Gautam N. Allahbadia1 , Goral Gandhi2 and Akanksha Allahbadia2
Department of Assisted Reproduction, Rotunda-Blue Fertility Clinic & Keyhole Surgery Center, Rotunda – The Center for Human Reproduction, 36, Turner Road, B-Wing, 101, Bandra W, Mumbai, Maharashtra, 400 050, India
Department of Assisted Reproduction, Rotunda – The Center for Human Reproduction, 36, Turner Road, B-Wing, 101, Bandra W, Mumbai, Maharashtra, 400 050, India
Gautam N. Allahbadia (Corresponding author)
Mild stimulation is defined as the method when exogenous gonadotropins are administered at lower doses, and/or for a shorter duration in gonadotropin-releasing hormone (GnRH) antagonist co-treated cycles, or when oral compounds (antiestrogens, aromatase inhibitors) are used for ovarian stimulation for in vitro fertilization (IVF), with the aim of limiting the number of oocytes obtained to fewer than eight. The ideology that obtaining increased quantity of oocytes leads to better pregnancy rates might be unjustified and contradictory. Retrieval of a modest number of oocytes following mild stimulation is associated with higher implantation rates compared with patients following conventional stimulation. With data to suggest comparable outcomes between mild ovarian stimulation and conventional stimulation protocols but fewer complications, lower costs, and significantly fewer dropouts in mild protocols, there is merit in considering these patient-friendly approaches. The mild stimulation approach, especially when linked to selected single embryo transfer, may represent an important step towards the objective of an easier IVF, more tolerable and problem-free for patients, and cheaper for both patients and the society, with yet an acceptable effectiveness in terms of live birth rates. The issue of embryo cryopreservation is important to consider during discussion of the pros and cons of mild stimulation. Although live birth rates have traditionally been reported per cycle of IVF treatment, more attention is now being given to the cumulative live birth rate from a course of treatment including multiple fresh and frozen embryo transfers. Natural cycle IVF and minimal stimulation IVF are here to stay. The IVF Lite protocol based on a minimal stimulation protocol including Clomiphene citrate and human menopausal gonadotropin (hMG), vitrification, and cryopreserved remote embryo transfers (rET) has yielded much higher pregnancy rates than fresh transfers. IVF Lite includes embryo accumulation and vitrification (ACCU-VIT) over a few cycles for poor responders and older women. For women with previous IVF failures and hyper-responders, we can complete the ACCU-VIT segment in one cycle. IVF Lite is the future of assisted reproduction. In the future, more data on live birth rates in both mild and conventional stimulation IVF is still required for proper and accurate comparison.
Mild stimulationGnRH antagonistsAntiestrogensAromatase inhibitorsConventional stimulation protocolsSingle embryo transferNatural cycle IVFMinimal stimulation IVFIVF LiteVitrificationACCU-VITRemote embryo transfers (rET)
With the evolution of patient-friendly assisted conception procedures, routine IVF is being challenged by simpler methodologies. These include:
· Natural cycle IVF (nIVF) (Matsuura et al. 2008)
· Minimal stimulation IVF (msIVF) (Kim et al. 2009; Teramoto and Kato 2007)
· IVF Lite (minimal stimulation IVF + vitrification + accumulation of embryos + remote embryo transfer) (msIVF + ACCUVIT+ rET) (Zhang et al. 2010; Gandhi et al. 2014)
Mild stimulation protocols reduce the mean number of days of stimulation, the total amount of gonadotropins used, and the mean number of oocytes retrieved (Kim et al. 2009). The proportion of high-quality and euploid embryos seems to be higher compared with conventional stimulation protocols, and the pregnancy rate per embryo transfer is comparable (Matsuura et al. 2008). Moreover, the reduced costs, the better tolerability for patients, and the less time needed to complete an IVF cycle make mild approaches clinically and cost-effective over a given period of time. However, further prospective randomized studies are needed to compare cumulative pregnancy rates between the two protocols. Natural cycle IVF (nIVF), with minimal stimulation, has been recently proposed as an alternative to conventional stimulation protocols in normo- and poor-responder patients (Matsuura et al. 2008; Kawachiya et al. 2012; Schimberni et al. 2009).
Minimal Stimulation IVF initially was introduced for women with low ovarian reserve (Kim et al. 2009; Weghofer et al. 2004), with previous multiple IVF failures (Teramoto and Kato 2007), and over the last 5 years, the indications have expanded to older women (Pelinck et al. 2006) and hyperresponders (Craft et al. 1999). Weghofer et al. (2004) published a study to determine whether minimal stimulation with short-term application of low-dose recombinant follicle-stimulating hormone (r-FSH) together with a gonadotropin-releasing hormone (GnRH) antagonist represents a cost-effective treatment regimen for patients with elevated FSH levels, aged 40 and above. Eighty-five IVF cycles using minimal ovarian stimulation and 85 cycles with a standard long-stimulation protocol in women aged 40 and above who had slightly increased FSH levels were included. Patients on the long protocol underwent standard cycle monitoring and stimulation. In contrast, women with minimal stimulation had transvaginal sonography initiated on day 8 of the menstrual cycle and at a follicle size of 13 mm. They were administered 0.25 mg of GnRH antagonist and 75 IU recombinant FSH daily until ovulation induction. Minimal stimulation cycles resulted in a clinical pregnancy rate of 8.2 % per started cycle and 10 % per embryo transfer (ET), whereas the control group yielded a clinical pregnancy rate of 10.6 % per started cycle and of 10.7 % per ET (not statistically significant). The authors concluded that in women aged 40 and above with abnormal FSH levels, minimal stimulation protocol achieves similar pregnancy rates to a standard protocol and thus, represents a cost-effective alternative (Weghofer et al. 2004).
Zhang et al. (2010) described a minimal stimulation protocol christened “mini IVF.” This protocol requires a reliable method for embryo cryopreservation, such as vitrification, because of the negative impact of Clomiphene citrate on the endometrium and since cryopreserved embryo transfers with this protocol have yielded much higher pregnancy rates than fresh transfers. In this series, patients were not denied treatment based on their day-3 FSH value or ovarian reserve (Zhang et al. 2010). Yet, very acceptable pregnancy rates were achieved (20 % for fresh embryo transfers and 41 % for cryopreserved embryo transfers) (Zhang et al. 2010). These results strengthen the argument for a mini-IVF protocol and vitrification as an alternative to standard conventional IVF stimulation protocols.
The IVF Lite protocol similar to the “mini-IVF” protocol (Gandhi et al. 2014) based on a minimal stimulation protocol including Clomiphene citrate and hMG, vitrification, and cryopreserved remote embryo transfers (rET) has yielded much higher pregnancy rates than fresh transfers (Gandhi et al. 2014). IVF Lite includes embryo accumulation and vitrification (ACCU-VIT) over a few cycles for poor responders and older women. For women with previous IVF failures and hyper-responders, we can complete the ACCU-VIT segment in one cycle. We have since 2011 (Gandhi et al. 2014) expanded the indications of IVF Lite to:
· Women with low ovarian reserve (poor responders)
· Women with previous multiple IVF failures
· Women above the age of 40 years
· Women with previous ovarian hyperstimulation syndrome (OHSS) and polycystic ovary syndrome (PCOS) patients (hyperresponders)
Over the last 30 years, IVF treatment has improved with recognizable developments in laboratory performance in terms of fertilization techniques, culture techniques for embryo development, embryo selection, and cryopreservation of surplus embryos over and above improved ovarian stimulation protocols (Fauser et al. 2005). However, the introduction of mild stimulation protocols is still met with resistance in many units, and the common reason is the lack of robust evidence to influence the current clinical practice in IVF.
Effectiveness is actually the core of discussion when dealing with “mild” stimulation strategy. To date, too few properly designed studies are available to allow a scientific, conclusive judgment. What is definitely needed is a series of randomized controlled trials (RCTs) comparing, in different subsets of IVF patients, “mild” stimulation protocols with the conventional GnRH agonist protocols or, alternatively, with stimulation regimens using GnRH antagonists with high gonadotropin doses. To be fully informative, these studies should come from different research groups and should be properly weighted and designed, also involving vitrified-thaw cycles.
The ideology that obtaining increased quantity of oocytes leads to better pregnancy rates might be unjustified and contradictory (Devreker et al. 1999). Studies that evaluated the relationship between the number of oocytes retrieved and the pregnancy outcomes reported an increase in pregnancy rates with a maximum of 15 eggs (Kably Ambe et al. 2008; Sunkara et al. 2011) and eventually a plateau or decline in positive outcomes with an excess number of oocytes (Sunkara et al. 2011; Melie et al. 2003; Van der Gaast et al. 2006). Furthermore, a recent meta-analysis suggests that the retrieval of a modest number of oocytes following mild stimulation is associated with higher implantation rates compared with patients where the same number of oocytes is retrieved following conventional stimulation (Verberg et al. 2009). With data to suggest comparable outcomes between mild ovarian stimulation and conventional stimulation protocols but fewer complications, lower costs, and significantly fewer dropouts in mild protocols (Verberg et al. 2009; Heijnen et al. 2007), there is merit in considering these patient-friendly approaches.
The two main complications associated with the use of assisted reproduction techniques, ovarian hyperstimulation syndrome and multiple pregnancies, could be eliminated by milder ovarian stimulation protocols and the increased use of a single embryo transfer (SET) policy. A retrospective, cohort study was performed in private infertility center to evaluate the embryological and clinical results of a large exclusively SET program according to patient age (lower or equal to 29, 30–34, 35–39, 40–44 and equal or higher than 45 years) (Kato et al. 2012). A total of 7244 infertile patients underwent 20,244 cycles with a Clomiphene-based minimal stimulation or natural cycle IVF protocol during 2008. Following oocyte retrieval, fertilization, and embryo culture, a total of 10,401 fresh or frozen single-embryo transfer procedures were performed involving cleavage-stage embryos or blastocysts. Successful oocyte retrieval rate (78.0 %) showed no age-dependent decrease until 45 years. Fertilization (80.3 %) and cleavage (91.1 %) rates were not significantly different between age groups. Blastocyst formation (70.1–22.8 %) and overall live birth rates (35.9–2 %) showed an age-dependent decrease. Frozen-thawed blastocyst transfer cycles gave the highest chance of live birth per embryo transfer (41.3–6.1 %). High fertilization and cleavage rates were obtained regardless of age, whereas blastocyst formation and live birth rates showed an age-dependent decrease. An elective single embryo transfer program based on a minimal ovarian stimulation protocol yields acceptable live birth rates per embryo transfer in infertile patients up until their mid-forties. However, in very advanced age patients (equal or higher 45 years old), success rates fall below 1 % (Kato et al. 2012).
A 3-year, retrospective, single center cohort study was conducted in a private infertility center to determine cumulative live birth rates (LBRs) per scheduled oocyte retrieval following minimal ovarian stimulation/natural cycle IVF in unselected infertile patients (Bodri et al. 2014). A total of 727 consecutive infertile patients were analyzed who underwent 2876 (median 4) cycles with scheduled oocyte retrieval from November 2008 to December 2011. Natural cycle IVF or Clomiphene-based minimal ovarian stimulation was coupled with single embryo transfer and increased use of delayed vitrified-warmed blastocyst transfer. Main outcome measures were crude and expected age-specific cumulative LBR per scheduled oocyte retrieval. Crude cumulative LBRs were 65 %, 60 %, 39 %, 15 %, and 5 % in patients aged 26–34, 35–37, 38–40, 41–42, and 43–44 years, respectively. No live births occurred in patients aged ~45 years. Dropout rates per cycle were 13–25 %. Success rates gradually reached a plateau, with few additional live births after six cycles. Most of the expected success rate was reached within 6 months with almost maximal rates within 15 months of the first oocyte retrieval. Acceptable cumulative LBRs were reached with an exclusive minimal ovarian stimulation/single embryo transfer policy, especially in patients aged <38 years but also in intermediate-aged patients (38–40 years) (Bodri et al. 2014).
In vitro fertilization productivity rate is an index defined as the sum of all live births from either fresh or frozen embryo transfers arising from a single oocyte collection. A recent retrospective analysis over 9 continuous years used this index to understand the potential impact on pregnancy rates of milder stimulation regimens with associated reduced egg numbers (Stanger and Yovich 2013). The productivity rate per collection increased in a linear and significant rate as more oocytes were recovered, more embryos frozen, and more frozen embryo transfers contributed to pregnancy. This observation was true for women aged <35 years and less so for women aged 35–39 years but not for women aged 40 years and older. The contribution of frozen embryo transfer to the productivity rate rose in a linear manner, reaching over 40 % of all live births with nine oocytes. The number of live births per oocyte, pronuclear embryos, and thawed embryos decreased significantly, but the number of live births per embryo transferred (fresh or frozen) rose with rising oocyte numbers, reflecting increasing opportunity for embryo selection. This study suggests that optimal benefits with minimal risks are gained from a model that includes both fresh and frozen transfers under stimulation, generating between 8 and 12 eggs (Stanger and Yovich 2013).
The issue of embryo cryopreservation is important to consider during discussion of the pros and cons of mild stimulation. Although live birth rates have traditionally been reported per cycle of IVF treatment, more attention is now being given to the cumulative live birth rate from a course of treatment including multiple fresh and frozen embryo transfers (Luke et al. 2012). Some authors have used the term “total reproductive potential” to describe the chance of live birth from a single fresh IVF cycle, including all fresh and frozen embryo transfers which utilized eggs from one fresh cycle (Stern et al. 2012). In a recent randomized trial (Heijnen et al. 2007), the mean number of embryos cryopreserved per cycle was under 1 (0.9 for mild treatment, 0.6 for standard treatment), despite a mean age of under 33 years. This low number of embryos available for cryopreservation is an important consideration.
A large prospective, randomized study was designed to compare the “mild” protocol with Clomiphene citrate, low-dose gonadotropins and a GnRH antagonist (CC/Gn/GnRH-ant protocol) with the “long” protocol with a GnRH agonist and high-dose Gn for controlled ovarian hyperstimulation (COH) of patients with expected poor ovarian responsiveness undergoing IVF (Revelli et al. 2014). A total of 695 women with clinical, endocrine, and ultrasound characteristics suggesting a low ovarian reserve and a poor responsiveness to COH were recruited and randomly assigned to receive the CC/Gn/GnRH-ant “mild” protocol (mild group, n = 355) or the “long” protocol with high-dose Gn (long group, n = 340). The “mild” stimulation led to significantly shorter follicular phase, lower consumption of exogenous Gn, and lower peak estradiol level than the “long” regimen. With the “long” protocol, significantly fewer cycles were canceled due to the lack of ovarian response; further, it obtained significantly more oocytes, more mature oocytes, more embryos, and a thicker endometrium. As for the final IVF outcome, however, the two stimulation regimens yielded a comparable implantation rate, clinical pregnancy rate, and ongoing pregnancy rate at 12 weeks. Revelli et al. summarized that the “mild” CC/Gn/GnRH-ant stimulation protocol is a valid alternative to the long protocol with high Gn dose as it obtains a comparable success rate and requires significantly less medications, with an obvious economical advantage (Revelli et al. 2014).
With more widespread use of mild stimulation protocols, more and more singular reports which are rare today are being published (Check et al. 2011). In vitro fertilization-embryo transfer with intracytoplasmic sperm injection (ICSI) was performed for a 45-year-old woman with a peak serum follicle-stimulating hormone (FSH) level of 29 mIU/mL and a history of failing to conceive in five previous IVF-ET cycles at a younger age. A minimal FSH stimulation protocol was used. A fresh transfer of a seven-cell embryo was performed on day 3. A successful pregnancy and delivery ensued. This case report establishes a precedent that a successful pregnancy following IVF-ET is possible in a woman whose serum FSH is >15 mIU/mL and is 45 years of age (Check et al. 2011).
For the past several years, 4–5 % of the cycles in the United States have been performed using preimplantation genetic diagnosis (PGD) (Ginsburg et al. 2011; Society of Assisted Reproductive Technology Clinic Outcome Reporting System 2010). Indications in the United States include screening for aneuploidy, unbalanced translocations, single gene disorders, and sex selection (Ginsburg et al. 2011). The percentage of PGD cycles could increase in the coming years as there have been significant advances regarding comprehensive screening of the entire karyotype, rapid return of results, and trophectoderm biopsy (Treff and Scott 2012). The prevailing wisdom has been that there is an advantage to having as many embryos as possible available for biopsy for couples undergoing PGD. A well-known randomized controlled trial challenged that assumption. The rate of detected aneuploidy (as detected by day-3 embryo biopsy for ten chromosomes) was higher with a long agonist protocol and FSH 225 IU daily compared with a milder protocol utilizing FSH 150 IU daily and GnRH antagonist (Baart et al. 2007). The mean number of embryos without detected aneuploidy (1.8) was similar between the two groups, suggesting that the higher dose protocol led to retrieval of some additional oocytes that were not chromosomally normal. While intriguing, it is difficult to be certain if these findings will be replicated in the world population undergoing IVF with comprehensive chromosome screening using current methodologies and trophectoderm biopsy.
A recent publication by Jones (2011) reported on seven roads traveled to make assisted reproductive technology (ART) the success it is today and suggested seven more roads to be traveled to continue to improve. Among them is to make ART safe, accessible, and available to most infertile couples. Furthermore, it is a public health challenge to make ART available, affordable, and accessible with minimal adverse effects without compromising the effectiveness. Gentle ovarian stimulation protocols, such as “IVF Lite,” have several potential advantages over conventional IVF protocols, including less medication and fewer injections, producing fewer eggs, but eggs of higher quality (Gandhi et al. 2014). Patient acceptability of the milder stimulation protocols is better. IVF Lite gives pregnancy rates (PRs) comparable to conventional IVF in patients with a normal ovarian reserve. IVF Lite gives PRs much better than conventional IVF in older patients, patients with previous conventional IVF failures, poor responders, and hyper-responders. Further prospective randomized studies are needed to compare cumulative pregnancy rates between the two protocols. In cost-conscious environments, IVF Lite is probably the type of IVF that is going to be the future (Allahbadia 2014).
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