The story of assisted reproduction through the last three decades

The world has witnessed many developments in the field of assisted reproduction since the birth of Louise Brown in 1978, a product of in-vitro fertilization. What has happened in the last thirty-four years or so is a story to be told: A story of realization, discoveries, execution, performance and triumph. Following closely in the heels of this first assisted reproductive technology, were the development and execution of other incredible techniques: freezing of gametes and embryo and their subsequent successful use for reproduction (1983, 1985), pre-implantation genetic diagnosis by embryo biopsy(1990), Intra-cytoplasmic sperm injection (1991), use of testicular sperms from azoospermic males to have them father their own genetic child and cryopreservation of ovarian and testicular tissue in cancer patients for future fertility preservation.
Louise’s birth was not a chance occurrence but a result of years of dedicated research. At the time, achieving an implantation rate of more than 2-3% per embryo transferred was unthinkable. Researchers set upon the task of improving this implantation and thereby the success rate, mainly by focussing on methods to increase oocyte recovery, better culture conditions, improving transfer techniques and luteal support.
Within 20 years, the implantation rates in various laboratories had crossed 15-20%. However, to have the highest pregnancy rates, 3 to 4 embryos were transferred in every IVF cycle. What this meant was that the chances of all embryos implanting and hence leading to multiple births also increased which greatly increased the associated risks of perinatal mortality and morbidity.
Therefore, the focus shifted towards developing methods to improve IVF success rates, while reducing twin and triplet pregnancies. The approach was to develop screening methods to identify the most viable embryo, so that transfer of fewer healthy embryos would result in a higher proportion of singleton pregnancies.
One method used was to prolong culture of embryos in vitro by optimizing culture conditions, so that natural selection of only the more viable embryos (blastocysts day 5 embryo) for transfer came to the fore.
Another way of knowing whether the embryo was robust enough to implant was by checking if it was genetically normal, and this was achieved by biopsying cell/s from the embryo. This cell was then subjected to cytogenetic techniques like FISH to determine aneuploidy; or to molecular techniques like PCR to determine a known point mutation on a particular chromosome.
A third way to pick up the most viable embryo was to check their metabolic health through what is known as “metabolomics”. This involves profiling each embryo based on the quality and quantity of their excretome, as well as by assessing the oxygen uptake by embryos.
What currently seems to be holding the world’s attention is the visual documentation of growth and cleavage-rates of embryos through an incubator-mounted, time lapse camera which is simply termed the “time lapse” or “dynamic morphometric analysis”.
While advances were being made within the embryology lab, exciting changes were also happening in the world of gonadotropins. The urinary gonadotropins were slowly giving way to the self administered, purified, recombinant gonadotropins. Better timing of oocyte retrieval, due to avoidance of pre-mature LH surge, could be attained with the use of GnRH analogues (agonists from 1983 onwards, and antagonists from 1999 onwards). Recently, to ease the pain of daily injections, long acting Gonadotropin injection (elonva), which need only be given once in seven days, has been developed. Also, work is underway to prepare an oral formulation of gonadotropins.
With better stimulation techniques, the ovarian response often over-stepped the desired mark of safety, leading to ovarian-hyper-stimulation syndrome, a life threatening iatrogenic condition. Advancements towards reverting to soft stimulation protocols to lessen the incidence of ovarian hyper-stimulation and yet obtain adequate number of oocytes and embryos to maintain good pregnancy rates are being made.
One of the many controversial areas of assisted reproduction has been cloning. Animal cloning has been achieved by the process of somatic cell nuclear transfer (1996). The same technique has been employed for cloning of human embryos as well (2009). The human fertilization and embryology authority prohibits cloning of human embryos for the purpose of reproduction since it deems to totally bypass nature’s law of sexual reproduction. Whether the first cloned human will ever be born is yet to be known.
For future generations, by working on a background of these achievements, one can only hope that their task of making assisted reproduction more efficient and complication-free, more available to a wider range of patients, and more socially and economically acceptable, would become easier.

Sir Ganga Ram Hospital

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Genesis Clinic

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