GnRHa trigger and modified luteal support with one bolus of hCG should be used with caution in extreme responder patients

Dear Sir, We read with interest the retrospective report by Seyhan et al. (2013) presenting five cases of early ovarian hyperstimulation syndrome (OHSS) in OHSS high-risk patients, following GnRHa trigger and modified luteal phase support with one bolus of 1500 IU hCG. As we have performed the majority of randomized controlled trials (RCTs) in this field, we feel an urge to further comment on the paper, although the report was previously accompanied by an editorial (Bodri, 2013). Seyhan et al. (2013) in their two-centre retrospective analysis included 23 patients at risk of developing OHSS, defined as ‘a high number of follicles ≥12 mm during the late follicular phase’. Patients received a GnRHa trigger followed by a bolus of 1500 IU hCG on the day of oocyte retrieval (Humaidan et al., 2005; Humaidan, 2009; Humaidan et al., 2010). If a decision was made to go ahead with an embryo transfer a standard luteal phase support was added to the protocol. A total of six patients (26%) developed severe OHSS of whom five patients developed early onset OHSS (22%). Of these patients three had their embryo transfer cancelled and two received a dual embryo transfer. The authors analyzed possible risk factors of OHSS and concluded that the only significant parameter was the number of follicles measuring 10–14 mm on the day of trigger, being significantly higher in the patients who developed severe early OHSS. This made the authors conclude that it would be prudent to avoid hCG luteal rescue and instead freeze all embryos in women with a total of ≥18 follicles with 10–14 mm diameters. GnRHa trigger followed by a modified luteal phase support with one bolus of 1500 IU hCG was developed by our group through a series of trials (Humaidan et al., 2005; Humaidan et al., 2010) mainly involving normal responder patients. However, in our RCT from 2010, including 302 patients (Humaidan et al., 2010), more than one-third of the patients in the GnRHa triggered as well as the hCG triggered groups had .14 follicles ≥11 mm on the day of trigger, a level previously suggested to distinguish between the OHSS risk patient and the patient at low risk of OHSS (Papanikolaou et al., 2006). No patient developed OHSS in the GnRHa triggered group versus 2% after hCG trigger. In our latest RCT including a total of 384 patients (Humaidan et al., 2013) we randomized 118 patients considered at risk of OHSS to either GnRHa trigger followed by the previously described modified luteal phase support or trigger with 5000 IU hCG. Risk of OHSS was a priori determined as the presence of 15–25 follicles ≥11 mm on the day of triggering final oocyte maturation. Importantly, patients with .25 follicles were excluded from this study based on the results of a previous pilot study in OHSS risk patients (Humaidan, 2009). In this new large RCT, no OHSS case was seen after GnRHatrigger and modified luteal phase support when compared with two moderate late-onset OHSS cases (3.4%) after hCG trigger. Reassuringly, no statistical difference in ongoing clinical pregnancy rates between the two trigger concepts was observed. Thus, in patients with up to 25 follicles, we feel quite confident with the use of GnRHa trigger followed by a modified luteal phase support with one bolus of 1500 IU hCG. Above 25 follicles we recommend a ‘freeze all’ policy. If for some reason a decision to perform a fresh transfer is made in this type of OHSS high-risk patient, it is our clinical experience that luteal supplementation with hCG postGnRHa trigger should only be performed in the well-informed patient with great caution and employing a lower dose of hCG. Regarding the Seyhan et al. paper (2013) our main concern and utter surprise is the fact that the authors still decided to proceed with a bolus of 1500 IU hCG in patients who had as many as 50–65 oocytes retrieved. This conduct seems to us unethical, jeopardizing the health of the patient when it would have been more prudent to ‘freeze all’ after GnRHa trigger without any risk whatsoever of OHSS development in the patient. Although GnRHa trigger and modified luteal phase support has allowed fresh transfer in OHSS risk patients, there is clearly an upper biological limit above which it would be unrealistic to believe that all OHSS cases could be avoided. In these cases we call upon the sound clinical judgment of the treating clinician. We also question the upper cut-off value of ≥18 follicles measuring 10–14 mm suggested by Seyhan et al. (2013), as these results derive from a retrospective analysis including 23 OHSS risk patients only. Moreover, in their paper, this cut-off value is severely jeopardized by the discrepancy between the follicular count on the day of trigger and the actual number of oocytes retrieved in several of their patients. In conclusion, GnRHa trigger followed by a modified low-dose early luteal hCG support will provide patients who on the day of trigger have developed up to 25 follicles .11 mm with the opportunity to proceed to fresh embryo transfer with good ongoing pregnancy rates and no OHSS according to the results of our latest RCT. However, until ongoing studies have defined the minimal hCG activity needed in patients with .25 follicles ≥11 mm, we firmly recommend GnRHa trigger followed by a ‘freeze all’ policy to avoid any risk of OHSS development.