Minimal Simulation and Natural Cycle In Vitro Fertilization


Minimal Simulation and Natural Cycle In Vitro Fertilization, Allahbadia, G and Nitzschke, M, 2015

Preface (Allahbadia, G and Nitzschke, M)


Dr. Daiter’s summary of this chapter

After a brief history of Assisted Reproductive Technology (ART), the book’s authors describe the major problems associated with the current conventional method of IVF using high doses of stimulation medications.  These include:


  1. high multiple pregnancy rate.  This is less often encountered when elective single embryo transfer is performed, however, it does remain a major problem in a lot of centers around the world
  2. reduced egg and embryo quality following high dose controlled ovarian hyperstimulation.  The authors point to literature concluding that a woman is only capable of producing 2-3 genetically normal oocytes (eggs) per cycle and that the other remaining (supernumerary) eggs and embryos that result from aggressive stimulation protocols will therefore not result in a live birth
  3. exposure to the risk of ovarian hyperstimulation syndrome (OHSS).  OHSS is a potentially life threatening condition that results from the over reaction of the patient to high dose of stimulation medication, which occurs as severe OHSS possibly requiring hospitalization in 2-4% of all stimulated IVF cycles worldwide
  4. reduced endometrial receptivity to an embryo trying to implant.  The high (markedly supra physiological) circulating doses of estrogen and progesterone that are associated with conventional stimulation protocols for IVF result in accelerated endometrial development, which results in a de-synchronization of the normal relationship between embryo and endometrial development and reduces the likelihood of implantation within the (normally narrow) window of uterine receptivity.

As a potential solution to these problems, the use of natural cycle IVF or minimal stimulation IVF may eliminate or reduce these risks.  In natural cycle IVF the natural selection process that normally occurs within the body (ovaries) is thought to always select the best egg for ovulation.  By eliminating, or significantly reducing, stimulation medication the cost of treatment is significantly reduced and the risks of treatment are either eliminated or markedly reduced.

Natural cycle IVF is not offered at many IVF centers around the world, for reasons that the authors believe to include:


  1. natural cycle IVF is “not efficient.”  The authors point out that this depends on how efficiency  is being judged or determined, stating that they believe natural cycle IVF is the most efficient IVF option available.  Most studies on natural cycle IVF report a live birth rate of about 20% per oocyte retrieved, which is excellent
  2. natural cycle IVF is very difficult to learn.  Natural cycle IVF requires frequent interpretation of the patient’s hormonal patterns in order to find the correct time to trigger ovulation and retrieve the eggs

As natural cycle IVF becomes more popular once again, it is likely that it will be used preferentially for some specialized groups of patients for whom it would be especially beneficial, including:


  1. “so-called poor responders”  Patients with low ovarian reserve do not respond well to conventional controlled ovarian stimulation largely since their baseline serum FSH concentration is already elevated and they have few antral follicles, so these patients rarely produce more than 4-5 follicles with stimulation.  Mild stimulation generally produces the same number of mature eggs as aggressive stimulation protocols, so the use of less medication is logical in this group of patients since it reduces cost and complications.
  2. Patients over 40 years age.  This patient group is stated to be particularly sensitive to high FSH levels and FSH fluctuations during ovarian stimulation, which may increase the likelihood of aneuploidy in eggs and embryos obtained from these patients undergoing conventional stimulation protocols.  The authors propose that aneuploidy may be reduced for women over 40 that undergo mini IVF protocols versus conventional IVF protocols.

Dr. Daiter’s review of this chapter

The authors make several important points to consider in this preface.

The major problems associated with conventional protocols for ovarian stimulation, using high doses of FSH containing medications along with a GnRH agonist or GnRH antagonist, do put patients at risk for higher order multiple pregnancies (twins, triplets, or more), ovarian hyperstimulation syndrome especially in PCOS patients, and most likely reduced implantation rates due to impaired endometrial receptivity.  I am not so certain the ability to only produce 2-3 genetically normal eggs per cycle is universally true, but it does seem to be the case for most patients.

It is reassuring to see that the authors have many studies from centers around the world that support the clinical efficiency of natural cycle IVF comparing the reproductive potential to conventional IVF “egg for egg” (of course, conventional IVF retrieves many more eggs per cycle compared to natural cycle IVF) when the clinic has significant expertise in timing events based on hormone values.

The patients that would particularly benefit from natural cycle or mini IVF are noted to include patients with (1) a history consistent with “poor ovarian response” or (2) patients over 40 years of age.  This is true, but I also think that this list should include: (3) patients with PCOS (who would benefit significantly from lower exposure to the risk of OHSS), (4) patients with a medical condition that makes aggressive controlled ovarian hyperstimulation contraindicated (such as breast cancer that is estrogen or progesterone receptor positive), (5) patients who would prefer more natural IVF cycles for a variety of personal or moral reasons, and (6) patients who just cannot afford to undergo conventional IVF but require IVF to conceive (severe tubal problems, severe male factor, unexplained infertility without pregnancy following less aggressive treatments).

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