Highly individualized egg retrieval (HIER), unquestionably, is CHR’s most important recent innovation brought to the practice of IVF, and we are absolutely convinced that, like many other CHR contributions to IVF before, it will quickly be picked up by IVF centers all around the world.
HIER started a number of years ago, when CHR noted that, as one would expect, the center’s IVF outcomes progressively declined with advancing age up until age 43. After that age, the slow progressive decline, however, significantly accelerated, with almost no pregnancies and live births accomplished (most IVF centers till today believe that women above 42 should be automatically advanced into egg donation). CHR investigators at that point speculated that the cause for this sudden decline had to lie with the quality of eggs, and egg quality, of course, had to depend on what was happening within follicles. They, therefore, decided to investigate the molecular biology of the follicular microenvironment at time of egg retrieval in healthy controls (i.e., young egg donors), middle-aged IVF patients and IVF patients above age 43.
See a graphic showing the length of time each stage of egg (follicle) maturation takes.
The findings were nothing but astonishing, and were described in a publication in a prestigious medical journal [Wu et al., J Endocrinol 2015;226(3):167-180]: Women above age 43 were found to have overwhelming evidence for what medically is called premature luteinization of follicles. In practical terms this means that, as women get older, the biological processes within follicles speed up. As a consequence, if the timing of egg retrieval in older women is maintained like in younger women, the eggs one obtains are “hard-boiled” rather than “soft-boiled,” or in medical lingo atretic rather than mature and, therefore, unusable.
Based on these findings, CHR investigators decided to enhance egg retrievals in women above age 43 and, lo and behold, ended up with more transferrable embryos and significantly improved pregnancy rates. With early retrieval, IVF pregnancy rates were double those with regular retrieval.
But this was not the end of the story for HIER. In the initially published study, the target population of patients were women above age 43, and CHR investigators had arbitrarily chosen a range of 16mm as lead follicle size (in place of the routine range of 18-22mm) to trigger the follicles with human chorionic gonadotropin, hCG). Since this study was published, CHR investigators also established that women with POA, similarly to older women, also accelerate their intra-follicular metabolisms. With early retrievals, benefits to pregnancy rates in POA patients were even larger than in older women above age 43, at triple the pregnancy rates compared to regular retrieval schedule. Moreover, 16-18mm lead follicle size was, indeed, confirmed to offer best results, with smaller and bigger follicle sizes at time of hCG trigger resulting in clearly lower pregnancy chances.
Likely, the most remarkable discovery made by CHR investigators, however, was that 16mm follicle size at trigger was also not the last word yet: They since learned that, as patients age, follicle sizes at which hCG triggers have to be given must continue to shrink in parallel. Considering that CHR now quite routinely treats women between ages 45 and 49 with use of their own eggs, hCG triggers at 12mm lead follicle size are no longer uncommon. CHR’s oldest woman ever to conceive and deliver with use of her own eggs at age 47 and 10 months, was, indeed, triggered at 12mm lead follicle size.
Early retrievals affect IVF cycles in additional ways: They, of course, shorten stimulation cycles and some patients have to be triggered after only 2-3 days of gonadotropin stimulation. Because cycles are dramatically shortened, there is no longer a need to prevent premature ovulation. Neither agonist nor antagonists are, therefore, needed in such cycles.
In summary, HIER is really what this acronym stands for, highly individualized egg retrieval. Its significance also carries over into the embryology laboratory, where CHR investigators have also started individualizing how oocytes are treated that come from HIER cycles. Specifically, since early retrievals can be expected to mildly increase the number of premature eggs, CHR embryologists now in many HIER cycles do not automatically “strip” oocytes of their cumulus cells, as is routine practice in IVF. Instead, again based on highly individualized criteria, they may culture those oocytes with the cumulus cells still attached overnight, strip the cumulus cells the following morning, and fertilize the eggs with intracytoplasmic sperm injection only then, rather than on the previous day.
Because of all of these changes introduced to CHR’s IVF program since 2013, the center’s IVF population and IVF cycle outcomes have quite significantly changed. Our patient population is getting older and older, and pregnancies and live births are no longer limited to women under age 43. As already noted, we, indeed, established last year at almost age 48 what, likely, represents the oldest autologous IVF pregnancy ever reported that resulted in a healthy birth.
Pregnancy rates, and more so live birth rates, at these very advanced ages are, of course, still quite low but they are clearly better than they were only a few years ago before we introduced HIER. We are convinced you will hear more about HIER in coming years. Remember, however, like so many other infertility innovations, you heard it here first, coming from CHR!
This is a part of the January 2018 CHR VOICE.
Norbert Gleicher, MD, FACOG, FACS
Norbert Gleicher, MD, leads CHR’s clinical and research efforts as Medical Director and Chief Scientist. A world-renowned specialist in reproductive endocrinology, Dr. Gleicher has published hundreds of peer-reviewed papers and lectured globally while keeping an active clinical career focused on ovarian aging, immunological issues and other difficult cases of infertility.
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