Dual Trigger in IVF—A SWOT Analysis

Evolution of Dual Trigger

A study in 1973 demonstrated that GnRH agonists given intravenously can induce the LH surge.^[1] In the early 1990s, two small case series demonstrated that a bolus of GnRHa was shown to effectively trigger final oocyte maturation.^[2,3] However, the initial randomised trials comparing GnRHa and hCG triggers in normal responder patients using standard luteal support showed very low live birth rates of 4–6% in the GnRHa group.^[4,5]

Schachter et al. demonstrated significantly improved ongoing pregnancy rates in completed antagonist IVF cycles with dual triggering, using a combination of hCG (5000 IU) and GnRH agonist (triptorelin 0.2 mg).^[6] They suggested that the GnRH agonist helps in displacing the antagonist binding to endometrial receptors, thereby unblocking ‘pro-implantation post-receptor events’ which had been potentially interfered with by the GnRH antagonist treatment in the pre-ovulatory phase.

Physiology of Dual Trigger

In a normal menstrual cycle, GnRH neurones in the mediobasal hypothalamus release GnRH in hourly pulses into the hypothalamo-hypophyseal portal system. Anterior pituitary gonadotrophs respond to this by releasing FSH and LH in hourly pulses. These gonadotropins act synergistically on the ovary to induce follicular growth and rising oestradiol levels (the two-cell, two-gonadotropin model).^[7] The rising oestradiol level (and a small rise in progesterone) at mid-cycle induces the release of GnRH from the hypothalamus, mediated by Kisspeptin^[8] released by neurones in the periventricular and arcuate nuclei of the hypothalamus. The positive feedback created, leads to a huge increase in the magnitude of LH and FSH pulses, commonly referred to as the ‘LH surge.’ The LH surge typically lasts for 48 hours, followed by a plateau maintained for 14 hours; the FSH surge is known to accompany the LH wave but with a smaller amplitude. Both are vital for ovulation, which occurs some 36–40 hours after the onset of the surge.

The LH surge is imperative for ovulation as it causes the resumption of oocyte meiosis and luteinisation of granulosa cells. But basic science studies in animals have also established a role for the FSH surge—e.g. in rats, a midcycle FSH surge determines which follicles will develop adequately in the following three cycles.^[9] FSH promotes the formation of LH receptors on granulosa cells, expansion of the cumulus, and resumption of oocyte meiosis, leading to nuclear maturation.^[10] Hyaluronic acid synthesis leading to cumulus expansion allows the COC to become free-floating in the follicular fluid. LH/FSH and progesterone activate proteolytic enzymes in the follicular fluid to digest the collagen layer of the follicle wall and cause ovulation.

In conventional IVF treatment, hCG has been most commonly used as a surrogate for the natural endogenous LH surge following controlled ovarian hyperstimulation.^[11] However, the half-life of hCG is longer than that of endogenous LH, and as a result, the biological effect is maintained for several days, thereby increasing the risks of OHSS. Further, the hCG trigger does not mimic the FSH surge seen in physiology.

The alternative ovulation trigger, GnRHa, binds to the GnRH receptor, inducing a surge of both LH and FSH, which mirrors physiology in some respects. Following GnRHa, there is a rapid rise in LH, peaking at 4 hours and then a (slower) decline, returning to near baseline at 24 hours, thereby limiting the duration of the LH surge to about 24–36 hours, with no accompanying plateau due to early luteolysis and corpus luteum dysfunction. This contrasts with the physiological surge, which has 3 distinct phases, viz. the ascending phase (14 hours), plateau (14 hours), and descending phase (20 hours), lasting a total of 48–54 hours, as described by Shoham et al.^[12]

Although there is a distinct advantage of reducing the risk of OHSS with GnRH agonist trigger, the poor corpus luteum function because of inadequate LH impairs endometrial receptivity and leads to decreased implantation and higher pregnancy losses.^[5]

A dual trigger strategy, with a single dose of hCG and GnRHa as an ovulation trigger, has been proposed as a means of combining the benefits of both GnRH agonist and HCG. ^[13,14]

Strengths

Improved Oocyte Maturation Rate

FSH surge following a dual trigger has been found to influence oocyte maturation by expansion and stimulation of oocyte-cumulus complexes to secrete a meiosis-activating substance that assists the resumption of the meiotic division.^[17] Yan et al. designed a prospective study in a normo-responder population with more than 50% immature eggs in previous fresh cycles where hCG had been used as an ovulation trigger and recently showed a significantly greater proportion of Meiosis II (MII) oocytes with the use of a dual trigger, translating into a higher number and better-quality embryos, and consequently, better cumulative clinical pregnancy rates.^[18]

In an older retrospective study in a similar population by Fabris et al., patients with more than 50% immature oocytes in a previous IVF cycle triggered with human chorionic gonadotropin (hCG) had a significantly higher yield of mature oocytes in subsequent cycles triggered with both gonadotropin-releasing hormone agonist (GnRH-a) and hCG in comparison to that for hCG alone.^[19]

Improved Fertilisation Rate

A retrospective cohort study by Elias et al., involving 427 patients with a history of a poor fertilisation rate of <20% in at least two prior intracytoplasmic sperm injection (ICSI) cycles, found that the combination of GnRH-a and hCG trigger in subsequent ICSI cycles resulted in increased oocyte maturity, fertilisation, clinical pregnancy, and live birth rates compared with previous hCG trigger alone.^[20]

A prospective observational study by Pereira et al. in 318 patients with poor fertilisation in ICSI cycles, a second ICSI cycle with a similar stimulation protocol and combined GnRH-a and hCG trigger compared their outcomes. Dual trigger had higher odds of mature oocytes and fertilisation and higher odds of ICSI cycles resulting in day-3 embryo transfers. The odds of clinical pregnancy and live birth were 5.42 and 5.25 times higher, respectively, in the combined trigger group compared to the hCG group.^[21]

Overcomes Risks of GnRHa-Only Trigger

Although the use of GnRH-a-only triggers has significantly decreased the risk of OHSS in modern IVF practice, clinicians are often worried about the risk of suboptimal response to a GnRH-a-only trigger, leading to the lack of an adequate LH surge, mandatory for the full maturation of the oocyte. Myers et al., in their study of 424 fresh IVF cycles, noted the incidence of this to be 5.2% and identified those at risk to have a history of long-term contraceptive therapy, low baseline FSH and LH levels, needing a longer period of ovarian stimulation, and having a low LH level following trigger (LH < 15IU/L).^[22] The addition of hCG, even at a low dose in these situations, may be useful to maintain oocyte maturation and achieve high ongoing pregnancy and live birth rates without increasing the risk of OHSS.^[13,14] The combination of hCG and GnRHa, with or without additional luteal support with oestrogen and progesterone, also tends to minimise the risk of luteal phase deficiencies likely to be induced by the short duration of the LH surge by a GnRHa-only trigger, which affects the life span and quality of the corpus luteum and consequently endometrial receptivity and implantation.^[23]

Hence, the dual trigger would be a reasonable and more physiologic approach to enhance oocyte maturity and endometrial receptivity, thereby improving overall IVF/ICSI cycle outcomes in patients with a history of negative results due to low mature oocyte percentage and luteal phase defects after standard hCG or GnRHa triggers.

Weakness

Similar Euploidy Rate

A retrospective cohort study conducted in a total of 385 preimplantation genetic diagnoses for aneuploidy (PGT-A) cycles found similar rates of euploidy between the dual trigger and HCG trigger.^[28]

Similar Embryological Parameters

Embryo quality, one of the most important outcome parameters in an IVF cycle, can be objectively assessed in modern practice, facilitated by the Time-lapse monitoring system (TMS). Although correlation of morphokinetics by the TMS with live-birth rates are not fully established, as evident by their rating on the HFEA Traffic light system, they have been used to observe the differences in embryo quality in various types of trigger groups.^[29]

Oron et al. analysed 3352 embryos formed following ovulation triggering with hCG, dual trigger, and GnRHa-only. The division timing durations (tPB2, tPNf, t2–t7) were found to be much shorter in the GnRH-agonist group compared to the other groups. GnRH-agonist trigger had the highest top-quality cleavage embryo rate when compared to hCG and dual trigger.^[30] However, in another study of 4859 embryos, the same authors did not find any significant differences in morphokinetic parameters between embryos formed following dual triggers or hCG-only triggers.^[31]

Therefore, the use of dual triggers did not demonstrate any significant differences in objective parameters of embryo quality compared to hCG or GnRHa triggers.

Increased Cost of Treatment

It is well-known that one of the main barriers deterring patients from seeking and health authorities from offering IVF treatment is the cost burden. Despite being a significant determinant of the choice of protocol and specific medications, there is a paucity of literature on the cost-benefit analysis of various novel interventions in IVF, including the dual trigger. A recent abstract presented that the dual trigger incurred a higher net cost of 175 US dollars, compared to the hCG trigger, but also delivered 13% higher live birth rates.^[32] The authors showed that for every $13 extra cost of a second GnRHa trigger added to the conventional hCG trigger, there was an increase of 1% in the LBR. However, these costs will vary between health systems, and the benefits may vary depending on the population studied.

Opportunities

Empty Follicle Syndrome

Empty follicle syndrome (EFS) is defined as no retrieved oocytes after meticulous aspiration of follicles after ovarian stimulation in IVF treatment. Stevenson and Lashen classified these cases in a systematic review into genuine and false types, in a ratio of occurrence of 1:2.^[33] In the genuine type (33% of cases), optimal hCG levels were present on the day of oocyte retrieval, whereas in the false type (67% of cases), serum hCG levels were found to be low due to either error in the administration or poor bioavailability of the triggering agent.^[33]

In their review article, Kim and Jee suggested the use of GnRH agonist trigger as a remedial measure to induce an endogenous LH surge to boost oocyte maturation and release^[34] based on published case reports of successful oocyte recovery in an antagonist cycle.^[35] This was reiterated in a retrospective study by Noushin et al. in 13 patients with a history of genuine empty follicle syndrome over a period of 6 years, where the dual trigger and delayed oocyte recovery resulted in a significant improvement (P < 0.01) in the number of mature oocytes retrieved, oocyte maturation index, number of fertilised oocytes, and number of embryos available for embryo transfer in the dual trigger group.^[36]

Poor Responders

Poor responders (PR) comprise 5.6–35.1% of the patient population undergoing IVF, with a risk of suboptimal outcome, based on a wide spectrum of definitions to delineate this group of patients.^[37] The European Society of Human Reproduction and Embryology (ESHRE) defined poor responders by the Bologna Criteria, defined as women having at least two of the following three criteria: (1) advanced maternal age above 40 or any other risk factor for poor ovarian response; (2) a previous poor ovarian response (cycles cancelled or less than 3 oocytes retrieved with a conventional protocol); (3) an abnormal ovarian reserve test (antral follicle count <5–7 follicles or anti-Mullerian hormone (AMH) <0.5–1.1 ng/mL).^[38] Subsequent criticism of this definition led to the development of the POSEDION criteria to predict the different clinical classes of poor responders.^[39]

Noushin et al. had observed in their study of ‘genuine empty follicle syndrome’ that, women with reduced ovarian reserve are expected to be poor responders to stimulation as well as at a higher risk of empty follicle syndrome.^[36] Consequently, the use of dual triggers in this group of patients represents a remarkable opportunity for improving their IVF performance and outcome. The first study of a dual trigger in poor responders was done by Chen et al.,^[40] showing a significantly higher number of total as well as mature oocytes collected from patients who had the dual trigger compared to those who had hCG but with no differences in fertilisation rate, number of viable embryos, implantation rate, clinical pregnancy, or miscarriage rates.

Since then, different authors have tried to establish the benefit of a dual trigger in poor responders; however, the results are diversified and depend on the exact definition of the poor responder and the outcome parameters chosen by the respective authors, as summarised in Table 2.^[41–47]

Women of advanced age are a heterogeneous population and overlap with poor ovarian responders or patients with diminished ovarian reserve.

However, despite the potential selection bias in these groups of patients, the dual trigger seems to improve varying aspects of the outcome consistently in poor responders across all the studies.

Normoresponders

The term ‘normoresponder’ or normal responder commonly refers to a patient who is expected to have an average response to ovarian stimulation; in other words, they are expected to produce a reasonable number of eggs without an increased risk of OHSS.

The evidence around the use of dual triggers in normoresponders is heterogeneous. Most studies show an increase in oocyte retrieval rate, rate of mature oocytes, and fertilisation rate across the entire population [Table 3].^[48–52]

Dual trigger treatment offers better outcomes compared with conventional hCG trigger without significant increase in the risks and could be potentially considered for all normal responder patients, as a universal trigger.

Threats: Ohss and High Responders