|Year : 2014 | Volume
| Issue : 1 | Page : 22-28
IVF Lite - A new strategy for managing poor ovarian responders
Goral N Gandhi, Gautam N Allahbadia, Sakina Kagalwala, Aaisha Khatoon, Ritu Hinduja, Akanksha Allahbadia
Rotunda The Center for Human Reproduction, Mumbai, India
|Date of Web Publication||14-Feb-2014|
Goral N Gandhi
Rotunda The Center for Human Reproduction, Mumbai
Source of Support: None, Conflict of Interest: None
Background: Previous trials have shown that neither conventional IVF nor natural cycle IVF is an effective treatment option for poor ovarian responders. However, none of the trials has examined the efficacy of accumulating embryos with serial minimal stimulation cycles, vitrifying the resulting embryos and transferring them in a remote cycle (IVF Lite protocol). Women with poor ovarian reserves, who commonly do not respond to conventional stimulation protocols, are left with few options when planning a family. The current study was undertaken to evaluate the efficacy of serial minimal stimulation in vitro fertilization (msIVF) cycles with vitrification of embryos for treatment of poor ovarian responders (PORs) as compared to conventional IVF protocols. Materials and Methods: This is a retrospective data analysis of PORs from June 2010 to November 2012. A total of 222 patients were included in the study. Ninety-seven patients underwent serial minimal stimulation cycles with vitrification and embryo banking (IVF Lite Group) and 125 patients underwent conventional controlled ovarian stimulation for IVF. The patients identified as PORs based on the Bologna criteria were included in the analysis. In the IVF Lite group, embryos were vitrified using Cryotec vitrfication protocol on Day 3. Once six embryos were banked with us, a frozen embryo transfer was planned. A maximum of 3 embryos were transferred. Main outcome measure was the clinical pregnancy rate defined as positive fetal heartbeat at 12 weeks of pregnancy. Results: There was no significant difference in the number of metaphase II (MII) oocytes retrieved between the both groups. The difference in the number of gonadotropins units required to produce one MII oocyte between the two groups was statistically highly significant: 680.4 units for the IVF Lite group and 4956.2 units for the conventional IVF group. The IVF Lite group had a higher percentage of good grade embryos. In the IVF Lite group, each patient underwent an average of 2.96 cycles of embryo accumulation before planning a frozen embryo transfer. An average of 6.2 embryos were accumulated for each patient. The clinical pregnancy rate (CPR) per embryo transfer was higher in the IVF Lite group (27.81%) than the conventional IVF group (15.15%). The CPR per patient was much higher in the IVF Lite (48.45%) than the conventional IVF group (24.0%). Conclusion: The results obtained in the current study demonstrate that the IVF Lite protocol consisting of ms-IVF, ACCU-VIT and rET is a very successful approach in treating poor responders. Very favorable rates of pregnancy can be achieved with IVF Lite protocol.
Keywords: Embryo accumulation, embryo vitrification, in vitro fertilization Lite, minimal stimulation, poor ovarian responders, poor response
|How to cite this article:|
Gandhi GN, Allahbadia GN, Kagalwala S, Khatoon A, Hinduja R, Allahbadia A. IVF Lite - A new strategy for managing poor ovarian responders. IVF Lite 2014;1:22-8
|How to cite this URL:|
Gandhi GN, Allahbadia GN, Kagalwala S, Khatoon A, Hinduja R, Allahbadia A. IVF Lite - A new strategy for managing poor ovarian responders. IVF Lite [serial online] 2014 [cited 2022 Jan 18];1:22-8. Available from: http://www.ivflite.org/text.asp?2014/1/1/22/127087
| Introduction|| |
Garcia et al., first described a poor responder patient in 1983, about 30 years ago.  Many studies have been published since then about the potential treatment approaches for poor ovarian responders (PORs). ,,, However, a satisfactory treatment approach to improve the outcomes for this particular group of patients has not been established. In 2011, the European Society for Human Reproduction and Embryology (ESHRE) reached a consensus on the minimal criteria required to define poor ovarian response (POR). The acronyms POR and PORs were also proposed to be entered into conventional assisted reproduction treatment terminology to deﬁne poor ovarian response and poor ovarian responders, respectively, at the same meeting by ESHRE. 
Minimal stimulation protocols were evolved with the intention of providing a more natural stimulation for IVF. These protocols have been shown to have many advantages over conventional ovarian stimulation protocols, the main one being production of fewer but better quality oocytes. ,,,,,,,,,,,
Kyrou et al., in a systematic review and meta-analysis of 22 randomized controlled trials in poor responders, compared different protocols. This meta-analysis concluded that none of the reviewed protocols was successful in significantly increasing the success rates for PORs. 
The low number of embryos available for transfer poses a great challenge in the management of PORs.  A potential management of poor responders is to create a sufficient pool of embryos by accumulating vitrified good-grade embryos over several minimal stimulation cycles. This would potentially make the chances of success for poor responders similar to normal responders. This management, however, is unthinkable without an outstanding vitrification program. The option of accumulating embryos has become a promising reality with the advent of vitrification technologies.
The aim of the current study was to evaluate the efficacy of serial minimal stimulation IVF (msIVF) cycles with vitrification and accumulation (ACCU-VIT) of embryos followed by a remote frozen embryo transfer for the treatment of poor responders as compared to conventional IVF protocols.
| Materials and Methods|| |
This is a retrospective data analysis of PORs who underwent treatment at Rotunda - The Center for Human Reproduction, Mumbai, India between 1 June 2010 and 30 November 2012. The patients identified as PORs based on the Bologna criteria  were included in the analysis.
IVF Lite protocol
The IVF Lite protocol consists of msIVF + ACCU-VIT + rET
Clomiphene citrate (Ovofar, MSD, India) 50 mg per day was started on day 2 or day 3 of the menstrual cycle and was continued for 10 days till maturity of follicles was established by ultrasound guidance. Maturity was said to have been achieved when the lead follicle size reached 21-22 mm; 150 IU of human menopausal gonadotropin (hMG) [HUMOG, Bharat Serums and Vaccines Ltd. (BSVL), India] was added on day 5 and continued till the desired follicular size was achieved. Gonadotropin-releasing hormone (GnRH) antagonist cetrorelix (Ciscure, Emcure, India) 0.25 mg was added to the stimulation when the lead follicle size was 18 to 19 mm in diameter. When adding cetrorelix, the dose of hMG was increased by 75/150 IU at the discretion of the treating physician. Cetrorelix was continued till the day of the human chorionic gonadotropin (hCG) trigger; 10,000 IU of hCG (HUCOG, BSVL, India) was given when the lead follicle size was 21 to 22 mm in diameter. Oocyte retrieval was performed under ultrasound guidance 32 to 34 hours after the hCG trigger.
The retrieved eggs were fertilized using either IVF or intracytoplasmic sperm injection (ICSI) and the resulting embryos were vitrified on day 3 using vitrification (Cryotech, Japan).
Back-to-back cycles of msIVF followed by ACCU-VIT were performed till about six top-grade (grades A and B) embryos were accumulated per patient.
An rET was performed when adequate embryos were accumulated. The embryos were warmed using the Cryotec (Cryotech, Japan) warming protocol. The warmed embryos were transferred on day 4, after preparing the endometrium with estradiol valerate tablets (Progynova, Zydus Healthcare, India) which was started from day 3 or 4 of the menstrual cycle after a baseline scan was done to rule out any ovarian cyst and to measure endometrial lining. Standard luteal support was started four days prior to embryo transfer and continued for 12 days. Embryo transfers were performed under transabdominal ultrasound guidance using a Wallace Sureview (Smiths Medical International Ltd, United Kingdom) embryo transfer catheter.
Stimulation was started on day 2 of the menstrual cycle with an initial dose of 300 to 450 IU of biosimilar recombinant follicle-stimulating hormone (bs-recFSH) (Foligraf, BSVL, India) along with buserelin (Busag, Zydus Gynova, India) 0.25 mg daily after ruling out ovarian cysts of >10 mm on transvaginal ultrasound. Day 5 onward, the dose of bs-recFSH was adjusted according to the ovarian response seen on transvaginal ultrasound performed every two days. When the lead follicle reached a diameter of 18-19 mm 10,000 IU of hCG (HUCOG, BSVL, India) was given, and ultrasound-guided oocyte retrieval was done approximately 34 hours later. Fresh embryos were transferred on day 3. Embryo transfers were performed under transabdominal ultrasound guidance using a Wallace Sureview (Smiths Medical International Ltd, United Kingdom) embryo transfer catheter. Adequate luteal support was given.
| Results|| |
A total of 97 PORs underwent treatment with IVF Lite protocol and 125 PORs underwent treatment with conventional IVF stimulation protocol.
The mean values for age, basal blood FSH, and anti-Mullerian hormone (AMH) were comparable in the IVF Lite and conventional IVF groups [Table 1]. For the IVF Lite group, a total of 97 patients underwent 287 treatment cycles. For the conventional IVF group, a total of 125 patients underwent 277 treatment cycles. The percentages of cancellation of cycles due to poor response, cycles with no oocytes retrieved, and cycles with failed fertilization were also similar in both the groups [Table 2].
It is interesting to note that there was no statistical difference in the number of metaphase II (MII) eggs in both the groups. However, the percentage of MII oocytes retrieved was 78.06% for the IVF Lite group and 47.6% for the conventional IVF group (statistically significant, P < 0.01) [Table 3]. The difference in the number of gonadotropin units required to produce one MII egg between the two groups was statistically highly significant: 680.4 units for the IVF Lite group and 4956.2 units for the conventional IVF group, P < 0.05 [Table 2].
The fertilization and cleavage rates were similar in both the groups. The average number of good-grade embryos per cycle was 1.69 in the IVF Lite group and 1.04 in the conventional IVF group [Table 3]. It is interesting to note the significant difference in the percentage of good-grade embryos between the two groups (P < 0.01).
[Table 4] shows the clinical outcome. The number of embryos transferred per cycle was similar in both the groups (1.75 and 1.77, respectively, in IVF Lite and conventional IVF), though the number of good-grade embryos transferred was higher in the IVF Lite group. Clinical pregnancy rate (CPR) per embryo transfer was 27.81% in the IVF Lite group and 15.15% in the conventional IVF group. The CPR per patient was 48.45% in the IVF Lite group which is much higher than the 24.0% CPR per patient in the conventional IVF group. It is important to note that the IVF Lite group did not have a single cycle with cancelled embryo transfer. In the conventional group, 10.41% of the patients did not have any embryo transfer.
[Table 5] shows the embryological outcomes of the vitrified warmed embryos. For the IVF Lite group, an average of 6.2 embryos was accumulated per patient; 169 warming cycles were performed for 97 patients. An average of 1.88 embryos was warmed per cycle; 97.34% of embryos survived the vitrification-warming process. An average of 1.75 embryos was transferred.
[Figure 1] shows the number of cycles required to accumulate a minimum of six good-grade embryos for each patient before the embryo transfers were performed. All the patients required more than one stimulation cycle. Thirty patients accumulated the required number of embryos in two cycles, and 43 patients had to undergo three stimulation cycles. There were 22 patients who required four stimulation cycles, and two patients required five stimulation cycles to accumulate adequate embryos.
|Figure 1: Number of cycles required to accumulate minimum six embryos for the IVF Lite group|
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[Figure 2] shows the number of attempts required to achieve pregnancy in the IVF Lite group. Twenty-four patients achieved pregnancy in the first attempt of frozen embryo transfer and 14 patients achieved pregnancy in the second attempt. There were eight patients who achieved pregnancy in the third attempt of frozen embryo transfer, and one patient who required four attempts of frozen embryo transfer to be pregnant.
|Figure 2: Number of embryo transfer cycles required to achieve a pregnancy for IVF Lite group|
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[Figure 3] shows the number of attempts required to achieve pregnancy in the conventional IVF group. This group had all fresh embryo transfers. Nine patients achieved pregnancy in the first attempt, 15 patients achieved pregnancy in the second attempt. There were six patients who achieved pregnancy in the third attempt. No patients tried more than three attempts of stimulation cycles with the conventional IVF protocol.
|Figure 3: Number of embryo transfer cycles required to achieve a pregnancy for Conventional IVF group|
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| Discussion|| |
POR is not a rare occurrence in ovarian stimulation. The incidence of POR is 9.24% in patients undergoing IVF treatment. 
Tarlatzis et al., in their elegant systematic review evaluating all the existing ovarian stimulation protocols applied to poor responders, concluded that the exhausted ovarian apparatus is unable to react to any stimulation, no matter how powerful this might be.  The ideal stimulation for poor responders still remains a challenge, as the hypothesized diminished oocyte cohort cannot be reversed within the limits of our present capabilities. 
The current study was set out to assess the application of IVF Lite protocol  as a new strategy for managing these patients.
IVF Lite (ms-IVF + ACCU-VIT + rET)
Zhang et al.,  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 because cryopreserved embryo transfers with this protocol have yielded much higher rates of pregnancy than fresh transfers. In this series, the patients were not denied treatment based on their day-3 FSH value or ovarian reserve.  Yet, acceptable rates of pregnancy were achieved (20% for fresh embryo transfers and 41% for cryopreserved embryo transfers).  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  based on a minimal stimulation protocol including clomiphene citrate and hMG, vitrification, and cryopreserved rETs has yielded much higher pregnancy rates than fresh transfers.  . IVF Lite includes ACCU-VIT over a few cycles for PORs.
Unlike standard stimulation protocols, minimal stimulation protocols do not require a resting cycle between two treatment cycles. The women with poor ovarian reserves can have back-to-back consecutive cycles before their follicular reserve is depleted. It maximizes the already limited life span of the ovaries, allowing the patients to store embryos while production of oocytes is still active. This gives a very favorable pregnancy rate per time spent by the patient, which is of utmost significance in this group of patients who are in a race against time to beget their own genetic offspring.
The reliance on clomiphene citrate, with its negative impact on the endometrium, required a very reliable method of embryo cryopreservation. These are the patients who produce only one or two good-grade embryos per cycle. We have to try all that we can to ensure that we get pregnancies out of these embryos. A highly efficient vitrification program is extremely critical to minimize loss of embryo and maximize the chances of pregnancy. The study center chose the latest Cryotec vitrification method developed by Dr Masashige Kuwayama.
The vitrification method was developed to overcome the harmful effects of ice crystal formation that occurs during the slow-freezing method. Traditionally, slow-freezing protocols were used to freeze all kinds of human embryos, but clinically, satisfactory results were not obtained.  Furthermore, the results were not consistent. There are many papers in the literature that prove that vitrification is a more secure method of cryopreservation. Vitrification implants fewer traumas to the cells and is therefore a more effective means of cryopreservation of embryos than slow freezing. 
The Cryotec vitrification method (Cryotech, Japan) chosen by the study center has many advantages
over the previous methods of vitrification of Dr Kuwayama.  Now, with major improvement in the solutions and the newly designed vitrification plates, a new method called Cryotec has been developed (Cryotech, Japan). The Cryotec vitrification solution has no added serum or synthetic serum supplements. It is a completely chemically defined solution and is stable for a year at 4-8°C. It contains trehalose instead of sucrose. This overcomes the problem of endotoxicity due to sucrose.  The Cryotec vitriplates have a special holder for the Cryotec; thus, the focus remains the same while washing the embryos in vitrification solution and placing them on the Cryotec.  The study center chose this method owing to its numerous advantages, which all cumulatively add up to an extremely high survival rate of the embryo.
The difference in the embryo transfer cancelation rate between the two groups is noteworthy. Most patients find it difficult to accept and cope with the terrible consequence of no embryo transfer.  Many of them turn to ovum donation, whereas many quit. In the current study, none of the patients in the conventional IVF group continued treatment beyond the third attempt, as indicated in [Figure 3]. The conventional IVF group showed a high cancellation rate of embryo transfer. With ACCU-VIT, as we have extremely high survival rates of embryos, there was not a single patient who had oocytes retrieved in multiple cycles and no embryo transfer. The thought of having multiple chances of accumulating embryos at a much lower cost and trauma increases the acceptance and willingness of the patient to accumulate embryos to mimic the situation of normoresponder patients.
Interestingly, there was no significant difference in the number of MII oocytes between the two groups. The IVF Lite group had MII oocytes comparable to the conventional IVF group, with significantly less gonadotropins used. The IVF Lite group had a significantly higher percentage of good-grade embryos than the conventional IVF group. This suggests that when minimal stimulation is used, a cohort of few but better quality oocytes is obtained.
The CPR per patient was significantly higher in the IVF Lite group which confirms the efficacy of this approach for managing PORs. The CPR observed in this study for poor responder patients in the IVF Lite group is comparable to the success rate in normal responding patients. ,
Many patients in the IVF Lite group were pregnant using only 2-3 of their accumulated embryos. They still have 3-4 surplus embryos stored, with the study center allowing them the opportunity to have a second child in the future if they so wished. This chance would otherwise be most likely denied to them with conventional IVF.
The small sample size and the retrospective, nonrandomized nature of the analysis are limiting factors of this study. However, the results are very encouraging. We are now looking at the cost benefits of applying this protocol to all groups of patients.
| Conclusion|| |
The results obtained in the current study demonstrate that the IVF Lite protocol consisting of ms-IVF, ACCU-VIT, and rET is a very successful approach in treating poor responders. Very favorable rates of pregnancy can be achieved with IVF Lite protocol, imparting a new hope to patients who would otherwise have a very small chance of having their own genetic children.
| Acknowledgment|| |
The authors wish to thank the entire team at Rotunda. The Center for Human Reproduction, Mumbai. Part of this data has been accepted for presentation at the Annual Meeting of ESHRE, 8-10 July 2013, London, United Kingdom.
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| Authors|| |
Goral Gandhi has been the Laboratory Director at Rotunda- The Center for Human Reproduction since its inception in the year 2000. She obtained a Masters degree in Applied Biology from King Edward Memorial Hospital, Mumbai University in 1992 for her thesis on "External and internal quality control in Laboratories". Her research activities are geared towards developing innovative culture and cryopreservation methodologies to improve clinical pregnancy outcomes. Current research projects are focused on fertility preservation in female patients through egg banking and application of latest vitrification methods to improve and enhance treatment outcomes.
[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]