Towards Single Embryo Transfer: an embryologist’s perspective

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Since the beginning of clinical IVF, the transfer of multiple embryos has been practiced so that pregnancy rates were maximized for the patient. More than one embryo was replaced so that at least one would have a good chance of implantation. Typically, in recent years we would routinely transfer 3 (or 4 in cases of repeated failure or advance maternal age) day 2 or 3 embryos for an approximate 35-40% chance at a pregnancy.   On average, 25-30% of those pregnancies were multiples, and up to 20 % of those were triplets or more. These figures obviously depended upon the number of embryos transferred. As we have seen a decrease in the number of embryos replaced but not a decrease in twin pregnancies, due to optimization of culture techniques, the need for serious consideration toward replacing only one embryo has become one of safety for the patient and resulting babies.

Multiple pregnancies and births have been shown to be associated with fetal abnormalities such as low birth weight, birth defects, infant death as well as adverse maternal outcomes like anemia and hypertension. (Kissin et al 2001). A large study based on 50,819 IVF transfers was performed in 2001 in the US. It was found that 54% of babies born from ART were multiples. The incidence of multiples in the general population is only 3%. The reason is obvious; multiples are due to hyper-stimulation protocols, and replacing more than one embryo.

In Canada, the multiple rate for 2003 IVF/ICSI pregnancies was 36.5 %( ranging from 18-67%). (Gunby et.al 2006,in press). Reynolds et al (2006) recently analyzed 506 072 IVF cycles performed in the US in between the years of 1996 and 2002. This researcher found that although the proportion of cycles in which 3 or more embryos were transferred decreased significantly, the multiple gestation rate associated with those cycles in which only 2 embryos were transferred, increased significantly among all groups. One may attribute this ( in theory) to the advance in technology in the past years, primarily to blastocyst transfer, assisted hatching, increased optimization of embryo culture, to name a few. These are some examples where the efficiency of the technology has increased to the point where we put back fewer embryos but do not decrease pregnancy rates or multiple rates. Fraternal triplet rates however have decreased significantly since the transfer of three embryos has largely been replaced with transfer of two or in some cases one blastocyst.

Depending on the infertility diagnosis, it is well documented that up to 52% of oocytes retrieved can be abnormal, (Kuliev 2003) meaning that the fertilization rates, or development rates, clinical pregnancy rates and live birth rates can be affected by diagnosis. Also, laboratory techniques and practices may also have been a variable in the distant past. In some cases, even though the oocyte started out normal, the lab procedures used could actually add a negative variable to the oocyte causing it to either not implant or miscarry after implantation in some cases (Munne et al 1998). Temperature instabilities, pH fluctuations or volatiles in the lab air are three examples of serious variables that can affect the outcome of a cycle. Even though current lab techniques and protocols are much more stable and closely controlled and monitored, the innate variables in the oocyte cohort and sperm are still factors that can affect the outcome of a cycle, warranting the replacement of at least two embryos (down from 3-4 of about a decade past).   Many aspects of the methods and procedures of the IVF lab have changed in the last 10 or so years that have improved outcome so that fewer embryos may be replaced without compromising pregnancies rates. With the case of blastocyst transfer we have been able to largely reduce the amount of embryos transferred down to 2 or in some cases down to one and in doing so the triplet rate has decreased to almost zero but the twin rate however, is still high.

Non-invasive indicators, for the assessment of embryo quality, throughout development in the IVF Lab are largely the routine when evaluating the embryos for transfer. For single embryo transfer (or any transfer, for that mater) it is necessary to identify the most “viable” embryo in the cohort with out compromising chances of pregnancy or the health of that embryo or the resulting baby.   Hence, morphological markers are the main tool in assessment of the embryo before transfer. In using these clues and assessing certain time frames for a specific event or cell stage, one may use a “list” of morphological criteria to make an opinion on the most viable embryo without using too much subjectivity ( Racowsky et al 2003). Certain characteristics used are as follows:

Gamete morphology: The quality of egg and sperm assessed even before fertilization. DNA integrity of the sperm, count, motility, and morphology are all useful when used together with all other criteria.

Pronuclear morphology: The morphology of the bodies inside the pronucleus at fertilization were shown to have some bearing on prediction of a viable embryo, however this is still controversial since these bodies are not static within a developing “2PN” ( fertilized egg).

Early cleavage: The early development of a 2 cell embryo from a 2 PN.

Fragmentation: of the cytoplasm of the embryo during development.

Symmetry: of the cell resulting from the development of the embryo.

Absence of multinucleation: cells resulting from the development should only have one nucleus.

Development to expanded blastocyst: Embryo has activated own genome and is developing to physiological point where body expects it to be before implantation.

Morphological criteria at separate stages of development, when used individually or collectively, have some predictive value to help the embryologist choose the most likely viable embryo for single embryo transfer. However we do know that morphological markers are not all as exact as we would like.

Research is moving forward with other means of selecting the most viable embryo with even more certainty. Preimplantation genetic diagnosis of an embryo would in theory be an excellent addition to the regime of single embryo transfer. Embryos would all be checked at day 3 of development for viable chromosomal complement and only a normal embryo transferred. This technique is important because even though chromosomal complement may be abnormal in a developing embryo, the morphology may look absolutely normal to the embryologist. For certain patients this may be very helpful. One caveat of this technique is the expense. The technology involved in labeling and counting the chromosomes is very detailed and at the moment very expensive.

As our technique and knowledge increases regarding embryo culture and embryo selection, our results also get better and more efficient. Having to transfer two or more embryos in the past to maintain a reasonable pregnancy rate was necessary. How ever as the methods become better and more efficient the pregnancy rates and multiple birth rates increased in frequency as well. Now we are faced with the ultimate challenge in human IVF, the culture of embryos so that we can select that one embryo that will most likely implant without adding any negative variables and without decreasing the chance at a pregnancy. The ultimate result is a high pregnancy rate with no multiples. Some European countries have taken a proposal to their government, stating that multiple births are a financial burden on the parents and the State, and dangerous for the resulting offspring but multiple embryos are replaced to maximize pregnancy rates and the financial out lay of the couple for their right to bear children. The Clinics in these countries proposed that the government cover the costs for the IVF cycle using single embryo transfer. The result was that couples went though IVF with single embryo transfer resulting in less multiple births and hence less cost to the patient, and lower overall long term health care costs for the country; “a win, win situation.” It is believed that our technology is ready for this challenge without causing a decrease in the chances of a couple to achieve a pregnancy and decreasing the burden of multiples upon the parents, society and most importantly the health of the resulting babies. As we move toward the idea and the eventual realty of single embryo transfer we do so with responsibility and open minds in hopes of routinely transferring single embryos with increased results and decreased risks to mother and baby.