The majority of IVF patients intuitively recognize that the more embryos transferred the greater will be the chance of their getting pregnant. However in their preoccupation with conceiving as quickly as possible they often tend to ignore the serious and sometimes life-endangering risks to both mothers and children associated with of multiple pregnancies (particularly with triplet pregnancies of greater) that are far more likely to occur when multiple embryos are transferred at a time. The important question that all women undergoing IVF should ask is “What is the number (of embryos) that will maximize my chances of getting pregnant while minimizing risks?”
In certain Scandinavian countries, single embryo transfer is the norm. Such countries are willing to trade a lower pregnancy rate for increased safety and reduced social and personal complications. Left-over embryos are frozen and held for subsequent dispensation at the behest of the patient(s). This policy is a wise one, given that The cumulative pregnancy rate (fresh + frozen embryo transfers) is no lower than when multiple embryos are transferred at a time, but the risk of a multiple gestation is near zero. While this means more transfers are usually needed per patient and it drives up the cost of IVF it is preferred because the price to pay is much lower than having to cover the cost of treating premature babies (much more common in cases of multiple pregnancies and in comparison with the cost of raising twins or triplets is considerably lower. Some women, hoping to optimize the chance of a pregnancy opt for a multiple embryos transfer, believing that fetal reduction is an option in the event that a high order multiple pregnancy should occur. The option of doing a fetal reduction to reduce fetal number is however not without risk. The procedure may result in the loss of all fetuses and often has have significant psychological consequences.
It is incumbent upon the treating physician to counsel the IVF patient/couple regarding their decision as to how many embryos to transfer. In the process of such deliberations s, the following factors should be considered:
Legality: In certain countries it is illegal to transfer more than two embryos and in some cases it is only permissible to transfer one at a time. In the United States, our governing body, The American Society for Reproductive Medicine (ASRM) and its subsidiary, the Society for Assisted Reproductive Technology (SART), have established non-binding recommendations to limit the number of embryos being transferred. Unfortunately such policies and/or recommendations do not take important considerations such as the age of the egg provider, the developmental status and quality of the embryos into consideration into account (see below). They almost uniformly disregard the fact that a cleaved (early) embryo is less likely to propagate a pregnancy than is an advanced embryos (blastocyst) and that the transfer of a quality blastocyst derived from a young woman’s egg is several times more likely to develop into a baby that a morphologically equivalent blastocyst, derived from the egg of a woman in her mid-forties. Thus a decree that regardless of the age of the egg provider, the same number of embryos should be transferred is irrational, bureaucratic and prejudicial to many older women undergoing IVF.
Age: As a woman ages, beyond her mid-thirties, there is an inevitable decline in the percentage of chromosomally normal (euploid) eggs. In the early thirties about one in two mature eggs will be euploid. By age 40 years this will have declined to about one in six and by her mid forties, fewer than one in ten eggs will be euploid. Since it is largely the egg (rather than the sperm) that upon fertilization will determine the chromosomal integrity of the embryo, it follows that advancing maternal age increases the percentage of embryos with numerical chromosomal irregularities (aneuploidy). Since aneuploid embryos are “incompetent” (by and large unable to propagate viable pregnancies, it follows that the older the woman, the less capable her embryo will be of propagating a pregnancy. By way of example, a morphologically perfect (“high grade”) embryo derived from the fertilized egg from a 30 year old is probably at least three times more likely to be “competent” that a similarly graded embryo derived from a 40 year old’s egg and six times more likely, than a similarly graded embryo derived from the egg of a woman aged 44. This is why the transfer of multiple embryos to women in their 40’s is far less likely to result in multiple pregnancies than for women in their mid-thirties. It is also the reason why the transfer of three advanced embryos (blastocysts) at a time to a woman of 30-35 years of age carries a 25%-35% risk of a multiple pregnancy while the transfer of the same number of embryos to the uterus of a woman in her early to mid forties would be associated with a less than 10% risk of multiples. So, while it is inadvisable to transfer more than two (2) advanced embryos to the uteri of women in their mid thirties, it is acceptable top transfer 3 advanced embryos at a time to women of 39-43 years of age and even four (4) at a time to women of >43 years.
Embryo Genetic “competency”: It is primarily the chromosomal integrity of the embryo that determines its ability to propagate a viable pregnancy. The introduction of Preimplantation Genetic Sampling (PGS) using Comparative Genomic Hybridization (CGH) and more recently, (the upgrade to) Next Generation Gene Sequencing (NGS) for whole genome chromosomal evaluation (full karyotyping) of embryos allows us to assess embryo “competency” has largely eliminated the effect of age on embryo implantation and birth rate per embryo transferred.
As stated above, advancing age of the woman is associated with a progressive decline in embryo “competency” as well as an ever decreasing percentage of euploid embryos. This translates into lower pregnancy rates, a rising rate of miscarriage and a commensurate increase in the incidence of aneuploid birth defects such as Down syndrome. However, once PGS analysis defines an embryo as “euploid”, the influence of age on its “competency” largely dissipates, leveling the playing field. This is why the selective identification and transfer of PGS selected embryos (even if it requires advance banking over several IVF cycles of ovarian stimulation/egg retrieval and fertilization with ET in a subsequent cycle) is gaining such popularity in older women and those with diminished ovarian reserve (DOR)…..Finally, at last , through PGS-embryo selection and banking, older women and those with diminishing ovarian reserve (PGS) now finally have a reasonable expectation of becoming parents through IVF.
With PGS embryo selection it is in my opinion, never justifiable to transfer more than two (embryos at a time, regardless of the age of the egg provider.
Embryo and Blastocyst Grading: There are a variety of systems used to microscopically (morphologically) evaluate (grade) embryos on day 3, day 4 or day 5-6 following fertilization. Virtually all day 3 embryo microscopic grading systems (the commonest time for such assessment) use criteria such embryo size and shape, the number, clarity and symmetry of the embryo’s cells (blastomeres), fragmentation (debris inside the embryo resulting from blastomere disintegration), thickness of the embryo’s envelopment (zona pellucida) etc. in an attempt to assess the potential of that embryo to develop into a blastocyst by day 5-6 and upon being transferred to the uterus, go on to propagate a viable conceptus.
As it divides into more and more cells, many chromosomally abnormal embryos arrest their development. Those that fail to develop into blastocysts within 5-6 days of being fertilized, are almost always chromosomally abnormal and “incompetent” (i.e. are incapable of developing into viable concepti).
Blastocyst microscopic grading systems (done on day 5 or 6 post fertilization) assess the expansion of the blastocyst (the fluid cavity or blastocele size, within), the cellularity of the inner cell mass-ICM (which develops into the baby) and of the trophectoderm-TE located on the outside of the blastocyst and which will ultimately form the placenta and membranes.
There are several other factors that should influence the decision on how may embryos to transfer at a time:
- Alloimmune Implantation Dysfunction: Most alloimmune implantation dysfunction is associated with what is referred to as a “partial” DQ alpha genetic match between the partners plus NK cell activation (NKa). Here there is a 50;50 chance that any embryo will contain the male partner’s DQ alpha genotype and that when such an embryo reaches the uterine cavity it will evoke activation of uterine NK cells. When such a matching embryo evokes a local NKa reaction, no immunotherapy can counter its adverse effect on implantation. Since it is not presently possible to identify those embryos that contain the matching DQ alpha it is always advisable to transfer a single embryo at a time. Ultimately when a non-matching, euploid embryo reaches the uterus of a woman treated with Intralipid and steroids, it will have an excellent chance of propagating a viable pregnancy. Transferring more than one embryo at a time in such cases, increases the possibility that one of the embryos will match, evoke an aggravated NK cell response and thwart pregnancy altogether. That, in my opinion, is why only one embryo should be transferred at a time in such cases.
- Anatomical Uterine Factors: Certain uterine abnormalities such as a unicornuate uterus, a polyfibroid uterus, a post-surgical uterus that has much reduced size and cases of cervical incompetence, are often associated with a reduced capacity of the uterus to stretch during pregnancy. In such cases transferring a single embryo at a time represents prudent strategy.
- Physical well-Being of the patient: Complications such as pregnancy induced hypertension, placental separation, Cesarean delivery are all much more likely in cases of multiple pregnancy. Since women with ill health (diabetes, gross obesity, cardiac disease etc. are much more vulnerable to such occurrences, it is advisable to not transfer more than one embryo at a time in such cases.
- Patient Preference: Some patients, for economic, social and professional reasons are not interested in having a multiple pregnancy. It is their right to much such deliberations. In such cases, single embryo transfers should be done.
So, how many embryos should you transfer? The answer varies based on your age and prognosis.