A mandatory step in the ovarian stimulation for IVF is firstly the gonadotropin dose and secondly the protocol. Regarding the prediction of hyper-response, recent evidence suggests the superiority of AMH over antral follicle count [¹¹,¹²]. In a prospective cohort of 262 IVF cycles with 8% moderate and severe OHSS, Lee et al showed that an AMH cut-off value of 3.36 ng/mL gave a sensitivity of 90.5% and a specificity of 81.3% to predict OHSS [¹¹,¹²]. Regarding the antral follicle count, Kwee et al have shown that a cut off level of > 14 antral follicles gave the highest sensitivity (82%) and specificity (89%) and also the highest accuracy. With a prevalence of 15% for high response (defined as > 20 oocytes in an IVF treatment), the accuracy was 88% [¹³]. According to these thresholds, a woman considered to be at high risk of developing OHSS should be stimulated with low doses of gonadotropins and preferably co-treated with a GnRH antagonist. Nevertheless, individualization of doses and protocol utilized depends on the clinical experience of the treating physician.

Although we use certain cut-off values and our clinical experience to avoid hyperstimulation, we many times fail and the patients ends-up with an excessive ovarian response. As mentioned, Papanikolaou and colleagues have shown that the first prerequisite for OHSS development is the development of multiple follicles and specifically more than 18 follicles with a diameter above 11 mm and/or above 5000 pg/ml Estradiol [²,¹⁴]. Thus, from the late follicular phase and onwards, it becomes clear which patient is potentially at high-risk of developing OHSS. Therefore, a modification of the ovarian stimulation should be applied, either decreasing the dose of gonadotropins or administering the triggering bolus of hCG earlier (when three follicles reach the size of 17 mm). In GnRH antagonist protocols, this has been shown to be more efficient compared to later administration at a larger follicular size [¹⁵,¹⁶]. Both these actions intend to induce the regression of small and medium sized follicles initially recruited, which will decrease the risk of OHSS.

Once the patient has met the criterion set above, the clinician has two options for triggering ovulation: either to administer a lower dose of HCG (250 mcg rec-HCG or 3,300 to 5000 IU urinary hCG), which is the traditional way, applicable in GnRH agonist as well as GnRH antagonist protocols [¹⁶]; or to administer GnRHa for final oocyte maturation (0.2 mg Triptorelin or 0.5 mg Buserelin or 1 mg Leuprolide), the innovative way, applicable only in the Antagonist protocol [¹⁷].

On the first day after the oocyte retrieval, a decision should be made whether to proceed with luteal phase support and subsequently embryo transfer or to freeze all embryos. On this day, the physician will have performed an ultrasound measuring the quantity of fluid in the pouch of Douglas and the ovarian volume; he should also assess the physical condition of the patient i.e. the degree of pain, discomfort, use of painkillers, and breathing difficulty [¹⁵]. In addition, the number of fertilized oocytes will be known. Taking these facts into account and adding the efficacy of the cryopreservation program of the unit, a decision can be made whether to proceed with the embryo transfer or to freeze all embryos.

Prior to a day-5 transfer, an ultrasound should be performed in combination with blood tests (Hematocrit, WBC, PLT, PT, aPTT, Fibrinogen, D-Dimers, Urea, Creatinine, ALT, AST, gGT, ALP, K, Na, Total Protein, Albumin) to identify patients at high risk of developing severe late onset OHSS. If the evaluation is reassuring a single blastocyst transfer can be performed, followed by vitrification of spare blastocysts [²⁵]. If a patient is considered at high risk of developing OHSS - as might often be the case if hCG triggering has been utilized - the embryo transfer should be cancelled. For units working with slow freezing only or having low blastocyst development rates, an alternative option is to freeze half of the embryos at the cleavage stage and allow the rest to develop into blastocysts. If the condition of the patient permits it, a blastocyst transfer is performed and surplus embryos are cryopreserved.