Do more embryos increase the chance of pregnancy?

The aim of pharmacological stimulation in IVF is to develop multiple follicles, so that multiple oocytes can be retrieved. From these oocytes several embryos are produced; the best are selected for transfer to the uterus, while the rest are cryopreserved for future use.

The intuitive expectation would be that the more oocytes retrieved, and the more embryos produced, the higher the chance of pregnancy. The reality is more nuanced — and has important practical consequences for how each woman is stimulated.

How does prolonged stimulation affect the endometrium?

During ovarian stimulation, oestradiol levels produced by the simultaneous development of multiple follicles reach — and often exceed — ten times the levels seen in a woman’s natural cycle. These supraphysiological oestradiol concentrations act on the endometrium, reducing its receptivity at the implantation window — and consequently reducing the chance of pregnancy in a fresh cycle.

Why does the progesterone level on the day of triggering matter?

Alongside the rise in oestradiol, a significant proportion of women show a premature rise in progesterone during ovarian stimulation. When the progesterone level on the final day of stimulation exceeds 1.5 ng/ml, the chance of pregnancy in a fresh cycle is significantly reduced (Kolibianakis 2002; Venetis 2013). The phenomenon is seen with both GnRH agonist and GnRH antagonist protocols, and is attributed to premature endometrial maturation that becomes “out of phase” with the embryo at the time of transfer.

Does prolonging stimulation harm the outcome?

Once adequate follicular development has been achieved, extending the stimulation phase by more than 2 days — in pursuit of additional oocytes — is associated with a reduced chance of pregnancy in a fresh cycle. The detrimental effect comes from the combination of excessively high oestradiol and premature progesterone rise. Extended stimulation does not, therefore, deliver a simple “more embryos = better outcome”.

When do more embryos actually help?

When the freeze-all strategy is used and transfer is performed in a subsequent cycle, the question of endometrial receptivity in the stimulation cycle no longer affects the outcome. In that setting, a larger number of high-quality embryos increases the cumulative live-birth rate — the probability of a live birth across all successive transfers performed from a single oocyte retrieval. Important nuance: while the live-birth rate per fresh cycle peaks at around 15 oocytes in women under 35 and then declines (Sunkara 2011), the cumulative live-birth rate — which accounts for all subsequent frozen transfers — does not show a clear plateau in the available data, only a progressively diminishing marginal gain per additional oocyte (Polyzos & Sunkara 2015; Drakopoulos 2016). In practice, the maximum number of oocytes that can be safely retrieved is limited by the risks of ovarian hyperstimulation and by the woman’s inherent ovarian reserve.

What is the contemporary strategy?

The aim is not maximal ovarian stimulation, but optimal. That means individualising the gonadotrophin dose based on markers of ovarian reserve (AMH, AFC); ending stimulation once adequate follicular development is reached, without extra days “for more oocytes”; monitoring progesterone on the day of triggering and planning freeze-all if it is elevated; and choosing fresh or frozen transfer on the basis of the specific cycle conditions, rather than as a blanket rule.

Extension of the follicular phase should be considered with great care and undertaken only when clinical circumstances require it. Otherwise we deliver more embryos to the couple while at the same time reducing their chance of pregnancy in the fresh cycle.

Summary.
The answer is not yes or no, but depends on context. In a fresh cycle, pushing for more embryos through prolonged stimulation may reduce the chance of pregnancy, due to the effect of supraphysiological oestradiol and premature progesterone rise on the endometrium. With a freeze-all strategy, a larger number of high-quality embryos increases the cumulative live-birth rate — but with clear ceilings beyond a certain number of oocytes. The contemporary aim is optimal — not maximal — ovarian response.