O-111 Conventional stimulation remains the gold standard
Authors: Bosch Aparicio E 
Published: June 2023

Abstract

Ovarian stimulation (OS) remains a crucial step of IVF process since cycle outcomes per cycle after OS are remarkably higher when compared to a natural or modified natural cycle. Within the concept of OS, two approaches are purposed: On one hand, “mild” stimulation claims for the use of low doses of gonadotrophins in order to yield a moderate number of eggs that should be enough to achieve a pregnancy. On the other, the so called “conventional” stimulation aims to maximize ovarian response, with the goal of obtaining the higher number of embryos that is possible and therefore increase the number of attempts per pick up to reach the highest chance of pregnancy for each patient in one cycle.
Defenders of mild stimulation, claim that obtaining oocytes beyond a certain response (classically eight eggs) is useless, since these surplus oocytes won’t be able to provide good quality embryos. In other words, this statement is based in a hypothesis according to which a soft stimulation of the ovaries would lead them to mature only the good quality eggs, while those of lower quality would not respond to these low doses and would remain immature in the ovaries. A few numbers of old studies performed with outdated technologies support this this concept.
However, a large body of evidence shows that the contrary is true. Old studies that related ovarian response to cycle outcome considering only the chances of achieving a live birth after just a fresh embryo transfer, showed that live birth rate increased as the ovarian response did up to around 15 oocytes, while it shows a “plateau” beyond this response. But moreover, more recent studies in which the cumulative live birth rate achieved after one live birth is achieved or until all viable embryos that were cryopreserved were transferred, shows that it improves linearly as the ovarian response does, starting to plateau only for ovarian responses larger than 35-40 eggs.
A very recent study that analyses more than 400,000 cycles from the Society for Assisted Reproductive Technology Clinic Outcome Reporting System (SART) confirms these figures. This large sample allows for stratified analysis according to age, BMI, AMH or infertility diagnoses that further confirm the findings. Altogether, these studies show that the concept of some kind of “oocyte quality selection” happens when a mild stimulation is used does not really happen. Large ovarian responses increase the number of good and bad quality oocytes equally.
The idea of ovarian stimulation hampering oocyte quality has been around for more than 30 years. Theorical concepts based on observations in the animal model suggested that this might be the case. However, studies in humans have been unable to prove this hypothesis. In this context, the best model to prove this concept is the intra-patient comparison between the non-stimulated and the conventionally stimulated cycle. Our group has performed two studies following this approach so far. In the first one, we included 46 oocyte donors. PGT-A was performed to the embryos obtained in both cycles, which at time was performed on day 3 embryos with FISH technology. The study showed that there were no significant differences in the aneuploidy rate between the 2 cohorts of embryos (34.8% vs 32.8%), suggesting no harm of ovarian stimulation. These findings have been recently confirmed in 40 infertile patients aged 30-38, in which PGT-A was done with a comprehensive chromosomal analysis using NGS after blastocyst biopsy.
In conclusion, research and clinical evidence show that conventional OS does not harm oocyte quality and increases the cumulative birth rate per oocyte pick-up, making it as the first choice for treating patients with IVF.

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