|Year : 2021 | Volume
| Issue : 2 | Page : 43-51
In vitro maturation (IVM) procedure in oncofertility patients: A systemic review
Mohd F Ahmad1, Yodo Sugishita2, Yuki Suzuki-Takahashi2, Hideyuki Iwahata2, Seido Takae2, Yuki Horage-Okutsu2, Nao Suzuki2
1 Department of Obstetrics & Gynaecology, Faculty of Medicine, National University of Malaysia, Kuala Lumpur Campus, Cheras, Malaysia
2 Department of Obstetrics & Gynaecology, St Marianna University School of Medicine, Kawasaki, Kanagawa, Japan
|Date of Submission||23-Feb-2022|
|Date of Acceptance||12-Jun-2022|
|Date of Web Publication||30-Dec-2022|
Prof. Nao Suzuki
Department of Obstetrics & Gynaecology, St Marianna University School of Medicine, Chrome-16-1 Sugao, Miyamae Ward, Kawasaki 216-8511
Source of Support: None, Conflict of Interest: None
Our review aims to evaluate the benefit of in vitro maturation (IVM) in a standard control ovarian stimulation among oncofertility patients. A thorough search for relevant studies was conducted via PubMed, Google Scholar, Scopus, Cochrane Library, and clinical.gov databases. Our primary outcome was the oocyte maturation rate (OMR), which measures the number of immature oocytes that progress to mature (MII) oocytes following IVM. Our secondary outcomes were the number of oocytes and embryo cryopreservation following IVM for future use. The initial search identified 150 studies. Eight studies were included in our review after duplication assessment, title and abstract screening, and subsequent complete text evaluation tailored to our inclusion criteria. A total of 1040 patients with cancer with a mean age of 32.68 years were included in our review, in which half of them were diagnosed with breast cancer (BC). Most of the cycles were unstimulated. Two studies compared IVM in either follicular or luteal phases, and one study compared the in vitro fertilization (IVF) cycle with or without IVM. Our review included 7711 oocytes with 4604 oocytes that progressed to MII, obtaining an overall OMR of 59.70%. Following IVM, 335 embryos and 2380 oocytes were cryopreserved for future use. The oocyte numbers and maturation were comparable among all the studies, except that prognostic and predictor BC affects the IVM outcome. Our review concluded that IVM improves the number of MII following IVF cycles with similar survival rates, meiotic resumption rates, and blastocyst formation upon fertilization. Thus, IVM is a beneficial strategy for oncofertility patients.
Keywords: Breast cancer, control ovarian stimulation, in vitro maturation, oncofertility, oocytes cryopreservation
|How to cite this article:|
Ahmad MF, Sugishita Y, Suzuki-Takahashi Y, Iwahata H, Takae S, Horage-Okutsu Y, Suzuki N. In vitro maturation (IVM) procedure in oncofertility patients: A systemic review. Onco Fertil J 2021;4:43-51
|How to cite this URL:|
Ahmad MF, Sugishita Y, Suzuki-Takahashi Y, Iwahata H, Takae S, Horage-Okutsu Y, Suzuki N. In vitro maturation (IVM) procedure in oncofertility patients: A systemic review. Onco Fertil J [serial online] 2021 [cited 2023 Feb 4];4:43-51. Available from: https://www.tofjonline.org/text.asp?2021/4/2/43/366152
| Key Messages:|| |
The IVM improves the number of MII following IVF cycles with similar survival rates, meiotic resumption rates, and blastocyst formation upon fertilization.
| Introduction|| |
The maturation of immature (GV) oocytes in unique culture media is defined as an in vitro maturation (IVM). These media composed of complex microenvironment that was invented to promote the development of the ultrastructural and nuclear-cytoplasmic maturation of GV oocytes since the 1960s.,, The hallmarks of the invention were seen in 1994 where the first baby was born following IVM using an oocytes donor. Since that, IVM becomes an additional strategy in improving the outcome of in vitro fertilization (IVF) mainly to reduce the risk of ovarian hyperstimulation syndrome in susceptible patients. However, the uptake of IVM in IVF is not well established. The oocytes’ insecurity following the IVM leads to the low implementation in the most reproductive center. Nevertheless, the current data show a good pregnancy outcome, mainly for polycystic ovarian syndrome (PCOS)., To date, more than 5000 babies were delivered following IVM worldwide. Therefore, the potential indication of IVM had evolved from PCOS women to poor responders, poor ovarian reserve, and fertility preservation (FP) strategy for oncofertility patients planning for gonadotoxic chemotherapy. As an FP strategy, IVM is vital to improve limited ovarian stimulation, time-concerning primary cancer treatment. The risk of nongrowing follicles within the short-time frame will lead to GV oocytes previously discarded as not suitable for cryopreservation. Thus, traditionally, there will be low oocyte numbers per cycle, which leads to poor FP outcome. Nowadays, the supplementation of IVM in IVF had tremendously improved the outcome. The number of mature (MII) oocytes’ yield following IVM-FP ovarian cycle is reported to be better with or without ovarian stimulation. Despite that, the uptake of IVM for FP has remained low as the evidence is limited., Hence, our systematic review aimed to discuss and clarify IVM’s issues in FP strategy among oncofertility patients.
| Materials and methods|| |
Registration and searching strategy
The review was registered under the prospective international register of systematic reviews (PROSPERO: CRD42021250391) and executed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. A comprehensive literature search strategy was done in March 2021, identifying the relevant studies within 20 years (2000–2020) via electronic database PubMed using the term: “In Vitro Maturation” OR “IVM” OR “in vitro techniques” [MeSH Terms] AND “fertility preservation” OR “cryopreservation.” For the search using Google Scholar and Scopus, the aliettite: “In Vitro Maturation” AND “oncofertility” OR “fertility preservation” was used. Subsequent to that, the relevant articles were also searched within Clinical. Trial.gov and Cochrane Review. In improving our searching for potential articles, we used the reference lists obtained from relevant articles and conducted a manual search to maximize the number of related evidence.
Criteria for study inclusion
Any studies comparing oocytes outcome following IVM, including MII oocyte numbers yield and ability to cryopreserve; survival and meiosis resumption rates (MRR), fertilization rates, and cumulative live birth among oncofertility patients were considered eligible. The study design is limited to interventional studies, excluding any case series and case reports, in vitro and animal studies, narrative or systematic review, and meta-analysis with only English language articles was considered. All titles and abstracts were reviewed, and two reviewers reviewed the full text of the included studies to confirm eligibility and reduce the interrater reliability. Discrepancies between ratings of inclusion on studies were discussed between the two reviewers until a consensus was reached.
Quality analysis and data extraction
We evaluate the quality and risk of bias among included studies using the NIH tool for observational studies by rating the variable as 1 for yes and 0 for no or nonapplicable. A total score of 14 variables will further categorize them as poor (0–5), fair (6–9), or good (10–14) conducted studies. A minimum of the fair score study was included in this review ([Table 1]). Otherwise, the data were extracted based on the authors’ last name, the year of publication, number, and age of participants, ovarian phase of IVF cycle either stimulated or not, study intervention, outcome, MII oocytes numbers yield and ability to cryopreserve, survival and MRR as well as the conclusion of each study.
| Results|| |
We retrieved 150 potential articles. After the duplication exclusion via Endnotes and the removal of ineligible studies, 66 studies remained. The titles and abstracts were screened, and further exclusion was conducted, narrowing the selection to 20 studies. Subsequently, six studies were excluded because full reports were not retrieved. Three studies were noneligible because IVM was not the primary intervention, and another three studies were excluded because the full text was not retrieved. Finally, eight studies were deemed appropriate and included in this review [Figure 1]. The features of the studies are presented in [Table 1]. Our reviews comprised one abstract presentation, three supplementation congress abstracts, and four original articles. The primary intervention in these studies was IVM procedure in patients with cancer for oocyte or embryo cryopreservation for FP.
Demographic profile of the included studies
A total of 1040 cancer patients with a mean age of 32.68 years were included in our review, and about half of them were diagnosed with breast cancer (BC).,,, Another three studies did not state the type of cancer, whereas one study included patients with various cancer diagnoses.,,, All of the studies were prospective, except for one retrospective research conducted by Oktay et al.,,,,,,, Most cancer patients underwent IVM via unstimulated cycles, three patients were stimulated, and one patient was not stated. Two studies compared IVM usage during follicular phase and luteal phase (LP) of the ovarian cycle., One of the included studies did compare the IVF cycle with or without IVM. All these comparison variables revealed a similar outcome, namely, MII oocyte yield following IVM. Interestingly, one of the included studies evaluated the effect of prognostic and predictor BC on IVM outcome and concluded that it might affect its outcome. These studies consolidated the IVM procedure to improve the MII yield following IVF cycles with similar survival rates (SR), MRR, and blastocyst formation upon fertilization. A total of 7711 oocytes retrieved among the cancer population were included in this review. Following IVM, 4604 oocytes achieved MII with overall oocyte maturation rate (OMR) of 59.70%. Based on data from six out of eight included studies, about 335 embryos and 2380 oocytes were cryopreserved [Table 2].
|Table 2: Summary of results from eight studies included in the systemic review|
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| Discussion|| |
The outcome in our systemic review reflected that the usage of IVM is an excellent strategy to improve the outcome of oocytes and embryo cryopreservation for FP. To our knowledge, this is the first systemic review assessing the role of IVM procedure in oncofertility patients. The current implementation of IVM was much scatted. Most of the reproductive specialists did not implement it as one of the reproductive services in their center., Traditionally, IVM is considered an alternative option in IVF—mainly required an additional culture of GV oocytes aiming for progression into MII oocytes [Figure 2]. However, available opinions by ASRM recommended that IVM should be used as a first-line treatment in the appropriate circumstances depending on patients’ profiles.,
|Figure 2: Ovarian tissue cryopreservation (OTC) with IVM: (A) OTC standard protocol—the dissection of ovarian tissue fragment 1 cm3 for cryopreservation; (B) the aspiration of visible follicles with a needle to harvest possible oocytes before ovarian cortex dissection; (C) GV oocytes harvest cultured with IVM media aiming for maturation (MII); at least 24–72 h as oocytes from OTC, usually class 4–5, thus required longer IVM culture hours as compared to standard IVM (D)|
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Oncofertility cases as an indication for IVM procedure
The development of oncofertility services since 2005 did change the landmark of reproductive services worldwide. The advancement of cryobiology leads to a silver lining of FP, with many live births reported among cancer survivors. However, the current cryopreservation procedure is time-consuming, focusing on developing dominant follicles to harvest MII oocytes. This scenario poses a risk of delaying the primary cancer treatment., Therefore, the strategy of using IVM is proposed to overcome it. Growing evidence had shown that the quality of oocytes and the progression of the embryo following the fertilization of post-IVM procedure is comparable to standard MII oocytes. The limited time frame for ovarian stimulation led to nonstimulated or LP cycles and did not affect the overall outcome of yield oocytes.,, Furthermore, by selecting IVM, it is proven to enhance the numbers of cryopreservation oocytes and thus improved the FP treatment outcome.
IVM procedure and the type of cancer
Although most of the evidence reported more on BC survival, the other types of cancer also postulated to have a similar IVM procedure outcome. Most of the evidence shows that the AMH level is vital for IVM outcome rather than the type of cancer. Nevertheless, there is a report that ovarian reserve was significantly lower in BC than the other types of cancer, thus affecting the outcome of the number of MII oocytes yield post-IVM. In addition to that, the prognostic factor in BC such as SBRIII and HERS2+ was also reported to have a significant adverse effect on the number of OMR and mean maturation rates following the IVM procedure. Therefore, thorough counseling is paramount to ensure that an informed decision can be made in anticipating a more unsatisfactory outcome in this group of patients.
Ovarian cycle and the usage of stimulation agent for IVM procedure
The controversial issue previously leans toward control ovarian stimulation (COH) for cancer survival. The risk of the reactivation of cancer cells due to increased estrogen concentration following COH leads to a low uptake of FP treatment. However, established recommendations had shown that with antiestrogen supplementation, e.g., an aromatase inhibitor, during COH in the follicular phase, the level of estrogen surge can be controlled without jeopardizing the cycle outcome. Nevertheless, this recommendation is not widely practiced despite the low possibility of cancer recurrence. Therefore, an unstimulated IVF cycle, regardless of the ovarian phase with additional IVM procedures, had a comparable outcome.,,, The number of MII oocytes’ yields following the unstimulated cycle was acceptable without the risk of hyperstimulation and the risk of cancer cell activation. This strategy had become a valuable option for FP treatment among oncofertility patients.
The dynamic aspect maturation of in vitro oocytes and pregnancy outcome
The insecurity of IVM is confined to the quality of yield MII oocytes. The common argument is the risk of a poor oocyte quality leading to low pregnancy rates following fertilization. However, the maturation of oocytes following IVM had been proven to be similar to the standard MII oocytes regardless of the standard or unstimulated cycle.,,, The role of FSH and LH in the standard cycle is mainly confined to in vivo maturation. The vital role for in vitro oocyte maturation lies in the LH or HCG surge that triggered the nuclear and cytoplasmic maturation. Once this is achieved, the SR and MRR will be similar to the standard in vivo MII oocytes. Therefore, most articles reported that the pregnancy rates following post-IVM fertilized oocytes are comparable with the standard IVF outcome., The latest successful pregnancy following IVM in BC women consolidates the evidence on the dynamic process of post-IVM oocytes maturation is optimum, thus purposes that IVM can be an ideal FP strategy for oncofertility patients.
The limitation of this review is that the number of included studies is small, although the synchronization of IVM outcome can be extracted. The outcome of pregnancy rates is limited because most oncofertility patients aim for gamete banking rather than pregnancy to complete primary cancer treatment. Therefore, further follow-up and analysis are paramount in assessing the pregnancy rates among cancer survivors to consolidate the post-IVM pregnancy rates in the future.
| Conclusion|| |
The usage of IVM among oncofertility patients should be considered a valuable strategy to optimize the FP outcome without risking the primary cancer treatment. In addition, our review revealed an increase in oocyte number, leading to higher cryopreservation outcomes without affecting the fertilization. Therefore, IVM is beneficial as an adjunct in the standard COS for oncofertility patients.
We would like to thank all the staff in reproductive outpatient clinic and reproductive center who contributed to this study.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
Conceptualization, design, the definition of intellectual content, experimental studies, and article editing were done by all the authors. The literature search and clinical studies were done by AMF, YS, YST, and YHO. AMF, HI, ST, and NS made the data acquisition and analysis. AMF did article preparation, and others reviewed the final article. Nevertheless, YS, YST, and NS acted as guarantors to initiate the review. Otherwise, all authors have read and agreed to the final version of the article.
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[Figure 1], [Figure 2]
[Table 1], [Table 2]