IVM Concerns: Large Offspring Syndrome

July 7, 2010Carole 2 Comments »

The European Society of Human Reproduction and Embryology (ESHRE) made IVF news last week when Dr Peter Sjoblom, unit manager of Nurture, the Nottingham University IVF clinic at Queen’s Medical Centre (Nottingham, UK), and his colleagues reported that in vitro maturation (IVM)  of human eggs before fertilization resulted in a higher incidence of overweight babies, requiring cesarean section for delivery.  THe miscarriage rate and length of gestation also appeared higher for babies conceived with IVM eggs. Their study looked at babies conceived naturally or through the use of IVM with IVF,  IVF alone or IVF with ICSI. Babies born from natural conception or IVF with or without ICSI were less likely to be overweight at birth, suggesting that something associated with in vitro maturation of eggs may be the trigger. The observed association of IVM with abnormally large birthweight is consistent with Large Offspring Syndrome that has been reported and studied in livestock animals for the better part of twenty years. It was commonly observed when cattle embryos were cloned to increase the number of offspring with certain desirable traits.

In calves, Large Offspring Syndrome was associated with breathing difficulties, problems with suckling and increased chance of sudden death shortly after birth. It is important to note that no such effects have been reported in overweight human babies. In fact, Large Offspring Syndrome was thought to only occur in livestock, not humans, until this troubling report. In 2013, ASRM published a committee opinion that the IVM should be considered experimental until more data was available on the health of children born using this technique.

What is in vitro maturation? In vitro maturation bypasses the normal stimulation protocols and the egg retrieval is performed with no ovarian stimulation or a very minimal stimulation. Because stimulation drugs are used little or not at all, it is sometimes promoted as a low-cost IVF option. Another reason IVM is used is for women with polycystic ovarian syndrome (PCOS) who tend to have an increased risk of ovarian hyperstimulation syndrome (OHSS) from the routine stimulation protocols. OHSS can result in dangerous life-threatening complications.

IVM process. Immature eggs are collected by egg retrieval, then cultured in the lab for a period of days until the eggs complete the maturation program and push out one polar body, signaling that maturation is complete and the egg is ready to be fertilized. The problem is that although we can get mature eggs this way, we don’t understand how it happened on a molecular level. We do know that during egg maturation and during early embryonic development, our genes are being modified. During egg maturation, the DNA is being modified by poorly understood maternal factors to make genes more or less active in a process called genetic imprinting. Genetic imprinting involves molecular changes like the addition of a methyl group to a molecule of DNA. It’s very subtle chemical change but has profound effects on how the genetic program runs because specific gens can be preferentially turned off or on. We know from studies in livestock animals that in vitro culture conditions can affect imprinting. Because it doesn’t happen consistently in all offspring produced by IVM, it’s difficult to nail down the root causes of Large Offspring Syndrome.

Scientists know that culture conditions should mimic nature as closely as possible so that imprinting and embryo development can proceed normally but understanding nature is still at the research stage. Ammonia in the medium from the breakdown of amino acids in the medium was shown to cause a problem with embryo culture and media makers took pains to find culture media recipes that minimized the ammonia load in the media. The problem is, although media have improved dramatically as shown by the improved pregnancy rates over the last decade, perfecting in vitro culture, at last for IVM is still a work in progress.

With IVM, we are asking the culture medium to do the work of the ovarian follicle, an incredibly complex system. Scientists are still trying to understand how the ovary works to create mature eggs. We can use stimulation drugs to goose the ovary into making more eggs but we have an incomplete understanding of every molecular pathway involved so mimicking an ovary with a culture system is no small feat. We aren’t there yet.

Because there is no real funding of IVF research in this country, IVF clinics and patients end up being the research labs and research subjects. We extrapolate a lot from cattle and sheep IVF protocols but cross-species comparisons eventually fall short of the exact knowledge we need to provide safe clinical IVM culture techniques in the clinic.

Some of the cutting-edge research being done with IVM is happening through the Oncofertility Consortium which has an NIH-funded grant to study better methods of fertility preservation for cancer patients.  Their basic research studies are described here if you are interested. Cancer patients often don’t have many options and extraction and freezing of ovarian tissue for future IVM may be the only option due to the need for immediate cancer treatment or pre-pubertal age of the patient.

The bottom line is that I would probably avoid IVM for the moment if I had other options. Well-intentioned scientists and clinicians are looking for safe clinical IVM protocols but recent evidence that Large Offspring Syndrome can occur in babies conceived using in vitro matured eggs suggest that current IVM protocols are not yet optimized.  If you have  PCOS and have had difficult stimulations before, you might need to shop around for an RE with a lot of experience stimulating PCOS ovaries. Non-traditional stimulation protocols using Letrozole have been used with success to stimulate PCOS ovaries without increasing the risk of OHSS.

© 2010 – 2015, Carole. All rights reserved.

2 Responses to this entry

  • Julie Says:

    Hi Carole, I know this is an old post. I’m curios as to whether there are any new findings in this area. Have IVM methods been refined to reduce the risk?

  • Carole Says:

    Dear Julie,
    I haven’t heard much about IVM and don’t think it’s been widely adopted. It is still more in the research realm, than clinic. IVM is still not needed for most patients so the impetus to bring it into widespread use is really not there. Best Wishes, Carole

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