© Springer India 2015
Gautam N. Allahbadia and Markus Nitzschke (eds.)Minimal Stimulation and Natural Cycle In Vitro Fertilization10.1007/978-81-322-1118-1_1212. Lessons Learned and Future Challenges
(1)
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
(2)
Department of Assisted Reproduction, Rotunda – The Center for Human Reproduction, 36, Turner Road, B-Wing, 101, Bandra W, Mumbai, Maharashtra, 400 050, India
Abstract
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.
Keywords
Mild stimulationGnRH antagonistsAntiestrogensAromatase inhibitorsConventional stimulation protocolsSingle embryo transferNatural cycle IVFMinimal stimulation IVFIVF LiteVitrificationACCU-VITRemote embryo transfers (rET)Introduction
With the evolution of patient-friendly assisted conception procedures, routine IVF is being challenged by simpler methodologies. These include:
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:
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Women with low ovarian reserve (poor responders)
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Women with previous multiple IVF failures
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Women above the age of 40 years
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Women with previous ovarian hyperstimulation syndrome (OHSS) and polycystic ovary syndrome (PCOS) patients (hyperresponders)
Discussion
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).
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