Abstract
A narrative review of the management of controlled ovarian stimulation in patients undergoing preimplantation genetic testing is presented. An electronic search was performed to identify research publications that addressed ovarian stimulation and preimplantation genetic testing published until December 2017. Studies were classified in decreasing categories: randomized controlled trials, prospective controlled trials, prospective non-controlled trials, retrospective studies and experimental studies. The aim of controlled ovarian stimulation has shifted from obtaining embryos available for transfer to yielding the maximum embryos available for biopsy to increase the odds of achieving one euploid embryo available for transfer, without the distress of inducing ovarian hyperstimulation syndrome or inadequate endometrium receptivity as vitrification and deferred embryo transfer usually will be planned. The present narrative review summarizes all treatment-related variables as well as stimulation strategies after controlled ovarian stimulation that could help patients undergoing an in vitro fertilization cycle coupled with preimplantation genetic testing, including the number of oocytes needed to achieve one healthy live birth, oral contraceptive pill usage, the role of mild ovarian stimulation or random-start stimulation, the stimulation protocol and type of gonadotropin of choice, the novel progesterone protocols, agonist or dual trigger as a final oocyte maturation trigger, the accumulation of oocytes/embryos and the optimal interval before proceeding with a subsequent controlled ovarian stimulation or the optimal medication to link stimulation cycles. The discussion is being presented according to how questions are posed in clinical practice. The aim of ovarian stimulation has shifted from obtaining embryos available for transfer to yielding the maximum embryos available for biopsy to increase the odds of achieving one euploid embryo available for transfer.
Introduction
Previous years have shown great progress in the field of human assisted reproductive technology (ART), largely thanks to the ability of embryologists and reproductive physicians to consider new strategies for improving the practice of in vitro fertilization (IVF). Notably, one of these breakthroughs has been the implementation of preimplantation genetic testing (PGT) of embryos, a technology introduced by Handyside et al. (1989) that allows controlling, before transfer, if all 24 chromosomes are normal within an embryo. Several improvements have been made to the technology, such as biopsy day (Scott et al. 2013a ), amplification method (Sermon et al. 2016) or platform upgrades to analyze the amplified DNA (Sermon et al. 2016) that have enhanced its validity and propelled its adoption. Even though PGT has become a common tool to filter embryos before transfer, scarce information is available regarding the optimal controlled ovarian stimulation (COS) strategy in patients undergoing IVF with the intention to genetically evaluate their embryos.
Traditionally, the goal of COS with exogenous gonadotropins has been to maximize oocyte yield in an effort to overcome the high rate of gamete and embryo attrition (Pellestor et al. 2006, Rodriguez-Purata et al. 2015). Nevertheless, the objective of COS in patients undergoing PGT has been inherently adapted. Fundamentally, COS has changed from purely obtaining one suitable embryo available for transfer to obtaining the maximum number of embryos available for biopsy in order to increase the odds of achieving one euploid embryo available for transfer.
Furthermore, in the same manner that COS is tailored according to patient demographic variables such as antimullerian hormone (AMH) (Lensen et al. 2018), antral follicle count (AFC) (Lensen et al. 2018) or basal follicle-stimulating hormone (FSH) (Lensen et al. 2018), the concept of fitting COS in order to compliment a patient’s infertility diagnosis has also been utilized, for example in patients who experience poor ovarian response (POR) (Polyzos & Devroey 2011) or in patients undergoing fertility preservation (FP) for medical (Dahhan et al. 2017) and non-medical reasons (Stoop et al. 2014). In this regard, specific subsets of patients have particular requirements during their treatment, and endpoints in mind should be thought with the final aim that these patients seek.
The question being, in the era of modern ART, is there an optimal stimulation strategy for patients or couples undergoing an IVF cycle with the aim of sustaining PGT that maximizes reproductive potential? For the purpose of this review, studies related to ovarian stimulation reporting live birth (LB) in PGT cycles or the clinically relevant outcome will be selected as a surrogate outcome of embryo euploidy.
Objective
The review surveys the current literature presented on critical clinical decisions regarding the management of COS for women undergoing IVF coupled with PGT. Additionally, the review is intended to offer professionals in the field of reproductive medicine a comprehensive clinical summary of the optimal stimulation strategy when incorporating PGT in IVF programs.
Materials and methods
Search
The current narrative review was designed to take a broad overview of the topic and attempted to integrate all available clinical and scientific evidence correlating the acquisition of euploid embryos through COS. The flow discussion will be presented according to how questions are posed in clinical practice. First, decisions before COS is started, followed by decisions presented during COS and, lastly, decisions after COS is finished:
For this narrative review, original studies were classified into five categories according to decreasing supporting evidence: randomized controlled trials (RCTs), prospective controlled trials, prospective non-controlled trials, retrospective studies and experimental studies. Studies included in lower categories were only used if enough evidence was not provided by high-quality studies. Reports in the form of abstracts were not considered for this review. The authors performed a systematic search of the literature for studies appropriate to the clinical questions on Medical Literature Analysis and Retrieval System Online (MEDLINE), PubMed, Embase, Cumulative Index to Nursing and Allied Health Literature and Cochrane Library (http://www.cochranelibrary.com). The authors additionally checked citations on the Web of Science and manually searched the references of the articles. Only articles in English were included. Searches were coordinated by an expert librarian and a statistician in November 2017 and December 2017. Search updates were conducted in April 2018. All records were screened for eligibility by two independent reviewers.
Quality assessment
Interpretation of the grades of recommendations (Vermeulen et al. 2017) is shown in Table 1. The grades of the recommendations are only based on the strength of the supporting evidence.
Interpretation on the grades of recommendations (Vermeulen et al. 2017).
| Grades of recommendations | Supporting evidence |
|---|---|
| A | Meta-analysis, systematic review or multiple randomized controlled trials (RCTs) (high quality) |
| B | Meta-analysis, systematic review or multiple RCTs (moderate quality)Single RCT, large non-randomized trial, case-control or cohort studies (high quality) |
| C | Single RCT, large non-randomized trial, case-control or cohort studies (moderate quality) |
| D | Non-analytical studies, case reports or case series (high or moderate quality) |
| GPP | Expert opinion |
Results
How many oocytes do we need?
The goal of COS is to allow the retrieval of many oocytes during a cycle of IVF (Trounson et al. 1981). COS compensates for inefficiencies in the following stages of the cycle such as oocyte maturation and insemination, embryo culture and transfer, and implantation (Fauser et al. 1999). Even though the basis of COS involves the administration of gonadotropins (Macklon et al. 2006), it is now very clear that a ‘one-size-fits-all’ approach does not exist and an individualized treatment approach can cater to a patient’s unique characteristics and maximizes success, eliminates iatrogenic risks and minimizes the risk of cycle cancellation (Scott et al. 2013a , b , La Marca & Sunkara 2014, Oudshoorn et al. 2017, van Tilborg et al. 2017a , b ).
On the other hand, PGT describes the procedure of removing one or more nuclei from embryos, blastomeres or trophectoderm cells, to test for mutations in gene sequence or aneuploidy before transfer selection (Practice Committee of Society for Assisted Reproductive Technology & Practice Committee of American Society for Reproductive Medicine (2008)). When performing COS for PGT, the goal is to obtain a maximum ovarian response, without distress of inducing ovarian hyperstimulation syndrome (OHSS) (Steward et al. 2014) or inadequate endometrium receptivity (Evans et al. 2014) at transfer.
The reduction in natural conception and moderate IVF success rates with age is attributed to both the decline of the ovarian reserve (Broekmans et al. 2009) and the increase in embryonic aneuploidy rate (Pellestor et al. 2006, Hassold & Hunt 2009, Franasiak et al. 2014). As a result, an increase in the practice of PGT during IVF has been observed (De Rycke et al. 2015). By permitting the selection of a euploid embryo before transfer, PGT has enhanced the efficiency of ART outcomes, particularly in patients with advanced maternal age, couples in which a severe male factor has been identified or in patients suffering repeated miscarriages or implantation failure (Munné et al. 2002, Harper & SenGupta 2012, Hodes-Wertz et al. 2012).
In essence, patients/couples looking to undergo PGT are not just expecting the identification of a transferable embryo, but the accumulation of as many embryos as possible in the minimal time attainable with the least plausible associated side effects.
Traditionally, a successful outcome when undergoing ART treatment denotes the ability to achieve a healthy singleton LB. Having this in mind, several studies reported that the most important factor that increases the odds of achieving the desired outcome is the number of oocytes retrieved, with 10–15 oocytes the considered optimal range (Meniru & Craft 1997, Kably et al. 2001, Letterie et al. 2005, van der Gaast et al. 2006, Edgar & Gook 2007, Patrizio & Sakkas 2009, Sunkara et al. 2011, Stoop et al. 2012, Fatemi et al. 2013, Ji et al. 2013, Steward et al. 2014, Baker et al. 2015, Drakopoulos et al. 2016, Vaughan et al. 2017).
Initially, studies conveyed there was a threshold number of oocytes after which, above and below, outcomes started to compromise (Meniru & Craft 1997, van der Gaast et al. 2006, Patrizio & Sakkas 2009, Sunkara et al. 2011). However, since this information was based only on fresh cycle outcomes, later studies incorporated the concept of cumulative LB rates (LBRs) (Fatemi et al. 2013, Drakopoulos et al. 2016, Toftager et al. 2017), largely because of the improvements and optimization made in cryopreservation methods (Cobo & Diaz 2011, Cobo et al. 2012) and the increasing use of the ‘freeze-only’ policy (Roque et al. 2013). Before the understanding that the quality of the frozen embryos and their reproductive potential were at least similar to those observed with fresh embryos (Roque et al. 2013, Rodriguez-Purata et al. 2016a ), the accepted concept was that there was a maximum probability of LB in a fresh cycle, as, when everything is taken into consideration, only a certain number of embryos were going to be transferred in the fresh cycle, regardless of how many embryos were available for subsequent frozen embryo transfer (FET) cycles.
To date, there are no studies evaluating the optimal number of oocytes needed to achieve one healthy LB through PGT. Since in most cases PGT involves the vitrification of all biopsied embryos as the turnaround time before genetic results are received is highly variable depending on the technology used (i.e. ploidy status, single-gene disorders, specific balanced translocations), success of COS can, therefore, be segmented into the optimal number of oocytes needed to obtain one blastocyst, then into the optimal number of blastocysts needed to obtain one euploid embryo, and, lastly, into the optimal number of euploid embryos needed to achieve a LB. Included studies are summarized in Table 2.
Studies evaluating the optimal number of oocytes, blastocysts and euploid embryos needed to achieve one healthy LB through PGT.
| Study | Variable | Metric | |
|---|---|---|---|
| Number of oocytes needed to obtain one embryo | |||
| Sunkara et al. (2011) | Retrospective study | Oocytes to LB | LBR increased up to 15 oocytesLBR plateaued between 15 and 20LBR declined beyond 20 oocytes |
| Stoop et al. (2012) | Retrospective study | MIIs to LB | 3.84% of MIIs result in LB4.5% from 23 to 37 years3.8% at 38 years0.8% at 43 years |
| Fatemi et al. (2013) | RCT double-blind | Good-quality embryos | 1.1 with 0–5 oocytes retrieved8.0 with >18 oocytes retrieved |
| Fatemi et al. (2013) | RCT double-blind | Cryopreserved embryos | 0.2 with 0–5 oocytes retrieved4.2 with >18 oocytes retrieved |
| Patrizio and Sakkas (2009) | Retrospective study | Usable embryos | 31.2% of oocytes retrieved |
| Ji et al. (2013) | Retrospective study | Usable embryos | 2 with 0–5 oocytes were retrieved9 with >16 oocytes were retrieved |
| Vaughan et al. (2017) | Retrospective study | Usable embryos | 0.1 with 1–3 oocytes retrieved1.0 with 4–9 oocytes retrieved2.5 with 10–14 oocytes retrieved4.1 with 15–25 oocytes retrieved6.7 with >25 oocytes retrieved |
| Number of blastocysts needed to obtain one euploid embryo | |||
| Franasiak et al. (2014) | Retrospective study | Aneuploidy | >40% at age 2525% at ages 26–3085% at age 43 |
| Franasiak et al. (2014) | Retrospective study | No-euploid embryo rate | 30% at age 22<10% at ages 26–3733% at age 4253% at age 44 |
| Labarta et al. (2012) | Prospective cohort study | Euploid embryo rate | 60% at ages <35 years |
| Labarta et al. (2017) | Prospective cohort study | Oocytes to euploid embryo | 3.4 MIIs to one euploid embryo2 euploid embryos with 1–12 oocytes3 euploid embryos with 13–16 oocytes5 euploid embryos with 17–23 oocytes6 euploid embryos with >23 oocytes |
| Ata et al. (2012) | Retrospective study | Proportion of patients with one euploid embryo | 1–4 blastocysts92.3% <35 years78.6% when 35–39 years60.7% when 40–4237.5% when >43 years5–7 blastocysts100% in <35 years97.2% when 35–39 years81.3% when 40–42 years66.7% when >43 years8–10 or >10 blastocysts Essentially 100% |
| Number of euploid embryos needed to achieve a live birth | |||
| Yang et al. (2012) | RCT, fresh | SET | 70.9% clinical PR69.1 ongoing PR |
| Scott et al. (2013a , b ) | RCT, fresh | 1.86 embryos transferred | Sustained IR: 66.4%LBR: 84.7% |
| Forman et al. (2013) | RCT, fresh and frozen | SET | Ongoing PR: 60.7% |
IR, implantation rate; LB, live birth; LBR live birth rate; MII, metaphase II oocytes; PGT, preimplantation genetic testing; PR, pregnancy rate; RCT, randomized controlled trial; SET, single embryo transfer.
Number of oocytes needed to obtain one embryo
Sunkara et al. reported a strong correlation between the number of oocytes and LBR, which rose with increasing number of oocytes up to 15, plateaued between 15 and 20 and steadily declined beyond 20 oocytes (Sunkara et al. 2011). It is worth mentioning that the study only analyzed fresh IVF cycle outcomes and did not take into account the impact of FET cycles on the cumulative LBR (Sunkara et al. 2011).
Stoop et al. referred that, overall, 3.83% of all retrieved mature oocytes result in a LB (Stoop et al. 2012). The authors reported that oocyte utilization rate (number of LBs per mature oocyte) depends largely on ovarian response between the ages of 23 and 37, and to a much lesser extent on age. But from the age of 38, the oocyte utilization rate depended largely on age, and to a lesser extent on ovarian response (Stoop et al. 2012). The oocyte utilization rate between the age of 23 and 37 remained constant with an average of 4.5%. But from ≥38 years, a significantly lower oocyte utilization rate was noted, declining from 3.8% at 38 years to 0.8% at 43 years (P < 0.001) (Stoop et al. 2012).
Fatemi et al. (2013) also showed how the average number of good-quality embryos increased with ovarian response: from 1.1 with 0–5 oocytes retrieved to 8.0 with >18 oocytes retrieved (recombinant FSH group). Accordingly, the number of cryopreserved embryos also increased with ovarian response: from 0.2 with 0–5 oocytes to 4.2 with >18 oocytes (Fatemi et al. 2013).
Given that some published studies do not report biopsiable embryos as an outcome, transferable or usable embryos were considered as a surrogate marker for biopsiable embryos with the objective of determining how many embryos would have been available if a PGT cycle would have been carried out. First, Patrizio and Sakkas published that 31.2% of the total oocytes collected develop into usable embryos (Patrizio & Sakkas 2009). Then, Ji et al. showed that the number of transferable embryos increased from 2 when 0–5 oocytes were retrieved to 9 when >16 oocytes were retrieved (Ji et al. 2013). Lastly, Vaughn et al. reported that the average usable blastocysts increased as the number of oocytes retrieved increased: 0.1 with 1–3 oocytes, 1.0 with 4–9 oocytes, 2.5 with 10–14 oocytes, 4.1 with 15–25 oocytes and 6.7 with >25 oocytes were retrieved (Vaughan et al. 2017).
Number of blastocysts needed to obtain one euploid embryo
The aneuploidy rate and the no-euploid embryo rate (risk of having no-euploid embryos within a single cohort) rises in a predictable way with age (Franasiak et al. 2014). It was found that aneuploidy rates reached >40% at age 25, reached the lowest level between the ages of 26 and 30 at around 25%, with a predictable and steady rise through age 43, at which point the rate plateaus at approximately 85% (Franasiak et al. 2014). The no-euploid embryo rate was nearly 30% at age 22, reached the lowest in women aged 26–37, then 33% at age 42 and was 53% at age 44. Interestingly, both the aneuploid rate and the no-euploid embryo rate in patients younger than 26 years were higher than in patients older than 26 years. Additionally, Labarta et al. also published a 60% euploid embryo rate in patients <35 years (25.4 ± 4.0) (Labarta et al. 2012).
More recently it has been published that a total of 3.4 metaphase II (MII) oocytes were needed to obtain one euploid embryo in patients <35 years (Labarta et al. 2017), and, considering the median value as a reference point, the authors observed that the mean of euploid embryos was 5.0 ± 2.4 (median 5.0) when the number of oocytes obtained was ≥median (17 oocytes), and it was 2.6 ± 1.4 (median 2.5) when ovarian response was below it (P < 0.001). Furthermore, when the number of euploid embryos was segregated by ovarian response, the authors observed ~2 euploid embryos with 1–12 oocytes, ~3 euploid embryos with 13–16 oocytes, ~5 euploid embryos with 17–23 oocytes and ~6 euploid embryos with >23 oocytes.
Lastly, according to Ata et al., when 1–4 blastocysts are obtained, 92.3% of patients <35 years will have one euploid embryo, 78.6% when 35–39 years, 60.7% when 40–42 and 37.5% when ≥43 years. Now, when 5–7 blastocysts are identified, 100% of patients <35 years will have one euploid embryo, 97.2% when 35–39 years, 81.3% when 40–42 and 66.7% when ≥43 years. Then, when 8–10 or >10 blastocysts are biopsied, essentially 100% of all patients will have at least one euploid embryo (Ata et al. 2012). This depicts that the more blastocysts biopsied, the higher the probability of obtaining at least one euploid embryo available for transfer, although at the same time, that probability decreases with increasing age.
Number of euploid embryos needed to achieve a LB
Three RCTs were identified reporting clinical pregnancy rates (PRs), ongoing PRs or LBRs (Yang et al. 2012, Forman et al. 2013, Scott et al. 2013b ). PGT is correlated with higher implantation rates (IR) and higher ongoing PRs when the same number of embryos are transferred in non-PGT cycles. By enhancing embryo selection with aneuploidy screening, a single euploid embryo with higher reproductive potential can be selected for transfer. Using this approach, elective single embryo transfer (SET) can be performed without compromising LBRs and improving the chance of having a healthy, term singleton delivery after IVF (Forman et al. 2014).
Yang et al. reported a clinical PR with PGT of 70.9% and an ongoing PR of 69.1% when a fresh euploid SET (Yang et al. 2012). Scott et al. reported sustained IRs (probability that an embryo will implant and progress to delivery) of 66.4% (with 1.86 embryos transferred) and a LBR of 84.7% (Scott et al. 2013b ). Lastly, Forman et al. reported a SET’s ongoing PR of 60.7% (Forman et al. 2013). Of note, this is the only RCT in which fresh and frozen ET cycles were accounted, and IRs were significantly improved with both strategies (60.7% after euploid SET vs 65.1% after untested two-blastocyst transfer; relative risk (RR): 0.9; 95% confidence interval (CI): 0.7–1.2) (Forman et al. 2013).
Treatment-related variables in PGT cycles
In conventional IVF, retrieving less than four oocytes is considered a POR, and the risk of POR increases when there is a low ovarian reserve (Ferraretti et al. 2011), whereas for PGT, the retrieval of <10 oocytes had been previously considered insufficient (Vandervorst et al. 1998). The cumulative probability of achieving a LB does not plateau at any level of ovarian response, reaching in the extreme high response (>30 oocytes) values above 75% and that the number of euploid embryos increases as the number of retrieved oocytes does (Ata et al. 2012, Labarta et al. 2017). Therefore, in PGT cycles, the preferred strategy is a stimulation protocol aiming to exploit the ovarian response as much as possible without incurring in adverse effects to the patient.
Contraceptive pill programming
Pretreatment with oral contraceptive pills (OCP) withholds natural hormone production and might help homogenize the development of the follicular cohort and help scheduling IVF cycles (Cédrin-Durnerin et al. 2007). In the most recent systematic review addressing the influence of hormone pretreatment in IVF cycles (Farquhar et al. 2017) multiple subgroups were used to evaluate OCPs combined with different GnRH-analog protocols (antagonist/agonist). Treatments were compared head-to-head or versus no treatment or placebo. Various of the comparisons included only one study with limited number of participants and methodological weaknesses, so many findings from this review should be considered with caution (Farquhar et al. 2017). With antagonist cycles in both groups, the LBR or ongoing PR was lower in the pretreatment group (OR: 0.74, 95% CI: 0.58–0.95; 6 RCTs; 1335 women; I 2 = 0%; moderate-quality evidence). There was insufficient evidence to determine whether the groups differed in rates of pregnancy loss (OR: 1.36, 95% CI: 0.82–2.26; 5 RCTs; 868 women; I 2 = 0%; moderate-quality evidence), multiple pregnancy (OR: 2.21, 95% CI: 0.53–9.26; 2 RCTs; 125 women; I 2 = 0%; low-quality evidence), OHSS (OR: 0.98, 95% CI: 0.28–3.40; 2 RCTs; 642 women; I 2 = 0%, low-quality evidence), or ovarian cyst formation (OR: 0.47, 95% CI: 0.08–2.75; 1 RCT; 64 women; very low-quality evidence) (Farquhar et al. 2017). These results are consistent with previous reports (Griesinger et al. 2010, 2015).
Given that comparable outcomes are obtained, it can be concluded that the benefits of cycle scheduling with OCPs (Garcia-Velasco et al. 2011) (equal distribution of workload in large busy units and staff distribution, avoiding weekend retrievals in small units, synchronization of follicular cohort, avoiding excessive incubator openings) outweigh the theoretical drawbacks (i.e. higher FSH consumption and longer duration of the stimulation). Additionally, it is particularly useful in PGT programs to try to avoid biopsy procedures over the weekend.
Stimulation strategy
Conventional vs mild stimulation
With the mild ovarian stimulation (MOS) approach, clinicians focus on optimizing patient care rather than obtaining the highest yield of oocytes, by minimizing treatment burden and risk of complications. MOS is associated with a greater safety profile in terms of the incidence of OHSS and of venous thromboembolism (Nargund et al. 2017). It is also found to be better tolerated by patients (Verberg et al. 2008) and less expensive (Nargund et al. 2017). Given that two meta-analyses of RCTs in normal responders demonstrated a lower number of retrieved oocytes in MOS (Verberg et al. 2009a , b , Matsaseng et al. 2013), it is not a strategy recommended for patients undergoing a PGT cycle.
Random-luteal phase stimulation
Largely, COS is usually started at the early follicular phase (day 2–3 of the cycle) for ~8–10 days, and the retrieval of mature follicles takes place around day ~13–15 of the cycle. Beginning the COS at any time of the cycle (‘random start’) has been a routine in FP (Martinez 2017) without observing any change in oocytes retrieved, regardless of cycle start day (Martínez et al. 2014, Ubaldi et al. 2016). This approach is based upon the recognition of the presence of multiple waves of follicle recruitment within a single inter-ovulatory period (Baerwald et al. 2012).
Ubaldi et al. (2016) compared the euploid blastocyst formation rates obtained after follicular vs random start with an identical COS protocol in patients with POR, performed in the same menstrual cycle. Stimulations were started on day 2 of a menstrual cycle and 5 days after the first vaginal oocyte retrieval, respectively. No significant differences were found in the number of MIIs (3.4 ± 1.9 vs 4.1 ± 2.5), or biopsied blastocysts per stimulated cycle (1.2 ± 1.2 vs 1.4 ± 1.7). Similarly, no differences were observed in the euploid blastocyst rate calculated either per biopsied blastocyst (46.9% vs 44.8%) or inseminated MIIs (16.2% vs 15.0%). The authors concluded that luteal phase stimulation significantly contributes to the final transferable blastocyst yield thus increasing the number of patients undergoing transfer per menstrual cycle (Ubaldi et al. 2016).
Notably, even though time is an important factor for all patients, it is crucial for those with a foreseeable rapid loss or decrease of fertility, including a malignancy that requires gonadotoxic treatment, removal of gonads or in poor-prognosis patients. Therefore, we think this strategy may be applied in situations where obtaining competent oocytes is an urgent task.
Stimulation protocol
Agonist vs antagonist protocol
To acquire multiple oocytes during an IVF cycle, exogenous gonadotropins are administered so that multiple competent follicles can mature (Macklon et al. 2006). A GnRH-agonist or antagonist is given concomitantly to prevent a premature endogenous LH peak that would otherwise induce ovulation too early. GnRH-agonists may be prescribed using a long or a short protocol (Siristatidis et al. 2015). In all cases, an oocyte maturation triggering agent with a bolus of r-hCG or a GnRH-agonist, or both together (Bosch et al. 2016) is required.
A recent Cochrane review included 73 RCTs and 12,212 participants, comparing GnRH-antagonist to long GnRH-agonist protocols (Al-Inany et al. 2016). There was no evidence of a difference in LBR between GnRH-antagonist and long GnRH-agonist (OR: 1.02, 95% CI: 0.85–1.23; 12 RCTs, n = 2303, I 2 = 27%, moderate-quality evidence). The evidence suggested that if the chance of LB following GnRH-agonist is assumed to be 29%, the chance following GnRH-antagonist would be between 25% and 33%. At the same time, GnRH-antagonist was associated with a 39% lower incidence of any grade of OHSS than GnRH-agonist (OR: 0.61, 95% CI: 0.51–0.72; 36 RCTs, n = 7944). Likewise, GnRH-antagonist was associated with a 53% lower incidence of cycle cancellation due to high risk of OHSS (OR: 0.47, 95% CI: 0.32–0.69; 19 RCTs, n = 4256) but also 1.3 times higher risk of cancellation due to poor response than those who were treated with GnRH-agonist (OR: 1.32, 95% CI: 1.06–1.65; 25 RCTs, n = 5230).
More recently, a systematic review and meta-analysis evaluated the effect of the type of GnRH analog used to prevent the endogenous LH surge, with special attention to differences in subset of patients and interventions (Lambalk et al. 2017). Fifty studies were included, of which 34 studies reported on general IVF patients, 10 studies reported on polycystic ovary syndrome (PCOS) patients and 6 studies reported on POR (Lambalk et al. 2017). In general IVF patients, ongoing PR was significantly lower in patients using an antagonist (RR: 0.89, 95% CI: 0.82–0.96). In women with PCOS or with POR, there was no evidence of a difference in ongoing PR between groups (RR: 0.97, 95% CI: 0.84–1.11 and RR: 0.87, 95% CI: 0.65–1.17, respectively). Subgroup analyses for various antagonist strategies compared to the long GnRH-agonist protocol showed a significantly lower ongoing PR when OCP pretreatment was combined with a flexible antagonist protocol (RR: 0.74, 95% CI: 0.59–0.91) while non-OCP, the RR was 0.84, 95% CI: 0.71–1.0. Subgroup analysis for the fixed antagonist protocol demonstrated no evidence with or without OCP (RR: 0.94, 95% CI: 0.79–1.12 and RR: 0.94, 95% CI: 0.83–1.05, respectively). Lastly, antagonist cycles resulted in statistically lower OHSS rates both in the overall IVF patients and in patients with PCOS (RR: 0.63, 95% CI: 0.50–0.81 and RR: 0.53, 95% CI: 0.30–0.95, respectively), with no data reported on patients with POR (Lambalk et al. 2017).
This meta-analysis showed that in relation to the odds of a sustained pregnancy in overall IVF patients and when evident ovarian dysfunction such as PCOS or POR are excluded, there is an absolute risk reduction of 3.6% in ongoing PR when a GnRH-antagonist was used (23.8% compared to 27.4% after the use of agonists). The number needed to harm was 28, that is for every 28 women treated with antagonist one less ongoing pregnancy would occur. On the other hand, use of antagonist instead of an agonist reduced the absolute rate of OHSS by 2.5%, with the number of women needed to prevent one case of OHSS being 40.
Given the moderate-quality evidence that the use of GnRH-antagonist compared with long-course GnRH-agonist protocols is associated with a substantial reduction in OHSS without reducing the likelihood of achieving LB (Al-Inany et al. 2016, Lambalk et al. 2017), the antagonist protocol is considered the recommended protocol in patients undergoing PGT. Additionally, it fosters the utilization of a GnRH-agonist for late oocyte maturation (alone or in combination with r-hCG), a strategy associated with decreasing OHSS risk (Griesinger et al. 2006, Shapiro et al. 2008, Youssef et al. 2014, Engmann et al. 2016, Eftekhar et al. 2017).
New models of suppression of endogenous LH surge
During luteal phase stimulation, endogenous progesterone secretion from the corpus luteum inhibits a spontaneous LH surge. Administering exogenous progesterone during the follicular phase has produced a similar effect and, consequently, a newer strategy for controlling the endogenous LH peak has been recently utilized: the so-called progesterone protocols (Massin 2017). Researchers have reported successful clinical outcomes with the use of medroxyprogesterone acetate (Kuang et al. 2015), micronized progesterone (Zhu et al. 2015, 2017a ) or dydrogesterone (Zhu et al. 2017b ) during COS without affecting the total oocytes collected or the quality of the embryos obtained. There are no previous studies evaluating this strategy in patients undergoing PGT. Given that an essential requisite would be that a fresh transfer is not programmed, theoretically, these protocols could be used in the PGT population. Further studies are necessary to confirm these judgments.
Stimulation medication
Type of gonadotropins
A recent Cochrane review included 42 trials with a total of 9606 couples comparing urinary (hMG, human menopausal gonadotropin) or recombinant gonadotropins (rFSH, recombinant FSH) (van Wely et al. 2011). Comparing rFSH to all other gonadotropins combined, irrespective of the GnRH analog used, did not result in any evidence of a statistically significant difference in LBRs (28 trials, 7339 couples, OR: 0.97, 95% CI: 0.87–1.08). There was similarly no evidence of a difference in the OHSS rate (32 trials, 7740 couples, OR: 1.18, 95% CI: 0.86–1.61). There was no evidence of a difference in LBs when rFSH was compared with purified urinary FSH (5 trials, n = 1430, OR: 1.26, 95% CI: 0.96–1.64) or when rFSH was compared with highly purified urinary FSH (13 trials, n = 2712; OR: 1.03, 95% CI: 0.86–1.22). Given this results, clinical choice of gonadotropin should depend solely on availability, convenience and costs (van Wely et al. 2011).
When comparing rFSH isoforms, two commercially available rFSH preparations are follitropin alfa (Gonal-F, Merck Serono, Geneva, Switzerland) and follitropin beta (Puregon, Organon, Oss, The Netherlands) are the most studied. Although both preparations are synthesized by the same recombinant technology resulting in identical dimeric FSH-alfa and FSH-beta subunits, they differ in the glycosylation and purification procedures. To our knowledge, there is only one recent study compared recombinant preparations. Orvieto et al. compared 198 in patients using follitropin alfa, and 68 in patients using follitropin beta (Orvieto et al. 2009). Although both groups achieved a comparable number of retrieved oocytes, the use of follitropin beta was associated with a tendency toward a lower clinical PR, and with significantly higher estradiol levels despite the use of significantly lower total gonadotropin dose. Unfortunately, there is no information on ongoing embryos, usable embryos nor LBR. With the recent addition of new molecules into the market (Elonva; Merck Sharp & Dohme de España, Spain; or Rekovelle; Ferring Pharmaceuticals, Madrid, Spain) further large studies are required to assess the effect of the different rFSH on COS variables and IVF outcome.
LH supplementation
As described in the classic ‘two cell-two gonadotropins’ theory, LH is needed to provide the granulosa cells with androgen precursors for estradiol biosynthesis by FSH (Short 1962). Thenceforth, when GnRH analogues prevent premature LH, surges and ovulation most likely deprive the growing follicles of LH. The question arises as to whether supplementation with LH, either recombinant (rLH) or as hMG, would have beneficial effects for growing follicles and may lead to better pregnancy outcomes.
Taking LBR as a surrogate marker of embryo euploidy, in a Cochrane review of 36 RCTs (8125 women) there was insufficient evidence to determine whether there was a difference between rLH combined with rFSH vs rFSH alone in LBR (OR: 1.32, 95% CI: 0.85–2.06; n = 499; studies = 4; I 2 = 63%, very low-quality evidence) (Mochtar et al. 2017). The most recent systematic review assessing the role of rLH supplementation in COS for ART in specific subgroups of patients was published by Alviggi et al. (2018). Six populations were investigated: (1) women with a hypo-response to rFSH monotherapy; (2) women with advanced age; (3) women co-treated with a GnRH-antagonist; (4) women with profoundly suppressed LH levels after an GnRH-agonist use; (5) normo-responder women to prevent OHSS; and (6) women with a POR to COS. rLH supplementation appears to be beneficial in two subgroups: (1) women with adequate pre-stimulation ovarian reserve parameters and an unexpected hypo-response to rFSH monotherapy and (2) women 36–39 years of age (Alviggi et al. 2018). Indeed, there is no evidence that rLH is beneficial in young (<35) normo-responders co-treated with a GnRH-antagonist. This is consistent with a previous study asserting better IRs in patients aged 36–39 years, compared to patients <35 years, when LH administration was added during an antagonist protocol (Bosch et al. 2011).
The use of rLH supplementation in women with suppressed endogenous LH levels caused by GnRH analogues and in POR remains controversial, whereas the use of rLH supplementation to prevent the development of OHSS warrants further investigation. Given that the type of patient that is more likely to undergo a PGT cycle, further RCTs in patients undergoing PGT on the effectiveness of rLH combined with rFSH in women with POR and in women of advanced age are required.
Oocyte maturation trigger
r-hCG vs GnRH-agonist trigger
In antagonist protocols, an oocyte maturation triggering medication is used, and due to the intact pituitary responsiveness, this agent can be r-hCG, a GnRH-agonist or both together (Bosch et al. 2016). Induction of final oocyte maturation with a bolus of GnRH-agonist instead of r-hCG, in PGT cycles would have several advantages: a significant reduction or avoidance of the risk of OHSS, a more physiologic stimulus for oocyte maturation since it causes both FSH and LH release, and a luteolytic effect since endometrial receptivity and luteal function are no longer important (Gonen et al. 1990, Humaidan et al. 2011).
A recent Cochrane review included 17 RCT (n = 1847) comparing the clinical outcomes of GnRH-agonist trigger vs r-hCG in women undergoing a GnRH-antagonist cycle (13 studies assessed fresh autologous cycles and four studies assessed donor–recipient cycles) (Youssef et al. 2014). Since the donor–recipient model could be inferred as COS in PGT (stimulation in one menstrual cycle and embryo transfer in another), no evidence suggested a difference between groups in LBR (OR: 0.92, 95% CI: 0.53–1.61; one RCT, 212 women) or ongoing PR (OR: 0.88, 95% CI: 0.58–1.32; three RCTs, 372 women, I 2 = 0%) in this subpopulation. Importantly, the authors found evidence of a lower incidence of OHSS in the GnRH-agonist triggered group than in the r-hCG group (OR: 0.05, 95% CI: 0.01–0.28; three RCTs, 374 women, I 2 = 0%) (Youssef et al. 2014).
Because of all this, GnRH-agonist as a final oocyte maturation trigger could be considered a useful option for patients who choose to avoid fresh transfers. Of note, appropriate selection of patients is of utmost importance, and those with hypothalamic dysfunction are not candidates for GnRH-agonist trigger as they may not reliably respond to GnRH-agonist administration (Engmann et al. 2016).
Dual trigger
Additionally, a dual trigger, the co-administration of GnRH-agonist and r-hCG, has been proposed to improve the oocyte yield while reducing OHSS risk (Shapiro et al. 2008). A recent RCT including 192 normal-responder IVF patients comparing triggering with 6500 IU r-hCG alone vs 6500 IU r-hCG plus 0.2 mg of triptorelin, found statistically higher mean number of retrieved oocytes, mature MII oocytes and ongoing embryos in the dual trigger group compared with r-hCG (Eftekhar et al. 2017). Therefore, in patients not at risk of OHSS, dual trigger could be considered a valuable option.
Strategies after ovarian stimulation
Fresh vs FET
FET cycles have traditionally been associated with the utilization of ‘leftover’ embryos, as the morphologically superior embryos are selected for fresh ET. This inherent bias may have affected former analyses and could have diminished early study’s FET cycles’ PRs. In this nature, it would be unfavorable to compare the quality of ‘second best’ embryos to their morphologically ‘superior’ siblings. Although there is an increasing number of studies supporting improved clinical outcomes after FETs (Roque et al. 2013, Evans et al. 2014), fresh ET protocols are typically more affordable, require little to no additional medications and allow the patients immediate transfer. However, in the context of PGT cycles, a successful fresh day 6 transfer approach obliges not only that expanded blastocysts be available on the morning of day 5 (Rodriguez-Purata et al. 2016b ), but also that at least one of these biopsied embryos is euploid, thereby also reducing the probability for a transfer in that cycle.
The most recent meta-analysis evaluating the effectiveness and safety of the freeze-only strategy compared to the conventional IVF strategy included four RCTs analyzing a total of 1892 women (Wong et al. 2017). The evidence was of moderate to low quality due to serious risk of bias and, for some outcomes, serious imprecision (Wong et al. 2017). Risk of bias was associated with unclear blinding of investigators for preliminary outcomes of the study, unit of analysis error and absence of adequate study termination rules (Wong et al. 2017). There was no evidence of a difference in cumulative LBR among freeze-only and a conventional IVF strategy (OR: 1.09, 95% CI: 0.91–1.31; 4 trials; 1892 women; I 2 = 0%; moderate-quality evidence) (Wong et al. 2017). This suggests that if the cumulative LBR is 58% following a fresh transfer, LBR following a freeze-only strategy would be between 56% and 65%. The authors concluded that, with moderate-quality evidence, one strategy is not superior to the other in terms of cumulative LBRs (Wong et al. 2017). In terms of OHSS risk, the prevalence was statistically lower after freezing all embryos when compared to the conventional IVF strategy (OR: 0.24, 95% CI: 0.15–0.38; 2 trials; 1633 women; I 2 = 0%; low-quality evidence) (Wong et al. 2017). This suggests that if the OHSS rate is 7% following a conventional IVF, the rate following a freeze-only strategy would be between 1% and 3% (Wong et al. 2017).
Two RCTs published recently not included in the meta-analysis (Shi et al. 2018, Vuong et al. 2018) also support these findings. Shi et al. randomly assigned 2157 women who were undergoing their first IVF cycle to fresh ET or embryo cryopreservation and FET in normo-ovulatory women, and the LBR did not differ significantly (50.2% and 48.7%, respectively; RR: 0.97; 95% CI: 0.89–1.06; P = 0.50) (Shi et al. 2018). Vuong et al. (2018) randomly assigned 782 infertile women without PCOS who were undergoing a first or second IVF cycle to receive either an FET or a fresh embryo, and the transfer of frozen embryos did not result in significantly higher LBRs than the transfer of fresh embryos (33.8% and 31.5%, respectively (risk ratio: 1.07; 95% CI: 0.88–1.31)) (Vuong et al. 2018).
Pertaining only to the transfer of euploid embryos, only one RCT (Coates et al. 2017) and one retrospective study (Rodriguez-Purata et al. 2016a ) have compared the two strategies. Coates et al. (2017) randomized 179 patients to either a fresh or a frozen ET. The intention-to-treat analysis considered all randomized patients in their original group of allocation regardless of achieving an ET. The IR was higher in the FET group (75%) compared with the fresh group (67%), but this difference was not significant (P = 0.3) (Coates et al. 2017). The ongoing PRs and LBRs were significantly higher for the FET group compared with the fresh group: ongoing PRs of 80% in FET vs 61% in fresh, P = 0.03; LBRs of 77% in FET vs 59% in fresh, P = 0.04 (Coates et al. 2017). Despite a strong trend toward improved LBRs with FETs, the ET strategy did not have a statistically significant effect on the probability of achieving a LB when adjusted for age and oocytes retrieved in a logistic regression model (OR: 2.1; 95% CI: 0.95–4.68; P = 0.68) (Coates et al. 2017). Rodriguez-Purata et al. retrospectively segregated patients into fresh-only (patients who transfer their best embryo in the fresh cycle), FET-only (patients who underwent a freeze-only cycle) and a FET in which a fresh transfer was previously performed (patients who did not achieved a pregnancy in the fresh cycle and were utilizing the second-best embryo). FET-only patients were associated with a higher LBR, even when a morphologically superior embryo was already used in a previous fresh ET (FET-only group 57.6%, FET with a previous fresh ET 47.7% and fresh-only 46.5%). FET-only patients were reported to have 1.6 times higher probability of achieving a LB when compared to patients that underwent a fresh ET (OR: 1.6 (95% CI: 1.14–2.13), P < 0.05) (Rodriguez-Purata et al. 2016a ).
In summary, either strategy can be an equitable option for patients. Nevertheless, freezing all embryos allows for the inclusion of all blastocysts in the cohort of embryos available for analysis, which potentially culminates in a higher proportion of patients reaching transfer. This approach also reduces uncertainty in scheduling procedures and prevents the unavoidable disappointment that patients undergo when informed that there are no suitable embryos for transfer. Lastly, as mentioned before, not transferring in the fresh cycle decreases the overall risk of OHSS. Consequently, FET is the recommended strategy when undergoing PGT.
Embryo accumulation/banking
For patients with a fair response for conventional IVF but insufficient for PGT (low number of embryos available for biopsy), performing repeated stimulation cycles in order to accumulate oocytes or embryos could be a suitable strategy to increase their odds of success, turning the patient into a ‘normal responder’ and render a pregnancy rate per patient and per ET comparable to those of PGT cycles with on stimulation cycle. Moreover, planning the stimulation and accumulation strategy before starting the procedure may avoid the sensation of failure in patients when the recommended number of oocytes or embryos is not achieved after one attempt.
In 2013, embryo banking was utilized in 27,564 out of 121,351 (22.7%) fresh non-donor ART cycles in the United States (Kushnir et al. 2016). Embryo banking cycles were more frequently performed with advancing female age, increasing from 15.5% in women <35 years to 56.5% in women >44 years old (Kushnir et al. 2016). In a study by Martinez et al., patients underwent one, two or three COS cycles until reaching ≥10 MIIs. There were no differences between groups in PRs per patient (36.8, 34.9 and 31.0%) or per ET (59.6, 56.8 and 60%, respectively) (Martínez et al. 2016). Patients with a more unfavorable ovarian reserve (lower AMH and AFC) who need three stimulation cycles can reach final outcomes comparable to patients who obtain the required number of oocytes or embryos after two stimulation cycles (Martínez et al. 2016).
Interval between stimulations
There are no studies published evaluating if there is an optimal time interval before proceeding with a subsequent COS.
In the animal model, repeated COS leads to modifications in associated somatic cells, size and transcriptional status of germinal vesicle-stage oocytes, reductions in in vitro meiotic competence, with no changes in in vivo maturation, and significant variations in oocyte adenosine triphosphate content according to oocyte types and stimulation cycles (Combelles & Albertini 2003). Nevertheless, comparable implantation/resorption rates and fetal counts were observed following the mating of animals subjected to repeated COS (Combelles & Albertini 2003). Collectively, these observations suggest that, in a mouse model, while repeated COS has specific effects on follicular oocyte quality, following ovulation in vivo, oocytes can be rescued from consequences of repeated COS (Combelles & Albertini 2003).
Medication used to link stimulations
No meta-analyses, RCTs or prospective studies were identified in neither conventional IVF nor IVF with PGT. There is one retrospective study performed to establish which medication is correlated with better outcomes in two subsequent stimulation cycles in patients undergoing embryo banking. The natural option would be to start a new cycle with a spontaneous menses (SM). A constrain associated with SM is its spontaneity, without possible previous scheduling. Furthermore, in many cases, the final number of euploid embryos is not yet known and counseling of that specific couple could be inappropriate (Rodriguez-Purata et al. 2018). Other options to defer menses until a suboptimal number of biopsied embryos are confirmed could be the use of vaginal micronized progesterone (VMP) or OCPs (Rodriguez-Purata et al. 2018). After ovulation, the corpus luteum produces high levels of progesterone to maintain endometrial receptivity after fertilization has occurred. In the absence of pregnancy, the corpus luteum degenerates, causing a decrease in circulating progesterone (Jabbour et al. 2006) that results sloughing of the upper two-thirds of the endometrium (Maybin & Critchley 2015). Therefore, it is theorized that if high progesterone levels are continued, menses could be deferred until the complete information about the total number of biopsied embryos is obtained. Also OCPs could be used; by prescribing combined OCPs during the luteal phase, LH and, consequently, GnRH, pulse frequency slows (Nippoldt et al. 1989), delaying the FSH-based follicle recruitment and consequently the start of a new cycle.
Rodriguez-Purata et al. (2018) compared whether SM, VMP or OCPs were associated with improved results when used to undergo a subsequent cycle. The difference in oocytes collected between first and second cycles was −0.9 in SM, −1.5 in VMP and +0.4 in OCPs. Although not statistically significant, more oocytes were retrieved in the second cycle when OCPs were used (9.0 ± 3.7 vs 9.4 ± 4.1), while fewer oocytes were retrieved when SM (9.4 ± 3.9 vs 8.5 ± 4.0) or VMP (9.8 ± 5.7 vs 8.2 ± 4.4) were utilized (Rodriguez-Purata et al. 2018). After adjusting for age, total gonadotropins used, total days of stimulation (second cycle) and treatment group in an ANCOVA model, no strategy was correlated with higher oocytes collected (power: 14.9%) or a higher difference of oocytes collected (power: 22.3%). Because of its practicality, OCP could be a more feasible option to link two cycles.
Interval to first FET
No meta-analyses, RCTs or prospective studies were identified in neither conventional IVF or IVF with PGT. Two retrospective studies have evaluated if the interval between the end of stimulation to transfer following a freeze-only cycle had an influence on clinical outcomes. Santos-Ribeiro et al. compared 333 FET cycles, segregated as either immediate (following the GnRH-agonist withdrawal bleeding) or delayed (by at least one menstrual cycle) transfer. Clinical PR was slightly statistically higher in the immediate FET group in the raw analysis (52.9% after immediate FET vs 41.6% after delayed-FET, P = 0.046) (Santos-Ribeiro et al. 2016). After a mixed-effects multivariable regression analysis, timing of FET no longer was correlated to clinical PR (adjusted OR: 0.62, 95% CI: 0.4–1.0; predicted clinical PR of 52.5% for immediate FET vs 41.8% for delayed-FET) (Santos-Ribeiro et al. 2016). More recently, Ozgur et al. published a similar analysis but with LB as the main outcome measure. Cycles were investigated in oocyte retrieval-to-FET interval groups of 32–46, 47–61, 62–76, 77–91 and ≥92 days, with the 47–61-day group used as the reference group. There were no significant differences in LB rates between the groups in the overall analysis (59.7%; 57.8%, OR: 0.9 (95% CI: 0.7–1.3), P = 0.6; 63.6%, OR: 1.2 (95% CI: 0.6–2.5), P = 0.7; 45.7%, OR: 0.6 (95% CI: 0.3–1.2), P = 0.1; 54.9%, OR: 0.8 (95% CI: 0.5–1.4), P = 0.5; respectively), as well as, in sub-analyses investigating LB in terms of single blastocyst transfer, trigger-type medication, oocyte number and patient’s age (Ozgur et al. 2018).
Association of ovarian stimulation and aneuploidy
COS has been proposed to influence oocyte maturation and the completion of meiosis, potentially mediating chromosomal aneuploidy and mosaicism (Verberg et al. 2009a ). Possible mechanisms for this effect include FSH-induced chromosome dysfunction in oocytes or recruitment of poor-quality oocytes when the process of naturally selecting a dominant follicle is overridden with ovarian stimulation.
Nine studies analyzing the impact of COS on euploidy rates have been published (Baart et al. 2007, Verpoest et al. 2008, Rubio et al. 2010, Massie et al. 2011, Ata et al. 2012, Labarta et al. 2012, 2017, Barash et al. 2017, Sekhon et al. 2017). Labarta et al. recently maintained that aneuploidy rate did not increase with ovarian response or gonadotropin dosage (Labarta et al. 2017). Also, the authors observed that the number of euploid embryos was inversely related to the ovarian sensitivity index (Huber et al. 2013), which correlates the amount of gonadotropins needed per oocyte obtained (Labarta et al. 2017). Several non-randomized studies have also determined that aneuploidy rate was not associated with the number of embryos generated (Ata et al. 2012, Barash et al. 2017, Sekhon et al. 2017).
Due to the fact that the number of euploid embryos available for transfer increases as the number of oocytes obtained does (it is fair to think that the number of euploid and aneuploid embryos increases in the same way as number of oocytes does), it is recommended to have in mind that the absolute number of euploid embryos at the end of a cycle seems more relevant for the prognosis of a patient than the proportion of euploid/aneuploid embryos (i.e. 33% of aneuploidy rate of a six-embryo cohort for a total of two euploid embryos would be less favorable than 40% of aneuploidy rate of a ten-embryo cohort for a total of four euploid embryos), especially considering cumulative pregnancy outcome as the optimal outcome.
Summary of findings
Up-to-date concepts decoupling ovarian and endometrial physiology have helped clinicians and embryologists in the individualization of treatment strategies in patients undergoing PGT, which has consequently developed particular characteristics (Table 3). First, it aims at obtaining a maximized number of oocytes and, consequentially, embryo development through more robust stimulation dosages. Second, it incorporates vitrification of all biopsied embryos due to the turnaround time before genetic results are received, which prevents endometrial receptivity displacement (Horcajadas et al. 2008). Third, it circumvents the risk of OHSS, as it exploits the use of antagonist protocol concomitant with a gonadotropin-realizing hormone (GnRH) agonist (GnRHa) trigger. And fourth, it fosters cycle segmentation by deferring embryo transfer to a subsequent menstrual cycle, which further decreases late OHSS risk, achieving an optimal embryo-endometrial synchrony. The resulting spectrum enables and promotes a COS that would otherwise be considered forceful.
To date, there are no studies evaluating the optimal number of oocytes needed to achieve one healthy LB through PGT. Hormone pretreatment with OCP facilitates IVF cycle scheduling. MOS is not a strategy recommended for patients undergoing a PGT cycle. Random-start stimulation may be applied in situations where obtaining oocytes is an urgent task. GnRH-antagonist is considered the protocol of choice in patients undergoing PGT. Clinical choice of gonadotropin should depend on availability, convenience and costs. Progesterone protocols could be used in the PGT population. GnRH-agonist as a final oocyte maturation trigger could be useful for women who for any given reason choose to avoid fresh transfers. In patients not at risk of OHSS, dual trigger could be considered a valuable option. The accumulation of oocytes/embryos could be a suitable strategy to increase the odds of success, turning low responder patients into a ‘normal responder’. There are no studies published evaluating if there is an optimal interval before proceeding with a subsequent COS or the optimal medication to link stimulation cycles. The total euploid embryo cohort size is an unequivocal prognosis factor in IVF treatments, and the number of euploid embryos has to be taken into account, more importantly than the proportion of euploid/aneuploid embryos.
Management of controlled ovarian stimulation for IVF with PGT: draft recommendations presented for consideration based on our review of evidence.
| Topic | Recommendation | Grade (1) |
|---|---|---|
| Pretreatment with OCPs | LBR or ongoing PR is observed lower in the OCP pretreatment groupThe benefits of cycle scheduling with the pill outweigh the theoretical drawbacks | B |
| Conventional vs mild stimulation | Mild ovarian stimulation is not a strategy recommended in patients undergoing an PGT cycle | A |
| Conventional vs random start | Random start may be applied in situations where obtaining competent oocytes is an urgent task | C |
| Agonist vs antagonist | Antagonist protocol is considered the recommended protocol in patients undergoing PGT | A |
| Type of gonadotropin | There are no studies published in patients undergoing PGTClinical choice of gonadotropin should depend on availability, convenience and costs | B |
| LH supplementation | There is insufficient evidence to make a recommendation for or against LH supplementation during COSBeneficial in two subgroups of patients:women with adequate pre-stimulation ovarian reserve parameters and an unexpected hypo-response to rFSH monotherapywomen 36–39 yearsStudies are required in women with poor ovarian response or with advanced age | C |
| LH suppression by progesterone | There are no studies published in patients undergoing PGTGiven that an essential requisite would be that a fresh transfer is not programmed, theoretically these protocols could be used in PGT | C |
| hCG vs GnRH-agonist trigger | GnRH-agonist could be useful for patients undergoing PGTPatients with hypothalamic dysfunction are not candidates for GnRH-agonist trigger | A |
| Dual trigger | In patients not at risk of OHSS, dual trigger could be considered a valuable option | GPP |
| Fresh vs FET | FET is the recommended strategy when undergoing PGTCryopreserving all embryos allows for inclusion of all blastocysts in the cohort of embryos available for analysis | A |
| Embryo accumulation | Patients with more unfavorable ovarian reserve can reach final outcomes comparable to patients who obtain the required number of oocytes or embryos | GPP |
| Interval between stimulations | There are no studies published in patients undergoing PGT | – |
| Medication used to link stimulations | There are no studies published in patients undergoing PGT | – |
| Interval to first FET | There are no studies published in patients undergoing PGTFETs done immediately after a freeze-all protocol appear to result in pregnancy rates comparable to deferred to a later time | C |
| COS and aneuploidy | There is insufficient evidence to make a recommendationThe absolute number of euploid embryos is more relevant than the proportion of euploid/aneuploid embryos | GPP |
Vermeulen et al. (2017), available from: https://www.eshre.eu/~/media/sitecore-files/Guidelines/Guidelines/Manual-for-guideline-development_update2017_final.pdf?la=en.
COS, controlled ovarian stimulation; FET, frozen embryo transfer; FP, fertility preservation; GnRH, gonadotropin-releasing hormone; hCG, human chorionic gonadotropin; IVF, in vitro fertilization; LBR, live birth rate; LH, luteinizing hormone; OCP, oral contraceptive pills; PGT, preimplantation genetic testing; OHSS, ovarian hyperstimulation syndrome.
Declaration of interest
The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of this review.
Funding
Funding for this work was not received. This research was performed under the auspices of ‘Càtedra d’Investigació en Obstetrícia I Ginecologia’ of the Department of Obstetrics, Gynaecology and Reproductive Medicine, Hospital Universitario Dexeus, Universitat Autònoma de Barcelona.
Acknowledgements
The authors are grateful to Dr Anna Veiga for her feedback on the manuscript.
References
Al-Inany HG, Youssef MA, Ayeleke RO, Brown J, Lam WS & Broekmans FJ 2016 Gonadotrophin-releasing hormone antagonists for assisted reproductive technology. Cochrane Database of Systematic Reviews 4 CD001750. (https://doi.org/10.1002/14651858.CD001750.pub4)
Alviggi C, Conforti A, Esteves SC, Andersen CY, Bosch E, Bühler K, Ferraretti AP, De Placido G, Mollo A & Fischer R et al. 2018 Recombinant luteinizing hormone supplementation in assisted reproductive technology: a systematic review. Fertility and Sterility 109 644–664. (https://doi.org/10.1016/j.fertnstert.2018.01.003)
Ata B, Kaplan B, Danzer H, Glassner M, Opsahl M, Tan SL & Munné S 2012 Array CGH analysis shows that aneuploidy is not related to the number of embryos generated. Reproductive Biomedicine Online 24 614–620. (https://doi.org/10.1016/j.rbmo.2012.02.009)
Baart EB, Martini E, Eijkemans MJ, Van Opstal D, Beckers NGM, Verhoeff A, Macklon NS & Fauser BCJM 2007 Milder ovarian stimulation for in-vitro fertilization reduces aneuploidy in the human preimplantation embryo: a randomized controlled trial. Human Reproduction 22 980–988. (https://doi.org/10.1093/humrep/del484)
Baerwald AR, Adams GP & Pierson RA 2012 Ovarian antral folliculogenesis during the human menstrual cycle: a review. Human Reproduction Update 18 73–91. (https://doi.org/10.1093/humupd/dmr039)
Baker VL, Brown MB, Luke B & Conrad KP 2015 Association of number of retrieved oocytes with live birth rate and birth weight: an analysis of 231,815 cycles of in vitro fertilization. Fertility and Sterility 103 931.e2–938.e2. (https://doi.org/10.1016/j.fertnstert.2014.12.120)
Barash OO, Hinckley MD, Rosenbluth EM, Ivani KA & Weckstein LN 2017 High gonadotropin dosage does not affect euploidy and pregnancy rates in IVF PGS cycles with single embryo transfer. Human Reproduction 32 2209–2217. (https://doi.org/10.1093/humrep/dex299)
Bosch E, Labarta E, Crespo J, Simón C, Remohí J & Pellicer A 2011 Impact of luteinizing hormone administration on gonadotropin-releasing hormone antagonist cycles: an age-adjusted analysis. Fertility and Sterility 95 1031–1036. (https://doi.org/10.1016/j.fertnstert.2010.10.021)
Bosch E, Labarta E, Kolibianakis E, Rosen M & Meldrum D 2016 Regimen of ovarian stimulation affects oocyte and therefore embryo quality. Fertility and Sterility 105 560–570. (https://doi.org/10.1016/j.fertnstert.2016.01.022)
Broekmans FJ, Soules MR & Fauser BC 2009 Ovarian aging: mechanisms and clinical consequences. Endocrine Reviews 30 465–493. (https://doi.org/10.1210/er.2009-0006)
Cédrin-Durnerin I, Bständig B, Parneix I, Bied-Damon V, Avril C, Decanter C & Hugues JN 2007 Effects of oral contraceptive, synthetic progestogen or natural estrogen pre-treatments on the hormonal profile and the antral follicle cohort before GnRH antagonist protocol. Human Reproduction 22 109–116. (https://doi.org/10.1093/humrep/del340)
Coates A, Kung A, Mounts E, Hesla J, Bankowski B, Barbieri E, Ata B, Cohen J & Munné S 2017 Optimal euploid embryo transfer strategy, fresh versus frozen, after preimplantation genetic screening with next generation sequencing: a randomized controlled trial. Fertility and Sterility 107 723.e3–730.e3. (https://doi.org/10.1016/j.fertnstert.2016.12.022)
Cobo A, de los Santos MJ, Castellò D, Gámiz P, Campos P & Remohí J 2012 Outcomes of vitrified early cleavage-stage and blastocyst-stage embryos in a cryopreservation program: evaluation of 3,150 warming cycles. Fertility and Sterility 98 1138.e1–1146.e1. (https://doi.org/10.1016/j.fertnstert.2012.07.1107)
Cobo A & Diaz C 2011 Clinical application of oocyte vitrification: a systematic review and meta-analysis of randomized controlled trials. Fertility and Sterility 96 277–285. (https://doi.org/10.1016/j.fertnstert.2011.06.030)
Combelles CMH & Albertini DF 2003 Assessment of oocyte quality following repeated gonadotropin stimulation in the mouse. Biology of Reproduction 68 812–821. (https://doi.org/10.1095/biolreprod.102.008656)
Dahhan T, Balkenende EME, Beerendonk CCM, Fleischer K, Stoop D, Bos AME, Lambalk CB, Schats R, van Golde RJT & Schipper I et al. 2017 Stimulation of the ovaries in women with breast cancer undergoing fertility preservation: alternative versus standard stimulation protocols: the study protocol of the STIM-trial. Contemporary Clinical Trials 61 96–100. (https://doi.org/10.1016/j.cct.2017.07.009)
De Rycke M, Belva F, Goossens V, Moutou C sr, SenGupta SB, Traeger-Synodinos J & Coonen E 2015 ESHRE PGD consortium data collection XIII: cycles from January to December 2010 with pregnancy follow-up to October 2011. Human Reproduction 30 1763–1789. (https://doi.org/10.1093/humrep/dev122)
Drakopoulos P, Blockeel C, Stoop D, Camus M, de Vos M, Tournaye H & Polyzos NP 2016 Conventional ovarian stimulation and single embryo transfer for IVF/ICSI. How many oocytes do we need to maximize cumulative live birth rates after utilization of all fresh and frozen embryos? Human Reproduction 31 370–376. (https://doi.org/10.1093/humrep/dev316)
Edgar DH & Gook DA 2007 How should the clinical efficiency of oocyte cryopreservation be measured? Reproductive Biomedicine Online 14 430–435. (https://doi.org/10.1016/S1472-6483(10)60889-9)
Eftekhar M, Mojtahedi MF, Miraj S & Omid M 2017 Final follicular maturation by administration of GnRH agonist plus HCG versus HCG in normal responders in ART cycles: an RCT. International Journal of Reproductive BioMedicine 15 429–434. (https://doi.org/10.29252/ijrm.15.7.429)
Engmann L, Benadiva C & Humaidan P 2016 GnRH agonist trigger for the induction of oocyte maturation in GnRH antagonist IVF cycles: a SWOT analysis. Reproductive Biomedicine Online 32 274–285. (https://doi.org/10.1016/j.rbmo.2015.12.007)
Evans J, Hannan NJ, Edgell TA, Vollenhoven BJ, Lutjen PJ, Osianlis T, Salamonsen LA & Rombauts LJF 2014 Fresh versus frozen embryo transfer: backing clinical decisions with scientific and clinical evidence. Human Reproduction Update 20 808–821. (https://doi.org/10.1093/humupd/dmu027)
Farquhar C, Rombauts L, Kremer JA, Lethaby A & Ayeleke RO 2017 Oral contraceptive pill, progestogen or oestrogen pretreatment for ovarian stimulation protocols for women undergoing assisted reproductive techniques. In Cochrane Database of Systematic Reviews. John Wiley & Sons, Ltd. (https://doi.org/10.1002/14651858.CD006109.pub3)
Fatemi HM, Doody K, Griesinger G, Witjes H & Mannaerts B 2013 High ovarian response does not jeopardize ongoing pregnancy rates and increases cumulative pregnancy rates in a GnRH-antagonist protocol. Human Reproduction 28 442–452. (https://doi.org/10.1093/humrep/des389)
Fauser BC, Devroey P, Yen SS, Gosden R, Crowley WF, Baird DT & Bouchard P 1999 Minimal ovarian stimulation for IVF: appraisal of potential benefits and drawbacks. Human Reproduction 14 2681–2686. (https://doi.org/10.1093/humrep/14.11.2681)
Ferraretti AP, La Marca A, Fauser BCJM, Tarlatzis B, Nargund G, Gianaroli L & ESHRE working group on Poor Ovarian Response Definition 2011 ESHRE consensus on the definition of ‘poor response’ to ovarian stimulation for in vitro fertilization: the Bologna criteria. Human Reproduction 26 1616–1624. (https://doi.org/10.1093/humrep/der092)
Forman EJ, Hong KH, Ferry KM, Tao X, Taylor D, Levy B, Treff NR & Scott RT 2013 In vitro fertilization with single euploid blastocyst transfer: a randomized controlled trial. Fertility and Sterility 100 100–7.e1. (https://doi.org/10.1016/j.fertnstert.2013.02.056)
Forman EJ, Hong KH, Franasiak JM & Scott RT 2014 Obstetrical and neonatal outcomes from the BEST Trial: single embryo transfer with aneuploidy screening improves outcomes after in vitro fertilization without compromising delivery rates. American Journal of Obstetrics and Gynecology 210 157.e1–157.e6. (https://doi.org/10.1016/j.ajog.2013.10.016)
Franasiak JM, Forman EJ, Hong KH, Werner MD, Upham KM, Treff NR & Scott RT 2014 The nature of aneuploidy with increasing age of the female partner: a review of 15,169 consecutive trophectoderm biopsies evaluated with comprehensive chromosomal screening. Fertility and Sterility 101 656.e1–663.e1. (https://doi.org/10.1016/j.fertnstert.2013.11.004)
Garcia-Velasco JA, Bermejo A, Ruiz F, Martinez-Salazar J, Requena A & Pellicer A 2011 Cycle scheduling with oral contraceptive pills in the GnRH antagonist protocol vs the long protocol: a randomized, controlled trial. Fertility and Sterility 96 590–593. (https://doi.org/10.1016/j.fertnstert.2011.06.022)
Gonen Y, Balakier H, Powell W & Casper RF 1990 Use of gonadotropin-releasing hormone agonist to trigger follicular maturation for in vitro fertilization. Journal of Clinical Endocrinology and Metabolism 71 918–922. (https://doi.org/10.1210/jcem-71-4-918)
Griesinger G, Diedrich K, Devroey P & Kolibianakis EM 2006 GnRH agonist for triggering final oocyte maturation in the GnRH antagonist ovarian hyperstimulation protocol: a systematic review and meta-analysis. Human Reproduction Update 12 159–168. (https://doi.org/10.1093/humupd/dmbib45)
Griesinger G, Kolibianakis EM, Venetis C, Diedrich K & Tarlatzis B 2010 Oral contraceptive pretreatment significantly reduces ongoing pregnancy likelihood in gonadotropin-releasing hormone antagonist cycles: an updated meta-analysis. Fertility and Sterility 94 2382–2384. (https://doi.org/10.1016/j.fertnstert.2010.04.025)
Griesinger G, Venetis CA, Tarlatzis B & Kolibianakis EM 2015 To pill or not to pill in GnRH-antagonist cycles: the answer is in the data already! Reproductive Biomedicine Online 31 6–8. (https://doi.org/10.1016/j.rbmo.2015.04.001)
Handyside AH, Pattinson JK, Penketh RJ, Delhanty JD, Winston RM & Tuddenham EG 1989 Biopsy of human preimplantation embryos and sexing by DNA amplification. Lancet 1 347–349. (https://doi.org/10.1016/S0140-6736(89)91723-6)
Harper JC & SenGupta SB 2012 Preimplantation genetic diagnosis: state of the ART 2011. Human Genetics 131 175–186. (https://doi.org/10.1007/s00439-011-1056-z)
Hassold T & Hunt P 2009 Maternal age and chromosomally abnormal pregnancies: what we know and what we wish we knew. Current Opinion in Pediatrics 21 703–708. (https://doi.org/10.1097/MOP.0b013e328332c6ab)
Hodes-Wertz B, Grifo J, Ghadir S, Kaplan B, Laskin CA, Glassner M & Munné S 2012 Idiopathic recurrent miscarriage is caused mostly by aneuploid embryos. Fertility and Sterility 98 675–680. (https://doi.org/10.1016/j.fertnstert.2012.05.025)
Horcajadas JA, Mínguez P, Dopazo J, Esteban FJ, Domínguez F, Giudice LC, Pellicer A & Simón C 2008 Controlled ovarian stimulation induces a functional genomic delay of the endometrium with potential clinical implications. Journal of Clinical Endocrinology and Metabolism 93 4500–4510. (https://doi.org/10.1210/jc.2008-0588)
Huber M, Hadziosmanovic N, Berglund L & Holte J 2013 Using the ovarian sensitivity index to define poor, normal, and high response after controlled ovarian hyperstimulation in the long gonadotropin-releasing hormone-agonist protocol: suggestions for a new principle to solve an old problem. Fertility and Sterility 100 1270–1276.e3. (https://doi.org/10.1016/j.fertnstert.2013.06.049)
Humaidan P, Kol S, Papanikolaou EG & Copenhagen GnRH Agonist Triggering Workshop Group 2011 GnRH agonist for triggering of final oocyte maturation: time for a change of practice? Human Reproduction Update 17 510–524. (https://doi.org/10.1093/humupd/dmr008)
Jabbour HN, Kelly RW, Fraser HM & Critchley HOD 2006 Endocrine regulation of menstruation. Endocrine Reviews 27 17–46. (https://doi.org/10.1210/er.2004-0021)
Ji J, Liu Y, Tong XH, Luo L, Ma J & Chen Z 2013 The optimum number of oocytes in IVF treatment: an analysis of 2455 cycles in China. Human Reproduction 28 2728–2734. (https://doi.org/10.1093/humrep/det303)
Kably A, Castelazo E & Barroso G 2001 Comparative analysis of multifollicular development with the application of recombinant FSH vs urinary FSH in the results of in vitro fertilization. Ginecologia y Obstetricia de Mexico 69 304–309.
Kuang Y, Chen Q, Fu Y, Wang Y, Hong Q, Lyu Q, Ai A & Shoham Z 2015 Medroxyprogesterone acetate is an effective oral alternative for preventing premature luteinizing hormone surges in women undergoing controlled ovarian hyperstimulation for in vitro fertilization. Fertility and Sterility 104 62.e3–70.e3. (https://doi.org/10.1016/j.fertnstert.2015.03.022)
Kushnir VA, Barad DH, Albertini DF, Darmon SK & Gleicher N 2016 Effect of embryo banking on U.S. national assisted reproductive technology live birth rates. PLoS ONE 11 e0154620. (https://doi.org/10.1371/journal.pone.0154620)
La Marca A & Sunkara SK 2014 Individualization of controlled ovarian stimulation in IVF using ovarian reserve markers: from theory to practice. Human Reproduction Update 20 124–140. (https://doi.org/10.1093/humupd/dmbib37)
Labarta E, Bosch E, Alamá P, Rubio C, Rodrigo L & Pellicer A 2012 Moderate ovarian stimulation does not increase the incidence of human embryo chromosomal abnormalities in in vitro fertilization cycles. Journal of Clinical Endocrinology and Metabolism 97 E1987–E1994. (https://doi.org/10.1210/jc.2012-1738)
Labarta E, Bosch E, Mercader A, Alamá P, Mateu E & Pellicer A 2017 A higher ovarian response after stimulation for IVF is related to a higher number of euploid embryos. BioMed Research International 2017 5637923. (https://doi.org/10.1155/2017/5637923)
Lambalk CB, Banga FR, Huirne JA, Toftager M, Pinborg A, Homburg R, van der Veen F & van Wely M 2017 GnRH antagonist versus long agonist protocols in IVF: a systematic review and meta-analysis accounting for patient type. Human Reproduction Update 23 560–579. (https://doi.org/10.1093/humupd/dmx017)
Lensen SF, Wilkinson J, Leijdekkers JA, La Marca A, Mol BWJ, Marjoribanks J, Torrance H & Broekmans FJ 2018 Individualised gonadotropin dose selection using markers of ovarian reserve for women undergoing in vitro fertilisation plus intracytoplasmic sperm injection (IVF/ICSI). Cochrane Database of Systematic Reviews 2 CD012693. (https://doi.org/10.1002/14651858.CD012693.pub2)
Letterie G, Marshall L & Angle M 2005 The relationship of clinical response, oocyte number, and success in oocyte donor cycles. Journal of Assisted Reproduction and Genetics 22 115–117. (https://doi.org/10.1007/s10815-005-4875-9)
Macklon NS, Stouffer RL, Giudice LC & Fauser BCJM 2006 The science behind 25 years of ovarian stimulation for in vitro fertilization. Endocrine Reviews 27 170–207. (https://doi.org/10.1210/er.2005-0015)
Martínez F & International Society for Fertility Preservation–ESHRE–ASRM Expert Working Group 2017 Update on fertility preservation from the Barcelona International Society for Fertility Preservation–ESHRE–ASRM 2015 expert meeting: indications, results and future perspectives. Fertility and Sterility 108 407–415.e11. (https://doi.org/10.1016/j.fertnstert.2017.05.024)
Martínez F, Clua E, Devesa M, Rodríguez I, Arroyo G, González C, Solé M, Tur R, Coroleu B & Barri PN 2014 Comparison of starting ovarian stimulation on day 2 versus day 15 of the menstrual cycle in the same oocyte donor and pregnancy rates among the corresponding recipients of vitrified oocytes. Fertility and Sterility 102 1307–1311. (https://doi.org/10.1016/j.fertnstert.2014.07.741)
Martínez F, Barbed C, Parriego M, Solé M, Rodríguez I & Coroleu B 2016 Usefulness of oocyte accumulation in low ovarian response for PGS. Gynecological Endocrinology 32 577–580. (https://doi.org/10.3109/09513590.2016.1141881)
Massie JAM, Shahine LK, Milki AA, Westphal LM & Lathi RB 2011 Ovarian stimulation and the risk of aneuploid conceptions. Fertility and Sterility 95 970–972. (https://doi.org/10.1016/j.fertnstert.2010.07.1088)
Massin N 2017 New stimulation regimens: endogenous and exogenous progesterone use to block the LH surge during ovarian stimulation for IVF. Human Reproduction Update 23 211–220. (https://doi.org/10.1093/humupd/dmw047)
Matsaseng T, Kruger T & Steyn W 2013 Mild ovarian stimulation for in vitro fertilization: are we ready to change? A meta-analysis. Gynecologic and Obstetric Investigation 76 233–240. (https://doi.org/10.1159/000355980)
Maybin JA & Critchley HOD 2015 Menstrual physiology: implications for endometrial pathology and beyond. Human Reproduction Update 21 748–761. (https://doi.org/10.1093/humupd/dmv038)
Meniru GI & Craft IL 1997 Utilization of retrieved oocytes as an index of the efficiency of superovulation strategies for in-vitro fertilization treatment. Human Reproduction 12 2129–2132. (https://doi.org/10.1093/humrep/12.10.2129)
Mochtar MH, Danhof NA, Ayeleke RO, Van der Veen F & van Wely M 2017 Recombinant luteinizing hormone (rLH) and recombinant follicle stimulating hormone (rFSH) for ovarian stimulation in IVF/ICSI cycles. In Cochrane Database of Systematic Reviews. John Wiley & Sons, Ltd. (https://doi.org/10.1002/14651858.CD005070.pub3)
Munné S, Sandalinas M, Escudero T, Márquez C & Cohen J 2002 Chromosome mosaicism in cleavage-stage human embryos: evidence of a maternal age effect. Reproductive Biomedicine Online 4 223–232. (https://doi.org/10.1016/S1472-6483(10)61810-X)
Nargund G, Datta AK & Fauser BCJM 2017 Mild stimulation for in vitro fertilization. Fertility and Sterility 108 558–567. (https://doi.org/10.1016/j.fertnstert.2017.08.022)
Nippoldt TB, Reame NE, Kelch RP & Marshall JC 1989 The roles of estradiol and progesterone in decreasing luteinizing hormone pulse frequency in the luteal phase of the menstrual cycle. Journal of Clinical Endocrinology and Metabolism 69 67–76. (https://doi.org/10.1210/jcem-69-1-67)
Orvieto R, Nahum R, Rabinson J, Ashkenazi J, Anteby EY & Meltcer S 2009 Follitropin-α (Gonal-F) versus follitropin-β (Puregon) in controlled ovarian hyperstimulation for in vitro fertilization: is there any difference? Fertility and Sterility 91 1522–1525. (https://doi.org/10.1016/j.fertnstert.2008.08.112)
Oudshoorn SC, van Tilborg TC, Eijkemans MJC, Oosterhuis GJE, Friederich J, van Hooff MHA, van Santbrink EJP, Brinkhuis EA, Smeenk JMJ & Kwee J et al. 2017 Individualized versus standard FSH dosing in women starting IVF/ICSI: an RCT. Part 2: the predicted hyper responder. Human Reproduction 32 2506–2514. (https://doi.org/10.1093/humrep/dex319)
Ozgur K, Bulut H, Berkkanoglu M, Humaidan P & Coetzee K 2018 Frozen embryo transfer can be performed in the cycle immediately following the freeze-all cycle. Journal of Assisted Reproduction and Genetics 35 135–142. (https://doi.org/10.1007/s10815-017-1048-6)
Patrizio P & Sakkas D 2009 From oocyte to baby: a clinical evaluation of the biological efficiency of in vitro fertilization. Fertility and Sterility 91 1061–1066. (https://doi.org/10.1016/j.fertnstert.2008.01.003)
Pellestor F, Andréo B, Anahory T & Hamamah S 2006 The occurrence of aneuploidy in human: lessons from the cytogenetic studies of human oocytes. European Journal of Medical Genetics 49 103–116. (https://doi.org/10.1016/j.ejmg.2005.08.001)
Polyzos NP & Devroey P 2011 A systematic review of randomized trials for the treatment of poor ovarian responders: is there any light at the end of the tunnel? Fertility and Sterility 96 1058.e7–1061.e7. (https://doi.org/10.1016/j.fertnstert.2011.09.048)
Practice Committee of Society for Assisted Reproductive Technology & Practice Committee of American Society for Reproductive Medicine 2008 Preimplantation genetic testing: a Practice Committee opinion. Fertility and Sterility 90 S136–S143. (https://doi.org/10.1016/j.fertnstert.2008.08.062)
Rodriguez-Purata J, Lee J, Whitehouse M, Moschini RM, Knopman J, Duke M, Sandler B & Copperman A 2015 Embryo selection versus natural selection: how do outcomes of comprehensive chromosome screening of blastocysts compare with the analysis of products of conception from early pregnancy loss (dilation and curettage) among an assisted reproductive technology population? Fertility and Sterility 104 1460.e1–1466.e1. (https://doi.org/10.1016/j.fertnstert.2015.08.007)
Rodriguez-Purata J, Lee J, Whitehouse M, Duke M, Grunfeld L, Sandler B, Copperman A & Mukherjee T 2016 aReproductive outcome is optimized by genomic embryo screening, vitrification, and subsequent transfer into a prepared synchronous endometrium. Journal of Assisted Reproduction and Genetics 33 401–412. (https://doi.org/10.1007/s10815-016-0647-y)
Rodriguez-Purata J, Gingold J, Lee J, Whitehouse M, Slifkin R, Briton-Jones C, Copperman A & Sandler B 2016 bHatching status before embryo transfer is not correlated with implantation rate in chromosomally screened blastocysts. Human Reproduction 31 2458–2470. (https://doi.org/10.1093/humrep/dew205)
Rodriguez-Purata J, Devesa M, Parriego M, Pardos C, Rodriguez I, Polyzos NP, Martínez F & Coroleu B 2018 Linking back-to-back stimulation cycles with oral contraceptives or progestins in women undergoing embryo accumulation for preimplantation genetic testing, a retrospective study. Gynecological Endocrinology 34 955–960. (https://doi.org/10.1080/09513590.2018.1473363)
Roque M, Lattes K, Serra S, Solà I, Geber S, Carreras R & Checa MA 2013 Fresh embryo transfer versus frozen embryo transfer in in vitro fertilization cycles: a systematic review and meta-analysis. Fertility and Sterility 99 156–162. (https://doi.org/10.1016/j.fertnstert.2012.09.003)
Rubio C, Mercader A, Alamá P, Lizán C, Rodrigo L, Labarta E, Melo M, Pellicer A & Remohí J 2010 Prospective cohort study in high responder oocyte donors using two hormonal stimulation protocols: impact on embryo aneuploidy and development. Human Reproduction 25 2290–2297. (https://doi.org/10.1093/humrep/deq174)
Santos-Ribeiro S, Polyzos NP, Lan VT, Siffain J, Mackens S, Van Landuyt L, Tournaye H & Blockeel C 2016 The effect of an immediate frozen embryo transfer following a freeze-all protocol: a retrospective analysis from two centres. Human Reproduction 31 2541–2548. (https://doi.org/10.1093/humrep/dew194)
Scott RT, Upham KM, Forman EJ, Zhao T & Treff NR 2013 aCleavage-stage biopsy significantly impairs human embryonic implantation potential while blastocyst biopsy does not: a randomized and paired clinical trial. Fertility and Sterility 100 624–630. (https://doi.org/10.1016/j.fertnstert.2013.04.039)
Scott RT, Upham KM, Forman EJ, Hong KH, Scott KL, Taylor D, Tao X & Treff NR 2013 bBlastocyst biopsy with comprehensive chromosome screening and fresh embryo transfer significantly increases in vitro fertilization implantation and delivery rates: a randomized controlled trial. Fertility and Sterility 100 697–703. (https://doi.org/10.1016/j.fertnstert.2013.04.035)
Sekhon L, Shaia K, Santistevan A, Cohn KH, Lee JA, Beim PY & Copperman AB 2017 The cumulative dose of gonadotropins used for controlled ovarian stimulation does not influence the odds of embryonic aneuploidy in patients with normal ovarian response. Journal of Assisted Reproduction and Genetics 34 749–758. (https://doi.org/10.1007/s10815-017-0909-3)
Sermon K, Capalbo A, Cohen J, Coonen E, De Rycke M, De Vos A, Delhanty J, Fiorentino F, Gleicher N & Griesinger G et al. 2016 The why, the how and the when of PGS 2.0: current practices and expert opinions of fertility specialists, molecular biologists, and embryologists. Molecular Human Reproduction 22 845–857. (https://doi.org/10.1093/molehr/gaw034)
Shapiro BS, Daneshmand ST, Garner FC, Aguirre M & Thomas S 2008 Gonadotropin-releasing hormone agonist combined with a reduced dose of human chorionic gonadotropin for final oocyte maturation in fresh autologous cycles of in vitro fertilization. Fertility and Sterility 90 231–233. (https://doi.org/10.1016/j.fertnstert.2007.06.030)
Shi Y, Sun Y, Hao C, Zhang H, Wei D, Zhang Y, Zhu Y, Deng X, Qi X & Li H et al. 2018 Transfer of fresh versus frozen embryos in ovulatory women. New England Journal of Medicine 378 126–136. (https://doi.org/10.1056/NEJMoa1705334)
Short RV 1962 Steroids in the follicular fluid and the corpus luteum of the mare. A ‘two-cell type’ theory of ovarian steroid synthesis. Journal of Endocrinology 24 59–63. (https://doi.org/10.1677/joe.0.0240059)
Siristatidis CS, Gibreel A, Basios G, Maheshwari A & Bhattacharya S 2015 Gonadotrophin-releasing hormone agonist protocols for pituitary suppression in assisted reproduction. In Cochrane Database of Systematic Reviews. John Wiley & Sons, Ltd. (https://doi.org/10.1002/14651858.CD006919.pub4)
Steward RG, Lan L, Shah AA, Yeh JS, Price TM, Goldfarb JM & Muasher SJ 2014 Oocyte number as a predictor for ovarian hyperstimulation syndrome and live birth: an analysis of 256,381 in vitro fertilization cycles. Fertility and Sterility 101 967–973. (https://doi.org/10.1016/j.fertnstert.2013.12.026)
Stoop D, Ermini B, Polyzos NP, Haentjens P, De Vos M, Verheyen G & Devroey P 2012 Reproductive potential of a metaphase II oocyte retrieved after ovarian stimulation: an analysis of 23,354 ICSI cycles. Human Reproduction 27 2030–2035. (https://doi.org/10.1093/humrep/des131)
Stoop D, Cobo A & Silber S 2014 Fertility preservation for age-related fertility decline. Lancet 384 1311–1319. (https://doi.org/10.1016/S0140-6736(14)61261-7)
Sunkara SK, Rittenberg V, Raine-Fenning N, Bhattacharya S, Zamora J & Coomarasamy A 2011 Association between the number of eggs and live birth in IVF treatment: an analysis of 400,135 treatment cycles. Human Reproduction 26 1768–1774. (https://doi.org/10.1093/humrep/der106)
Toftager M, Bogstad J, Løssl K, Prætorius L, Zedeler A, Bryndorf T, Nilas L & Pinborg A 2017 Cumulative live birth rates after one ART cycle including all subsequent frozen–thaw cycles in 1050 women: secondary outcome of an RCT comparing GnRH-antagonist and GnRH-agonist protocols. Human Reproduction 32 556–567. (https://doi.org/10.1093/humrep/dew358)
Trounson AO, Leeton JF, Wood C, Webb J & Wood J 1981 Pregnancies in humans by fertilization in vitro and embryo transfer in the controlled ovulatory cycle. Science 212 681–682. (https://doi.org/10.1126/science.7221557)
Ubaldi FM, Capalbo A, Vaiarelli A, Cimadomo D, Colamaria S, Alviggi C, Trabucco E, Venturella R, Vajta G & Rienzi L 2016 Follicular versus luteal phase ovarian stimulation during the same menstrual cycle (DuoStim) in a reduced ovarian reserve population results in a similar euploid blastocyst formation rate: new insight in ovarian reserve exploitation. Fertility and Sterility 105 1488.e1–1495.e1. (https://doi.org/10.1016/j.fertnstert.2016.03.002)
van der Gaast MH, Eijkemans MJ, van der Net JB, de Boer EJ, Burger CW, van Leeuwen FE, Fauser BC & Macklon NS 2006 Optimum number of oocytes for a successful first IVF treatment cycle. Reproductive Biomedicine Online 13 476–480. (https://doi.org/10.1016/S1472-6483(10)60633-5)
van Tilborg TC, Torrance HL, Oudshoorn SC, Eijkemans MJC, Koks CAM, Verhoeve HR, Nap AW, Scheffer GJ, Manger AP & Schoot BC et al. 2017 aIndividualized versus standard FSH dosing in women starting IVF/ICSI: an RCT. Part 1: the predicted poor responder. Human Reproduction 32 2496–2505. (https://doi.org/10.1093/humrep/dex318)
van Tilborg TC, Oudshoorn SC, Eijkemans MJC, Mochtar MH, van Golde RJT, Hoek A, Kuchenbecker WKH, Fleischer K, de Bruin JP & Groen H et al. 2017 bIndividualized FSH dosing based on ovarian reserve testing in women starting IVF/ICSI: a multicentre trial and cost-effectiveness analysis. Human Reproduction 32 2485–2495. (https://doi.org/10.1093/humrep/dex321)
van Wely M, Kwan I, Burt AL, Thomas J, Vail A, Van der Veen F & Al-Inany HG 2011 Recombinant versus urinary gonadotrophin for ovarian stimulation in assisted reproductive technology cycles. In Cochrane Database of Systematic Reviews. John Wiley & Sons, Ltd. (https://doi.org/10.1002/14651858.CD005354.pub2)
Vandervorst M, Liebaers I, Sermon K, Staessen C, De Vos A, Van de Velde H, Van Assche E, Joris H, Van Steirteghem A & Devroey P 1998 Successful preimplantation genetic diagnosis is related to the number of available cumulus-oocyte complexes. Human Reproduction 13 3169–3176. (https://doi.org/10.1093/humrep/13.11.3169)
Vaughan DA, Leung A, Resetkova N, Ruthazer R, Penzias AS, Sakkas D & Alper MM 2017 How many oocytes are optimal to achieve multiple live births with one stimulation cycle? The one-and-done approach. Fertility and Sterility 107 397.e3–404.e3. (https://doi.org/10.1016/j.fertnstert.2016.10.037)
Verberg MFG, Eijkemans MJC, Heijnen EMEW, Broekmans FJ, de Klerk C, Fauser BCJM & Macklon NS 2008 Why do couples drop-out from IVF treatment? A prospective cohort study. Human Reproduction 23 2050–2055. (https://doi.org/10.1093/humrep/den219)
Verberg MFG, Macklon NS, Nargund G, Frydman R, Devroey P, Broekmans FJ & Fauser BCJM 2009 aMild ovarian stimulation for IVF. Human Reproduction Update 15 13–29. (https://doi.org/10.1093/humupd/dmn056)
Verberg MFG, Eijkemans MJC, Macklon NS, Heijnen EMEW, Baart EB, Hohmann FP, Fauser BCJM & Broekmans FJ 2009 bThe clinical significance of the retrieval of a low number of oocytes following mild ovarian stimulation for IVF: a meta-analysis. Human Reproduction Update 15 5–12. (https://doi.org/10.1093/humupd/dmn053)
Vermeulen N, Le Clef N, D’Angelo A, Tilleman K, Veleva Z & Nelen W 2017 Manual for ESHRE Guideline Development. European Society of Human Reproduction and Embryology, Grimbergen.
Verpoest W, Fauser BC, Papanikolaou E, Staessen C, Van Landuyt L, Donoso P, Tournaye H, Liebaers I & Devroey P 2008 Chromosomal aneuploidy in embryos conceived with unstimulated cycle IVF. Human Reproduction 23 2369–2371. (https://doi.org/10.1093/humrep/den269)
Vuong LN, Dang VQ, Ho TM, Huynh BG, Ha DT, Pham TD, Nguyen LK, Norman RJ & Mol BW 2018 IVF transfer of fresh or frozen embryos in women without polycystic ovaries. New England Journal of Medicine 378 137–147. (https://doi.org/10.1056/NEJMoa1703768)
Wong KM, van Wely M, Mol F, Repping S & Mastenbroek S 2017 Fresh versus frozen embryo transfers in assisted reproduction. Cochrane Database of Systematic Reviews 3 CD011184. (https://doi.org/10.1002/14651858.CD011184.pub2)
Yang Z, Liu J, Collins GS, Salem SA, Liu X, Lyle SS, Peck AC, Sills ES & Salem RD 2012 Selection of single blastocysts for fresh transfer via standard morphology assessment alone and with array CGH for good prognosis IVF patients: results from a randomized pilot study. Molecular Cytogenetics 5 24. (https://doi.org/10.1186/1755-8166-5-24)
Youssef MA, Van der Veen F, Al-Inany HG, Mochtar MH, Griesinger G, Nagi Mohesen M, Aboulfoutouh I & van Wely M 2014 Gonadotropin-releasing hormone agonist versus HCG for oocyte triggering in antagonist-assisted reproductive technology. In Cochrane Database of Systematic Reviews. John Wiley & Sons, Ltd. (https://doi.org/10.1002/14651858.CD008046.pub4)
Zhu X, Zhang X & Fu Y 2015 Utrogestan as an effective oral alternative for preventing premature luteinizing hormone surges in women undergoing controlled ovarian hyperstimulation for in vitro fertilization. Medicine 94 e909. (https://doi.org/10.1097/MD.0000000000000909)
Zhu X, Ye H & Fu Y 2017 aUse of utrogestan during controlled ovarian hyperstimulation in normally ovulating women undergoing in vitro fertilization or intracytoplasmic sperm injection treatments in combination with a ‘freeze all’ strategy: a randomized controlled dose-finding study of 100 mg versus 200 mg. Fertility and Sterility 107 379.e4–386.e4. (https://doi.org/10.1016/j.fertnstert.2016.10.030)
Zhu X, Ye H & Fu Y 2017 bDuphaston and human menopausal gonadotropin protocol in normally ovulatory women undergoing controlled ovarian hyperstimulation during in vitro fertilization/intracytoplasmic sperm injection treatments in combination with embryo cryopreservation. Fertility and Sterility 108 505.e2–512.e2. (https://doi.org/10.1016/j.fertnstert.2017.06.017)