枚胚胎均发育停滞在72~144 h。经胚胎植入前的遗传学筛查（preimplantation genetic screening,PGS）发现10枚胚胎中2枚为双亲来源整倍体,5枚为母源性三体,其余3枚均携带不确定的染色体异常。	[34]
2018年	中国一篇关于既往GTD病史的不孕患者行IVF/ICSI治疗的研究指出,虽然获卵数及可用胚胎数与无GTD史的继发不孕患者相比无差异,但是既往有GTD病史的患者移植日内膜厚度、移植后生化妊娠率、继续妊娠率都显著低于既往无GTD史的继发性不孕患者。	[35]
2018年	该研究中报道了1例33岁患者,有2次PHM病史和2次不明原因自然流产史,检测到患者携带KHDC3L纯合移码突变（c.44delA）,2次辅助生殖周期中所有胚胎均发育阻滞到D5/D6。	[24]
2020年	该研究中2例复发性葡萄胎患者行IVF-PGT。1例患者有6次葡萄胎病史,此次IVF经FISH检测13,18,21号染色体,没有可移植的胚胎,患者最终通过赠卵受孕。另1例患者有5次葡萄胎病史,此次IVF经FISH检测18号,X,Y染色体,最终移植了2枚XX[18] ×2的胚胎,后确诊为葡萄胎。	[36]

年份	内容	参考文献
1996年	该病例提示有复发性GTD病史的患者IVF更易形成三倍体受精卵。该病例中女方有2次复发GTD病史,其中1次组织病理学证实为CHM,1次临床诊断为宫角妊娠伴葡萄胎样改变。2次IVF-胚胎移植（ET）周期中形成三倍体胚胎的比例分别为21%和47%。	[31]
1997年	该病例是第一次将ICSI联合FISH技术应用到阻止复发性GTD发生的报道。该病例中女方因双侧输卵管堵塞行两次IVF,均因孕期β-hCG值异常人工终止妊娠。后经ICSI联合FISH技术,取卵MⅡ9枚,2PN 6枚,最终选取2枚男胚,移植后未孕。	[32]
2009年	该病例是第一次将ICSI和胚胎植入前的单倍型分析（preimplantation genetic haplotyping,PGH）应用到复发性父系来源CHM的报道,该病例中女方孕3产0（G3P0）,其中2次为葡萄胎病史,后经ICSI和STR技术,移植1枚胚胎后成功分娩出同卵双胎女婴。	[33]
2011年	该研究收集并分析了35例至少发生过1次葡萄胎的患者,其中7例携带NLRP7双等位基因变异,4例携带NLRP7杂合变异。该研究中3例携带NLRP7双等位基因变异的患者、2例携带NLRP7单基因变异的患者接受了辅助生殖技术治疗（PGT/PGH/FISH）。携带NLRP7双等位基因变异的患者未成功受孕,1例携带NLRP7单基因变异的患者接受了辅助生殖技术治疗后正常妊娠至24周（截止文章发表时）。	[6]
2017年	该研究是第一篇关于携带NLRP7基因变异患者早期体外胚胎发育的报道。该患者G5P0,5次葡萄胎病史,经筛查发现携带NLRP7纯合变异（c.2810+2T>G）。该病例中10枚胚胎均发育停滞在72~144 h。经胚胎植入前的遗传学筛查（preimplantation genetic screening,PGS）发现10枚胚胎中2枚为双亲来源整倍体,5枚为母源性三体,其余3枚均携带不确定的染色体异常。	[34]
2018年	中国一篇关于既往GTD病史的不孕患者行IVF/ICSI治疗的研究指出,虽然获卵数及可用胚胎数与无GTD史的继发不孕患者相比无差异,但是既往有GTD病史的患者移植日内膜厚度、移植后生化妊娠率、继续妊娠率都显著低于既往无GTD史的继发性不孕患者。	[35]
2018年	该研究中报道了1例33岁患者,有2次PHM病史和2次不明原因自然流产史,检测到患者携带KHDC3L纯合移码突变（c.44delA）,2次辅助生殖周期中所有胚胎均发育阻滞到D5/D6。	[24]
2020年	该研究中2例复发性葡萄胎患者行IVF-PGT。1例患者有6次葡萄胎病史,此次IVF经FISH检测13,18,21号染色体,没有可移植的胚胎,患者最终通过赠卵受孕。另1例患者有5次葡萄胎病史,此次IVF经FISH检测18号,X,Y染色体,最终移植了2枚XX[18] ×2的胚胎,后确诊为葡萄胎。	[36]