03-05-2025
IVF is expensive. Can recent cost-cutting technologies make a difference?
The year was 2004, the date was August 4, when our article, 'Inside the tube and closer to nature', was published as a letter to the editor, in the journal Reproductive Biomedicine, online. The founder-editor of the journal was the late Robert Edwards, Nobel prize winner in physiology and more famously known for being a pioneer in the field of IVF (in vitro fertilisation), credited for the birth of the world's first test tube baby. The article spoke of our experience with performing tubal procedures in IVF and their efficacy in successful pregnancy rates. The concept being: retrieval and transfer of the female oocytes into the ampullary portion of the fallopian tube, in its natural environment. Either these oocytes were loaded with sperms, or an intrauterine insemination was performed so that the sperms swam naturally towards their destination to fertilise with the oocyte. The concept of performing this was to reliably place gametes in their natural environment to enable fertilisation.
Mimicking nature is the intention of IVF, be it temperature control or the well-fortified culture media used and their growth periodically monitored in CO2 incubators. Now, tubal procedures have become obsolete. Advances in cell culture methods and the expense of anaesthesia and it being a laparoscopic procedure, sealed their fate.
Cutting costs in conventional IVF
But then again, we feel the urge to cut costs in conventional IVF. This compels us to research techniques that could possibly reduce the number of injections that are taken by women, known as controlled ovarian hyperstimulation, to yield more than just a few mature follicles in their ovaries. When these follicles, which are monitored by ultrasounds on alternate days, reach a mature size, we surgically aspirate them to retrieve oocytes.
The first method of cost cutting was to either perform a natural cycle IVF, or use minimal stimulation protocols with a combination of more tablets than injections. Depending on the individual's age, diagnosis and ovarian reserve, stimulation protocols are tailor-made for their needs. The other method, which is not new in the market is, invitro maturation of oocytes (IVM). In this method, we retrieve oocytes from follicles that are not fully mature (1.4 x 1.4 cm) and culture them in media, to which are added specific proportions of follicle-stimulating and luteinising hormones along with serum-derived protein and growth factors. This method cut short nearly half the cost of injections and also reduced risks of a potential complication called ovarian hyperstimulation syndrome. (OHSS). However, the American Society of Reproductive Medicine only recently, in 2021, declared it as non-experimental and its usage around the globe is much lower in comparison to conventional IVF. The reason being, lower success rates. Also, there is a learning curve in lab preparations for this process and it does remain challenging for regular use.
New learnings
The same year as IVM was gaining popularity as the new kid on the block, I was doing my Master's in clinical embryology (2004-2006) at the Jones Institute of Reproductive Medicine in Virginia, U.S.. For my final thesis, I decided to perform in vitro maturation on a select group of PCOS (polycystic ovarian syndrome) patients who were ideal, as they required more injections, and so were also at risk of OHSS. However, I soon realised the nuances of culturing immature oocytes outside of the body not only depended on stringent culture conditions but also the basic quality of oocytes. PCOS patients are a tricky group where quality is concerned. I had to abandon my research and convert it to a literature review instead.
Recently, a U.S.-based biotechnology company that works in reproductive health Gameto, grabbed headlines, with the introduction of 'Fertilo', which utilised ovarian support cells derived from stem cells, to literally recreate the ovarian environment, in vitro. These ovarian support cells are derived from human induced pluripotent stem cells (HIPSC) that overexpress a variety of transcription and growth factors. Not only that, they behave like the nourishing granulosa cells that respond to exogenous hormones and feed the oocyte in vivo. So instead of supplementing the hormones as discussed earlier, the ovarian stem cells formed the elixir in culture in which immature oocytes were incubated for 30 hours, following which a maturity check was performed and fertilisation was enabled by conventional methods such as IVF and ICSI. To test safety and efficacy, 20 patients were recruited. Once cleared, the remaining 20 patients were randomised to two groups, one using fertile and the other using conventional IVM. The success rates projected as maturation rate, ongoing pregnancies and live births is double in the Fertilo group in comparison to the IVM group.
The bias in the study however, is that the population was less than 37 years old and also had normal ovarian reserves. The success of this remains to be seen in a variety of diagnoses like older women, PCOS patients, those with low ovarian reserves etc. In this subset of patients, the current refined stimulation protocols have actually yielded much better results than a decade ago, including a reduction in OHSS.
Proceeding with caution
There are many factors that need to be considered before plucking a gamete out of its natural environment and subjecting it to in vitro conditions. The oocyte maturation process requires an intact meiotic spindle, proper nuclear maturation whereby there is resumption of meiosis (cell reduction division) and cytoplasmic maturation that enables accumulation of growth factors, leading to normal fertilisation and growth in vitro. Apart from these processes, disruption of epigenetic events from maternally expressed genes could result in poor integrity of embryos post fertilisation.
In conclusion, newer culture methods and research methodologies that cut costs and complications are most welcome; however, elaborate multicentre studies and a follow-up of the pregnancies and births are required to ensure that results are on par, or better than conventional and time-tested IVF methods.
The real test of IVF is not merely pregnancy rates, but how well the babies are doing 20 years into the future.
(Dr. Priya Selvaraj is Director, GG Hospital, Fertility Research and Women's Specialty Centre, Chennai. She can be reached at drpriya@
