Is it Time to Consider Chromosomal Analysis of All Embryos Before Embryo Transfer?
The quest to achieve the best possible outcomes with in-vitro fertilization has led to the use of embryo biopsy to determine the genetic makeup of an embryo before it is transferred to the uterus. The first attempts to do this utilized technology called polymerase chain reaction (PCR). Within the past decade this technology was widely accepted and applied before randomized studies had proven its benefit. In general, embryos were biopsied on day 3 of embryonic life. Unfortunately randomized controlled studies that have now been published have failed to show a benefit of this technology. More recently various new technological platforms have been develop which allow analysis of all 24 chromosomes rather than just a select few, as was the case with PCR. There are several laboratory platforms that may be utilized to perform these analyses including array comparative genomic hybridization (aCGH), single nucleotide polymorphisms (SNP) and quantitative polymerase chain reaction (qPCR). These technologies achieve greater accuracy and are more comprehensive.
Additionally, there has been a shift in terms of when to perform the embryo biopsy. The most recent studies suggest that it is best to perform embryo biopsies on day 5 of embryonic life when the embryo has reached the blastocyst stage of development. Studies have shown that once an embryo has been biopsied on day 5 and been found to have normal chromosomal makeup (euploid), it has a 65-70% chance of successful implantation. One study revealed that transferring a single normal (euploid) embryo achieves the same success rate as the transfer of two non-biopsied embryos while essentially eliminating the chance of twins. It has been proven that embryos biopsied on day 5 of embryonic life (trophectoderm biopsy) do not result in a lower implantation rate when compared to non-biopsied embryos.
ADVANTAGES OF DAY 5 BIOPSY AND CHROMOSOME ANALYSIS
The advantages of day 5 embryo biopsy appears to have the following advantages:
1- SINGLE EMBRYO TRANSFER - Since the screened embryos have a greater implantation rate, single embryo transfer can be performed leading to a reduced incidence of twins.
2- LOWER MISCARRIAGE RATES - Because all 24 chromosomes are being screened with the current technologies, miscarriage rates are significantly lower.
3- FEWER PREGNANCY TERMINATIONS - The need to perform 2nd trimester pregnancy terminations because of chromosomal abnormalities is eliminated.
4- PSYCHOLOGICAL BENEFITS - We will not be transferring embryos destined to be miscarried, women will no longer suffer the emotional consequences of pregnancy loss, nor will they have a 3 month delay in their attempts to conceive.
CAUTIONS AND CONCERNS
While chromosomal analysis of embryos is very exciting and likely to result in improved outcomes for our patients, there are still concerns and questions to be answered before widespread application of day 5 (trophectoderm) embryo biopsy and 24-chromosome analysis:
1- LOW RESPONDERS - Studies thus far have included primarily good prognosis patients who respond well to ovarian stimulation and are most likely to produce at least some chromosomally normal embryos. Patients who are older or low responders will likely produce fewer blastocysts and fewer chromosomally normal embryos. It remains to be seen whether blastocyst biopsy in this group of patients will result in an improved per cycle success rate when compared to the non-biopsied low responder group.
2- BIOPSY EFFECTS -Studies done thus far have suggested that embryo biopsy, specifically trophectoderm biopsy, does not appear to adversely affect implantation. However, as more and more programs adopt tropectoderm biopsy, it is possible that differences in technical expertise among embryologists may be identified, leading to inconsistent results. In addition, pregnancies following trophectoderm biopsy need to be studied carefully to identify obstetrical and perinatal issues related to the loss of these cells.
3- CRYOPRESERVATION EFFECTS -Cryopreservation of biopsied blastocysts does not appear to adversely impact implantation, however more studies looking specifically at outcomes with biopsied frozen blastocysts, compared with non-biopsied frozen blastocysts.
4- COST -Blastocyst biopsy, transportation of cellular material to the laboratory, and the actual genetic analysis of the biopsied cells, all have costs which at this time are largely the patient’s responsibility.
5- EMBRYO HANDLING - There is some concern that increased manipulation and handling of the embryo, which must take place during the biopsy procedure, may lead to errors, mishaps, and possible damage to the embryo.
6- ERRORS – Embryo biopsy material may be read as falsely positive or falsely negative due to errors inherent in the technology. An embryo may be diagnosed as chromosomally abnormal when in fact it is normal and vice versa. The reported error rate reported in the most recent studies is low at 1-2%, but remains a consideration to be considered when counseling patients.
Day 5 embryo biopsy with 24-chromosome analysis appears to be a very promising approach leading to higher implantation rates, lower miscarriage rates, and fewer multiple births. Larger randomized controlled studies are needed to determine if the advantages of this technology apply to all groups of patients, especially the low responding and older patients. Large randomized controlled trials are needed to carefully examine the obstetrical, neonatal, and long-term outcomes among the children born following the application of this treatment. In addition, costs of this technology will need to come down to enable more patient’s access to this treatment.