Submitted by FertilityLab Fri 07/06/2012
A new study reported at this week’s European Society of Human Reproduction and Embryology (ESHRE) meeting suggests that fresh embryo transfer may not be in your best interest if you want to maximize your pregnancy chances. Professor Miguel Angel Checa from the Hospital Universitari del Mar in Barcelona, Spain performed a systematic review of 64 IVF studies , including three randomised trials occurring before December 2011. Dr Checa reviewed 633 IVF/ICSI cycles in which 316 were randomised to fresh embryo transfer and 317 to FET. The surprising result was that the relative probability of pregnancy was higher (RR=1.31) for patients who had frozen embryo transfers rather than fresh. The on-going pregnancy rate was 38% for fresh and 50% for frozen embryo transfers. How can we explain this outcome which runs counter to “fresh is best”? It has long been known that the highest pregnancy (70-80%) rate in any program is usually obtained with patients who use donor eggs. Most of this success has been attributed to the fact that donors are typically much younger than the recipient patient so that egg quality is enhanced. But another factor may well be that endometrial receptivity is optimized, or at least not jeopardized, in the recipient. Much lower hormone levels are needed to promote a receptive endometrium than are typically experienced for superovulation. In fact, the excessive estradiol levels reached in a fresh IVF cycle are likely to be less than optimal for promoting endometrial receptivity which is necessary for successful embryo implantation. In his presentation at ESHRE, Dr. Checa referenced recent studies that show that the normal DNA pattern found in receptive endometrium is disrupted after exposure to high estradiol levels. In the old days, fresh was best because frozen was lousy. Pregnancy rates used to be extremely poor with cryppreserved embryos, especially with slow freeze protocols. With the advent of vitrification techniques, labs are increasingly reporting FET pregnancy rates comparable to fresh rates. If vitrification can preserve embryo quality so it is the same as fresh, it may be possible to optimize the diverse hormonal levels needed for superovulation and for endometrial receptivity by splitting these two parts of IVF into two treatment cycles, one devoted to embryo production and one devoted to endometrial receptivity and implantation. There are some hurdles to overcome if this two-step IVF replaces the current “fresh transfer failure followed by FET” model. Patients will have to forgo the immediate emotional payoff of a transfer and wait a month (or more) for the embryo transfer. Clinics would have to rethink their fee schedules so that patients don’t pay more than they would for a fresh cycle. There are some added costs from freezing all the embryos in a fresh cycle and and subsequently thawing for FET but the added revenue from long-term embryo storage of the extra embryos if the first transfer results in an on-going pregnancy should offset any lost revenue. Furthermore, clinics that offer this approach must have excellent freezing protocols so that “as good as fresh” embryos are available post-freezing/thawing. Even if this approach yielded only slightly enhanced pregnancy rates, it could completely eliminate the most severe risk of superovulation stimulation, namely ovarian hyperstimulation syndrome (OHSS). OHSS is a syndrome with a host of symptoms which can range to mild to severe. Symptoms can include abdominal bloating, mild to severe abdominal pain, mild to significant water weight gain, decreased urination and shortness of breath. Complications can become so severe that they can be life threatening including symptom such as blood clots, kidney failure, severe electrolyte imbalance and fluid build-up in the chest and abdomen. Pregnancy aggravates these symptoms and makes them more severe. Currently, if OHSS is suspected, the fresh transfer is delayed and all embryos are frozen pending a future transfer when the risk of OHSS is past. OHSS is poorly understood in that not all patients predictably have symptoms even if very high estradiol levels are reached. Other patients experience extreme symptoms even with only slightly elevated estradiol levels. In the short time frame in which the decision must be made to transfer the fresh embryos, it is not always clear which patients are most at risk for severe complications from OHSS if a pregnancy occurs. A pregnancy amplifies and aggravates the symptoms and in some cases jeopardizes the pregnancy as well as the patient. Waiting for a frozen embryo transfer allows the patient’s symptoms to reveal themselves and then subside prior to transfer and prevents the chance of pregnancy in a severe OHSS patient which can induce the most severe complications, including death. Dr. Checa’s study is only the first of several that are looking at the same question. If studies from several investigators all suggest that frozen transfers achieve better pregnancy rates, it may be time to reconsider whether the fresh cycle transfer as the best approach to achieving high pregnancy rates in the safest manner possible.