A total of 387 patients underwent GnRH antagonist rescue between January 2004 and May 2010 and thus comprised the study group. During the same time period, 271 patients met criteria for the comparison group with a serum oestradiol concentration ≥4000 pg/ml on day of HCG administration. A total of 2620 assisted cycles were performed during the study period. Patients in the study and comparison groups were similar with respect to age, body mass index, gravidity, parity and diagnosis (). Because patients at highest risk for OHSS received antagonist rescue, the basal antral follicle count was significantly higher in the antagonist rescue group (22.2 versus 18.7; P < 0.001). Use of intracytoplasmic sperm injection and MDF protocol was similar between the two groups. The temporal distribution of the proportion of patients in each group was similar annually from 2004–2010. Of those receiving the GnRH antagonist, 323 patients received it for 1 day, 58 patients for 2 days and six patients for 3 days.
Baseline demographics and IVF protocol differences between the GnRH antagonist rescue and comparison groups.
The peak oestradiol concentrations on the day after HCG administration were similar between the two groups (antagonist rescue 5773 pg/ml versus comparison 5940 pg/ml). Patients in the antagonist rescue group had a higher number of follicles aspirated, oocytes retrieved, mature oocytes and fertilized oocytes (2PN) (). However, this was primarily a function of more follicles, as the percentage oocyte yield, oocyte maturity and fertilization rate were similar between the two groups.
Patients in the GnRH antagonist rescue group had more high-grade cleavage-stage embryos (grade 1 or 2) (4.0 versus 2.9; P
< 0.001) because they had more fertilized oocytes. However, the distribution of embryos at each grade was not significantly different (), supporting similar embryo quality between the groups. Patients in the GnRH antagonist rescue and comparison groups had similar numbers of expanded blastocysts, blastocysts and morulas. The GnRH antagonist rescue group had higher overall numbers of early blastocysts per patient (5.4 versus 3.7; P
< 0.01). The distribution of embryos at each stage of blastocyst development was not different between the two groups (). Patients in the GnRH antagonist rescue group were further stratified by age groups (<35, 35–37, 38–40 and 41–42 years) and embryo quality at the cleavage and blastocyst stage was compared between the four age groups. No statistically significant differences were noted in embryo quality between any of the age groups receiving GnRH antagonist rescue (Supplementary Figure 1
, available online only). However, this analysis may be limited by the relatively small number of patients in the oldest age group.
Day-3 embryo grading and blastocyst development in the antagonist rescue and comparison groups. (A) High-grade embryos were classified as embryos grade I and II combined. (B) Blastocyst development. There were no statistical differences.
There was no difference in clinical pregnancy rates between the two groups (antagonist rescue 51.9% versus comparison 49.1%) (). Live-birth rates were also similar between the two groups (antagonist rescue 41.4% versus comparison 36.9%). Rates of biochemical pregnancy and spontaneous abortion were not different between the two groups. Within the antagonist rescue group, the live-birth rates were 42%, 34% and 67% in patients receiving 1, 2 and 3 days of antagonist rescue, respectively.
There was no difference in the rate of cycle cancellation prior to HCG administration due to severe risk of OHSS between the two groups (antagonist rescue 1.5% versus comparison 1.1%). Four patients in the antagonist rescue group (1%) and one patient in the comparison group (0.4%) developed signs of severe OHSS after oocyte retrieval but prior to embryo transfer and therefore had all embryos cryopreserved to mitigate the risk of worsening OHSS. The overall rate of severe OHSS was 1.2% (32/2620 cycles) during the study period. Consistent with the fact that all patients at high risk for OHSS were treated with antagonist rescue, the rate of OHSS was higher in the antagonist rescue cohort (8.0% versus 0.4%; P < 0.01). No adjunct treatments for mitigating OHSS risk (i.e. dopamine agonist, albumin) were given to any patient.
displays the mean serum oestradiol trends in the comparison group and in patients receiving 1, 2 and 3 days of GnRH antagonist rescue. The mean serum oestradiol for all antagonist rescue patients fell by 35% on the first day of GnRH antagonist treatment. Subsequently, the mean oestradiol rose by 96% in response to HCG administration. In patients receiving 2 days of antagonist rescue, oestradiol concentrations remained relatively stable on day 2 of antagonist treatment (mean 4% rise). In patients receiving 3 days of antagonist rescue, serum oestradiol concentrations also remained relatively stable on days 2 and 3 of antagonist (means –9% and 12%, respectively). The peak oestradiol concentrations on the day after HCG administration were not significantly different between the three groups, regardless of how many days of antagonist.
Figure 2 Mean serum oestradiol concentrations (pg/ml) as measured at each point during stimulation. Day 4 refers to day 4 of stimulation; 1 day of gonadotrophin-releasing hormone antagonist: n = 323; 2 days of antagonist: n = 58; 3 days of antagonist: n = 6; control: (more ...)
On the day prior to antagonist rescue, patients treated with MDF had higher mean oestradiol concentrations than patients treated with LA (3095 versus 2875 pg/ml, respectively; P
= 0.05). However, serum oestradiol concentrations were not statistically different between the two protocols on the day after antagonist administration or the day after HCG. GnRH antagonist rescue reduced the mean serum oestradiol concentrations by 38% in patients receiving MDF and by 34% in patients receiving LA (Supplementary Figure 2
The mean oestradiol change in patients receiving less than one, one, two or three vials of HMG on the day of GnRH antagonist rescue was analysed (Supplementary Figure 3
). Oestradiol changes in response to antagonist were –45% in patients receiving less than one vial of HMG, –37% for one vial of HMG, –10% for two vials of HMG and 2% for three vials of HMG. The fall in oestradiol concentrations for patients receiving less than one or one vial of HMG was significantly greater than those receiving two or three vials (P
Compared with patients who did not develop OHSS, antagonist rescue patients who went on to develop severe OHSS had higher basal antral follicle counts (29.1 versus 21.6; P < 0.001) and more follicles >10 mm on the day of HCG (35.1 versus 27.5; P < 0.001). While patients who developed OHSS had higher oestradiol concentrations on the day of GnRH antagonist rescue (4752 versus 4287 pg/ml; P = 0.03), the two groups had similar oestradiol concentrations on the day after antagonist administration (3068 versus 2953 pg/ml). Despite having similar oestradiol concentrations on the day of HCG administration, patients who developed OHSS had higher peak oestradiol concentrations 1 day after HCG than patients who did not develop OHSS (6806 versus 5684 pg/ml; P < 0.001).
There was no significant difference in the rate of severe OHSS in GnRH antagonist rescue patients based upon threshold values of oestradiol on the day of HCG administration (). However, the rate of severe OHSS was found to increase in patients with higher oestradiol concentrations on the day that GnRH antagonist was initiated (). Rates of severe OHSS were 16% in patients with oestradiol concentrations 5000 pg/ml (5000–8390 pg/ml) on the day of antagonist start and 25% in patients with oestradiol concentrations 6000 pg/ml (6000–8390 pg/ml). While oestradiol concentrations on the day of HCG were not associated with severe OHSS because of antagonist suppression of oestradiol, the number of follicles ≥10 mm measured by transvaginal ultrasound were correlated to severe OHSS risk (). The percentage of patients with OHSS was 13%, 17% and 24% in patients with 10–30, 10–35 and 10–40 follicles, respectively. The percentage of patients with OHSS was not statistically different in patients receiving 1, 2 and 3 days of antagonist (8.0%, 8.6% and 0%, respectively).
Figure 3 Threshold graphs showing the rates of severe ovarian hyperstimulation syndrome (OHSS) above various cut-off values of oestradiol and follicle number in the GnRH antagonist rescue group according to threshold values of: (A) oestradiol measured on day of (more ...)