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The genomic basis of sporadic and recurrent pregnancy loss: a comprehensive in-depth analysis of 24,900 miscarriages

Published:March 22, 2022DOI:https://doi.org/10.1016/j.rbmo.2022.03.014

      HIGHLIGHTS

      • Large spectrum of genomic imbalances cause sporadic and recurrent pregnancy loss.
      • Polyploidy is the second most common abnormality associated with pregnancy loss.
      • Segmental chromosomal aneuploidies are common.
      • Analysis of multiple POC samples provide insight into possible predispositions to RPL.

      Abstract

      Research question

      What is the genetic cause of sporadic and recurrent pregnancy loss and does the frequency and nature of chromosomal abnormalities play a role? Types and frequency of all identifiable chromosomal abnormalities were determined to inform our understanding, medical management and recurrence risk for patients experiencing pregnancy loss.

      Design

      Genome-wide single-nucleotide polymorphism-based chromosomal microarray (SNP-CMA) were used to evaluate 24,900 products of conception samples from various forms of pregnancy losses.

      Results

      Sporadic miscarriage (64.7%) or recurrent pregnancy loss (RPL) (22%) were the most common referrals. Clinically significant abnormalities were observed in 55.8% (13,910) of samples, variants of uncertain significance in 1.8%, and normal results in 42.4%. In addition to autosomal trisomies (in 36% of samples), polyploidy and large segmental imbalances were identified in 7.8% and 2.8% of samples, respectively. Analysis of sequential samples from 1103 patients who had experienced RPL provided important insight into possible predispositions to RPL.

      Conclusions

      This expansive chromosomal microarray analyses of pregnancy loss samples illuminates our understanding of the full spectrum, relative frequencies and the role of genomic abnormalities in pregnancy loss. The empiric observations described here provide useful insight for clinicians and highlight the importance of high-resolution genomic testing for comprehensive evaluation and risk assessment of individuals experiencing pregnancy loss.

      KEYWORDS

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      References

        • Baasanjav B.
        • Usui H.
        • Kihara M.
        • Kaku H.
        • Nakada E.
        • Tate S.
        • Mitsuhashi A.
        • Matsui H.
        • Shozu M.
        The risk of post-molar gestational trophoblastic neoplasia is higher in heterozygous than in homozygous complete hydatidiform moles.
        Hum. Reprod. 2010; 25: 1183-1191https://doi.org/10.1093/humrep/deq052
        • Bell K.A.
        • Van Deerlin P.G.
        • Haddad B.R.
        • Feinberg R.F.
        Cytogenetic diagnosis of "normal 46,XX" karyotypes in spontaneous abortions frequently may be misleading.
        Fertil. Steril. 1999; 71: 334-341https://doi.org/10.1016/s0015-0282(98)00445-2
        • Bennett J.
        • Obringer A.C.
        • Williams H.J.
        • Wenger S.L.
        Cytogenetic analysis in various tissues of pregnancy loss.
        Genet. Med. 2006; 8: 136https://doi.org/10.1097/01.gim.0000196824.98461.f0
        • Buza N.
        • McGregor S.M.
        • Barroilhet L.
        • Zheng X.
        • Hui P.
        Paternal uniparental isodisomy of tyrosine hydroxylase locus at chromosome 11p15.4: spectrum of phenotypical presentations simulating hydatidiform moles.
        Mod. Pathol. 2019; 32: 1180-1188https://doi.org/10.1038/s41379-019-0266-0
        • Carp H.
        • Toder V.
        • Aviram A.
        • Daniely M.
        • Mashiach S.
        • Barkai G.
        Karyotype of the abortus in recurrent miscarriage.
        Fertil. Steril. 2001; 75: 678-682https://doi.org/10.1016/s0015-0282(00)01801-x
        • Dhillon R.K.
        • Hillman S.C.
        • Morris R.K.
        • McMullan D.
        • Williams D.
        • Coomarasamy A.
        • Kilby M.D.
        Additional information from chromosomal microarray analysis (CMA) over conventional karyotyping when diagnosing chromosomal abnormalities in miscarriage: a systematic review and meta-analysis.
        BJOG. 2014; 121: 11-21https://doi.org/10.1111/1471-0528.12382
        • Eggermann T.
        • Brück J.
        • Knopp C.
        • Fekete G.
        • Kratz C.
        • Tasic V.
        • Kurth I.
        • Elbracht M.
        • Eggermann K.
        • Begemann M.
        Need for a precise molecular diagnosis in Beckwith-Wiedemann and Silver-Russell syndrome: what has to be considered and why it is important.
        J. Mol. Med. (Berl.). 2020; 98: 1447-1455https://doi.org/10.1007/s00109-020-01966-z
        • Ford H.B.
        • Schust D.J.
        Recurrent pregnancy loss: etiology, diagnosis, and therapy.
        Rev. Obstet. Gynecol. 2009; 2: 76-83
        • Foyouzi N.
        • Cedars M.I.
        • Huddleston H.G.
        Cost-effectiveness of cytogenetic evaluation of products of conception in the patient with a second pregnancy loss.
        Fertil. Steril. 2012; 98: 151-155https://doi.org/10.1016/j.fertnstert.2012.04.007
        • Fritz B.
        • Aslan M.
        • Kalscheuer V.
        • Ramsing M.
        • Saar K.
        • Fuchs B.
        • Rehder H.
        Low incidence of UPD in spontaneous abortions beyond the 5th gestational week.
        Eur. J. Hum. Genet. 2001; 9: 910-916https://doi.org/10.1038/sj.ejhg.5200741
        • Fritz B.
        • Hallermann C.
        • Olert J.
        • Fuchs B.
        • Bruns M.
        • Aslan M.
        • Schmidt S.
        • Coerdt W.
        • Müntefering H.
        • Rehder H.
        Cytogenetic analyses of culture failures by comparative genomic hybridisation (CGH)-Re-evaluation of chromosome aberration rates in early spontaneous abortions.
        Eur. J. Hum. Genet. 2001; 9: 539-547https://doi.org/10.1038/sj.ejhg.5200669
        • Garner E.I.
        • Goldstein D.P.
        • Feltmate C.M.
        • Berkowitz R.S.
        Gestational trophoblastic disease.
        Clin. Obstet. Gynecol. 2007; 50: 112-122https://doi.org/10.1097/GRF.0b013e31802f17fc
        • Golfier F.
        • Raudrant D.
        • Frappart L.
        • Mathian B.
        • Guastalla J.P.
        • Trillet-Lenoir V.
        • Vaudoyer F.
        • Hajri T.
        • Schott A.M.
        First epidemiological data from the French Trophoblastic Disease Reference Center.
        Am. J. Obstet. Gynecol. 2007; 196 (e1-172.e1725): 172https://doi.org/10.1016/j.ajog.2006.10.867
        • Hook E.B.
        • Warburton D.
        Turner syndrome revisited: review of new data supports the hypothesis that all viable 45,X cases are cryptic mosaics with a rescue cell line, implying an origin by mitotic loss.
        Hum. Genet. 2014; 133: 417-424https://doi.org/10.1007/s00439-014-1420-x
        • Levy B.
        • Sigurjonsson S.
        • Pettersen B.
        • Maisenbacher M.K.
        • Hall M.P.
        • Demko Z.
        • Lathi R.B.
        • Tao R.
        • Aggarwal V.
        • Rabinowitz M.
        Genomic imbalance in products of conception: single-nucleotide polymorphism chromosomal microarray analysis.
        Obstet. Gynecol. 2014; 124: 202-209https://doi.org/10.1097/AOG.0000000000000325
        • Ljunger E.
        • Cnattingius S.
        • Lundin C.
        • Annerén G.
        Chromosomal anomalies in first-trimester miscarriages.
        Acta Obstet. Gynecol. Scand. 2005; 84: 1103-1107https://doi.org/10.1111/j.0001-6349.2005.00882.x
        • Maisenbacher M.K.
        • Merrion K.
        • Kutteh W.H.
        Single-nucleotide polymorphism microarray detects molar pregnancies in 3% of miscarriages.
        Fertil. Steril. 2019; 112: 700-706https://doi.org/10.1016/j.fertnstert.2019.06.015
        • Maisenbacher M.K.
        • Merrion K.
        • Pettersen B.
        • Young M.
        • Paik K.
        • Iyengar S.
        • Kareht S.
        • Sigurjonsson S.
        • Demko Z.P.
        • Martin K.A.
        Incidence of the 22q11.2 deletion in a large cohort of miscarriage samples.
        Mol. Cytogenet. 2017; 10 (Published 2017 Mar 9): 6https://doi.org/10.1186/s13039-017-0308-6
        • Mateu-Brull E.
        • Rodrigo L.
        • Peinado V.
        • Mercader A.
        • Campos-Galindo I.
        • Bronet F.
        • García-Herrero S.
        • Florensa M.
        • Milán M.
        • Rubio C.
        Interchromosomal effect in carriers of translocations and inversions assessed by preimplantation genetic testing for structural rearrangements (PGT-SR).
        J. Assist. Reprod. Genet. 2019; 36: 2547-2555https://doi.org/10.1007/s10815-019-01593-9
        • Menasha J.
        • Levy B.
        • Hirschhorn K.
        • Kardon N.B.
        Incidence and spectrum of chromosome abnormalities in spontaneous abortions: new insights from a 12-year study.
        Genet. Med. 2005; 7: 251-263https://doi.org/10.1097/01.gim.0000160075.96707.04
        • Nguyen N.M.P.
        • Khawajkie Y.
        • Mechtouf N.
        • Rezaei M.
        • Breguet M.
        • Kurvinen E.
        • Jagadeesh S.
        • Solmaz A.E.
        • Aguinaga M.
        • Hemida R.
        • Harma M.I.
        • Rittore C.
        • Rahimi K.
        • Arseneau J.
        • Hovanes K.
        • Clisham R.
        • Lenzi T.
        • Scurry B.
        • Addor M.C.
        • Bagga R.
        • Nendaz G.G.
        • Finci V.
        • Poke G.
        • Grimes L.
        • Gregersen N.
        • York K.
        • Bolze P.A.
        • Patel C.
        • Mozdarani H.
        • Puechberty J.
        • Scotchie J.
        • Fardaei M.
        • Harma M.
        • Gardner R.J.M.
        • Sahoo T.
        • Dudding-Byth T.
        • Srinivasan R.
        • Sauthier P.
        • Slim R.
        The genetics of recurrent hydatidiform moles: new insights and lessons from a comprehensive analysis of 113 patients.
        Mod. Pathol. 2018; 31: 1116-1130https://doi.org/10.1038/s41379-018-0031-9
        • Nguyen N.
        • Ge Z.J.
        • Reddy R.
        • Fahiminiya S.
        • Sauthier P.
        • Bagga R.
        • Sahin F.I.
        • Mahadevan S.
        • Osmond M.
        • Breguet M.
        • Rahimi K.
        • Lapensee L.
        • Hovanes K.
        • Srinivasan R.
        • Van den Veyver I.B.
        • Sahoo T.
        • Ao A.
        • Majewski J.
        • Taketo T.
        • Slim R.
        Causative Mutations and Mechanism of Androgenetic Hydatidiform Moles.
        Am. J. Hum. Genet. 2018; 103: 740-751https://doi.org/10.1016/j.ajhg.2018.10.007
        • Passerini V.
        • Ozeri-Galai E.
        • de Pagter M.S.
        • Donnelly N.
        • Schmalbrock S.
        • Kloosterman W.P.
        • Kerem B.
        • Storchová Z.
        The presence of extra chromosomes leads to genomic instability.
        Nat. Commun. 2016; 7 (Published 2016 Feb 15): 10754https://doi.org/10.1038/ncomms10754
        • Pauta M.
        • Grande M.
        • Rodriguez-Revenga L.
        • Kolomietz E.
        • Borrell A.
        Added value of chromosomal microarray analysis over karyotyping in early pregnancy loss: systematic review and meta-analysis.
        Ultrasound Obstet. Gynecol. 2018; 51: 453-462https://doi.org/10.1002/uog.18929
        • Practice Committee of the American Society for Reproductive Medicine
        Evaluation and treatment of recurrent pregnancy loss: a committee opinion.
        Fertil. Steril. 2012; 98: 1103-1111https://doi.org/10.1016/j.fertnstert.2012.06.048
        • Raca G.
        • Artzer A.
        • Thorson L.
        • Huber S.
        • Modaff P.
        • Laffin J.
        • Pauli R.M.
        Array-based comparative genomic hybridization (aCGH) in the genetic evaluation of stillbirth.
        Am. J. Med. Genet. A. 2009; 149A: 2437-2443https://doi.org/10.1002/ajmg.a.33083
        • Reddy U.M.
        • Page G.P.
        • Saade G.R.
        The role of DNA microarrays in the evaluation of fetal death.
        Prenat. Diagn. 2012; 32: 371-375https://doi.org/10.1002/pd.382
        • Reddy U.M.
        • Page G.P.
        • Saade G.R.
        • Silver R.M.
        • Thorsten V.R.
        • Parker C.B.
        • Pinar H.
        • Willinger M.
        • Stoll B.J.
        • Heim-Hall J.
        • Varner M.W.
        • Goldenberg R.L.
        • Bukowski R.
        • Wapner R.J.
        • Drews-Botsch C.D.
        • O'Brien B.M.
        • Dudley D.J.
        • Levy B.
        NICHD Stillbirth Collaborative Research Network. Karyotype versus microarray testing for genetic abnormalities after stillbirth.
        N. Engl. J. Med. 2012; 367: 2185-2193https://doi.org/10.1056/NEJMoa1201569
        • Robberecht C.
        • Schuddinck V.
        • Fryns J.P.
        • Vermeesch J.R.
        Diagnosis of miscarriages by molecular karyotyping: benefits and pitfalls.
        Genet. Med. 2009; 11: 646-654https://doi.org/10.1097/GIM.0b013e3181abc92a
        • Sahoo T.
        • Dzidic N.
        • Strecker M.N.
        • Commander S.
        • Travis M.K.
        • Doherty C.
        • Tyson R.W.
        • Mendoza A.E.
        • Stephenson M.
        • Dise C.A.
        • Benito C.W.
        • Ziadie M.S.
        • Hovanes K.
        Comprehensive genetic analysis of pregnancy loss by chromosomal microarrays: outcomes, benefits, and challenges.
        Genet. Med. 2017; 19 (2017): 83-89https://doi.org/10.1038/gim.2016.69
        • Sebire N.J.
        • Lindsay I.
        Current issues in the histopathology of gestational trophoblastic tumors.
        Fetal Pediatr. Pathol. 2010; 29: 30-44https://doi.org/10.3109/15513810903266120
        • Shaffer L.G.
        • McCaskill C.
        • Adkins K.
        • Hassold T.J.
        Systematic search for uniparental disomy in early fetal losses: the results and a review of the literature.
        Am. J. Med. Genet. 1998; 79: 366-372
        • Shearer B.M.
        • Thorland E.C.
        • Carlson A.W.
        • Jalal S.M.
        • Ketterling R.P.
        Reflex fluorescent in situ hybridization testing for unsuccessful product of conception cultures: a retrospective analysis of 5555 samples attempted by conventional cytogenetics and fluorescent in situ hybridization.
        Genet. Med. 2011; 13: 545-552https://doi.org/10.1097/GIM.0b013e31820c685b
        • Sunde L.
        • Lund H.
        • J Sebire N.
        • Grove A.
        • Fisher R.A.
        • Niemann I.
        • Kjeldsen E.
        • Andreasen L.
        • Hansen E.S.
        • Bojesen A.
        • Bolund L.
        • Nyegaard M.
        Paternal Hemizygosity in 11p15 in Mole-like Conceptuses: Two Case Reports.
        Medicine (Baltimore). 2015; 94: e1776https://doi.org/10.1097/MD.0000000000001776
        • Takahashi K.
        • Kobayashi T.
        • Kanayama N.
        p57(Kip2) regulates the proper development of labyrinthine and spongiotrophoblasts.
        Mol Hum. Reprod. 2000; 6: 1019-1025https://doi.org/10.1093/molehr/6.11.1019
        • Usui H.
        • Nakabayashi K.
        • Maehara K.
        • Hata K.
        • Shozu M.
        Genome-wide single nucleotide polymorphism array analysis unveils the origin of heterozygous androgenetic complete moles.
        Sci. Rep. 2019; 9 (Published 2019 Aug 29): 12542https://doi.org/10.1038/s41598-019-49047-7
        • van den Berg M.M.
        • van Maarle M.C.
        • van Wely M
        • Goddijn M.
        Genetics of early miscarriage.
        Biochim. Biophys. Acta. 2012; 1822: 1951-1959https://doi.org/10.1016/j.bbadis.2012.07.001
        • Wang Y.
        • Li Y.
        • Chen Y.
        • Zhou R.
        • Sang Z.
        • Meng L.
        • Tan J.
        • Qiao F.
        • Bao Q.
        • Luo D.
        • Peng C.
        • Wang Y.S.
        • Luo C.
        • Hu P.
        • Xu Z.
        Systematic analysis of copy-number variations associated with early pregnancy loss.
        Ultrasound Obstet. Gynecol. 2020; 55: 96-104https://doi.org/10.1002/uog.20412
        • Zhang Y.X.
        • Zhang Y.P.
        • Gu Y.
        • Guan F.J.
        • Li S.L.
        • Xie J.S.
        • Shen Y.
        • Wu B.L.
        • Ju W.
        • Jenkins E.C.
        • Brown W.T.
        • Zhong N.
        Genetic analysis of first-trimester miscarriages with a combination of cytogenetic karyotyping, microsatellite genotyping and arrayCGH.
        Clin. Genet. 2009; 75: 133-140https://doi.org/10.1111/j.1399-0004.2008.01131.x
        • Zheng X.Z.
        • Qin X.Y.
        • Chen S.W.
        • Wang P.
        • Zhan Y.
        • Zhong P.P.
        • Buza N.
        • Jin Y.L.
        • Wu B.Q.
        • Hui P.
        Heterozygous/dispermic complete mole confers a significantly higher risk for post-molar gestational trophoblastic disease.
        Mod. Pathol. 2020; 33: 1979-1988https://doi.org/10.1038/s41379-020-0566-4

      Biography

      Dr Trilochan Sahoo is a board-certified cytogeneticist and Laboratory Director at Invitae. Following fellowship training, he served as Laboratory Director at Baylor College of Medicine, Signature Genomics, Quest Diagnostics and Combimatrix. His work included implementation of chromosomal microarrays in clinical genetics and discovery of a number of genomic disorders.
      Key message
      The spectrum of genomic imbalances or abnormalities that cause or contribute to pregnancy loss is vast. Extensive analysis of products of conception samples by single nucleotide polymorphism based high-resolution microarrays allows us to catalogue the nature and frequency of these abnormalities with great accuracy.