Confined placental mosaicism and the association with pregnancy outcome and fetal growth: a review of the literature

Abstract

Background: Chromosomal mosaicism can be detected in different stages of early life: in cleavage stage embryos, in blastocysts and biopsied cells from blastocysts during preimplantation genetic testing for aneuploidies (PGT-A) and later during prenatal testing, as well as after birth in cord blood. Mosaicism at all different stages can be associated with adverse pregnancy outcomes. There is an onward discussion about whether blastocysts diagnosed as chromosomally mosaic by PGT-A should be considered safe for transfer. An accurate diagnosis of mosaicism remains technically challenging and the fate of abnormal cells within an embryo remains largely unknown. However, if aneuploid cells persist in the extraembryonic tissues, they can give rise to confined placental mosaicism (CPM). Non-invasive prenatal testing (NIPT) uses cell-free (cf) DNA released from the placenta in maternal blood, facilitating the detection of CPM. In literature, conflicting evidence is found about whether CPM is associated with fetal growth restriction (FGR) and/or other pregnancy outcomes. This makes counselling for patients by clinicians challenging and more knowledge is needed for clinical decision and policy making.

Objective and rationale: The objective of this review is to evaluate the association between CPM and prenatal growth and adverse pregnancy outcomes. All relevant literature has been reviewed in order to achieve an overview on merged results exploring the relation between CPM and FGR and other adverse pregnancy outcomes.

Search methods: The following Medical Subject Headings (MESH) terms and all their synonyms were used: placental, trophoblast, cytotrophoblast, mosaicism, trisomy, fetal growth, birth weight, small for gestational age and fetal development. A search in Embase, PubMed, Medline Ovid, Web of Science, Cochrane Central Register of Controlled Trials (CENTRAL) and Google Scholar databases was conducted. Relevant articles published until 16 July 2020 were critically analyzed and discussed.

Outcomes: There were 823 articles found and screened based on their title/abstract. From these, 213 articles were selected and full text versions were obtained for a second selection, after which 70 publications were included and 328 cases (fetuses) were analyzed. For CPM in eight different chromosomes (of the total 14 analyzed), there was sufficient evidence that birth weight was often below the 5th percentile of fetal growth standards. FGR was reported in 71.7% of CPM cases and preterm birth (<37 weeks of delivery) was reported in 31.0% of cases. A high rate of structural fetal anomalies, 24.2%, in cases with CPM was also identified. High levels of mosaicism in CVS and presence of uniparental disomy (UPD) were significantly associated with adverse pregnancy outcomes.

Wider implications: Based on the literature, the advice to clinicians is to monitor fetal growth intensively from first trimester onwards in case of CPM, especially when chromosome 2, 3, 7, 13, 15, 16 and 22 are involved. In addition to this, it is advised to examine the fetuses thoroughly for structural fetal anomalies and raise awareness of a higher chance of (possibly extreme) premature birth. Despite prematurity in nearly a fifth of cases, the long-term follow-up of CPM life borns seems to be positive. More understanding of the biological mechanisms behind CPM will help in prioritizing embryos for transfer after the detection of mosaicism in embryos through PGT-A.

Keywords: aneuploidy; birth weight; chorionic villi sampling; embryonic development; fertilization in vitro; fetal growth retardation; mosaicism; pregnancy; pregnancy outcome; trisomy.

Figure 1.

Schematic illustration of pre- and post-implantation development. (A) A blastocyst at day 5 of embryonic development. Two cell types can be defined at this early stage: the trophectoderm (TE) and the inner cell mass (ICM). The extra embryonic TE develops into two tissues of the fetal part of the placenta, the syncytioblast and cytotrophoblast. Short-term culture villi (STC- villi) studies examine the cytotrophoblast. The ICM will develop into the epiblast (eventually the fetus) and the hypoblast (eventually the mesenchymal core). Long- term culture villi (LTC-villi) studies examine the mesenchymal core. Because of their same origin (i.e. the ICM), the LTC-villi is a better reflection of the fetus than the STC-villi. (B) The different cell types after implantation on the 13th day of the embryonic development. (C) Confined placental mosaicism (CPM) can be categorised into the three subtypes, depending on the cell lineage(s) affected.

Figure 2.

From blastocyst cells to prenatal scenario. (A) Three different scenarios arise if only diploid cells are retrieved through biopsy in blastocyst stage. (B) When both diploid and trisomic cells are biopsied, three different scenarios can also arise. If the mosaicism is only found in the trophectoderm and not within the inner cell mass (ICM), confined placental mosaicim (CPM) type 1 develops. (C) If all biopsied cells appear to be trisomic, even in the ICM, as a result of trisomic rescue, the epiblast will eliminate the trisomic cells and will only consist of diploid cells, thus CPM type 2 or 3 can develop.

Figure 3.

Flowchart of the search strategy and study selection process.

Figure 4.

Overview of premature births for all chromosomes separately, divided into a term (>37 weeks), premature birth (≥32 and <37 weeks) and extreme premature birth (<32 weeks).

Figure 5.

Analyses of low birth weights. (A) Analysis of birth weight below the 10th percentile (<p10). (* <p = 0.05). (B) Analysis of birth weight below the 5th percentile (<p5). (* <p = 0.05). (C) Analysis of birth weight below the 3rd percentile (<p3). (* <p = 0.05).