A safer, friendlier IVF

The ultimate goal of IVF is to achieve pregnancy through the transfer of one or more embryos into the uterus. To reach that goal, the woman first receives medication so that multiple follicles develop in the ovaries, each containing an oocyte.

Oocyte retrieval and fertilisation?

Once the follicles reach the appropriate size, oocyte retrieval is performed: the oocytes inside them are aspirated from the ovaries with a fine needle under light anaesthesia. In the laboratory, the oocytes are fertilised with the partner’s sperm, and the resulting embryos are transferred to the uterus a few days later.

Why does the choice of medication matter?

The choice of stimulation protocol and gonadotrophin dose is one of the most decisive steps in IVF. It affects both the number of oocytes retrieved and the burden the woman experiences — physical, psychological, and the risk of serious complications such as ovarian hyperstimulation syndrome. Research over recent years has shown that equivalent or better pregnancy rates can be achieved with regimens that are markedly friendlier and safer.

GnRH agonists — the older approach?

Traditional stimulation protocols were based on GnRH agonists, compounds introduced into IVF in 1984. Agonist therapy has two serious drawbacks. First, its duration is long: about one month elapses between the first injection and oocyte retrieval. The prolonged treatment is a physical and psychological burden on the couple, and because more than one cycle is often required, this cumulative burden can lead to premature abandonment of the effort. Second, the risk of ovarian hyperstimulation syndrome — the most serious complication of treatment — is higher than with modern protocols.

GnRH antagonists — the contemporary approach?

The serious drawbacks of agonists focused research on how to make IVF friendlier and safer for the woman. The answer came with the use of GnRH antagonists. The antagonist protocol shortens treatment from 25–30 days to just 10–12. The current Cochrane meta-analysis (Al-Inany 2016) confirms that the antagonist protocol delivers equivalent live-birth rates to agonists while halving the risk of ovarian hyperstimulation and the related hospital admissions. The antagonist protocol is today the treatment of choice in the major reproductive medicine centres worldwide.

Is there an alternative to daily FSH injections?

Yes. Corifollitropin alfa (ELONVA) is a long-acting form of recombinant FSH. A single subcutaneous injection covers the first 7 days of ovarian stimulation, replacing the equivalent daily FSH injections. It is used in combination with a GnRH antagonist protocol. From day 8 onward, if additional stimulation is needed, conventional daily FSH is administered until the cycle is complete. ELONVA substantially reduces the number of injections and improves the patient’s experience without changing live-birth rates (Devroey 2009; Pursue trial 2014).

How is ovarian hyperstimulation prevented today?

OHSS prevention no longer rests on protocol choice alone. Current practice combines several tools to minimise the risk: individualisation of the gonadotrophin dose based on markers of ovarian reserve (AMH, AFC); the antagonist protocol, which allows the alternative of triggering with an agonist; triggering of ovulation with a GnRH agonist instead of hCG in women with a high response — a strategy that practically eliminates severe OHSS; the freeze-all strategy in high-risk patients, with transfer in a subsequent cycle once the ovaries have settled; and administration of cabergoline in selected cases.

Is the same drug dose appropriate for every woman?

No. Ovarian response varies considerably between women, even at the same age. Modern practice individualises the gonadotrophin dose based on markers of ovarian reserve — AMH (anti-Müllerian hormone) and antral follicle count (AFC). This individualisation minimises both the risk of poor response (too low a dose) and the risk of hyperstimulation (too high a dose), and allows most women to complete their cycle safely.

What is PPOS (progestin-primed ovarian stimulation)?

In this more recent protocol, the LH surge during stimulation is suppressed using an oral progestin (most often dydrogesterone or medroxyprogesterone acetate) instead of injectable GnRH antagonist. PPOS has shown live-birth rates comparable to the antagonist protocol, at lower cost and with fewer injections. Because progestin alters the endometrium, fresh embryo transfer is not possible in a PPOS cycle — all embryos are cryopreserved and transferred in a subsequent thaw cycle. PPOS therefore has its place particularly when a freeze-all strategy is planned anyway (e.g. PGT-A, high response, polycystic ovary syndrome).

Simple, safe and effective IVF — long demanded by couples and the medical community alike — is now a reality. Infertile couples, in their effort to bring a healthy child into the world, expect nothing less.

Summary.
The evolution of ovarian-stimulation protocols over the past two decades has made IVF substantially friendlier and safer. The GnRH antagonist protocol is the treatment of choice today: shorter, equally effective, and half the risk of hyperstimulation. Combined with individualisation of the dose, GnRH agonist triggering in high-risk patients, and the freeze-all strategy where needed, contemporary IVF delivers the same pregnancy rates with dramatically reduced burden and risk to the woman.