Sneha Sathe1 , Goral Gandhi2 and Gautam N. Allahbadia2
Consultant Reproductive Medicine, Nova IVI Fertility, Mumbai, Maharashtra, 400 088, India
Department of Assisted Reproduction, Rotunda – The Center for Human Reproduction, 36, Turner Road, B-Wing, 101, Bandra W, Mumbai, Maharashtra, 400 050, India
Sneha Sathe (Corresponding author)
Gautam N. Allahbadia
Over the last three decades, several different ovarian stimulation protocols for in vitro fertilization (IVF) have been proposed and tried. The most commonly used gonadotropin-releasing hormone (GnRH) agonist long protocol has several advantages like good predictability, easier cycle management, lower cancellation rates, a higher number of oocytes and embryos, and better pregnancy rates. However, its use has been plagued with unpredictable multiple births and morbidity of ovarian hyperstimulation syndrome (OHSS). In addition to being physically and emotional stressful, it is costly and is unaffordable to a significant number of patients.
In the mild stimulation protocols, the mean number of days of stimulation and the total amount of gonadotropins used is reduced, and the mean number of oocytes retrieved is lower but the proportion of high quality embryos is higher. The per cycle success rates maybe lower, but cumulative pregnancy rates are comparable to conventional IVF. The fewer side effects, better patient tolerability, and reduced costs decrease the stress and burden associated with IVF, decreasing the dropout rates and encouraging couples to perform more attempts, thereby improving cumulative pregnancy rates.
There are a spectrum of protocols for mild IVF varying from the use of Clomiphene citrate (CC) alone, gonadotropins alone, or Clomiphene followed by gonadotropins, with or without GnRH antagonist. The CC/gonadotropin/GnRH antagonist protocol takes advantage of the synergistic effect of CC and gonadotropins on follicular growth. The gonadotropins also counteract the antiestrogenic effect of CC on the endometrium, and the antagonist started in the mid-follicular phase effectively prevents the luteinizing hormone (LH) surge.
The implementation of mild ovarian stimulation for IVF in clinical practice is definitely justified and is worth pursuing.
Mild IVFConventional IVFInfertilityClomipheneGonadotropinshMGFSHGnRH agonistGnRH antagonistOvarian stimulation
Assisted reproductive technology
Controlled ovarian hyperstimulation
Human chorionic gonadotropin
Human menopausal gonadotropin
International Society for Mild Approaches in Assisted Reproduction
In vitro fertilization
Ovarian hyperstimulation syndrome
In vitro fertilization (IVF) is a very complex treatment process, and for the patients concerned, it involves considerable physical, emotional, social, and financial burden. The objective of any responsible IVF strategy should be to optimize all of the steps in the process in order to achieve the desired treatment aim, i.e., the birth of a healthy child.
Over the past 30 years, IVF treatment has evolved in several aspects. The first successful IVF procedure was performed in the natural cycle (Steptoe and Edwards 1978). The technique of natural cycle IVF was soon replaced by the concept of controlled ovarian hyperstimulation (COH) with the aim of increasing the number of oocytes and allowing the selection of embryos for transfer, thereby increasing the possibility of success (Macklon et al. 2006; Oehninger and Hodgen 1990; Fauser et al. 2005). COH is now an integral part of IVF treatment.
The competition among IVF clinics all over the world is based on pregnancy rates. The more the oocytes, the more the embryos and the more the pregnancies are; this general principle is followed and has become the way of working in the IVF world. In some countries, the public health system or private insurance companies offer a limited number of free or budget (discounted) IVF cycles, and hence, doctors as well as patients consider the retrieval of a higher number of oocytes important and relevant. In IVF centers offering shared cycles, it is beneficial when a patient produces enough eggs to provide for herself as well as surplus eggs for donation. The fact that all retrieved oocytes do not get fertilized and all fertilized oocytes do not result in pregnancies indicates an overall insufficiency of the IVF laboratory. A high number of retrieved oocytes compensates for this laboratory insufficiency.
In most IVF centers, the protocol aim is to collect a maximum number of oocytes in order to allow the selection of the best embryos for transfer and provide surplus embryos for cryopreservation, allowing future embryo transfers without undergoing ovarian hyperstimulation.
The currently used conventional ovarian stimulation protocols are physically and emotionally demanding and are associated with potentially serious complications. The aim of mild IVF protocols is to develop safer and more patient-friendly treatment approaches which are cost-effective and in which the risks are minimized.
In this chapter, we will first delve into the concerns associated with conventional IVF which encouraged the need to develop milder stimulation strategies. We will then define mild IVF and detail the various studies published in literature with emphasis on the mild stimulation protocol using Clomiphene citrate (CC), human menopausal gonadotropin (hMG), and gonadotropin-releasing hormone (GnRH) antagonists.
Concerns with Conventional Ovarian Stimulation for IVF
For several decades now, the most popular IVF protocol has been the long agonist regimen (Macklon et al. 2006; FIVNAT 1996). In this protocol, GnRH agonist is administered from the mid-luteal phase of the preceding cycle followed by gonadotropins for ovarian stimulation after menses (Huirne et al. 2004; Daya 2000). The long agonist protocol allows good predictability, implies a low cancellation rate, and gives a relatively high number of preovulatory follicles and retrieved oocytes and hence, a higher number of embryos available for transfer, thus leading to a satisfactory pregnancy rate (Hughes et al. 1992; Neveu et al. 1987; Filicori et al. 1996).
Conventional ovarian stimulation using the long agonist protocol successfully eliminates the LH surge but requires a higher dosage of gonadotropins and a longer duration of treatment (Zarek and Muasher 2011). The several adverse effects of conventional IVF are listed below.
High Dropout Rates
The conventional IVF regimens are complex, expensive, and time-consuming and require weeks of daily injections with intense monitoring and frequent visits to the clinic. This leads to considerable emotional stress and discomfort. The most common cause of dropout from IVF programs is the physical and psychological stress associated with it (Verberg et al. 2008a; Olivius et al. 2004). High dropout rates, well above 50 %, have been reported in the literature (Olivius et al. 2004; Land et al. 1997; Schroder et al. 2004). Discontinuation of treatment before achieving a pregnancy deprives couples of an optimal cumulative chance of pregnancy and thus, lowers the overall success of the IVF program.
The practice of transferring multiple embryos in order to maximize pregnancy rates increases the risk of multiple pregnancy (Hazekamp et al. 2000), and this is directly related to the number of high quality embryos transferred (Staessen et al. 1992; Roseboom et al. 1995; Yaron et al. 1997). In Europe and the USA, approximately 25 % and 35 % of IVF pregnancies, respectively, are twins or higher-order multiples (Verberg et al. 2007). Multiple pregnancies are associated with an increased risk of preterm birth, stillbirth, low birth weight, congenital malformations, neonatal and infant deaths, and long-term morbidity and disability among survivors (Hazekamp et al. 2000). Perinatal mortality rates are at least fourfold higher in twin and at least six-fold higher in triplet births compared with singleton births (The ESHRE Capri Workshop Group 2000).
Multiple pregnancies are also associated with a higher risk of obstetric complications like preeclampsia and eclampsia, antepartum hemorrhage, preterm labor, and surgical and assisted delivery (Hazekamp et al. 2000). The financial consequences of multiple pregnancy are substantial. Compared to singletons, obstetric care costs are 2.1-, 4.5-, and 7-fold higher for twins, triplets, and quadruplets, respectively (The ESHRE Capri Workshop Group 2000).
Ovarian Hyperstimulation Syndrome (OHSS)
Ovarian hyperstimulation syndrome is a potentially serious complication of IVF. Severe OHSS is characterized by the growth of multiple large follicles with massive extravascular protein-rich fluid shift which may lead to hypovolemia, hemoconcentration, oliguria, and electrolyte disturbance and, in the most severe cases, thromboembolism and death (Mozes et al. 1965; Elchalal and Schenker 1997). Severe OHSS is observed in about 0.2–1.0 % of all assisted conception cycles (Smitz et al. 1990; Brinsden et al. 1995; Roest et al. 1996). The occurrence of OHSS further increases the IVF costs. The cost for the treatment of OHSS has been calculated to range from $400 to $553 per day depending on the treatment strategy, and for canceled cycles, the cost can go over $6000 (Wittenberger et al. 2005).
Costs associated with assisted reproductive technology (ART) can be characterized as “direct” costs and “indirect” costs (Collins 2009). The direct costs include costs for medication, consultations, laboratory charges, ultrasound procedures, and IVF procedures (oocyte retrieval and embryo transfer); hospital charges; fees for anesthesia; and administrative and overhead charges. The financial impact from the indirect costs like travel expenses, lost wages, and costs incurred due to complications like OHSS and multiple pregnancy is also significant. When evaluating the overall cost, all these factors should be taken into consideration.
Definition of Mild IVF
Concerns over the adverse effects associated with conventional IVF led to the reintroduction of mild stimulation protocols (Collins 2009; Muasher et al. 2006; Muasher and Garcia 2009; Nargund and Frydman 2007). Also, the marker of a successful IVF cycle has now moved from the outcome of a single cycle to the singleton birth rate over a given time period (Heijnen et al. 2004; Grunfeld et al. 2008). A better understanding of ovarian physiology, process of follicle recruitment and dominant follicle selection, the introduction of GnRH antagonists into clinical practice, and the marked improvement in the IVF laboratory have led to a renewed interest in mild stimulation protocols.
A “mild” IVF cycle is defined by the International Society for Mild Approaches in Assisted Reproduction (ISMAAR) association either as (a) a stimulation regimen in which gonadotropins are administered at a lower-than-usual dose and/or for a shorter duration in a GnRH antagonist co-treated cycle or (b) a stimulation regimen in which oral compounds (e.g., antiestrogens) are used either alone or in combination with gonadotropins and GnRH antagonists (Nargund et al. 2007).
The Key Role of GnRH Antagonists
Although not mandatory for mild IVF (Fernandez-Shaw et al. 2009), the introduction of GnRH antagonists (Albano et al. 2000; Olivennes et al. 2000; Fluker et al. 2001) has allowed the development of mild IVF protocols (Tarlatzis et al. 2006). The mechanism of action of GnRH antagonist is by competitive blockade of the GnRH receptor, leading to an immediate, rapid, and reversible suppression of gonadotropin secretion (van Loenen et al. 2002; Verberg et al. 2009). Unlike agonists, GnRH antagonists do not induce an initial flare of gonadotropin secretion and hence, can be initiated in the mid to late stimulation phase. This allows the endogenous intercycle follicle-stimulating hormone (FSH) rise to commence ovarian stimulation while still being effective in suppressing the premature luteinizing hormone (LH) surge (Verberg et al. 2009).
Compared to the long agonist protocol, the GnRH antagonist protocol requires fewer injections of analog, fewer doses of gonadotropins, and fewer days of stimulation and is associated with a lower incidence of severe OHSS (Al-Inany et al. 2006).
Although initial studies suggested a detrimental effect on pregnancy rates following GnRH antagonist compared with agonists (Tarlatzis et al. 2006; Al-Inany et al. 2006), a recent meta-analysis (Kolibianakis et al. 2006) which included 22 randomized controlled trials (RCTs) showed no significant difference in the probability of live birth.
Clomiphene Citrate (CC)
Clomiphene citrate is an estradiol antagonist that targets receptors at the hypothalamus and inhibits negative as well as positive feedback, resulting in ovarian stimulation and suppression of LH. Since it requires an intact hypothalamic-pituitary-ovarian axis, it cannot be combined with GnRH agonist for pituitary suppression (Macklon et al. 2006).
Clomiphene citrate was one of the first preparations used for ovarian stimulation in IVF (Trounson et al. 1981; Marrs et al. 1983; Quigley et al. 1985). Reported outcomes with CC alone are variable, but in general, pregnancy rates appear higher when compared with natural cycle IVF (MacDougall et al. 1994; Ingerslev et al. 2001) but lower when compared with conventional gonadotropin/GnRH agonist protocols (Dhont et al. 1995). The low pregnancy rates with CC in spite of successful ovarian stimulation may be due to its antiestrogenic effect on the endometrial receptivity and cervical mucus (Markiewicz et al. 1988; Roumen 1997; Sereepapong et al. 2000). The main advantages of CC are oral administration, easy availability, and low cost.
Several different gonadotropin preparations have been successfully used for controlled ovarian stimulation in IVF. In the earlier days of IVF, hMG was most commonly used, followed by purified urinary FSH (uFSH) and more recently recombinant FSH (r-FSH) and recombinant LH (r-LH) (Macklon et al. 2006).
There are a spectrum of protocols for mild IVF varying from the use of Clomiphene alone, gonadotropins alone, or Clomiphene followed by gonadotropins, with or without GnRH antagonists. Studies conducted so far also vary in the starting dose of CC and gonadotropin, day of initiation, daily or alternate-day gonadotropins, fixed or flexible antagonist dosing, etc. There is no evidence regarding the optimal mild stimulation regimen (Verberg et al. 2009).
Gonadotropin/GnRH Antagonist Regimen
Based on the FSH window concept (Fauser and van Heusden 1997), with the aim to induce multifollicular development, low-dose gonadotropin stimulation is initiated in the mid-follicular phase on cycle day 5 (Schipper et al. 1998). GnRH antagonist is added when at least one follicle is ≥14 mm and final follicular maturation is obtained with human chorionic gonadotropin (hCG) 10,000 IU.
Low-dose gonadotropins (150 IU) used in mild stimulation cycles demonstrate equivalent pregnancy rates when compared with the standard dosage of 225 IU (Hoomans et al. 1999; Wikland et al. 2001; Yong et al. 2003).
Compared to the long agonist protocol, the gonadotropin/GnRH antagonist protocol requires shorter duration of stimulation and a significantly lower total dose of gonadotropins (Hohmann et al. 2003; Hejinen et al. 2007; Baart et al. 2007) while maintaining a comparable pregnancy rate per cycle (Hohmann et al. 2003; Baart et al. 2007). One study (Hejinen et al. 2007) reported significantly lower pregnancy rates per cycle in the mild stimulation group, but the cumulative live birth rate after 1 year of IVF treatments was comparable in the two groups.
The use of CC combined with gonadotropins for ovarian stimulation has been described since the 1980s (Quigley et al. 1985; Lopata 1983; Vargyas et al. 1984). Due to the synergistic effect of these compounds, the amount of gonadotropin required is lower and so are the costs (Ronen et al. 1988; Tummon et al. 1992). The addition of gonadotropins also counteracts the detrimental effects of the CC on the endometrium (Ronen et al. 1988).
Compared to the long agonist protocol, the CC/gonadotropin protocol requires fewer ampoules of gonadotropins and shorter duration of stimulation and has a lower incidence of OHSS. One study (Dhont et al. 1995) reported a higher cancellation rate and a lower pregnancy rate with the CC/gonadotropin protocol, while a more recent study (Weigert et al. 2002) demonstrated similar pregnancy rates.
Teramoto and Kato (2007) conducted a large study (43,433 cycles) in Japan using a protocol of CC (100 mg from cycle day 3 till the day before the trigger injection) and gonadotropin (150 IU on alternate days starting on cycle day 8) and reported a mean number of 2.2 oocytes retrieved and a live birth rate of 11 % per started cycle. More recently, another large study (20,244 cycles) was reported from Japan by Kato et al. (2012). Using a similar protocol combined with single embryo transfer, they reported a 78.0 % oocyte retrieval rate and 80.3 % fertilization rate with no age-dependent decrease until 45 years. 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 %) depending on age. Using a very similar protocol to the Japanese study, Zhang et al. (2010) reported a pregnancy rate of 20 % with fresh embryo transfer and 41 % with cryopreserved-thawed embryo transfer.
CC/Gonadotropin/GnRH Antagonist Regimen
The adjunctive use of gonadotropins with CC may be able to overcome the antiestrogenic effects of CC on the endometrium, but the problem of premature LH surge still remains. More than two decades ago, with the introduction of GnRH agonists, the CC/gonadotropin stimulation regimen was largely abandoned. In recent years, the introduction of GnRH antagonists into clinical practice has changed this scenario and had led to a renewed interest in the mild IVF regimen using Clomiphene, gonadotropins, and GnRH antagonist. The characteristics of the trials using Clomiphene citrate, gonadotropins, and GnRH antagonist have been summarized in Table 10.1.
Characteristics of trials involving ovarian stimulation with the Clomiphene citrate/gonadotropin/GnRH antagonist protocol for IVF/ICSI
Study group protocol
Control group protocol
Williams et al. (2002)
Retrospective controlled trial
Patients <40 years in their first IVF cycle
CC 100 mg days 3–7
FSH 150 IU day 9 onward. With or without GnRH antagonist. hCG 10,000 IU when leading follicle >18 mm and at least two other follicles >16 mm (n = 55)
Leuprolide long regimen with r-FSH 150–300 IU. hCG 10,000 IU when leading follicle >18 mm and at least two other follicles >16 mm (n = 55)
Oocytes retrieved 4.8 ± 2.6 versus 16.2 ± 7.5. Pregnancy rate 37 % versus 41 % (NS). Ampoules used 5.7 ± 4.2 versus 25 ± 7.5
CC 100 mg days 3–7.
FSH 150 IU day 9 onward. With Ganirelix (n = 10)
CC 100 mg days 3–7
FSH 150 IU D9 onward. Without Ganirelix (n = 10)
Oocytes retrieved 4.9 ± 3.1 versus 3.1 ± 1.0 (NS). Pregnancy rate
75 % versus 30 % (NS)
Premature LH surge 0 versus 5 % (NS)
Fiedler and Ludwig (2003)
Randomly selected normal cycling women
CC 100 mg days 5–9. hMG or FSH 150 IU day 9 onward. Antagonist 0.25 mg day 10 onward (n = 1354)
Long agonist protocol (n = 4704)
Oocytes retrieved 5.2 ± 3.5 versus 7.9 ± 4.2
Pregnancy rate 31.3 % versus 33.9 % (NS)
Lin et al. (2006)
Randomized controlled trial
Couples with male factor infertility, in their first ICSI cycle
CC/hMG/Cetrorelix protocol (n = 60)
Buserelin long protocol (n = 60)
Oocytes retrieved 11.1 ± 4.0 versus 17.3 ± 5.8. Pregnancy rate 41.7 % versus 40 % (NS). Ampoules used 18.9 ± 3.0 versus 38.9 ± 12.2
Mansour et al. (2003)
Couples with male factor infertility in their first ICSI cycle
CC 100–150 mg days 2–6. hMG 150 IU days 6–10. Antagonist 0.25 mg when leading follicle reached 16 mm (n = 33)
Decapeptyl long protocol (n = 156)
Pregnancy rate 24 % versus 59 %.
Hwang et al. (2003)
Couples with male factor infertility undergoing ICSI
CC 100 mg days 3–7
hMG 150 IU alternate days. Antagonist 2.5 mg when leading follicle reached 14 mm (n = 40)
Pregnancy rate 40 %. Ongoing pregnancy rate 35 %. No premature LH surge
Engel et al. (2002)
Prospective nonrandomized trial
Women between 18 and 39 years of age in their first IVF cycle
CC/hMG/antagonist (n = 54)
CC/r-FSH/antagonist (n = 53)
Pregnancy rate 25.9 % versus 13.2 % (NS)
Premature LH surge 16.7 versus 26.4 (NS)
Ampoules used 19.9 ± 8.7 versus 19.4 ± 8.9 (NS)
Stimulation days 7.1 ± 2.1 versus 6.8 ± 2.0 (NS)
Outcomes were significantly different unless stated otherwise
Studies (Williams et al. 2002; Fiedler and Ludwig 2003; Lin et al. 2006; Karimzadeh et al. 2010) comparing the CC/gonadotropin/GnRH antagonist protocol to the standard long agonist regimen report similar pregnancy rates in both groups despite a lower number of oocytes in the mild stimulation group. There is a significant reduction in the number of ampoules of gonadotropin used, the number of treatment days, and the costs. Only one non-randomized comparative study (Mansour et al. 2003) reported significantly lower pregnancy rates following ovarian stimulation with a CC/hMG protocol with GnRH antagonist compared with a long GnRH agonist protocol.
Hwang et al. (2003) reported on a combined protocol of CC/gonadotropin/GnRH antagonist with mean number of 8.0 oocytes retrieved and an ongoing pregnancy rate of 35 % per started cycle. The mild stimulation regimen used varies in the different studies. In most studies, a protocol of 100 mg Clomiphene citrate for 5 days soon after the onset of menses is combined with low-dose gonadotropins. The starting dose of gonadotropins, day of initiation, daily or alternate-day injection, and fixed or flexible antagonist dosing vary from study to study.
It has been debated whether hMG or r-FSH should be used in the CC/gonadotropin/GnRH antagonist protocol. Engel et al. (2002) reported that both treatment groups (hMG and rFSH), yielded comparable results concerning gonadotropin dose, stimulation days, and pregnancy rate. Interestingly, one study (Yanaihara et al. 2008) reported that in CC/gonadotropin/GnRH antagonist cycles, when the circulating level of LH is less than one-third at the time of hCG than it was at the beginning of stimulation, both pregnancy and implantation rates are significantly reduced. This observation suggests the relevance of using gonadotropins containing LH or hCG rather than FSH alone in this protocol. Also, mounting evidence indicates that LH or hCG activity during ovarian stimulation treatment is capable of modulating folliculogenesis by reducing the number of small or intermediate-sized follicles (Platteau et al. 2006). The positive effects of exogenous LH or hCG activity derived from hMG on folliculogenesis, embryo quality, and endometrial receptivity have been addressed in large randomized trials (Platteau et al. 2006; Filicori et al. 2002, 2005).
Few studies have evaluated the use of this regimen in poor responders. The first study (Craft et al. 1999) which included only 18 patients compared the CC/gonadotropin/GnRH antagonist protocol to their response in previous long agonist cycles. Smaller cycle cancellation rate, better oocyte yield, and lower gonadotropin requirement were observed in the mild group. Takahashi et al (Takahashi et al. 2004) studied this protocol in 40 poor responders with previous multiple IVF failures using the long agonist protocol. They noted that the ovarian response using the mild protocol was comparable to that obtained in the previous attempts with the long regimen, but the blastocyst development rate and ongoing pregnancy rate (41.2 %) were significantly higher with the mild protocol. D’Amato et al (D’Amato et al. 2004) in a prospective randomized study of poor responders and older women compared a sequential protocol of CC/FSH/GnRH antagonist with the long GnRH agonist protocol and reported a significantly lower cancellation rate, higher peak estradiol level, more retrieved oocytes, and higher pregnancy and implantation rates in the antagonist group. Only in the antagonist group, the results were comparable in younger (<35 years) and older (>35 years) women. In this study, however, high-dose FSH was used and hence, the observations only indicate that this regimen with low-dose gonadotropins may be suitable for poor responders and older women.
Advantages of Mild IVF
Similar Live-Birth Rate
In mild IVF protocols, low doses of gonadotropins are used and cycles are of short duration. There is no need to wait before starting the next new cycle and treatment can be repeated in consecutive cycles offering attractive cumulative pregnancy rates over a time frame. Heijnen et al. (2007) compared mild IVF with single-embryo transfer to conventional IVF with two-embryo transfers. They observed that the mild approach resulted in an equal cumulative chance of term live birth after a year of treatment while significantly reducing the total costs and multiple births.
Mild stimulation regimens significantly reduce the risk of severe OHSS (Hejinen et al. 2007; Karimzadeh et al. 2010). Studies have shown that the risk of severe OHSS is lower in the GnRH antagonist protocol as compared with the GnRH agonist protocol (Al-Inany et al. 2006; Kolibianakis et al. 2006). Furthermore, the antagonist protocol allows the use of GnRH agonist to trigger final oocyte maturation instead of hCG, further reducing the risk of OHSS (Humaidan et al. 2009). Mild IVF protocols combined with single embryo transfer are associated with a significantly lower risk of multiple pregnancy (Hejinen et al. 2007; Kato et al. 2012).
Reduced Discomfort and Dropout Rates
In mild IVF using the CC/gonadotropin/GnRH antagonist protocol, the painful and expensive injections of conventional IVF in the initial part of the cycle are substituted by inexpensive oral medications, reducing patient discomfort and improving compliance. Mild protocols decrease the number of visits to the clinic so that there is very little interference with work schedules and other regular commitments. Mild IVF is associated with fewer side effects and stress related to treatment and cycle cancellation compared with conventional IVF (Højgaard et al. 2001; de Klerk et al. 2006). There is an increased likelihood that patients will continue treatment following a failed attempt and therefore, compensate for the lower pregnancy rate per cycle following mild stimulation (Verberg et al. 2008a).
Beneficial Effect on Oocyte and Embryo Quality and Endometrial Receptivity
A recent meta-analysis (Verberg et al. 2008b) suggested that the retrieval of a modest number of oocytes following mild stimulation is associated with a distinctly higher implantation rate when compared to the same number of oocytes retrieved following conventional stimulation. A low number of oocytes retrieved following conventional IVF is associated with a poor clinical outcome. This could mean that the milder ovarian stimulation interferes less with the process of natural follicle selection and results in better oocyte quality. Furthermore, mild approaches might also improve endometrial receptivity and luteal function which are altered following conventional ovarian stimulation.
Higher pregnancy rates and live birth rates were obtained in frozen-thawed embryo transfer cycles compared to fresh cycles (Kato et al. 2012; Zhang et al. 2010). This might be related to the antiestrogenic effect of CC on the endometrium in fresh cycles which, in contrast, is abolished in hormonal replacement frozen-thawed embryo transfer cycles.
Mild IVF entails limited use of gonadotropins, a lower risk of OHSS, and when combined with single embryo transfer (SET) a lower risk of multiple pregnancy. Zhang et al. (2010) reported a cost reduction per live birth of 66 % when using the mild protocol, and this did not include the costs associated with the management of OHSS and multiple pregnancy which are far more common with conventional IVF.
Eijkemans et al. (2006) reported comparable cumulative term live birth rates after one year (43.4 % versus 44.7 %,) in the mild and conventional IVF groups, with significantly lower total costs per term live birth within a year in the mild group.
Disadvantages of Mild IVF
World over, success rates are calculated and quoted as success rates per cycle; hence mild approaches invariably fall short when compared with conventional IVF. Following mild IVF, there is reduced likelihood of having surplus embryos for cryopreservation, reducing the overall efficacy of a single stimulated cycle. Since there are fewer oocytes to start with, there is no room for suboptimal laboratory performance. Mild protocols usually require more than one cycle to achieve success. Hence, this form of IVF needs proper counseling so that patients are aware and are prepared for multiple attempts.
The considerations related to different approaches in ovarian stimulation are presented in Table 10.2.
Considerations related to different approaches in ovarian stimulation
Current ovarian stimulation approaches
Mild stimulation approaches
Aiming for maximum number of oocytes
Time-consuming and complex stimulation regimens
Much patient discomfort
Short-term complications: ovarian hyperstimulation syndrome (OHSS)
Long-term health consequences uncertain
High dropout rates
Supraphysiological steroid levels with possible implications
Emphasis on additional pregnancy chances from cryopreserved embryos
Emphasis on maximizing pregnancy rates per cycle
Cheaper (making IVF more accessible for a broader patient population)
Reduced chances for complications
Reduced chances for discomfort
Reduced chances for dropout
Effects on oocyte quality
Effects on endometrial receptivity
Emphasis on maximizing chances for healthy children born per started treatment at reasonable cost, patient discomfort, and chances for complications
From Verberg et al. (2009). Reprinted with permission from the Oxford University Press
Evidence in favor of mild IVF is accumulating in the literature, and its use is becoming a widespread practice around the world. Mild IVF protocols seem to be suitable for most indications for conventional IVF. Mild IVF regimens employ the use of low-dose gonadotropins and are of short duration. The fewer side effects, better patient tolerability, and reduced costs decrease the stress and burden associated with IVF, decreasing the dropout rates and encouraging couples to perform more attempts, thereby improving cumulative pregnancy rates. The mild stimulation approach, especially when combined with single embryo transfer, may represent an important step toward the objective of an easier patient-friendly IVF, cost-effective for both patients and society, while still having an acceptable effectiveness in terms of live birth rates.
An important concern regarding the use of a mild treatment strategy remains the reduction in the per cycle chance of pregnancy. It is essential to redefine IVF success as singleton (or twin) live birth rate assessed over a time frame rather than per started cycle.
There are a spectrum of protocols for mild IVF varying from the use of Clomiphene alone, gonadotropins alone, or Clomiphene followed by gonadotropins, with or without GnRH antagonist. The CC/gonadotropin/GnRH antagonist protocol takes advantage of the synergistic effect of CC and gonadotropins on follicular growth. The gonadotropins also counteract the antiestrogenic effect of CC on endometrium, and the antagonist started in the mid-follicular phase effectively prevents the LH surge.
Up to now, studies on mild IVF protocols have been limited by small sample sizes, few randomized studies, and ill-defined end points. What is definitely needed is properly designed randomized controlled trials (RCT) comparing mild IVF protocols with conventional long agonist protocols in different subsets of infertility patients. These studies should come from different research groups and should also include freeze-thaw cycles.
Finally, the chances for IVF success should be balanced against patient discomfort, risk of complications, and costs. The implementation of mild stimulation into standard clinical practice appears to be justified and is worth pursuing.
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