Journal Pre-proofs

Review article

Triggering of ovulation for GnRH-antagonist cycles in normal and low ovari‐

an responders undergoing IVF/ICSI: a systematic review and meta-analysis of
randomized trials

Fang-Fang He, Wenhui Hu, Lin Yong, Yu-Mei Li

PII: S0301-2115(23)00320-2
DOI: https://doi.org/10.1016/j.ejogrb.2023.08.014
Reference: EURO 12985

To appear in: European Journal of Obstetrics & Gynecology and

Reproductive Biology

Received Date: 24 February 2023

Revised Date: 1 June 2023
Accepted Date: 15 August 2023

Please cite this article as: F-F. He, W. Hu, L. Yong, Y-M. Li, Triggering of ovulation for GnRH-antagonist cycles
in normal and low ovarian responders undergoing IVF/ICSI: a systematic review and meta-analysis of
randomized trials, European Journal of Obstetrics & Gynecology and Reproductive Biology (2023), doi: https://
doi.org/10.1016/j.ejogrb.2023.08.014

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Triggering of ovulation for GnRH-antagonist cycles in
normal and low ovarian responders undergoing IVF/ICSI：
a systematic review and meta-analysis of randomized trials

Fang-Fang Hea , Wenhui Hua, Lin Yonga , Yu-Mei Lib,*

aChengdu Jinjiang District Maternal and Child Health Hospital Reproductive
Medicine Centre, Chengdu, People’s Republic of China
bDepartment of Assisted Reproduction, Xiangya Hospital, Central South University,
Changsha, People’s Republic of China

*Corresponding author. Address: Department of Assisted Reproduction, Xiangya Hospital, Central

South University, Changsha 410008, People’s Republic of China.

E-mail address: liyumei@csu.edu.cn (Y-M. Li).

ABSTRACT

Objective: To conduct a systematic review and meta-analysis of all randomized

controlled trials (RCTs) that investigated whether dual triggering [a combination of
gonadotropin-releasing hormone (GnRH) agonist and human chorionic gonadotropin
(hCG)] of final oocyte maturation can improve the number of oocytes retrieved and
clinical pregnancy rate in low or normal responders undergoing in-vitro
fertilization/intracytoplasmic sperm injection (IVF/ICSI) cycles using a GnRH-
antagonist protocol.

Study design: Studies up to October 2022 were identified from PubMed, Scopus,
Cochrane Library and Web of Science. The risk of bias of included studies was
assessed. Dichotomous outcomes were reported as relative risks (RR), and continuous
outcomes were reported as weighted mean differences (WMD) with 95% confidence
intervals (CI). The primary outcomes were number of oocytes retrieved, number of
mature [metaphase II (MII)] oocytes, clinical pregnancy rate and ongoing pregnancy
rate; other IVF outcomes were considered as secondary outcomes.

Results: Seven studies were identified, and 898 patients were eligible for inclusion in
this meta-analysis. The results showed that the number of oocytes retrieved
[WMD=1.38 (95% CI 0.47–2.28), I2=66%, p=0.003, low evidence], number of MII
oocytes [WMD=0.7 (95% CI 0.35–1.05), I2=42%, p<0.0001, moderate evidence],
number of embryos [WMD=0.68 (95% CI 0.07–1.3), I2=67%, p=0.03, low evidence]
and number of good-quality embryos [WMD=1.14 (95% CI 0.35–1.93), I2=0%,
p=0.005, moderate evidence] in the dual trigger group were significantly higher than
in the hCG trigger group. The results of the ovarian response subgroup analysis
showed significant differences in all of these outcomes in normal responders, and no
differences in any of the outcomes in low responders, except for the number of MII
oocytes. In low responders, clinical pregnancy rates may be improved in the dual
trigger group [RR =2.2 (95% CI 1.05–4.61), I2=28%, p=0.04, low evidence].

Conclusion: Dual triggering by GnRH agonist and hCG improved oocyte maturity
and embryo grading for normal responders in GnRH-antagonist cycles. Dual
triggering for final oocyte maturation may improve clinical pregnancy rates in low
responders.

Keywords:

GnRH agonist

hCG

Randomized trial

Systematic review

Meta-analysis
1. Introduction

Spontaneous ovulation is preceded by surges in follicle-stimulating hormone

(FSH) and luteinizing hormone (LH), which induce eventual oocyte maturation.
Similarly, the final maturation of the follicle is extremely important in the in-vitro
fertilization (IVF) technique. Antagonist protocols are available for all populations,
and, in recent years, the proportion of antagonist cycles has been increasing in
domestic fertility centres. The choice of an individualized trigger is crucial for better
pregnancy outcomes. The use of a gonadotropin-releasing hormone agonist (GnRHa)
combined with human chorionic gonadotropin (hCG), known as ‘dual triggering’, is
gradually being advocated by investigators. In the traditional triggering method, hCG
is applied to mimic the physiological LH peak to promote the final maturation of
oocytes and luteal formation; however, due to the long half-life of hCG, there is a risk
of ovarian hyperstimulation syndrome (OHSS) [1]. The application of GnRHa instead
of hCG induces LH/FSH peaks similar to the natural cycle, and the endogenous LH
peak caused by GnRHa is shortened, which reduces the risk of OHSS in patients
while effectively inducing oocyte maturation [2]. Theoretically, triggering with
GnRHa minimizes the risk of OHSS, and the addition of hCG rescues the luteal
function. However, there are few studies comparing the effects of dual triggering for
follicle maturation application in antagonist protocols, and the results of related
studies varied between normal and low responders.

Previous studies suggested that dual triggering may be associated with increased
clinical pregnancy and livebirth rates compared with hCG triggering [3–6]. In low
responders, the use of dual triggering for final oocyte maturation significantly
improved the number of oocytes retrieved, number of metaphase II (MII) oocytes [7],
fertilization rate, livebirth rate and clinical pregnancy rate [8–10], but some studies
have also shown that dual triggering did not improve oocyte maturation, clinical
pregnancy rate, ongoing pregnancy rate and other IVF cycle outcomes [11–13]. A
recent meta-analysis incorporating retrospective studies and randomized controlled
trials (RCTs) found that dual triggering in finale oocyte maturation is advantageous
compared with hCG triggering among low responders [14]. Similarly, in normal
responders, the number of oocytes retrieved, number of MII oocytes [15,16], number
of fertilized (2PN) oocytes, number of embryos [3] and number of good-quality
embryos [17] were significantly higher in the dual trigger group, but there was no
evidence that dual triggering was superior to hCG triggering in terms of clinical
pregnancy rate [18,19], early miscarriage rate [20], livebirth rate [16,17,21] and
cumulative livebirth rate [22]; most of these were retrospective studies. The purpose
of the present study was to summarize evidence from RCTs evaluating the use of dual
triggering with GnRHa and hCG to trigger final oocyte maturation in patients
undergoing IVF, and to analyse whether dual triggering is as effective as hCG
triggering in terms of oocyte and pregnancy outcomes.

2. Materials and methods

This systematic review was based on the Preferred Reporting Items for
Systematic Reviews and Meta-Analysis (PRISMA) statement [23] (Registration No.:
CRD 42022368379).

2.1. Inclusion and exclusion criteria

Inclusion criterion: (1) RCTs comparing the effects of dual triggering and hCG
triggering on final oocyte maturation in women undergoing IVF/ICSI.

Exclusion criteria: (1) High ovarian response to controlled superovulation; history

and present signs of OHSS. (2) Endocrine disorders (hyperprolactinemia, diabetes
mellitus, thyroid dysfunction, congenital adrenal hyperplasia or Cushing's syndrome,
polycystic ovary syndrome), uterine anomaly disorders, repeated implantation failure,
and severe male factors. (3) Reviews, conference abstracts, case reports, observational
studies, and research protocols. (4) GnRHa and hCG 40 and 34 h prior to oocyte pick-
up, respectively (double triggering).

2.2. Search methods

Two authors independently searched PubMed, EMBASE, Cochrane Library, Web of

Science, and other databases until October 2022. The search terms were ‘GnRH
agonist’, ‘dual-trigger’, ‘hCG-triggered’, ‘IVF/ICSI’ and ‘RCT’. The detailed search
terms and methods are given in Table S1 (see online supplementary material). In
addition, a manual search of reference lists of eligible studies and previous meta-
analyses was undertaken to identify relevant studies.

2.3. Study selection

Two authors independently reviewed all titles and abstracts according to

predetermined inclusion criterion, and then carefully reviewed the complete
manuscripts of the studies considered for inclusion. Any disagreements regarding the
included studies were resolved by a third author.

2.4. Data extraction

Two authors independently extracted data from the included studies, including
publication details (first author's name and year of publication), methodology (study
design), participant characteristics (inclusion and exclusion criteria),
intervention/comparison (trigger method, sample size, drug and dose) and luteal phase
support (Table 1). Moreover, information was extracted about the randomization
process, allocation concealment and blinding to assess the risk of bias. Two authors
extracted data independently, and disagreements were resolved by discussion with a
third author. When a study with multiple papers was identified, the main trial report
was used as a reference, and supplementary information was added from the other
papers.

<insert Table 1 near here>

2.5. Quality assessment and publication bias

Disagreements between the two authors regarding the quality of evidence were
resolved through discussion with a third author when necessary. The Cochrane Risk
of Bias Assessment Tool was used to assess the risk of bias in the included RCTs. The
assessment included: (1) randomization scheme generation; (2) allocation scheme
concealment; (3) blinding; (4) blinded evaluation of study outcomes; (5) data
completeness; (6) selective reporting of results; and (7) other biases. For each of these
eight items, a ‘low bias’, ‘high bias’ or ‘unclear’ (lack of relevant information or
uncertainty about bias) judgement was made (Fig. S1, see online supplementary
material).

2.6. Outcome measures and data analysis

The primary outcomes were number of oocytes retrieved, number of MII oocytes,
clinical pregnancy rate and ongoing pregnancy rate. Secondary outcomes were
number of 2PN oocytes, number of embryos, number of high-quality embryos,
implantation rate, biochemical pregnancy rate, miscarriage rate and livebirth rate.
Meta-analysis was performed using Manager 5.4 software. Dichotomous variables
have been expressed as relative risk (RR) and 95% confidence interval (CI), while
continuous variables have been expressed as weighted mean differences (WMD) and
95% CI. p<0.05 was considered to indicate significance. The test for heterogeneity
between studies was described using I2=50%. If there was no or little heterogeneity
(I2<50%), the results were combined using a fixed-effects model; if there was
significant heterogeneity (I2>50%), the reasons for heterogeneity were analysed, and
if there was no significant clinical heterogeneity, the results were combined using a
random effects model. GRADE assessment [24] was used to independently evaluate
the overall quality of evidence for each outcome by two authors. Based on the Grade
approach, the quality of evidence was estimated based on the risk of bias,
inconsistency, indirectness, imprecision and publication bias, classifying evidence as
very low, low, moderate or high. Publication bias analysis was not performed as the
number of studies was too low to allow the detection of an asymmetric funnel.

3. Results

The PRISMA flow chart of the review process is shown in Fig. 1. Eight studies
were identified, including 898 patients eligible for inclusion in the meta-analysis, 633
normal responders, 265 low responders, 454 patients in the dual trigger group and 444
patients in the hCG trigger group. Four articles included normal responders
[15,16,25,26], three articles included low responders according to the Bologna criteria
[7,12], and one article excluded high responders, with a subgroup analysis of patients
with reduced ovarian reserve with anti-Mullerian hormone <1.4 [28]. Table 1
summarizes the detailed inclusion and exclusion criteria for each study.

<insert Fig 1 near here>

3.1. Number of oocytes retrieved

All eight studies reported the number of oocytes retrieved, with heterogeneity
among studies (I2>50%), and the combined statistic was calculated using a random
effects model. The meta-analysis showed that dual triggering was associated with a
significant increase in the number of oocytes retrieved [WMD=1.38 (95% CI 0.47–
2.28), I2=66%, p=0.003, low evidence] (Fig. 2A). It was speculated that the
heterogeneity may have originated from different responder populations. In order to
explore whether dual triggering benefits both normal and low responders, a subgroup
analysis was performed. This found that the number of oocytes retrieved in the dual
trigger group was not significantly different from the hCG trigger group in low
responders [WMD=0.49 (95% CI -0.38 to 1.37, I2=55%, p=0.27], but in the normal
responders, the number of oocytes retrieved was higher in the dual trigger group
[WMD=2.12 (95% CI 1.16–3.08), I2=10%, p<0.0001] (Fig. 2A). Also, subgroup
analysis was performed according to different hCG trigger doses, and this showed that
the number of oocytes in the dual trigger group was not significantly different from
the hCG trigger group for hCG 6500 IU, hCG 5000 IU and hCG 10000 IU (Fig. 2B).
In the hCG 6500 IU group, there was greater heterogeneity [WMD=1.5 (95% CI -0.45
to 3.46), I2=86%, p=0.13). Further subgroup analysis according to different ovarian
responses in the hCG 6500 IU group is needed, but there was only one report of low
responders. In normal responders, the number of eggs obtained by dual triggering was
higher than that for hCG triggering.

<insert Fig 2 near here>

3.2. Number of MII oocytes

Seven articles reported the number of MII oocytes. The meta-analysis found that dual
triggering was associated with a significant increase in the number of MII oocytes
[WMD=0.7 (95% CI 0.35–1.41), I2=42%, p<0.001, moderate evidence] (Fig. 3A);
similarly, a subgroup analysis was performed and showed that normal responders
[WMD=1.34 (95% CI 0.63–2.05), I2=0%, p=0.0002] and low responders
[WMD=0.50 (95% CI 0.09–0.9), I2=46%, p=0.02] in the dual trigger group had a
significantly higher number of MII oocytes (Fig. 3A). In addition, subgroup analysis
was performed according to different hCG trigger doses. The number of MII oocytes
in the dual trigger group did not differ significantly from three hCG trigger groups
(Fig. 3B).

<insert Fig 3 near here>

3.3. Clinical pregnancy rate

Data regarding clinical pregnancy rate were available to be extracted and synthesized
in six studies. The meta-analysis displayed an increased clinical pregnancy rate in the
dual trigger group compared with the hCG trigger group [RR=1.49 (95% CI 1.1–
2.01), I2=8%, p=0.01, moderate evidence]. Clinical pregnancy rates were compared
between normal and low responders; two studies included low responders, and a
significant increase in clinical pregnancy rates was found in the low responders
[RR=2.2 (95% CI 1.05–4.61), I2=28%, p=0.04]; four studies included normal
responders, but no difference in clinical pregnancy rates was found [RR=1.37 (955 CI
0.98–1.91), I2=0%, p=0.07] (Fig. 4).
<insert Fig 4 near here>

3.4. Ongoing pregnancy rate

Only two studies of normal responders reported ongoing pregnancy rates. The
meta-analysis found no significant difference in ongoing pregnancy rates between the
dual trigger group and the hCG trigger group [RR=1.19 (95% CI 0.72–1.97), I2=0%,
p=0.5, low evidence] (Fig. 5) [27].

<insert Fig 5 near here>

3.5. Number of embryos

Six studies compared the number of embryos between the dual trigger group
and the hCG trigger group. The meta-analysis showed that dual triggering was
associated with a significant increase in the number of embryos [WMD=0.68 (95% CI
0.07–1.3), I2=67%, p=0.03, low evidence] (Fig. 6); similarly, a subgroup analysis
found a significant increase in the number of embryos in the dual trigger group in
normal responders [WMD=1.41 (95% CI 0.69–2.13), I2=0%, p=0.0001); however, no
significant difference was found in the low responders [WMD=0.22 (955 CI -0.62 to
1.06), I2=80%, p=0.6].

<insert Fig 6 near here>

3.6. Number of 2PN oocytes

Four studies reported the number of 2PN oocytes, of which one included
normal responders and three included low responders. Significant heterogeneity was
found in these studies, and therefore a random effects model was used. There was no
significant difference in the number of 2PN oocytes between the two groups
[WMD=0.9 (95% CI -0.38 to 2.17), I2=81%, p=0.17, very low evidence] (Fig. 7); the
sensitivity analysis, excluding the one study conducted in normal responders, proved
the same point (p=0.37) [15].

<insert Fig 7 near here>

3.7. Number of high-quality embryos

Only two studies of normal responders reported the number of high-quality

embryos, and the meta-analysis showed that dual triggering was associated with a
significant increase in the number of high-quality embryos [WMD=1.14 (95% CI
0.35–1.93), I2=0%, p=0.005, moderate evidence] (Fig. 7).

3.8. Implantation rate

Only two studies reported implantation rates, and the meta-analysis showed no
significant difference between the dual-trigger group and the hCG trigger group
[RR=1.62 (95% CI 0.68–3.88), I2=60%, p=0.28, low evidence] (Fig. 9).

3.9. Biochemical pregnancy rate

Biochemical pregnancy rates were reported in five articles, of which three

included normal responders and two included low responders. The meta-analysis
showed no significant difference in biochemical pregnancy rates between the dual
trigger group and the hCG trigger group [RR=1.66 (95% CI 0.94–2.94), I2=0%,
p=0.08, moderate evidence]. The subgroup analysis did not find differences in
biochemical pregnancy rates in normal responders [RR=1.11 (95% CI 0.4–3.11),
I2=0%, p=0.85] or low responders [RR=1.99 (95% CI 1–3.95), I2=21%, p=0.05] (Fig.
8).

<insert Fig 8 near here>

3.10. Miscarriage rate

Two studies of normal responders reported miscarriage rates, and the meta-
analysis showed no significant difference between the dual trigger group and the hCG
trigger group [RR=1.07 (95% CI 0.38–3.01), I2=36%, p=0.89, low evidence] (Fig. 9).

<insert Fig 9 near here>

3.11. Livebirth rate

Two studies of normal responders reported livebirth rates, and the meta-
analysis showed no significant difference between the dual trigger group and the hCG
trigger group [RR=1.41 (95% CI 0.89–2.24), I2=0%, p=0.15, low evidence] (Fig. 9).

4. Discussion

This study reviewed seven RCTs, including 898 women, to examine whether
dual triggering was beneficial in normal and low responders. Number of oocytes
retrieved, number of MII oocytes, number of embryos and number of high-quality
embryos were significantly higher in the dual trigger group compared with the hCG
trigger group in normal responders. These results are consistent with the findings of
several studies demonstrating that dual triggering promotes oocyte maturation and
embryo grading in normal responders, but no significant differences in IVF pregnancy
outcomes were identified [16–18,22,25,26]. In low responders, there may have been
an increase in the number of MII oocytes and clinical pregnancy rate in the dual
trigger group. Similarly, the results of the recent meta-analysis on the effect of dual
triggering on reproductive outcomes in low responders exhibited an increase in
clinical pregnancy and livebirth rates [14].

To further improve IVF success rates, the triggering of final follicle maturation
antagonists is gradually becoming a subject of research interest. Previous studies have
shown that FSH and LH are significantly elevated after GnRHa treatment [29,30].
Gonen et al. first used GnRHa as the final trigger for oocyte maturation in 1990 [31].
Subsequently, many studies have shown that using GnRHa to induce ovulation by
inducing an LH surge is effective and has a lower risk of OHSS than the traditional
hCG trigger. A Cochrane review reported that triggering final oocyte maturation with
GnRHa in fresh IVF autologous cycles was effective in preventing OHSS [32];
however, it significantly decreased ongoing pregnancy and livebirth rates, and a
significantly higher rate of early miscarriage was reported with the use of a GnRHa
trigger compared with an hCG trigger. These adverse pregnancy outcomes were
attributed to defective luteal function and reduced endometrial tolerance [30,33,34].
Later, strategies for eventual follicular maturation and luteal support continued to
improve. Furthermore, GnRHa triggering was not only used in high responders, but
combined triggering with simultaneous administration of GnRHa and reduced or
standard doses of hCG continued to be applied in normal and low responders.
Moreover, the risk of OHSS was reduced with GnRHa triggering, while added hCG
rescued luteal function, optimizing oocyte maturation, blastocyst rates and pregnancy
outcomes; however, the results of the studies are controversial. Therefore, RCTs on
normal and low responders were included in the present study to evaluate the effect of
dual triggering on oocyte maturity, embryo grade and clinical pregnancy outcome.

In the first prospective randomized study of dual triggering, the administration of

treprostinil (0.2 mg) during GnRHa antagonist IVF cycles increased the rate of
ongoing pregnancy significantly compared with the hCG (5000 IU) trigger [35]. Lin
et al. showed that the number of MII oocytes, total number of oocytes, implantation
rate, clinical pregnancy rate and livebirth rate were significantly higher in the dual
trigger group than in the hCG trigger group [3], which was confirmed by Kim et al.
[5]. A prospective RCT by Decleer et al. showed no significant difference in the
number of oocyte complexes and implantation rates [36]. A meta-analysis by Chen et
al. found no significant differences between the two groups in terms of total number
of oocytes retrieved and MII oocytes, number of 2PN oocytes and implantation rate;
however, the number of high-quality embryos and the rate of ongoing pregnancy were
significantly higher in the dual trigger group. These results may be related to the small
sample size and the absence of a defined population, so the study results deserve
further confirmation.

Subsequently, there has been an increase in studies comparing dual triggering

with hCG triggering by applying antagonists in different populations, but the results
have been inconsistent. In several recent studies, Zhou et al. reported no differences in
the mean number of oocytes retrieved, implantation rate, clinical pregnancy rate or
livebirth rate in a comparison of dual triggering with hCG triggering in normal
responders [37]. Alleyassin et al. showed that dual triggering increased the number of
high-quality embryos [25], with no differences in other outcomes. Haas et al. showed
that dual triggering increased the number of mature oocytes and blastocysts, and
improved IVF outcomes [15], but did not find differences in the rates of fertilization,
clinical pregnancy or live birth in these subsequent studies [16–19,22], which were all
studies on normal responders. Similarly, the present study found that the number of
oocytes retrieved, number of MII oocytes, number of embryos and number of high-
quality embryos were increased significantly in normal responders. GnRHa triggering
induced a surge of LH and FSH, mimicking the natural cycle, which may provide an
advantage for oocyte maturation. Moreover, elevated FSH levels activate oocyte
meiosis and restoration of ovarian cumulus expansion, and GnRHa triggering
activates GnRH receptors on granulosa cells, which regulate ovulation [38]. Griffin et
al. stated that dual triggering in hCG-triggered patients with a history of 25%
immature oocyte retrieval increased oocyte maturation rates by up to 75% [4].
However, the present study found no significant difference in the number of 2PN
oocytes, clinical pregnancy rate, persistent pregnancy rate, implantation rate,
biochemical pregnancy rate, miscarriage rate or livebirth rate, which contradicts the
findings of a recent meta-analysis in which the dual trigger group showed an increase
in clinical pregnancy and livebirth rates [39]. However, only two studies were
included in the analysis of implantation rate, livebirth rate and persistent pregnancy
rate, and more studies with larger sample sizes and better designs are needed for
better evidence.

Among low responders, Oliveira et al. found, consistent with three previous
studies [10], greater numbers of oocytes retrieved, mature oocytes and 2PN oocytes in
the dual trigger group. This result was subsequently confirmed by Lin et al. [9].
Defining low response according to the Bologna criteria, Zhang et al. showed that the
oocyte rate and mature oocyte rate were significantly higher in the dual trigger group
than in the control group, with no significant differences in the number of available
embryos, and rates of fertilization, implantation, clinical pregnancy and miscarriage
between the two groups [11]. Eser et al. and Eftekhar et al. demonstrated that dual
triggering did not improve oocyte maturation, clinical pregnancy rate or ongoing
pregnancy rate [12,13]. In the present study, the number of MII oocytes and clinical
pregnancy rate appeared to be efficient in the dual trigger group. However, the studies Commented [AW1]: Please clarify
included had less data on implantation rate, miscarriage rate, livebirth rate and onging
pregnancy rate in low responders, and no relevant conclusions were obtained. The
results of a recent meta-analysis indicated that the livebirth rate was increased in low
responders by dual triggering, and the analysis was based on the results of three
retrospective studies [14]. It is likely that the use of GnRHa could displace the
antagonist from receptors in the endometrium, as well as from receptors in
gonadotropin-producing cells. After displacement, activation of previously blocked
GnRH receptors (putatively) may lead to late postreceptor effects (e.g. protein
synthesis) in endometrial cells that could lead to improvement in implantation [35].
Another possible explanation for the improved outcome of GnRHa-triggered cycles
may be the induction of an FSH surge in addition to an LH surge, which is thought to
help restore the meiotic process in some oocytes, conferring some advantages to the
developing embryo. Two of the studies in this review included low responders
according to the Bologna criteria, but one study that did not use these criteria was also
included [28] which may have impacted the results. Thus, further research is required
to determine whether dual triggering in low responders improves clinical pregnancy
outcomes. A recent study stated that the use of dual triggering for final oocyte
maturation may improve clinical pregnancy rates and livebirth rates in IVF cycles in
patients who meet Poseidon Group 4 criteria [40]. Another study investigated
antagonist double triggering vs single triggering in women of advanced age, and
found that the use of GnRHa and hCG as dual triggers did not result in more oocytes
or improved pregnancy outcomes [21]. The concept of dual triggering represents a
combination of GnRHa and standard hCG, administered 40 and 34 h before egg
retrieval, respectively. Dual triggering has been used successfully to treat patients
with empty follicle syndrome and a history of immature egg retrieval or low/poor
oocyte production [41], but it remains controversial whether luteal phase support
programmes can compensate for the negative effects of GnRHa. Therefore,
personalized luteal support in fresh antagonist cycles is still a hot topic. Future
research should examine the population, dosage and duration of drug use more
precisely, and more prospective RCTs are needed to explore this issue. The present
study included RCTs of dual triggering vs hCG triggering in antagonist regimens,
designed according to the PRISMA statement, which is the gold standard for the level
of evidence [42], and undertook separate analyses for normal and low responders.

This meta-analysis has several limitations worth considering. First, only seven
studies met the inclusion criteria, and not all studies reported variables for each
analysis. Second, the quality of some of the studies was only moderate, as subjects
and assessors were not blinded or specified. Third, the drugs used for dual triggering
and the doses varied between studies, and it remains unclear whether different doses
would affect outcomes. Fourth, clinical factors, such as race and age, in each study
may also be a source of bias. Most of the studies were from foreign scholars, and their
applicability in the Chinese population needs to be explored further. Fifth, each study
used different luteal support medications, and it should be investigated whether this
affected outcomes such as clinical pregnancy rate and miscarriage rate. Finally, some
indicators included limited data, and the impact on livebirth rate and clinical
pregnancy rate should be investigated further. Large-scale and high-quality RCTs are
required to confirm this inference and fully address the magnitude of this effect.

In conclusion, this systematic review suggested that dual triggering with

GnRHa and hCG improved oocyte maturity and embryo grading for normal
responders to GnRH-antagonist cycles. Dual triggering for final oocyte maturation
may improve clinical pregnancy rates in low responders.

Conflict of interest

None declared.

Funding

None.

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Fig. 1. PRISMA flow diagram of the review process.

Records identified from:

Databases (n=2856)
PubMed (n=97)
Identification

Cochrane Library (n=717)

Embase (n=1044)
Web of Science (n=998)
Other source (n=4)

Study titles screened Studies excluded (n=2631）

(n=2860)
Screening

Reports sought for retrieval Reports after duplicates removed

(n=200) (n=81)

Reports assessed for eligibility Full-text studies excluded:

(n=119 ) Reviews (n=11)
Conference abstract (n=37)
Non-randomized trial (n=52)
No population group (n=9)
No raw data (n=1)
Double trigger (n=2)
 Studies included in meta-analysis
Included

(n=7)
 Fig. 4 Meta-analysis of studies reporting clin ical pregnancy rate

Fig. 5 Meta-analysis of studies reporting ong oing pregnancy rate

Fig. 6 Meta-analysis of studies reporting the number of embryo

Fig. 8 Meta-analysis of studies reporting bio chemical pregnancy rate

Author Inclusion Exclusion Triggerin Sample Interventi Comparis luteal
criteria criteria g size on on phase
(year) support

Ali et al. First ICSI >40 Four 160 250 IU of 250 IU of Intramusc
(2020) cycle; years; leading recombin recombin ular
aged <40 azoosper ant hCG ant hCG progester
years; mic follicles and （80） one 25
BMI 18– males; reached GnRH mg twice
30 kg/m2; AMH <1 at least a （80） daily
AMH >1 ng/ml mean of
ng/m; 15–17
normal, mm
mild or diameter
moderate
male
factor
infertility

Alleyassi 18–40 Day 3 Two 126 hCG hCG 50 mg

n (2018) years old; FSH >10; follicles 5000 IU 10,000 intramusc
BMI 18– AMH and IU ular
35 kg/m2; <1.1; reached GnRH （63） progester
day 3 high risk 17 mm agonist one daily,
FSH <10; of diameter 0.2 mg 400 mg
regular ovarian Cyclogest
menstrual hyper- （63） twice a
cycle 25– stimulatio day
35 days; n
candidate syndrome
for IVF (>16
for any follicles
reasons in the last
such as ultrasoun
unexplain d before
ed the final
infertility, oocyte
tubal induction
factor and );
ovulation endocrine
dysfuncti disorders
ons or such as
mild male diabetes
factor mellitus,
infertility hyperprol
actinaemi
a, thyroid
dysfuncti
on,
congenita
l adrenal
hyperplas
ia,
cushing
syndrome
,
polycysti
c ovarian
syndrome
, an
anomaly
confirme
d by hSG
or uterine
hysterosc
opy;
severe
male
factor
(azosper
mia
needed
TESE or
PESA);
previous
history
and
existing
signs of
ovarian
hyperstim
ulation
 syndrome

Eftekhar Aged <42 Endocrin Leading 192 hCG hCG 400 mg

et al. years; e follicles 6500 IU 6500 IU vaginal
(2017) BMI 18– disorders; reached and （93） progester
30 kg/m2; polycysti 17 mm in GnRH one
moderate c ovarian diameter agonist supposito
ovarian syndrome 0.2 mg ries twice
response ; UA; （99） a
RIF;
azoosper day Commented [AW2]: Please spell out in footnotes
mia; day
3 FSH
≥10 IU/l
or AMH
≤1.0
ng/mL

Haas et Age 18– E2 >15,0 Dominant 146 hCG hCG 200 mg

al. (2020) 41 years; 00 follicles 10,000 10,000 micronize
BMI 18– pmol/l; reached IU and IU and d
35 kg/m2; moderate an GnRH placebo progester
AMH >1 –severe average agonist (78) one in
ng/ml; endometr diameter 0.5 mg vaginal
AFC 6– iosis of 18–20 (77) ovules
20; FSH mm three
<20 IU/l; times
first three daily
IVF
cycles

Eftekhar Low Endometr Three 80 hCG hCG Vaginal

et al. responder ial follicles 6500 IU 6500 (41) progester
(2018) s defined polyps; with 18- and one 400
with the presence mm GnRH mg twice
Bologna of diameter agonist a day
criteria endocrine 0.2 mg
disorders (39)
(such as
hyperprol
actinaemi
a,
hypothyr
oidism),
pre-
implantat
ion

genetic
diagnosis
 cycles
and non-
fresh
embryo
transfer
cycles.

Maged Low Women Three 160 hCG hCG 400 mg

(2021) responder with follicles 10,000 10,000 of natural
s defined ovarian were >14 IU and IU(80) progester
with the cysts, mm and GnRH one
Bologna endometr at least agonist
criteria iosis, one 0.2 mg
hydrosalp follicle (80)
inx, reached a
mean
and those diameter
with ≥17 mm
endocrino
logical
disorders
such as
hyperprol
actinaemi
a, thyroid
or

adrenal
disorders

Mahajan Age 24– High At least 76 hCG hCG None

(2017) 43 years; responder 5000 IU 10,000
AMH <4 s; three and IU (38)
ng/ml; AMH >4 follicles GnRH
ng/ml; were >18 agonist 1
AFC/ovar AFC/ovar mm mg (38)
y <12 y >12

ICSI, intracytoplasmic sperm injection; IVF, in-vitro fertilization; BMI, body mass index; AFC,
antral follicle count; AMH, anti-Mullerian hormone; FSH, follicle-stimulating hormone; hCG,
human chorionic gonadotrophin; TESE, testicular sperm extraction; PESA, percutaneous
epidydimal sperm aspiration; GnRH, gonadotrophin-releasing hormone.

Table 1

Characteristics of included studies