The decision on how many embryos to transfer confronts most IVF physicians and their IVF patients. It is driven by a goal that both share in common, namely that of optimizing the chance of IVF treatment resulting in pregnancy. Clearly, the more embryos transferred, the greater the likelihood of success. However, there is overwhelming evidence to show that the more embryos transferred to the mother’s uterus, the greater the risk of a multiple pregnancy resulting and the higher the multiple, the higher the risk to both mother and babies. Pregnancy complications such as miscarriage, pre-eclampsia, late pregnancy bleeding, an increased incidence of cesarean section, post-delivery hemorrhage etc., are all much more prevalent, placing the mother at risk. Preterm delivery is also much more likely to occur and the earlier the baby is born, the less equipped it is to cope with extrauterine existence, placing it at great risk of complications such as respiratory distress, impaired neurologic and visual development and necrotizing enterocolitis …..to name but a few . While such complications do occur with a twin pregnancy, their incidence and severity increases exponentially with high order multiples (triplets or greater). In fact, in such cases the likelihood that at least one of the babies not surviving the ravages of premature delivery or being left severely developmentally impaired is about 50:50.
Since the higher the number of embryos transferred the greater the chance of a multiple pregnancy, it is incumbent on the treating physician to minimize the number he/she delivers into the uterine cavity with IVF. When deciding on the number of embryos to transfer, the patient’s chance for success (her prognosis) needs to be considered. The younger the woman, the better the microscopic quality of the embryos (their grade), the stage of development of the embryos (cleaved or blastocyst) , the chromosomal integrity of available embryos as assessed by preimplantation genetic sampling (PGS); and the number of supernumerary embryos left over for cryopreservation (freezing) and storage, are factors that should all be taken into consideration. In general, it is recommended that fewer embryos that have reached the blastocyst stage (day 5-6 after fertilization) be transferred than if the transfer were to be done earlier at the cleavage stage (day 2-3 after fertilization). This is because, the further an embryo has advanced in development the greater the likelihood that it will propagate a viable pregnancy.
Consider the fact that when comparing singleton with twin and triplet pregnancies:
*Twins have 3-times, and triplets, a 6-times greater perinatal mortality rate.
* Twins have 6-times, and triplets, an 11-times greater likelihood of developing cerebral palsy.
* Twins are 50% and triplets 80% more likely to be born prematurely.
*Mothers of twins are 3-times, and mothers of triplets, 7-times more likely to experience serious pregnancy-induced complications.
The anguish of losing one or more of your children at birth or watching them endure a life-long disability is a situation no parent would wish to face, yet it is a frequent consequence of multiple births. Why then do so many IVF practitioners still insist on transferring multiple embryos at a time? The following are the main reasons for this:
Most infertile patients simply do not perceive any great risk associated with multiple gestations, especially when it comes to twins. In fact most, consider multiple pregnancy to be a “bonus”…a favorable outcome. Faced with the high emotional and financial cost associated with IVF treatment, most couples prefer to complete their families in one attempt so as to “maximize the use of their resources.” In fact, when asked, almost 90% of couples undergoing IVF in the United States are desirous of having twins. Some are even interested or covet having high order multiples (triplets or beyond). Education is urgently needed to make IVF candidates fully aware of the risks associated with multiple gestations.
The inability to differentiate between embryos that will propagate a healthy pregnancy (i.e. “competent” embryos) and those that will not (“incompetent” embryos): Most IVF patients erroneously believe that a “pretty”, embryo (one given a high grade because it fulfils the microscopic criteria of “good quality”) should invariably make a baby. This is simply not the case. Consider the fact that such a microscopically “good quality” embryo from a 30-year-old has about an 8-times greater chance of resulting in a normal birth than would an identical looking embryo of a 45 year old! This confronts IVF practitioners with a “damned if you do, damned if you don’t” situation; driven by patient pressure to achieve a pregnancy and by competing market forces, they still too often choose to transfer multiple embryos, often with disastrous results. It is generally true that declining egg/embryo “competency”with advancing age justifies transferring more embryos in older women – especially in those over 40 years of age – but this still needs to be carefully measured against the risk of multiple gestations. Not only is multiple gestation the most common complication of infertility treatment, it has also become the most costly in terms of its social impact. If all of the factors associated with multiple gestations are considered, including the costs of antenatal maternal hospitalization, neonatal intensive care for premature infants, as well as the costs of chronic medical care, rehabilitation and special education, the projected annual cost of IVF-associated multiple gestations in the United States is approximately $1.5 billion as compared to about $550 million for all the other IVF cycles performed.
On the positive side is the fact that the last decade has seen a slight but significant decline in the IVF twin pregnancy rate from about 25% to about 22%, as well as a decline in the incidence of triplets from 5% to about 3%. Still, IVF multiple birth rates are about ten times higher than those associated with natural conception. Clearly, multiple pregnancy (especially high-order multiples) represents a complex problem that can no longer be justified as an acceptable outcome following IVF treatment.
Most in the IVF field are in agreement that it is probably best not to transfer more than 2 embryos at a time in younger women. The reason is that embryos derived from the eggs of a young woman (under 35 years) are much more likely to lead to a pregnancy than are those derived from older women. That is why most IVF programs in the United States therefore recommend transferring up to 2 embryos at a time in such cases. For women over 40, many still transfer 3 or even 4 embryos. For those between 35 and 40 years of age, 2-3.
What About Single Embryo Transfers: Advances in IVF technology have brought the noble goal of transferring a single embryo at a time without reducing the chance of a successful IVF, well within reach. Numerous studies have demonstrated that the cumulative birth rate after single embryo transfer (SET), followed by subsequent transfers of individually thawed left-over embryos, is as effective in achieving pregnancy as implanting multiple embryos at one time. And by this approach the risk of multiple births can be virtually eliminated. Moreover, using the SET approach, more than 80% of women under 40 years of age will deliver babies within first four single embryo transfers. At the same time, SET’s would likely cut the cost of health care per IVF baby by about $50,000 per live-birth.
A recent study found that, compared with singleton deliveries, the costs for twins, triplets and higher-order deliveries are approximately four, 11 and 18 times greater, respectively – mostly due to maternal and neonatal complications.
When we use the term “competent” embryo, we mean one which, upon being transferred to a “receptive” or “hospitable” uterus, will in most cases propagate a viable gestation. By far the single most important determinant of embryo “competency” is its karyotype (the number of chromosomes present). Aneuploid embryos (those with too many or too few chromosomes) are uniformly “incompetent” while “euploid” embryos (those with the correct number) are by and large “competent.” An incompetent embryo will not result in a normal pregnancy. In most cases it will either fail to implant or will miscarry early on. It follows that the ability to efficiently identify competent embryos for selective individual transfer would likely represent a “game changer” in the IVF arena.
In the past, the ability to select competent embryos for transfer has been thwarted by:
- Lack of reliability of microscopic morphologic (appearance) embryo grading.
- The inability of traditional pre-implantation genetic diagnosis/sampling (PGD/s) and chromosomal evaluation (karyotyping) by conventional Fluorescence In-Situ Hybridization (FISH) to be able to access all of the embryo’s chromosomes.
Let’s take a look at the merit and reliability of several current methods used to select the best embryo(s) for transfer:
- Microscopic Embryo Grading: Currently, most IVF centers culture embryos in groups and then perform a single microscopic evaluation (at 2, 3 or 5-6 days) prior to embryo transfer of one or more to the uterus. This approach is limited in scope and in its ability to reliably discriminate between “competent” and “incompetent” embryos, since chromosomally abnormal embryos are often identical in appearance to those that are normal. Embryos should be at 2 to 4 cells at 48 hours after egg retrieval and about 6-9 cells by 72 hours. The cells in an embryo are also referred to as “blastomeres.” Ideally the blastomeres should be of even size, and there should be less than 20% fragmentation, or blebbing. This is where portions of the embryo’s cells have broken off and are found lying free as debris inside its substance .Most IVF clinics “grade” each embryo using one of many scoring systems. Unfortunately, there is no agreement at all as to which system to use. But regardless of the microscopic grading system used, one thing is certain…they all lack reliability because they cannot evaluate the chromosomal integrity of the embryo.
- Blastocyst Embryo Transfer: A blastocyst is an embryo which has developed to the point of having 2 different cell components and a fluid cavity. Human embryos, in culture in an IVF lab, or developing naturally in the female body, usually reach the blastocyst stage by day 5 or 6 after fertilization. Many “incompetent” embryos are culled out as the embryo progresses to the blastocyst stage. Thus, those embryos that make it to blastocyst are far more likely than their day 2-3 counterparts to be competent. Embryos that do not reach blastocyst are in about 90% of cases chromosomally abnormal (aneuploid) and would not have been worthy of transfer earlier on anyway. Routinely taking embryos to blastocyst is thus a good idea since, if they do not make it, they are incompetent anyway.By waiting five or six days post fertilization to select and transfer only blastocysts to the uterus, we can improve the likelihood that those being transferred are the “competent” ones.
- Preimplantation Genetic Sampling (PGS) using Next Generation Gene Sampling (NGS) : This very promising method for embryo selection represents a real breakthrough in the IVF arena. NGS allows for identification of all 23 pairs of the chromosomes, providing a reliable method for differentiating between “competent” and “incompetent” embryos. Even without CGH embryo selection, “one embryo/one healthy baby” is now even more attainable. However, the introduction of CGH has made embryo selection much more scientific, virtually removing the incentive to transfer multiple embryos at a time. One of the perceived disadvantages of CGH embryo selection is the cost of such testing. However, while the performance of egg/embryo PGS does increase the cost per cycle of IVF, it actually lowers the “cost per IVF baby”. Since NGS testing requires several days to complete, the use of this technology usually requires that advanced embryos (blastocysts) be frozen and stored (cryostored) in a subsequent cycle. The separation of an IVF cycle into two separate phases to achieve this objective is referred to as Staggered-IVF (St-IVF). Cryostoring blastocysts allows sufficient time for the CGH testing to be completed.
- Embryo Vitrification (Ultra-rapid Freezing): Until about a decade ago, cryopreservation of human embryos had been somewhat problematic because it caused ice crystals to form inside the embryo, damaging or destroying it. The recent introduction of ultra-rapid freezing or vitrification (read the article on vitrification here) has changed all that. With vitrification, embryos are so rapidly frozen that no ice forms, yielding a post-thaw embryo survival rate of about 90%. Impressively, birth rates following the transfer of thawed, pre-vitrified embryos hardly differ from those using fresh embryos.
The Hippocratic Oath, states that the cardinal rule of medicine is “primum non nocera” (“foremost do no harm”). Since multiple pregnancy is the most serious complication of Assisted Reproductive Medicine, and IVF has been responsible for a virtual explosion in the incidence of twins and higher order multiples, those of us that practice medicine in this arena have a solemn responsibility to educate our patients and then to restrict the number of embryos we transfer at one time. Central to achieving this goal is to optimize the ability to select the most “competent” embryos for transfer.