The practice, known as a “dual trigger,” involves administering a GnRH agonist together with a low dose of hCG at the end of an ovarian stimulation cycle, rather than using the GnRH agonist on its own. The theoretical rationale is straightforward. GnRH agonist triggers reliably prompt the final maturation of eggs by triggering the body’s own luteinizing hormone surge, and they dramatically reduce the risk of ovarian hyperstimulation syndrome, or OHSS, because they clear from the body quickly. But a concern has persisted that agonist-only triggers leave the luteal phase — the hormonal environment after egg retrieval — less supportive than the natural sequence of events, potentially affecting both egg quality and the receptivity of the uterus. Adding a small dose of hCG, which mimics luteinizing hormone and has a longer biological half-life, was proposed as a way to rescue maturation quality and bolster endometrial preparation without reintroducing substantial OHSS risk. The new analysis set out to determine whether that hypothesis holds up when the available clinical evidence is pooled rigorously.

Led by Zhou Li and Lei Jin of the Reproductive Medicine Center at Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology in Wuhan, China, together with colleagues at Organon Research and Development in Shanghai, the research team systematically searched five major databases: PubMed, Embase, Web of Science, the Cochrane Library, and the China National Knowledge Infrastructure. Their goal was to identify randomized controlled trials and cohort studies that directly compared a dual trigger with a GnRH agonist trigger alone in high ovarian responders — women whose ovaries produce an unusually large number of follicles under stimulation, typically reflected in high anti-Müllerian hormone levels or high antral follicle counts. The study was prospectively registered with PROSPERO under registration number CRD420251003498.

The final evidence base comprised fourteen studies, of which only two were randomized controlled trials and twelve were observational cohort studies, encompassing a total of 4,427 women. The choice of population matters: high responders are precisely the patients for whom the agonist trigger was developed in the first place, precisely because traditional hCG triggers in these women can set off OHSS, a potentially serious condition in which the ovaries become grossly enlarged and fluid shifts out of the vasculature into the abdomen and chest. Moderate or severe OHSS can require hospitalization, paracentesis, and in rare cases can be life-threatening. Any strategy that trades a small gain in egg maturity for a meaningful rise in OHSS risk therefore deserves careful scrutiny in this group.

The meta-analysis evaluated two primary outcomes: the proportion of oocytes reaching metaphase II, the mature stage at which eggs can be fertilized, and the incidence of moderate or severe OHSS. Secondary outcomes included the number of retrieved oocytes, the number of embryos and high-quality embryos formed, the normal fertilization rate, clinical pregnancy rate, miscarriage rate, and live birth rate. Binary outcomes were pooled as relative risks and continuous outcomes as weighted mean differences, each with 95 percent confidence intervals to convey the precision of the estimates.

The results were sobering for advocates of the dual trigger. Across eleven studies, the dual trigger did not improve metaphase II oocyte rates compared with the GnRH agonist alone. The pooled weighted mean difference was 0.52 percentage points in favor of the dual trigger, but the confidence interval ranged from −1.37 to 2.42, crossing zero — meaning the difference was statistically indistinguishable from no effect at all. In practical terms, the extra hCG did not coax measurably more eggs to final maturity in these high-responder patients.

More troubling was the safety signal. Pooling data from ten studies, the researchers found that women receiving the dual trigger faced a dramatically elevated risk of moderate or severe OHSS: the relative risk was 4.42, with a 95 percent confidence interval of 2.44 to 8.01. In other words, women given the combined trigger were more than four times as likely to develop clinically significant OHSS as those given the agonist alone. Even at hCG doses of 1,000 international units or less — doses deliberately chosen by investigators to be low enough, in theory, to avoid stimulating the syndrome — the increased risk persisted, with a relative risk of 11.43 (95 percent CI: 1.49 to 87.73) across three studies, though the very wide interval reflects substantial statistical imprecision with so few events and studies. The authors caution that this subgroup finding should be interpreted with care, but the direction of the signal is consistent: even “low-dose” hCG is not necessarily benign in a population whose ovaries are already primed to overreact.

None of the prespecified secondary outcomes differed significantly between the two trigger strategies. Numbers of retrieved oocytes, embryos, and high-quality embryos, normal fertilization rates, miscarriage rates, and live birth rates were all statistically comparable. The one exception emerged in a subgroup analysis restricted to women undergoing fresh embryo transfer — that is, transfer of an embryo in the same cycle as the egg retrieval rather than after a freeze-all strategy. In that subgroup, drawing on four studies, the dual trigger was associated with a higher clinical pregnancy rate, with a relative risk of 1.33 (95 percent CI: 1.15 to 1.54). But the same subgroup also showed a raised OHSS risk — a relative risk of 6.29, with a confidence interval of 0.94 to 41.84 — and the authors emphasize that the pregnancy finding is exploratory, rests on limited studies, and comes bundled with the safety concern.

The mechanistic explanation for the OHSS signal is rooted in reproductive endocrinology. hCG has a half-life measured in days, far longer than the hours-long clearance of a GnRH agonist, and it sustains luteal activity — including the production of vascular endothelial growth factor by the corpora lutea — for a week or more after administration. VEGF increases vascular permeability, which is the fundamental physiological driver of OHSS. In a high responder with dozens of corpora lutea after retrieval, even a small bolus of hCG can amplify this cascade enough to tip a patient over the threshold into symptomatic disease. The meta-analysis suggests that this risk is not abolished by dose reduction in the very patients most vulnerable to it.

The study’s limitations deserve emphasis, and the authors are candid about them. Twelve of the fourteen included studies were cohort studies rather than randomized trials, and observational designs are vulnerable to selection bias — for example, clinicians may have preferentially assigned the dual trigger to patients they judged more resilient, or conversely to those needing extra luteal support. The small number of randomized trials means the highest-quality evidence is thin. The fresh embryo transfer subgroup finding, in particular, cannot be treated as practice-changing on the strength of four studies. The authors also note that cumulative live birth rates, which capture the total reproductive outcome of an entire stimulation-and-freezing cycle strategy, were not uniformly reported and could not be robustly synthesized.

What, then, should clinicians take away? For predicted high responders on GnRH antagonist protocols — now the dominant stimulation approach in many centers — the meta-analysis indicates that adding low-dose hCG to the agonist trigger does not buy measurable improvements in oocyte maturation or overall reproductive outcomes, while substantially raising the risk of moderate or severe OHSS. The finding reinforces the value of the freeze-all strategy: when embryos are frozen and transferred in a later, unstimulated cycle, the luteal-phase concerns that motivated the dual trigger largely evaporate, because the endometrium is prepared de novo with exogenous hormones rather than depending on the rescued corpus luteum. In a fresh-transfer context, the apparent pregnancy advantage of the dual trigger must be weighed against a OHSS risk that the pooled data suggest is far from negligible.

The research was supported by Organon (Shanghai) Pharmaceutical Technology Co., Ltd., and three of the co-authors — Xiaohan Shi, Xueqiong Lin, and Jue Wang — are employees of the company, a disclosure that underscores the importance of independent replication. Zhou Li and Lei Jin reported no conflicts of interest. The authors conclude that more randomized trials are needed to identify the best trigger options for high responders, but their synthesis offers a clear interim message: in this vulnerable population, the simple agonist trigger, paired where appropriate with a freeze-all approach, remains the strategy best supported by the accumulated evidence. As assisted reproduction continues to expand globally, studies like this one — pooling thousands of patient outcomes across dozens of clinics — play an increasingly vital role in separating endocrinologically plausible interventions from those that genuinely improve the lives of patients.