“Freeze All” – The Next Big Thing?
ADVERSE EFFECTS OF CONTROLLED OVARIAN STIMULATION
Since the earliest days of IVF treatment clinicians have had concerns about the status and general receptivity of the endometrium during the stimulated cycle. Controlled ovarian hyperstimulation results in extremely high estrogen levels that may accelerate endometrial development causing the endometrium to be ahead of the developing embryo. Early and exaggerated progesterone secretion may also factor into accelerated advancement of the endometrium. In addition, patients with endometriosis may experience activation of endometrial implants due to elevated estrogen levels. Once implants are activated they may adversely affect implantation.
Several large infertility centers have recently suggested that freezing all embryos that develop in a stimulated cycle rather than placing them in the uterine cavity may improve the pregnancy rate achieved as a result of that egg retrievl. Some programs have found that freezing all embryos that develop to the blastocyst stage, and holding them for future transfer in an unstimulated cycle significantly improves pregnancy and live birth rates. One of the advantages of freezing all of the embryos is that this allows for transfer of the best embryo(s) in a cycle that closely resembles the natural menstrual cycle.
IMPROVEMENT IN EMBRYO FREEZING TECHNOLOGY
Embryo freezing technology has advanced greatly in recent years. The first successful cryopreservation of human embryos was accomplished in 1984. Until recent years, most embryo cryopreservation involved a “slow freezing”. Specially designed freezers lower the temperature of embryos in a very slow and carefully controlled lowering of temperature. Over the past 5-6 years most IVF programs have changed the methodology of embryo freezing to a technique called “vitrification”. This technique involves extremely rapid freezing by plunging the embryo into liquid nitrogen. The temperature of the embryo is lowered from body temperature to minus 275 degrees Fahrenheit in a matter of seconds. Vitrification has very little (if any) negative impact on the embryo. Most studies have demonstrated improved pregnancy, and live birth rates with vitrification compared with slow freezing.
IMPROVED FROZEN EMBRYO QUALITY AND IMPROVED UTERINE ENVIRONMENT
Large studies are in progress to determine if freezing all embryos through vitrification followed by frozen/warmed embryo transfer in a non-stimulated cycle
improves pregnancy rates. Preliminary investigations have suggested that the patients most likely to benefit from this approach are as follows:
1 - Low ovarian responders
2 - High ovarian responders
3 – Endometriosis patients
4 – Patients with unexplained repeat implantation failure
5 – Patients who require a “lupron trigger” shot
to prevent ovarian hyperstimulation
Our preliminary experience with a “freeze all” approach included 18 patients who agreed to freeze all blastocysts that developed in a standard IVF cycle. Patients underwent controlled ovarian stimulation and trans-vaginal ultrasound guided egg retrieval. Eggs were either inseminated or underwent intra-cytoplasmic sperm injection (ICSI). All embryos achieving blastulation were vitrified and no fresh embryos were transferred in the stimulated cycle. When the patient menstruated, a non-lupron frozen embryo transfer protocol was initiated using oral estrogen in progressively increasing doses, followed by intra-muscular progesterone. One or two frozen/warmed blastocysts were transferred on the 6th day of progesterone support.
Patients included in this review had only one frozen embryo transfer. Of 18 patients who entered the “freeze all” treatment protocol, 16/18 (89%) had a positive quantitative beta hCG. Of the 16 patients who had an initial positive quantitative beta hCG, 14/18 (78%) have ongoing pregnancies.
This very small study has obvious deficiencies. It was retrospective and lacks power because of the small number of patients participating. The best design to investigate the value of “freeze all” is clearly the randomized control trial (RCT) with several hundred patients in each arm of the trial. Until these studies are published, it is wise to resist concluding that a “freeze all” approach is best for all patients. At this time it seems most logical that the “freeze all” approach might offer benefit to patients with unexplained repeat implantation failure, endometriosis, and those patients who receive a Lupron trigger to avoid ovarian hyperstimulation. We are encouraged with our initial "freeze all" experience and will continue to offer this approach on a selective basis while we continue to monitor our own data as well as other publications reporting on the "freeze all" approach.