{"paper_id":"ee3e93be-823d-475a-ba18-143b47caf87c","body_text":"Ovarian stimulation for assisted reproduction technology (ART) has three components: induction of multifollicular growth with gonadotropins, suppression of\nluteinizing hormone (LH) surge to prevent ovulation\nbefore egg retrieval and replacing the suppressed LH activity to induce oocyte maturation, which is also known\nas triggering. It is believed that the mode of triggering\nhas a significant impact on the efficacy and safety of the\nART treatment ( 1 ).\nHuman chorionic gonadotropin (hCG) is the traditional agent used to trigger oocyte maturation. Similarity between the beta subunits of LH and hCG molecules\nenable the latter to stimulate LH receptors on granulosa\ncells. However, the half-life of hCG is longer than LH\nand it induces longer stimulation of multiple corpora lutea following oocyte retrieval. This is associated with\nan increased risk of ovarian hyperstimulation syndrome\n(OHSS), a major risk of ovarian stimulation ( 2 - 6 ).\nA single bolus of a gonadotropin releasing hormone\nagonist (GnRH-a) also induces an endogenous LH\nsurge. The short duration of the GnRH-a induced LH\nsurge leads to luteolysis and significantly decreases the\nrisk of OHSS. However, luteolysis is associated with decreased pregnancy and increased miscarriage rates\nfollowing fresh embryo transfer in GnRH-a triggered\ncycles ( 7 - 10 ).\nThe addition of a small dose of hCG for luteal phase\nsupport restores clinical outcome to some extent, but\nmay increase the risk of OHSS, which justifies triggering without hCG in women at risk for OHSS ( 11 ).\nAnother suggested advantage of GnRH-a is the induction of an endogenous follicle stimulating hormone\n(FSH) surge simultaneous with the LH surge. The use\nof a GnRH-a to induce both endogenous LH and FSH\nsurges, and hCG trigger simultaneously known as the\n“dual trigger”, has been suggested to improve ART outcomes ( 12 - 15 ).\nIt is suggested that addition of a GnRH agonist to the hCG trigger in women with low\novarian reserve could improve the  in vitro  fertilisation (IVF) outcome ( 16 ,\n 17 ). However, whether the dual trigger is beneficial over the traditional hCG trigger for\nthe common ART patient is uncertain.\nThe present study aims to compare the laboratory and\nclinical outcomes of standard dose hCG trigger with a\ndual trigger of hCG and 1 mg leuprolide acetate.\n\nThe Koc University Clinical Research Ethics Committee, Istanbul, Turkey approved the protocol of this\nretrospective cohort study (2019.269.IRB1.049). All the\npatients had signed an informed consent for study participation.\nBetween January 2018 and September 2018, all women who planned to undergo egg retrieval for IVF/intracytoplasmic sperm injection (IVF/ICSI) at the Koc University Assisted Reproduction Centre, except for those\nat high risk for OHSS, were given the dual trigger in\nthe context of another study on granulosa cell function.\nThese patients constituted the dual trigger group. Women who received only the recombinant hCG (rhCG) trigger within three months immediately before and three\nmonths immediately after the dual trigger period constituted the hCG group. The authors were blinded to the\npregnancy outcomes at the time of matching.\nThe dual trigger consisted of 1 mg leuprolide acetate\n(Lucrin Daily, Abbott, USA, equivalent to 0.1 mg Decapeptyle) and 250 mcg (6000 IU) rhCG (Ovitrelle, Merck, Germany), while the conventional trigger was 250\nmcg (6000 IU) rhCG.\nWomen >45 years of age and with a history of recurrent pregnancy loss were excluded\nGonadotropins were started on the 2 nd  or 3 rd  day of the patient’s\nmenstrual cycle after ruling out ovarian or endometrial pathology by a transvaginal\nultrasound (TVUS) scan. The starting (rFSH) (Gonal F, Merck, Germany) dosage ranged between\n225 and 300 IU/day, according to ovarian reserve and body weight. Ovarian response to\ngonadotropins was evaluated by TVUS and serum oestradiol levels on the 5 th  or\n6 th  day of stimulation and every 1-3 days afterwards, based on clinical\njudgment. Daily administration of 25 mg GnRH antagonist (Cetrotide, Merck KGaA, Germany) was\nstarted when the leading follicle diameter reached 14 mm or serum oestradiol level exceeded\n200 ng/ml. Final oocyte maturation was triggered when two leading follicles were >17 mm.\nTransvaginal egg retrieval was performed 36 hours after the trigger. Conventional ICSI was\ncarried out and all embryos were cultured until the blastocyst stage. Luteal phase support\nwith 90 mg vaginal micronized progesterone gel twice a day (Crinone 8%, Merck, Germany) was\nstarted on the evening of egg retrieval and continued until a negative pregnancy test or the\n6th week of gestation.\nClinical pregnancy was defined as visualization\nof a gestational sac with a foetal heart beat by ultrasound at 6-7 weeks after embryo transfer. Ongoing\npregnancy was defined as a pregnancy that proceeded\nbeyond the 20 th  gestational week. Oocyte maturation\nrate referred to the proportion of metaphase II (MII)\noocytes to all collected oocytes per cycle. Implantation rate (IR) was calculated per cycle as the number\nof embryos with heart beat divided by the number of\nblastocysts transferred.\nContinuous variables were defined with mean (standard deviation) or median\n(25 th -75 th  percentile), and were compared between the groups with\nthe t test or Mann-Whitney U test depending on distribution characteristics. Categorical\nvariables were defined with numbers and percentages, and were compared between the groups\nwith the chi-square test and its derivatives as appropriate. P<0.05 were considered\nstatistically significant.\n\nThe study included 50 women in each group. Baseline\ncharacteristics of both groups were similar ( Table 1 ).\nAs shown in Table 2, the median number of oocytes collected (8 vs. 7, P=0.33), MII oocytes (6 vs. 5.5, P=0.41),\nblastocysts (1 in both groups), fertilisation (70% vs. 77%)\nand blastulation (30% vs. 28%) rates were similar in the\ndual trigger and hCG groups, respectively.\nFresh embryo transfer was performed in 30 out of 50\n(60%) women in the dual trigger group and in 26 out of\n50 (52%) women in the hCG group (P=0.43). Clinical\npregnancy rate (CPR, 28% vs. 22%, P=0.49) and ongoing pregnancy rate (OPR, 22% vs. 20% P=0.63) per\nwoman were similar in the dual and hCG trigger groups,\nrespectively. Pregnancy rate per transfer was 53.3%\nin the dual group and 53.8% in the hCG trigger group\n(P=0.96). CPR per transfer was 46.7% in the dual group\nand 42.3% in the hCG group (P=0.74). Both groups\nhad a miscarriage rate of 8% and there were no cases of\nOHSS during the course of the study.\nBaseline characteristics of women in the dual trigger and hCG only groups\nAll values are median (25 th -75 th  percentile). hCG; Human chorionic\ngonadotropin, IVF;  In vitro  fertilisation, and LH; Luteinizing\nhormone\nComparison of outcomes between the dual trigger and hCG only groups\n*; Values are median (25 th -75 th  percentile), hCG; Human chorionic\ngonadotropin, CPR; Clinical pregnancy rate, MII; Metaphase II, IR; Implantation rate,\nand LBR; Live birth rate.\nFresh embryo transfer was performed in 30 out of 50 (60%)\nwomen in the dual trigger group and in 26 out of 50 (52%)\nwomen in the hCG group (P=0.43). Clinical pregnancy rate\n(CPR, 28% vs. 22%, P=0.49) and ongoing pregnancy rate\n(OPR, 22% vs. 20% P=0.63) per woman were similar in the\ndual and hCG trigger groups, respectively. Pregnancy rate\nper transfer was 53.3% in the dual group and 53.8% in the\nhCG trigger group (P=0.96). CPR per transfer was 46.7%\nin the dual group and 42.3% in the hCG group (P=0.74).\nBoth groups had a miscarriage rate of 8% and there were no\ncases of OHSS during the course of the study.\n\nIn our study, universal use of dual trigger did not seem\nto provide any benefit regarding oocyte yield oocyte\nmaturation, fertilisation, blastulation, implantation or CPR/\nOPR compared to the hCG only trigger. However, the small\nnumber of samples is the shortcoming of this study.\nEffectiveness of dual triggering compared to hCG\nonly or GnRH a only triggering has been investigated in\na number of studies that vary greatly in design, methods\nand outcomes. Two randomised clinical trials (RCT)\nstudied the effect of dual trigger in normo-responders. In\nthe first one, Decleer et al. ( 18 ) studied 120 women <38\nyears of age who did not have polycystic ovarian syndrome\nor endometriosis. The mean number of retrieved oocytes\nwere similar between the dual trigger (5000 IU hCG and\n0.2 mg triptorelin acetate) and 5000 IU hCG trigger alone\ngroups, respectively. The shortcoming of their study was\nthe focus on day-3 embryos that had excellent quality.\nThis subjective perception of excellence did not translate\ninto better clinical outcomes as IR and OPR did not meet\nstatistical significance between the dual trigger and hCG\nonly groups. Moreover, day-3 embryo quality could be\na poor predictor of blastulation, and the number of good\nquality day-3 embryos is a questionable outcome measure\n( 19 - 21 ).\nEftekhar et al. ( 22 ) randomized 192 normal responders to\nreceive dual trigger or hCG only trigger. Although the mean\nnumber of oocytes (10.85 vs. 9.35) and embryos (6.86 vs.\n5.34) were statistically higher in the dual trigger compared\nto the hCG only group, there were no significant differences\nbetween implantation or CPR between the dual trigger and\nhCG only groups, respectively. In another RCT, Kim et al.\n( 23 ) compared dual trigger and hCG trigger alone for 60\nwomen in each group. They observed that although the\nnumber of oocytes retrieved, fertilised oocytes and good\nquality embryos were similar in both groups, embryo IR\n(24.7% vs. 14.9%), CPR per cycle (53.3% vs. 33.3%) and\nlive birth rate (LBR) (50.0% vs. 30.0%) were significantly\nhigher in the dual trigger group compared to the hCG\nonly group, respectively. They concluded that combined\nadministration of GnRH a with rhCG might be beneficial\nin improving endometrial receptivity and pregnancy rates\nin GnRH antagonist cycles for IVF.\nDing et al. ( 24 ) conducted a systemic review and meta-analysis to investigate the efficacy of dual trigger compared\nto hCG alone. In their four eligible RCTs that included 527\nwomen, they concluded that dual trigger was equivalent\nto hCG in triggering oocyte maturation and may be\nbeneficial in improving reproductive outcomes; however,\nthey emphasized that further intensive RCTs are needed to\ninvestigate the efficacy of dual trigger.\nLin et al. ( 25 ) retrospectively compared the hCG only\ntrigger and dual trigger in 376 normo-responder women,\nand reported that dual trigger significantly improved LBR.\nIn another study, they evaluated the outcome of dual trigger\nin 427 cycles with fresh embryo transfer in patients with\ndiminished ovarian reserve (antral follicle count of <5\nor serum AMH level of <1.1 ng/ml) ( 17 ). They reported\nsignificantly higher fertilisation rate, clinical pregnancy and\nLBR with dual trigger compared to hCG only triggering.\nSchachter et al. ( 26 ) examined the effect of dual trigger\nin a RCT of 200 cycles in women with history of at least\none failed IVF/ICSI cycle on the GnRH-a long protocol.\nAlthough the mean number of oocytes (7.9 vs. 9.9) and\nembryos (4.7 vs. 5.7) were similar between the dual trigger\n(5000 IU hCG plus 0.2 mg Triptorelin) and control (5000\nIU hCG) groups, there was a higher rate of OPR per\ntransfer reported in the dual trigger group with marginal\nsignificance.\nFabris et al. ( 27 ) studied 81 patients who had more than\n50% immature oocytes in a previous rhCG only triggered\nART cycle. The same women were given dual trigger in\nsubsequent 81 cycles. Although they reported a significantly\nhigher number of total and MII oocytes retrieved in the\ndual trigger group, it should be noted that any intervention\nalmost always provides significant improvement in the\nsecond round of before-after studies where the first cycles\nare selected from those with particularly bad results. These\nfindings are most likely explained by regression to the\nmean phenomenon, rather than a true biological effect ( 28 ,\n 29 ). Similarly, Griffin et al. ( 30 ) recruited 27 women with\nhistory of more than 25% immature oocytes (germinal\nvesicle or metaphase I) in their previous IVF cycles when\ntriggered with hCG alone and compared the outcome of\ndual triggering with their previous cycle in a retrospective\nstudy. The proportion of mature oocytes retrieved was\nalmost double with the dual trigger protocol compared to\ntheir previous hCG only trigger cycle (75% vs. 38.5%, OR:\n2.51). However, similar to the Fabris et al. ( 27 ) study, the\nincrease in oocyte maturation rate could likely be attributed\nto regression to the mean phenomenon.\nZhang et al. ( 31 ) compared dual trigger with hCG trigger\nonly in a retrospective cohort study of 1350 poor responder\npatients diagnosed according to the Bologna criteria for\npoor responders. They reported increased numbers of\nmature oocytes with the dual trigger; however, fertilisation\nrate, number of viable embryos, implantation, and clinical\npregnancy and miscarriage rates did not significantly differ\nbetween the groups.\nIn summary, most studies reported improved intermediate\noutcomes rather than clinically relevant endpoints such as IR or OPR, whereas RCTs and our study reported similar\nclinical outcomes with dual and hCG only triggering. In\naddition, another RCT that assessed the isolated effect of\nFSH exposure on the day of ovulation trigger also failed\nto demonstrate a beneficial effect on OPR/LBR over hCG\ntriggering alone ( 32 ).\nn the present study, we used dual triggering for all women\nexcept those who were at high risk for OHSS on the trigger\nday, regardless of ovarian reserve or their previous IVF\nhistory. Moreover, the authors were blind to the cycle and\nclinical outcomes during matching of the controls. Thus,\nselection bias was reduced by avoiding patient selection\nor physician preference. Still, the retrospective nature and\nthe size of the study are the weaknesses of this study. On\nthe other hand, use of any hCG, alone or in combination\nwith another agent, in patients at high risk for OHSS is not\ncurrently advised ( 33 ). Thus, this may not be a weakness\nbut a choice that helps the study more aptly reflect clinical\npractice\n\nBased on our study and previous RCTs, universal use of\ndual triggering does not seem to result in improved oocyte\nyield, oocyte maturation, fertilisation, IR, and CPR or\nOPR. Studies on dual triggering show conflicting results\non different patient groups; thus, its benefit for all women\nwho undergo IVF/ICSI lacks robust evidence and large,\nwell-designed trials should be conducted.","source_license":"CC-BY-4.0","license_restricted":false}