The results of this study demonstrate that the dual trigger comprising GnRHa and low-dose hCG (1000 IU or 2000 IU) for final oocyte maturation was associated with a significantly increased risk of moderate to severe OHSS compared to GnRHa trigger alone in high responders who underwent the freeze-all strategy. Moreover, we showed that the rates of oocyte maturation, fertilization, top-quality day 3 embryos, CLBR, and neonatal outcomes were comparable between the dual trigger and GnRHa single trigger. These results are crucial for guiding clinical practice and encouraging the use of GnRHa trigger alone in high responders in order to prevent the occurrence of moderate to severe OHSS and have no negative effects on pregnancy and neonatal outcomes for subsequent FET cycles.
OHSS is one of the serious iatrogenic complications in patients undergoing assisted reproductive technology and is characterized by increased vascular permeability, hemoconcentration, and fluid leakage to the third space, which can cause liver and/or kidney damage, thrombosis, and life-threatening events in severe cases . A variety of strategies have been developed to prevent and reduce the occurrence of OHSS, the most effective being the use of GnRHa instead of the traditional hCG to trigger final oocyte maturation in GnRH antagonist cycles [22, 23]. Engmann et al. showed that GnRHa trigger alone could be used to completely prevent the occurrence of OHSS in the fresh embryo transfer cycle in high responders . Another study also found that for patients with polycystic ovary syndrome treated with GnRH antagonist protocol, the most effective strategy to eliminate the incidence of moderate and severe OHSS was the GnRHa trigger for final oocyte maturation . The results of the present study are consistent with these conclusions. For high responders, the strategy of GnRHa trigger alone combined with the freeze-all policy can fully prevent the occurrence of moderate to severe OHSS.
The amplitude of the LH peak induced by GnRHa is smaller, and the duration is shorter, which may help to reduce the risk of OHSS [8, 25]. However, this is associated with insufficient corpus luteum function and decreased endometrial receptivity [9, 10, 26]. For the fresh embryo transfer cycle, the GnRHa trigger reduces the rates of embryo implantation, clinical pregnancy, and live birth, and increases the early miscarriage rate compared with hCG trigger . Elective cryopreservation of all embryos after GnRHa trigger and transfer in subsequent FET cycles maintains an excellent pregnancy rate [28, 29]. Therefore, considering the impaired endometrial receptivity and to prevent the occurrence of moderate to severe OHSS, anticipated high responders in our study who received the GnRHa trigger alone canceled fresh cycle transfer and transferred in subsequent FET cycles.
The LH and FSH peaks produced by GnRHa trigger are closer to the physiological condition, and combined with long half-life hCG, could improve luteal function and pregnancy outcomes in the fresh embryo transfer cycle compared to GnRHa trigger alone . However, for patients who adopt the freeze-all strategy to prevent OHSS, it is unclear whether it is necessary to add a small dose of hCG because enhanced corpus luteal function is not required in these patients, and there is a potentially increased risk of moderate to severe OHSS compared to GnRHa trigger alone. Neill et al.  showed that GnRHa trigger plus low-dose hCG 1000 IU can significantly increase the incidence of moderate to severe OHSS in the fresh embryo transfer cycle compared to GnRHa alone (6.0% vs. 0%), and there were no significant differences in the rates of clinical pregnancy and spontaneous miscarriage. Severe early OHSS requiring ascites drainage and hospitalization can occur even after combined GnRHa trigger and 1500 IU hCG for luteal rescue . Moreover, Jones et al. found that, compared with GnRHa single trigger in donated oocyte cycles, GnRHa trigger plus low-dose hCG 2000 IU was associated with a significantly increased incidence of OHSS (8.5% vs. 0.4%) . However, Shapiro et al. revealed that the ongoing pregnancy rate was significantly increased with the dual trigger, whereas the incidence of OHSS was comparable to that of GnRHa alone . Daniel et al. also showed that the dual trigger improved the probability of conception and live birth without increasing the risk of significant OHSS in high responders . The important reason for the inconsistency of conclusions may be due to the heterogeneity of the infertile population, small sample sizes, and different dosages of hCG. Our results suggest that, for high responders that undergo the freeze-all strategy, one disadvantage of using low-dose hCG with GnRH trigger is the risk of moderate to severe OHSS; thus, it may not be necessary to add a small dose of hCG for them.
Clinicians hesitate to use GnRHa trigger alone, mainly because some patients may not be able to produce sufficient LH levels because of their poor response to the GnRHa trigger, which affects the final oocyte maturation and may ultimately result in poor pregnancy outcomes . A study suggested that a dual trigger using GnRHa and low-dose hCG may be associated with a modest increase in oocyte yield, both in terms of number and maturity, compared to GnRHa single trigger . However, Jones et al. found that the dual trigger of GnRHa plus 2000 IU hCG did not improve the oocyte maturation rate compared with GnRHa single trigger for donated oocyte cycles . In addition, another study showed that the addition of hCG (1500–5000 IU) to GnRHa trigger did not improve the oocyte maturation rate in normal and low responders undergoing planned oocyte cryopreservation, and it suggested that GnRHa trigger alone is an appropriate choice for those patients regardless of the risk of OHSS . In this study, we expanded the sample size to better explore the effect of GnRHa trigger combined with different doses of hCG on oocyte maturation rate and embryo quality. The results showed that GnRHa plus low-dose hCG (1000 IU or 2000 IU) did not significantly improve the rates of oocyte maturation, available embryos, and top-quality embryos. Most importantly, there was no significant difference in CLBR. However, there was a significantly increased risk of moderate to severe OHSS. Therefore, our study suggests that, for high responders treated with the freeze-all strategy using the GnRH antagonist program, GnRHa single trigger does not affect the oocyte maturity and could prevent the occurrence of moderate to severe OHSS compared to the dual trigger. Moreover, the GnRHa trigger can also achieve satisfactory pregnancy outcomes in subsequent FET cycles.
To the best of our knowledge, no study has explored the effect of GnRHa plus low-dose hCG trigger on child safety. These results, for the first time, showed no significant difference in gestational age, birth height and weight, and low birth weight rate between the three groups stratified by singleton or twin, which suggested that the addition of low-dose hCG (1000 or 2000 IU) did not significantly improve embryo quality. Additionally, there was no significant difference in the CLBR during the subsequent FET cycles after whole embryo freezing between the three groups. This information seems important as it could encourage clinicians to use GnRHa trigger alone for the final oocyte maturation without concerns whether this strategy has an effect on embryo quality and neonatal outcomes for high-response patients.
This study has some limitations. First, it only included high responders, making the conclusions of this study unsuitable for patients with low and normal responses. In addition, the results of the study may be biased because of its retrospective nature; prospective studies are needed to verify the conclusions of this study. However, to the best of our knowledge, the number of patients included in this study for each group was larger than that of other similar studies, making the results of this study valuable for confidently guiding the use of GnRHa trigger alone for high responders without the addition of low-dose hCG.