Investigating the “Fetal Side” in Recurrent Pregnancy Loss: Reliability of Cell-Free DNA Testing in Detecting Chromosomal Abnormalities of Miscarriage Tissue

Author:

D’Ippolito Silvia1ORCID,Longo Giuliana2,Orteschi Daniela3,Busnelli Andrea45,Di Simone Nicoletta45ORCID,Pulcinelli Eleonora2,Schettini Giorgia6,Scambia Giovanni17,Zollino Marcella38ORCID

Affiliation:

1. Dipartimento della Salute della Donna, del Bambino e di Sanità Pubblica, Fondazione Policlinico Universitario A. Gemelli, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), 00168 Rome, Italy

2. BioRep Srl, Centro di Risorse Biologiche, Sapio Group, 20900 Milan, Italy

3. Dipartimento Universitario Scienze della Vita e Sanità Pubblica, Sezione di Medicina Genomica, Università Cattolica del Sacro Cuore, 00168 Rome, Italy

4. Department of Biomedical Sciences, Humanitas University, 20072 Milan, Italy

5. IRCCS Humanitas Research Hospital, 20089 Rozzano, Italy

6. Università Cattolica del Sacro Cuore, 00168 Rome, Italy

7. Dipartimento Universitario Scienze della Vita e Sanità Pubblica, Università Cattolica del Sacro Cuore, 00168 Rome, Italy

8. Genetica Medica, Fondazione Policlinico Universitario A. Gemelli, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), 00168 Rome, Italy

Abstract

(1) Background: The aim of our study is to evaluate whether cell-free DNA testing can overlap the genetic testing of miscarriage tissue in women with early pregnancy loss (EPL) and length of recurrent pregnancy loss (RPL); (2) Methods: We conducted a prospective cohort study at the Pregnancy Loss Unit of the Fondazione Policlinico Universitario A. Gemelli (IRCCS), Rome, Italy between May 2021 and March 2022. We included women with EPL and length of RPL. Gestational age was >9 weeks + 2 days and <12 weeks + 0 days of gestation corresponding to a crown rump length measurement of >25 and <54 mm. Women underwent both dilation and curettage for the collection of miscarriage tissue and for blood sample collection. Chromosomal microarray analysis (CMA) on miscarriage tissues was performed by oligo-nucleotide- and single nucleotide polymorphisms (SNP)-based comparative genomic hybridization (CGH+SNP). Maternal blood samples were analyzed by Illumina VeriSeq non-invasive prenatal testing (NIPT) to evaluate the cell-free fetal DNA (cfDNA) and the corresponding fetal fraction and the presence of genetic abnormalities; (3) Results: CMA on miscarriage tissues revealed chromosome aneuploidies in 6/10 cases (60%), consisting of trisomy 21 (5 cases) and monosomy X (one case). cfDNA analysis was able to identify all cases of trisomy 21. It failed to detect monosomy X. A large 7p14.1p12.2 deletion concomitant to trisomy 21 was, in one case, detected by cfDNA analysis but it was not confirmed by CMA on miscarriage tissue. (4) Conclusions: cfDNA largely reproduces the chromosomal abnormalities underlying spontaneous miscarriages. However, diagnostic sensitivity of cfDNA analysis is lower with respect to the CMA of miscarriage tissues. In considering the limitations when obtaining biological samples from aborted fetuses suitable for CMA or standard chromosome analysis, cfDNA analysis is a useful, although not exhaustive, tool for the chromosome diagnosis of both early and recurrent pregnancy loss.

Publisher

MDPI AG

Subject

General Medicine

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