The decision to transfer embryos on day 3 or day 5 is one that requires careful thought. In general, embryos that have formed blastocysts have a better chance of implanting successfully. Unfortunately, not all embryos will progress to the blastocyst stage outside of the body. This fact raises the question as to whether the embryos that fail to form a blastocyst would have initiated a pregnancy if they had been transferred back into the uterus on day 3. Some studies have, indeed, demonstrated acceptable pregnancy rates with day-3 transfers of embryos that were of marginal quality and that, based on historical data, would have been unlikely to form blastocysts in culture. Clearly, the pregnancy rate in the absence of an embryo transfer will be zero, whereas even embryos of borderline quality, if transferred on day 3, may potentially lead to a pregnancy. On the other hand, following normal fertilization inside the fallopian tube, the human embryo does not arrive into the uterus until after day 5 following ovulation. There may be improved synchronization between the embryo and endometrial lining when an embryo transfer is performed on day 5, possibly leading to enhanced implantation rates. Unfortunately, there is no way to do a study in which the exact same embryo is transferred on day 3 and day 5 in order to answer this question.
So how can you decide between a day-3 and a day-5 embryo transfer? Many clinics make the decision on day 3. If a patient has a certain number of high-quality embryos on day 3, then the embryos are maintained in culture for 2 additional days to allow for further embryo selection at the time of transfer. If the embryos fail to progress to the blastocyst stage, however, then there is no transfer—which often results in profound patient disappointment. If a limited number of embryos are available on day 3 and no embryo selection is needed, then the benefit of a day-5 embryo transfer may be limited to the improved synchronization between embryo and endometrium. In our Natural Cycle IVF program, we have become more and more convinced of the benefit of extended embryo culture. Some marginal-appearing day 3 embryos (4–5 cells) have developed into beautiful blastocysts and led to pregnancy and delivery. Some top grade 8-cell embryos have failed to divide after day 3, resulting in a cancelled embryo transfer. Some patients who failed to conceive with a top quality day-3 embryo have subsequently conceived with a day-5 transfer. The evidence remains anecdotal but very compelling to us and we have now decided to move all Natural Cycle IVF transfers to day 5.
One additional risk of a day-5 transfer is an increased rate of identical twinning. Carrying identical twins (monozygotic twins) is considered to be a higher-risk pregnancy than carrying fraternal twins (dizygotic twins). Identical twins often share a placenta (monochorionic twins) or may even be located within the same pregnancy sac (monoamniotic twins). Both of these conditions are associated with increased rates of pregnancy complications. Finally, a clinic’s success with embryo cryopreservation following extended culture should also be carefully considered. Although recent advancements with rapid freezing (vitrification) have resulted in excellent survival and pregnancy rates with blastocysts, not all clinics currently employ this technique. We believe that extended culture must go hand in hand with an excellent cryopreservation program in order to maximize patient success.