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10. The International Society for Mild Approaches in Assisted Reproduction (ISMAAR) Definitions for Mild Stimulation and Their Rationale for Assisted Reproductive Technologies
Keywords
Mild stimulationAssisted reproductive technologyISMAARIVFAdvanced reproductive agePoor ovarian response10.1 Introduction: Earlier Concerns for Ovarian Stimulation for In Vitro Fertilization
The first test-tube baby was delivered in 1978 in the United Kingdom. In vitro fertilization was performed during a natural cycle with laparoscopic oocyte retrieval [1]. This group lead by Drs. Edwards and Steptoe also studied granulosa cell steroid hormone production collected from follicles during a natural cycle or with human menopausal gonadotropin (HMG) stimulation followed by human chorionic gonadotropin (HCG) administration. They reported concerns about multiple asynchronous follicle development with HMG/HCG. The granulosa cells collected from follicles of various sizes in fact showed different progesterone and estradiol production. The authors discussed the potential adverse effects of multiple but asynchronous follicle development on oocyte maturation [2, 3].
The same pioneering British group tested gonadotropin treatment for ovarian stimulation in 100 cases. Mostly due to progesterone elevation before oocyte retrieval, they were never successful. In the United States, Howard W. and Georgeanna S. Jones started using gonadotropins to stimulate the ovaries despite Dr. Bob Edwards’ warning. Per Dr. Howard W. Jones memoir, “the trick might be to administer a smaller dose than Bob (Edwards) had used…. Two ampoules (pergonal) a day from 4th day of menstrual cycle continuing until day 6th or 7….we allowed the follicles to coast until oocyte retrieval…we often harvested 2,3, or even 4 follicles most with mature oocytes.” [4]. We have to consider that each ampoule of pergonal was 75 international units (IU). They did not use HCG for trigger first, but then they calculated from natural cycles that laparoscopic oocyte retrieval should be performed at 36 hours after HCG trigger, which was used as the luteinizing hormone (LH) surrogate. Eventually in December 1981, the same group delivered the first test-tube baby in the United States. Then in 1981, by using HMG, 55 women were stimulated; 31 of them had the transfer, and 7-term healthy live births resulted [4, 5].
10.2 Controlled Ovarian Stimulation Protocols for In Vitro Fertilization
Since the efficiency of the process seemed to improve with ovarian stimulation using gonadotropins, very fast innovation in ovarian stimulation drugs and the protocols followed. The terms controlled ovarian hyperstimulation (COH) and controlled ovarian stimulation (COS) were introduced with direct relevance to IVF although it has become highly debatable if these protocols deserve the term “controlled.” The doses of gonadotropins used in the stimulation protocols increased with a rationale that more oocytes would lead to better IVF outcomes. Thereafter, the concerns about complications like ovarian hyperstimulation syndrome, multiple pregnancies due to the transfer of high number of embryos, and high levels steroids and endometrial receptivity issues were associated with various prenatal complications. In addition, there were worries about the financial cost and the emotional burden of IVF with such high-dose protocols. Then some countries imposed strict embryo transfer policies to minimize multiple gestations.
10.2.1 Concerns with Conventional Controlled Ovarian Stimulation Protocols for In Vitro Fertilization
There are concerns that COS protocols for IVF may be associated with increased rates of embryonic aneuploidy and inferior IVF outcomes [6, 7]. High doses of FSH use which is associated with high estradiol levels may be associated with problems in chromosome segregation during meiosis [8]. In an earlier prospective randomized study, the chromosome abnormality rates for embryos developed from mild and conventional stimulation were 55% and 73%, respectively. Hence even some additional oocytes may be obtained with conventional stimulation, the euploid embryo outcome may be higher with mild stimulation, largely minimizing the importance of retrieving more oocytes with conventional stimulation [6].
It was also demonstrated that high concentrations of FSH added to the in vitro maturation medium increased the first meiotic division errors, with increased number of aneuploidy in in vitro matured human oocytes when the polar bodies and the oocytes were assessed with fluorescent in situ hybridization, although there were no differences between the low-dose FSH and very high-dose FSH treated group when the spindle morphology was assessed. Euploid and aneuploid oocytes showed comparable meiotic spindle visualization rates under PolScope as well [9].
A randomized controlled study conducted in women younger than 38 years of age compared eight-cell stage blastomere biopsy results testing for ten chromosomes with fluorescent in situ hybridization (FISH) in patients randomized to either mild stimulation antagonist (recombinant FSH 150 IU daily, started on day 5 of the menstrual cycle) or conventional FSH luteal agonist protocols (recombinant FSH dose 225 IU/daily, starting with withdrawal bleeding). The authors had to terminate the study early after interim analysis revealed a lower embryo aneuploidy rate with mild stimulation IVF. Actually, the number of euploid embryos with conventional stimulation was not higher than the mild stimulation group even with twice the number of embryos obtained with conventional stimulation. In addition, increased mosaic embryos with conventional stimulation was observed with concerns about higher doses of FSH that may also lead to mitotic segregation errors [6].
In another randomized dose-response trial for a new recombinant human FSH preparation, it was shown that increasing FSH dose for stimulation correlated with decreased fertilization rate and decreased blastocyst development per oocyte-recovered ratio [10].
Conventional stimulation protocols for IVF may affect ovarian follicular hormonal milieu. A cross-sectional study of leading follicular fluid samples has revealed that a conventional HMG (150–300 IU daily initiated day 3–5 of the menstrual cycle) stimulation with antagonist protocol resulted in lower AMH, testosterone, androstenedione, dehydroepiandrosterone, estradiol, and LH levels as compared to leading follicular fluid samples collected from women who underwent natural cycle IVF. Both treatment cycles were triggered by HCG (10,000 IU with conventional stimulation and 5000 IU with >18 mm follicle with natural cycle) [11]. Then recently the same researchers again studied the follicular fluid samples collected from first dominant follicle of patients who underwent natural cycle IVF or conventional stimulation IVF with HMG and GnRH antagonist. Follicular fluid obtained from conventional stimulation group contained more CD45+ leucocytes but fewer CD8+ cytotoxic T cells than those obtained from natural cycle IVF group. There were also differences between the levels of IL-8 and vascular endothelial growth factor (VEGF), former being lower and the latter being higher in conventional stimulation IVF group as compared to natural cycle IVF [12]. Therefore, the use of gonadotropins per se is associated with intrafollicular changes.
10.2.2 Clinical Data on Gonadotropin Doses and In Vitro Fertilization Outcomes in Women with Advanced Reproductive Age and/or Expected Poor Ovarian Response
Increasing the dose of gonadotropins to enhance oocyte yield in women with advanced reproductive age (ARA) may not work as rationalized. An earlier prospective double-blind multicenter study conducted in women between 30 and 39 years of age compared the fixed daily dose use of a recombinant (rec-) FSH preparation at either 150 IU or 250 IU for COS for IVF. The number of oocytes collected between the low- and high-dose groups was comparable. In younger women between the age of 30 and 33 years, high-dose regimen resulted in higher mean number of oocytes (14.8 versus 10.6) than the low-dose regimen. However, in advanced reproductive age group between 37 and 39 years of age, the mean number of oocytes was comparable between high- and low-dose protocols (8.1 versus 7.4, respectively). Advancing female age was associated with decreased oocyte yield regardless of the rec-FSH dose used. Average FSH concentrations on the day of hCG administration for triggering for final oocyte maturation was 13 IU/L in 250 IU group but only 9.3 IU in the 150 IU group. Again higher FSH levels did not help with the oocyte yield. When the secondary outcomes were assessed, it was obvious that the pregnancy rates were comparable between 150 IU and 250 IU groups. However, in the general patient population, those stimulated with 150 IU daily dose resulted in somewhat higher clinical pregnancy rates per started cycle or per embryo transfer than the 250 IU arm. The implantation rates seemed to be higher in the lower-dose group as well although none of these differences reached statistical significance. Therefore, increasing the daily dose of recombinant FSH did not compensate for age-related decrease in retrievable oocytes [13].
A recent Cochrane review analyzed whether individualized gonadotropin dosing based on ovarian reserve tests (AMH, basal FSH, antral follicle count) effects IVF outcome. The authors included 20 such clinical trials, but meta-analysis was limited due to heterogeneity. Lack of blinding also influenced the quality of the evidence. The authors concluded that modifying FSH dose for IVF according to low, normal, or high ovarian reserve patients did not affect live birth or ongoing pregnancy rates. Consequently, the current evidence did not justify increasing the standard daily dose of 150 IU in poor or normal responders [14].
Multicenter prospective cohort study and two embedded randomized controlled trials assessed the IVF/intracytoplasmic sperm injection (ICSI) outcomes of the women with antral follicle counts (AFC) < 11 who were randomized to individualized dosing with 450 IU (women with AFC ≤ 7) or 225 IU (women with AFC 8–10) of daily gonadotropins and standard daily 150 IU dose of gonadotropins. IVF/ICSI live birth outcomes were comparable between the general high-dose individualized dose group and the standard daily 150 IU dose group, while the cost was much higher for the high-dose group. The authors recommended starting 150 IU daily dose of gonadotropins to all women with regular cycles for IVF including those with predicted poor ovarian response (POR) per AFC [15, 16]. In addition, in women at ≤39 years of age, receiving standard fixed daily dose of 150 IU of recombinant FSH, the serum FSH levels on the day of trigger were not different between poor and normal responders. The authors concluded that POR is not due to low serum FSH levels achieved on the day of trigger. Therefore, increasing the dose of recombinant FSH above 150 IU daily dose may not be justified to improve outcomes in women with POR [17].
10.3 International Society for Mild Approaches in Assisted Reproduction (ISMAAR): Mild Stimulation Versus Minimal Stimulation
A large national registry study from the United States of autologous cycles performed between 2004 and 2012 suggested that with increasing FSH dose, regardless of the number of oocytes retrieved, the live birth rates declined. This was also true for the good prognosis patients as well. The authors suggested that perhaps the providers may avoid using high-dose FSH but noted that this study’s results does not support the use of minimal stimulation or natural cycle approaches for IVF [18]. Interestingly the lead author of this paper commented earlier that since its cost effectiveness was not established, the acceptability of mild stimulation protocols for IVF might not be acceptable for patients in the United States [19].
The European group though recently suggested that with the recent research evidence, the mild stimulation approaches for IVF should lead to their widespread acceptance [20]. This was entailing using more gentle approaches for ovarian stimulation for IVF and elective single embryo transfer. Then some societies and organizations started promoting low cost and safe IVF stimulation protocols. One of these organizations is the International Society for Mild Approaches in Assisted Reproduction (ISMAAR) [21].
The ISMAAR defines mild stimulation IVF when FSH or HMG is administered at a lower dose and/or shorter duration in a gonadotropin-releasing hormone (GnRH) antagonist co-treated cycle or when oral compounds, oral antiestrogens, or aromatase inhibitors are used either alone or in combination with gonadotropins with the aim of collecting fewer oocytes.
Mild stimulation IVF definition may be considered somewhat vague. Mild stimulation includes the stimulation protocols with reduced gonadotropin dose and/or duration leading to low cumulative doses of gonadotropins and perhaps aiming to develop 3–5 follicles per IVF cycle. The ISMAAR defines that the daily maximum dose of FSH or HMG should be 150 IU as the described threshold to differentiate between conventional controlled ovarian stimulation protocols for IVF. We agree with the daily dose threshold, but we also consider that the cycles including oral agents like clomiphene citrate or aromatase inhibitor letrozole may even require less cumulative FSH doses per treatment cycle. We chose to call such approaches as minimal stimulation for IVF as some others suggested [22].
10.3.1 Natural Cycle Paradigm for IVF
Natural cycle protocols have been revisited and implemented especially taking advantage of the advances in embryo freezing and the availability of GnRH antagonists. These protocols were especially gaining acceptance in patients with POR and/or diminished ovarian reserve (DOR).
In a small study involving DOR and ARA patients between the ages of 37 and 43 years, natural cycle IVF with ICSI resulted in comparable pregnancy rates as compared to those rates achieved with conventional stimulation in historical controls [23]. In a randomized controlled study, natural cycle IVF in women with history of POR (59 patients 114 cycles) has been shown to result in better implantation rates (14.9% vs 5.5%) than those achieved by GnRH agonist microdose flare protocol (70 women, 101 cycles). Otherwise, the patients treated with natural cycle IVF and those treated with GnRH agonist microdose flare showed similar pregnancy rates per cycle and per transfer. Especially those patients ≤35 years of age benefited better than older patients from natural cycle IVF in terms of pregnancy rates [24]. A small within-patient study has suggested that natural cycles may result in higher oocyte retrieval rates with higher clinical pregnancy rate per started cycle in patients with history POR with conventional IVF stimulation [25]. Considering the overall reduced adverse impact of such approaches in terms of decreased cost per cycle and possibly better endometrial receptivity and oocyte quality and possibility of doing multiple cycles at reduced cost as compared to conventional high-dose stimulation protocols, natural cycle approaches have been favored especially for DOR and ARA patients.
10.3.2 Mild Stimulation for IVF
In regard to mild stimulation, a prospective randomized study compared GnRH agonist long protocol to two flexible-start GnRH antagonist protocols, one commencing rec-FSH on day 2 of the cycle and the other one was commencing on day 5 of the cycle. Daily rec-FSH dose for GnRH antagonist protocols was kept at 150 IU. Although with day 5 rec-FSH start more cycles were canceled before oocyte retrieval, overall, the quality of the embryos were reported to be higher in day 5 start group. The transfer rate per oocyte retrieval as a result became higher with higher pregnancy rates in women with ≤4 oocytes retrieved in the group with day 5 rec-FSH start. This group showed the least median cumulative dose of rec-FSH use (1200 IU, while with GnRH agonist and GnRH antagonist, day 2 rec-FSH start used median of 1650 IU and 1350 IU, respectively). All treatment groups showed comparable pregnancy rates per started cycle suggesting that mild stimulation regimens are as effective as higher dose regimens in COS for IVF. This may be related to better oocyte and embryo quality with lower doses of FSH [26].
At least in normal to high responders, there are randomized trials demonstrating comparable or a trend of higher rate of good-quality embryos or blastocysts via mild stimulation approaches [26, 27].
In terms of elective single embryo transfer applications with mild stimulation, which entails cycle day 5 start of 150 IU/day rec-FSH and late follicular phase GnRH antagonist co-treatment in women younger than 38 years of age, the ongoing pregnancy rates of 28% per single embryo transfer were reported [28].
Recently the American Society for Reproductive Medicine (ASRM) recommended, “in patients who are classified as poor responders and pursuing IVF, strong consideration should be given to mild ovarian stimulation protocol….” This practice committee of ASRM recommendation is based on the findings that mild stimulation has low cost and comparable low pregnancy rates with conventional stimulation protocols [29]. This last suggestion may also be challenged since such protocols can be optimized if combined with the sole use of frozen embryo transfers as we discussed in this book.
10.4 Conclusion
Ovarian stimulation to increase oocyte yield was commenced in the early 1980s albeit starting with low gonadotropin doses. In a short time, controlled ovarian stimulation protocols evolved to include high daily doses of FSH. Shortly, many concerns about using high-dose FSH lead to revisiting the dose of gonadotropins to assure optimum outcomes. The efforts to increase oocyte yield in women with DOR and ARA by using high-dose conventional COS protocol did not result in the expected improvement in IVF outcomes. The ISMAAR proposed mild stimulation definition, and since then many studies supported their use especially in women with predicted POR, i.e., DOR and/or ARA. Natural cycle approaches to IVF found ground for DOR population. Mild and minimal stimulation approaches are beginning to have some acceptance from the assisted reproductive technology establishment as well.
