Time Capsule for IVF

If we put the progress in IVF methods that have occurred since Louise Brown’s birth in 1978 in a time capsule to be opened 100 years from now in 2112,  what are some of the milestones in it? What would people think of it when they found it?

First a preview of the pre-IVF time capsule. The the late thirties, an editorial published in the New England Journal Of Medicine  (NEJM 1937, 21 October) commented on the description of IVF described in Aldous Huxley’s 1932 science fiction novel “Brave New World. Unbeknownst to Huxley, scientists Pincus and Enzemann from Harvard were doing embryo implantation studies around that time which involved the transfer of embryos from one rabbit to another. These words from the 1937 editorial in NEJM describe the evolving science of IVF and speculate about the future, “Conception in a watch glass: The ‘Brave New World’ of Aldous Huxley may be nearer realization. Pincus and Enzmann have started one step earlier with the rabbit, isolating an ovum, fertilizing it in a watch glass and reimplanting it in a doe other than the one which furnished the oocyte and have thus successfully inaugurated pregnancy in the unmated animal. If such an accomplishment with rabbits were to be duplicated in the human being, we should in the words of ‘flaming youth’ be ‘going places.’”

Many of the early “methods” in IVF were far from ideal and speak more to the robustness of life to “find a way” even in circumstances that were far less from ideal.  These early successes were clearly NOT based on a deep understanding of the female reproductive cycle. The first IVF cycles were natural, not stimulated, so the ability to control follicle growth and final maturation through exogenous hormones that are the basis of modern IVF did not exist. Although there was early recognition that Clomid might be helpful , the deliberate use of gonadotropins was not introduced until 1981 (Introduction of Clomiphene Citrate and hMG in the IVF treatment protocol (Trounson AO, Leeton JF, Wood C, Webb J, Wood J. Pregnancies in humans by fertilization in vitro and embryo transfer in the controlled ovulatory cycle. Science 1981 8;212:681-2).

In the early days, physicians made their best guess on when the eggs might be mature, without the benefit of follicular ultrasound monitoring. That came later when methods for evaluation of follicle growth and size by  first abdominal ultrasound and then later by vaginal ultrasounds were developed. Today, superovulation medication is given and adjusted depending on feedback from routine “checks” of the induced cycle via ultrasound evaluation of follicular growth and blood work looking at hormone levels (primarily E2). Spontaneous LH surges to induce ovulation could easily wreck an IVF cycle in the early days. Now hCG is routinely given to stimulate the final maturation process in the eggs and also to give physicians a definite known end point when ovulation will occur so they can schedule the egg retrieval before ovulation occurs. In addition, medications can be given to prevent spontaneous premature LH surges.

In the early days, eggs were retrieved using laporascopic egg retrieval via an incision in the abdomen (major surgery) which is now replaced with  transvaginal oocyte retrieval (an outpatient procedure).  The original vaginal ultrasound with a sharp needle attached to puncture the follicles looked more like a medieval torture instrument than modern medical device.
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Embryo transfer catheters also have evolved over time. The early stiff catheters used in veterinary practice were eventually replaced by flexible softer tipped catheters when it was understood that minimizing or eliminating trauma to the cells lining the uterus helped improve implantation rates.

ICSI or sperm injection was wildly innovative in 1993 but now many programs perform almost 100% sperm injection to increase the odds that fertilization will occur. ICSI was preceded by partial zona dissection (PZD) and subzonal insemination (SUZI),   which opened up the zona for the placement of sperm beneath the zona but neither technique ensured that the sperm was able to penetrate the actual plasma membrane. PZD and SUZI are ancient tales of lore to new embryologists if they know about them at all.  IMSI is the newest modification of ICSI which may replace standard ICSI.  IMSI is a modification of ICSI sperm selection in which individual sperm are evaluated under much higher power using a modified microscope so that the shape of the sperm nuclei can be evaluated. It is too early to say whether this technique will replace ICSI or is just a fad.

Early culture medium was in no sense customized to the needs of gametes and then embryos as they grew in culture after fertilization. In fact, in the early days, eggs were fertilized and thrown back into the fallopian tubes (a procedure called zygote intrafallopian tube transfer or ZIFT) the next day because culture systems were so inferior to nature. Gamete intrafallopian tube transfer (GIFT) took it one step further and bypassed the IVF laboratory entirely by first collecting eggs and sperm and then dumping eggs and sperm back into the tubes (usually separated by a air bubble) preventing accidental mixing until the gametes were both in the Fallopian tubes. GIFT is the only technique which the Catholic doctrine found tolerable because fertilization occurred in the body, not in a dish. Except for religious reasons, GIFT is infrequently (if ever) performed in most modern programs. IVF has many advantages to GIFT and ZIFT including the ability of selection via extended culture of the most robust embryos, and limiting the  number of viable embryos that are available for implantation, minimizing multiple gestation pregnancies with their poor outcomes.

In the early days, culture to day 3 was as far as embryo could go without dying in culture so transfers had to happen on day 3, if not earlier. One well known clinic, as far as I know,  still transfers embryos on day 2 of culture.  Today, most clinics are culturing embryos for 5-6 days post-fertilization which allows them to reach the blastocyst stage, the appropriate stage for introduction into the uterus which may assist implantation through a better synchrony between embryo and uterus.

Embryo freezing methods were originally adopted from embryo freezing methods in cattle. These slow freezing methods are largely being replaced by vitrification, a sort of flash freezing of embryos. Vitrification was also first used routinely to freeze the embryos of other species, then slowly adopted for use in clinical IVF.

Assisted hatching methods have also evolved over time.  The first method were entirely mechanical, using sharp needles to cut away a piece of the zona. This method was replaced by using a fine stream of an acid solution (Acid Tyrodes) to dissolve a hole in the zona. This method is currently being replaced by even safer and easier methods employing laser technology.

Third party donation using sperm, eggs and embryos from donors and the use of surrogates are routine today. The earliest IVF was conducted only with married couples.

Genetic testing of cells biopsied from embryos is rapidly becoming routine. While selection of gender and other traits may be ethically problematic, the technical aspects are becoming easier every year. Biopsy for embryos to detect genetic disease is routine in many clinics. Earlier methods like polar body biopsy and single cell biopsy are largely being displaced by trophectoderm biopsy which provides more cells for testing and is therefore more likely to deliver accurate test results.

Since this evolution in reproductive medicine and IVF procedures occurred over a mere 34 years,  I can’t even predict how infertility methods will evolve in the next 100 years and how patients might react about these “time capsule” methods 100 years from now. Will it be considered quaint? primitive? or too radical?

In the future, will we be able to identify patients (via. advanced diagnostic tests) who are most likely to benefit from IVF?, thus sparing those who won’t benefit from needless expense and riding the hope-disappointment roller coaster without reward?  Will pre-implantation genetic testing be routine ?- or banned? Will the female ovary still be the limiting factor or will ovarian stem cell rejuvenation  (or donor transplantation) be routine? Will we need embryologists or will the entire process be programmed and managed by sophisticated robot incubators?

References:

IVF Worlwide Unit Directory IVF Timeline

American Experience: Timeline : The History of IVF

 

© 2012, Fertility Lab Insider. All rights reserved.

©2012 Fertility Lab Insider. All Rights Reserved.

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