Earlier this year, a comprehensive review of advanced fertility treatments demonstrated that the risk of serious complications as a result of advanced reproductive techniques (ART) was relatively low. Still, there is always an effort to try to reduce any adverse outcomes even further. One of the rare but more serious complications associated with successful IVF treatments is the risk of developing an ectopic pregnancy; a situation that results when the embryo migrates from where it had been placed within the patient’s uterus to another site, most commonly the fallopian tube. The frequency of ectopic pregnancy in patients that conceive through IVF is between 2% and 5%. Ironically, this is higher than the 2% to 3% incidence seen with naturally conceived pregnancies. New insights suggest what may be contributing to the elevated risk associated with ART and what steps that we can take to prevent it from happening
In order to better understand why IVF has a higher risk of ectopic pregnancy, let’s consider what we now know about implantation. The process whereby an embryo successfully establishes contact with the uterine lining is actually a coordinated event that depends upon the timing of several important factors. One major factor is development. The embryo must be develop to the blastocyst stage—where it appears as a fluid filled ball with a clump of cells concentrated at one location. It then must break out of its protective coating in a process called hatching. Another important factor is the hormonal milieu. The uterine lining must be hormonally prepared for the initial contact with the hatched blastocyst; there is typically a limited time period of about 36 hours during which the conditions are ideal for attachment (the first step towards implantation) to occur. A recent analysis compared several variables associated with different embryo transfer strategies.
For their study, they reviewed over 3,300 embryo transfers. They compared the developmental stage of the embryos as well as whether the embryo transfers were done during the same cycle as the egg retrieval (Fresh) or whether they had been cryopreserved and transferred later (Frozen). The difference between a Fresh transfer and a Frozen transfer is two-fold. Not all embryos develop at precisely the same rate. So with Fresh transfers, some embryos are more developed than others. In fact, they separated their analysis based upon whether it was 3, 5 or 6 days after the egg retrieval. In a natural cycle, an embryo typically enters the uterus 5 or 6 days after it is released from the ovaries. With Frozen embryos, they are actually preserved when they have reached a specific stage of development chosen by the IVF center. As a result most frozen embryos are at the morula stage (day 3) of development or the blastocyst stage where they are ready to hatch. Some embryos reach this preimplantation stage on the 5th day of development and others take until the 6th. If they do not make it by day 6 it is considered an unhealthy embryo. The other distinction is that Fresh transfers tend to be associated with higher than normal hormone levels as a result of the ovaries producing multiple mature eggs instead of just one or two. By contrast, the goal of a Frozen transfer is to create a hormonally balanced environment within the uterus that more closely represents what happens in a natural physiologic conception.
In order to try to differentiate both of these factors, this study compared Day 3-Fresh and Day 5-Fresh to Day 3-Frozen, Day 5-Frozen and Day 6-Frozen, The finding in this analysis was that risk of ectopic pregnancy was lowest for Day 5-Frozen embryo transfers. In fact, the calculated risk for those patients was far less than 1% suggesting that the ideal transfer strategy is to split the ART cycle to optimize the healthy pregnancy rate while minimizing the risk of ectopic pregnancy. A previous study also found that embryos that were judged to be of poorer quality—based upon their appearance under the microscope—also pose an elevated risk of ectopic pregnancy making the embryo grade a potential third factor to consider. There have also been two other studies that have also found that frozen embryo transfers (FET) have lower ectopic pregnancy rates than fresh embryo transfers.
Since many centers now have advanced freezing techniques to safely preserve embryos it makes sense for more patients to separate the process of ART into two parts; the first month to create the embryos and the second month to transfer them. Although this split cycle strategy lengthens the time from start to pregnancy, there is compelling evidence that for many patients it will improve their chance of having the highest pregnancy rate with the fewest possible complications and the lowest possible risk.