Aneuploidy Screening for Embryo Selection

Elpida Fragouli, Ph.D.; Dagan Wells, Ph.D.


Semin Reprod Med. 2012;30(4):289-301. 

In This Article

Abstract and Introduction


Chromosome abnormalities are extremely common in human oocytes and embryos and are associated with a variety of negative outcomes for both natural cycles and those using assisted conception techniques. Embryos containing the wrong number of chromosomes (aneuploidy) may fail to implant in the uterus, miscarry, or lead to children with serious medical problems (e.g., Down syndrome). Preimplantation genetic screening (PGS) is a method that seeks to improve the outcomes of assisted reproductive treatments, such as in vitro fertilization (IVF), by ensuring that the embryos chosen for transfer to the uterus are chromosomally normal. Here we summarize published and novel data concerning the frequency and variety of chromosomal abnormalities seen in oocytes and embryos at the cleavage and blastocyst stages of development. Clinical outcomes of studies using PGS are presented, and the controversy over the use of chromosome screening as a tool for embryo selection is discussed. We describe validation and preliminary clinical data from the new generation of methods being used for PGS, including comparative genomic hybridization (CGH), microarrays (aCGH and single nucleotide polymorphism arrays), and quantitative polymerase chain reaction. These methodologies allow comprehensive chromosomal analysis, provide high accuracy, and have yielded encouraging preliminary clinical data. The combination of advances in genetics and embryology seems poised to usher in a new era in the treatment of infertility.


Preimplantation genetic diagnosis (PGD) aims to identify embryos free of inherited genetic conditions, attributed either to mutations affecting the function of genes or abnormalities affecting the copy number of whole chromosomes or chromosomal regions. The selection and preferential transfer of genetically normal embryos provides a high probability that any pregnancy established will be healthy, reducing the possibility that termination may need to be considered and, in certain cases, assisting in the eradication of an inherited disease from a family.

PGD was developed >20 years ago and was initially used for determining the sex of embryos for couples at risk of transmitting an X-linked recessive disorder.[1] The procedure involves the generation of embryos using in vitro fertilization (IVF) techniques, followed by biopsy and testing of embryonic material. Sampling can take place at four different developmental stages: day 0 by removing the first polar body (PB) from the mature oocyte; day 1 by biopsying the second PB (the first PB may also be taken at this time) from the zygote; day 3 by removing one to two cells (blastomeres) from the cleavage-stage embryo, or days five to six by removing a small clump of trophectoderm (TE cells) from the blastocyst (reviewed in Harper and Harton[2]).

The polymerase chain reaction (PCR) was, and still remains, the principal method underlying the diagnosis of disorders caused by gene mutations in human embryos. To date, >200 genetic diseases have been diagnosed via PGD, the procedure being considered an increasingly effective alternative to prenatal diagnosis.[3] Until recently, chromosomal analysis depended on fluorescent in situ hybridization (FISH), used to reveal chromosome imbalances in the embryos of patients who carry a structural chromosome abnormality, such as a reciprocal or Robertsonian translocation, inversion, or deletion. However, FISH is rapidly being replaced by more comprehensive molecular cytogenetic methods, based on comparative genomic hybridization (CGH) or microarray technologies.[4–6]

Studies have shown that spontaneously arising aneuploidy is extremely common in human oocytes and embryos, and it most often results in developmental arrest, implantation failure, or spontaneous abortion.[7,8] Because the transfer of a chromosomally abnormal embryo is unlikely to result in a healthy live birth, it has been suggested that efforts should be made to identify and preferentially transfer euploid embryos. In theory, this practice should improve the implantation and pregnancy rates achieved after IVF. In the past 10 years, an increasing number of fertility clinics have adopted chromosome screening strategies to assist in the identification and transfer of viable embryos. This approach, commonly referred to as preimplantation genetic screening (PGS), has most often been targeted at patients considered to have an elevated risk of producing aneuploid oocytes and/or embryos, specifically couples who have experienced repeated implantation failure (RIF), or recurrent pregnancy loss, or where the female partner is of advanced reproductive age (ARA).[9]

The methodological approaches associated with PGS are almost identical to those used for PGD of chromosome rearrangements. In other words, embryos are generated using assisted reproductive technologies, and material is sampled either from the oocyte, cleavage-stage embryo, or, more recently, the blastocyst.[10–12] FISH has been the method of choice to examine chromosomes in the biopsied material, and various protocols have been described, scoring 5 to 12 chromosomes per oocyte or embryo.[11,13,14] However, as with PGD, more comprehensive methodologies, such as metaphase or array-CGH (aCGH), as well as single nucleotide polymorphism (SNP) microarrays, have been increasingly used to examine PBs, blastomeres, and TE samples.[4,12,15–19]

Even though PGS is closely related to PGD, its clinical application has proven to be far more controversial. During the past few years, debates have arisen concerning the diagnostic value of PGS using FISH, the effect of single or double blastomere biopsy on embryonic viability, and the impact of cleavage-stage mosaicism on accurate diagnosis of euploidy/aneuploidy. This review describes some of the scientific and clinical data obtained after PGS, using FISH, CGH, aCGH, or SNP microarrays to examine PBs, blastomeres, and TE samples. The controversy surrounding PGS is also described, and the current status and usefulness of this screening approach as a tool to select embryos is discussed.


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