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Preimplantation genetic screening

In the last 30 years, genetic testing techniques have been developed to identify chromosomally normal embryos in vitro, thereby potentially increasing the proportion of successful cycles with elective single-embryo transfer, and minimizing twin-pregnancy complications and miscarriages. This testing is termed "pre-implantation genetic screening" (PGS), in contrast to pre-implantation genetic diagnosis PGD), in which testing is performed for specific genetic defects. 

Today, PGS technologies have evolved to include screening of all 24 chromosomes (22 pairs of autosomes and the 2 sex chromosomes). Ongoing pregnancy rates of about 60% following single embryo transfer have been described in couples with a maternal age of 38 years whose embryos have undergone PGS. It has not, however, been definitively established that the cumulative delivery rates are better with PGS, although it has been argued that the reduction in miscarriage rates and maternal and neonatal complications due to multiple pregnancies justifies the expense of this technology.

Trends toward delayed childbearing have resulted in an increasing number of women of advanced maternal age seeking to become pregnant and in a consequent increase in demand for assisted reproductive technology, most commonly in-vitro fertilization (IVF). In such women, the proportion of aneuploid embryos can exceed 60%, with a risk of miscarriage of about 40%, potentially resulting in significant emotional and financial hardship for affected couples.

Indications for PGS

Commonly quoted indications for PGS include advanced maternal age, repeated implantation failure, recurrent miscarriage, severe male factor infertility, or subfertility (those who experience unrecognized embryonic losses and who are labelled clinically as infertile). It should be noted that the chances of selecting an euploid embryo mainly depend of the number of embryos produced during the procedure. When it is suspected that the couple has a major chromosomal risk due to advanced maternal age or severe male factors, it is mandatory to inform them of the low chance of achieving a pregnancy with the PGS procedure, unless the couple produces many embryos that provide one or two euploid embryos apt for transfer.

  • Advanced Maternal Age

Women at an advanced age have a greater chance of having aneuploid pregnancies because they have increased rates of producing aneuploid oocytes. Oocytes are always the same age as the woman. However, in males, sperm are produced every 65-75 days. Therefore, it might be said that sperm are not the same age as the male. The prolonged arrest of oocytes at meiotic prophase I mainly contributes to aneuploidy due to the decline in competence of the cytoplasm of the oocyte. The number and distribution of chiasmata during prophase I as the weak centromeric cohesion may be the main factor that predisposes aneuploidy that is inherent to age. In fact, the principal cause of oocyte aneuploidy is the precocious separation of sister chromatids rather than classic non-disjunction. In the male, the expected sperm aneuploidy rate is between 0.5 and 1% because the sperm is not the age of the male, but if the sperm is not ejaculated for prolonged periods, it could have a high rate of DNA fragmentation, which is also responsible for abnormal fertilization. Competent oocytes from young women can repair the DNA fragmentation of the sperm, but the oocytes from older women cannot. Therefore, women of advanced age have higher probabilities of having abnormal pregnancies that might end in miscarriage or in a malformed newborn. Most of these embryos are lost during pre or post implantation stages, while a minority come to term. That is why the possibility of miscarriage also increases with the age of the woman (Tab. 1).

  • Recurrent Pregnancy Loss (RPL)

Usually, RPL is defined as two or more consecutive pregnancies lost before 20 weeks of gestation. Different cytogenetic studies of miscarriages in the first trimester of pregnancy show that aneuploidy rates varied between 50% and 80%. Additionally, it has been documented that couples with RPL produce more aneuploid embryos than those who have not had RPL (Pellicer et al., 1999). According to some authors, PGS does not improve the rate of pregnancy in RPL, but increases the chance of birth at term (Platteau et al., 2005).

  • Recurrent IVF Failure (RIF)

RIF is usually defined as the failure of three or more IVF attempts with good quality embryo transfer. Some authors argue that these couples produce more embryos with aneuploidies. However, there is no evidence that PGS improves the rate of pregnancy or live IVF births.

  • Severe Male Factors

As mentioned above, the rate of aneuploidy in spermatozoa from fertile males with a normal spermiogram is much lower than that observed in oocytes, and aneuploidy also does not increase with age in men. On the other hand, sperm aneuploidies increase with the severity of OAT. These findings put in evidence the importance of the genetic risk assessment before the ICSI procedure to predict the chance of success. Now, with the possibility of PGS/PGD and lower costs, FISH is no longer used to assess sperm.

See full description of Preimplantation genetic screening

Embryonic biopsy

As preimplantation genetic screening/diagnosis can be performed on cells from different developmental stages, the biopsy procedures vary accordingly. Theoretically, the biopsy can be performed at all preimplantation stages, but only three have been suggested: on unfertilised and fertilised oocytes (for polar bodies, PBs), on day three (D3)cleavage-stage embryos (for blastomeres), on day 5/day 6 (D5/D6) blastocysts (for trophectoderm cells) and, more recently, attempts to perform blastocentesis in blastocysts on D5/D6 , as a new type of noninvasive embryo “biopsy” based on the presence of cells and DNA in the blastocoelic cavity.
The biopsy procedure always involves two steps: the opening of the zona pellucida and the removal of the cell(s). There are different approaches to both steps, including mechanical, chemical, and physical (Tyrode’s acidic solution) and laser technology for the breaching of the zona pellucida, extrusion or aspiration for the removal of PBs and blastomeres, and herniation of the trophectoderm cells.

Biopsy Techniques

Actually, all of biopsy techniques are invasive and involve some risk of loss of the embryo. Working with a simple cell is not easy and may yield no results. In this regard, the biopsy of blastocysts is most suitable. Blastocentesis is by now a new hope for less invasiveness. While none of these methods assures the proper constitution of the future embryo, they minimize the risk of the disorder that is being investigated. The best result was obtained via the biopsy of blastomeres on D3 with fresh transfer on the same day of the biopsy, or transfer on D4/D5. To remove one or two cells from the preimplantation embryo it is first necessary to perforate the zona pellucida. 

The perforation of the zona pellucida can be done by several methods:

a) mechanically, by cutting through the pellucida with a micropipette
b) chemically, by dissolving part of the pellucida with an acid solution; or
c) by laser, through modulating a laser beam via the optical system of a microscope.

Prior to biopsy, the preimplantation embryos can be placed in a suitable medium to loosen the cell junctions at room temperature. Then, the embryos are placed in separate microdrops composed of the medium for biopsy under oil and labeled. It is not convenient to have more than two embryos in a dish to minimize their time out of the incubator. Using a micromanipulator/microscope setup, the oocyte or the embryo that will be biopsied is placed in the center of the field and focused at a 400X magnification. The embryo or oocyte is fastened with a micropipette holder. The zona pellucida is perforated, and the polar bodies (PBI/PBII), or blastomeres are removed gently with an appropriate micropipette. When the biopsy is performed on D5, the zona pellucida is perforated on day 3 to facilitate the hatching of the blastocyst and to easily remove some cells of the trophectoderm. The cells will have to be collected according to the protocol of the genetic study indicated. If the indication is a FISH study, the removed cells are fixed on a slide, but if the indication is a PCR/CGH/NGS assay, the removed cells are collected in a small tube.

Biopsy of Polar Bodies (PB I/PBII)

In countries where embryo biopsy is prohibited, the pre-implantation genetic diagnosis can only be performed by biopsy of polar body I because the second polar body appears after the fertilization of the oocyte. Therefore, the biopsy of the second polar body would have the same connotation as the embryo biopsy.

The biopsy of the first PB prior to the fertilization of the oocyte evaluates the result of the first meiotic division. Because errors can also occur during the second division of the oocyte, it is necessary to also study the second PB to avoid misdiagnosis. The second division of the oocyte is completed when the sperm penetrates the oocyte. Therefore, the biopsy of the second PB is performed once the ovum has been fertilized. As PB biopsies do not allow the evaluation of male meiotic errors and/or errors that occur after fertilization of the egg, the biopsy of blastomeres is more preferred because it allows the assessment of both parental contributions and/or errors during cleavage. Polar body biopsy is only useful when women have a major risk of transmission of monogenetic diseases or aneuploidies inherent at the maternal age. As was mentioned above, to avoid misdiagnoses, both polar bodies should always be biopsied. When the purpose is to evaluate aneuploidies, both biopsies can be performed simultaneously. Instead, when the question is a monogenic disease, it is necessary to perform the biopsy in a sequential way. The biopsy of the first polar body prior to fertilization only indicates errors during the first meiotic division and/or whether the oocyte carries the same maternal mutation, always assuming that an interchange did not occur in the locus where the mutation maps to. 

PBI biopsy to assess aneuploidies is not optimal because there are other possibilities for segregation during the second division, without assuming that the first meiosis was normal or abnormal. Picture 1 shows the different possibilities of the second division after a normal first meiotic division, where two of three possibilities are abnormal. Picture 2 shows the different possibilities of the second division after a non-disjunction occurred during the first division; one of the six possibilities corresponds to an aneuploid rescue. Picture 3 shows the different possibilities during the second division after a premature separation of sister chromatids in the first meiotic division; two of six possibilities correspond to an aneuploidy rescue.

Polar body biopsy is also not ideal for monogenic diseases due to the possibility of crossing over. Picture 4 A shows a normal segregation without crossing over, while Picture 4 B shows a segregation after a crossing over event at the level of a mutated gene that is able to produce normal and abnormal oocytes.

In spite of the disadvantages indicated according to the ESHRE (European Society of Human Reproduction and Embryology) Consortium, 16% of the biopsies done correspond to those of polar bodies. Kuliev and Verlinsky (2004) studied more than 8,000 oocytes from women older than 35 years with FISH for chromosomes 13, 15, 16, 21 and 22 found that more than 50% had aneuploidy. Recently, a pilot study of the ESHRE PGD Consortium using aCGH in polar bodies from women over 40 years showed an aneuploidy rate of 75%.

Biopsy of Blastomeres in Cleaved Embryos on D3 

This is the type of biopsy used to remove one or two cells in embryos with more than six cells on D3 (Pic. 5). Embryologists have acquired great skill in performing this technique, but there is evidence that it decreases the rate of implantation. FISH or PCR analysis in a simple cell is a real challenge for specialists and for patients. It is not easy to work with a single molecule of DNA for chromosomal and genetic tests. However, this was the methodology used in the last 20 years. Indeed, 80% of the PGDs recorded by the ESHRE Consortium were D3 blastomere biopsies. During that time, fresh transfer was used to avoid cryopreservation. At first, the protocol mostly used for PGD/PGS was transfer on the same day of the biopsy. Improvement of sequential culture media allowed the prolonging of in vitro development until the fifth day, and transferring only those that reached the blastocyst stage. Biopsy on D3 achieved a clinical pregnancy rate of 18.7% and a take-home baby rate of 14.7%, with a misdiagnosis between 5 and 10%, according to records I-XIV of the ESHRE Consortium.

Blastocyst Biopsy on D5/D6

The blastocyst is the highest degree of development that an embryo can reach in vitro, and it is characterized by three elements: the inner cell mass, the outer cell layer or trophectoderm and the blastocoel (Pic. 6, 7). The blastocyst begins to form on the fifth day and is completed on the sixth.
A blastocyst usually has more than 100 cells. The majority will form the placenta, the chorionic villus and other extraembryonic structures. Only a small percentage of the ICM will differentiate into the embryo proper after implantation of the embryo in the endometrium. Therefore, the trophectoderm biopsy procedure is considered equivalent to the puncture of a chorionic villus, with the same limitations of not corresponding to the constitution of the embryo per se due to the possibility of mosaicism.
Once the decision to perform a trophectoderm biopsy is taken, it is preferable to perform the transfer in a deferred cycle, because not all blastocysts are obtained on D5, and the genetic studies demand time. This decision is very important because it allows better organization of the genetic laboratory assays. At present, there is sufficient evidence that the deferred transfer to the stimulated cycle has its advantages in terms of implantation, ongoing pregnancy and lower risk of genetic and epigenetic alterations.

Blastocentesis on D5/D6 blastocyst

Blastocentesis is a novel micromanipulation technique used to collect a 4 nL sample of blastocoelic fluid from living human embryos (Pic. 8). The blastocoelic fluid is investigate for the presence of DNA that could be amplified and analyzed as a substitute PGD and PGS.

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How can Miscarriage affect fertility

For women who experience only one miscarriage and who have no other associated major risk factors, the risk of adverse outcomes of future pregnancies is quite low and they have approximately 85% chance that their next pregnancy will be completely normal. After a miscarriage, the woman’s menstrual cycle returns to its normal state in about four to six weeks. After this period, the woman may again attempt to achieve a pregnancy. However, a more complex assessment of her health should be carried out by a gynaecologist, as it can take up to six months for her whole body to return to a completely healthy state after a miscarriage. Her psychological health should be also carefully assessed and any issues arising from the experienced miscarriage should be resolved before attempting to achieve another pregnancy.

Women with a history of RSA (recurrent spontaneous abortion) are exposed to higher rates of adverse maternal and fetal outcomes in their subsequent pregnancies. Patients who experienced more than 2 incidents of miscarriage are often exposed to elevated incidences of placental dysfunction disorders and cesarean section. Such patients should be considered as high risk obstetric population. Specific perinatal care and corresponding preventions of placenta diseases can be implemented to reduce the incidence of adverse pregnancy outcomes.

Pic. 1: Pregnancy outcomes
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