|Year : 2019 | Volume
| Issue : 1 | Page : 27-34
Assisted reproductive technology outcome in poor responders classified by patient-oriented strategies encompassing individualized oocyte number stratification
Madhuri Patil, Milind Patil, Radha Puchalapalli
Dr. Patil's Fertility and Endoscopy Clinic, Bengaluru, Karnataka, India
|Date of Web Publication||25-Jun-2019|
Dr. Madhuri Patil
No. 1, Uma Admirality, Bannerghatta Road, Bengaluru - 560 029, Karnataka
Source of Support: None, Conflict of Interest: None
Aim: This study aims to evaluate the assisted reproductive technology (ART) outcome among various subgroups of poor responders classified by Patient-Oriented Strategies Encompassing IndividualizeD Oocyte Number (POSEIDON) criteria. Successful end point of any ART treatment is live birth, which depends on various factors including adequate number of follicles being stimulated, adequate number of oocytes retrieved, and quality of oocytes, which in turn depends on ovarian response. Usually, success rate is low in women who respond poorly to controlled ovarian stimulation. Bologna criteria have been used in the past to identify poor responders. Heterogeneity of subgroups using the Bologna criteria makes it difficult to manage the poor ovarian responder group. Moreover, specific profiles of abnormal ovarian response like hypo and suboptimal and the age-related embryo/blastocyst aneuploidy rate, which could dramatically change the prognosis in women that have the same oocyte yield were not included in Bologna criteria. The main goal of this study was to evaluate the ART outcome among various subgroups of poor responders defined by the POSEIDON stratification.
Materials and Methods: In this retrospective cohort study, the clinical and laboratory records of 260 poor responder women undergoing their first ovarian stimulation and fresh embryo transfer cycle were reviewed. Patients were categorized into 4 groups according to the POSEIDON classification.
Results: There was no difference in the fertilization and cleavage rate across the groups, but the blastocyst formation rate was higher in younger patients and reached statistical significance (P < 0.001). Implantation rate is significantly high in women <35 years (P < 0.001). Clinical pregnancy rate (CPR) was statistically higher in Group 1b and Group 2b where ovarian reserve was adequate and more than 5 oocytes were retrieved irrespective of the age (P < 0.001). In those with low ovarian reserve, CPR was statistically higher in the women <35 years (P < 0.001). Live birth rate (LBR) is high in Group 1b and Group 2b where more than 5 oocytes were retrieved irrespective of the age (P = 0.029). In patients with low ovarian reserve though the LBR was more in women <35 years it did not reach statistical significance.
Conclusions: Poor responders are a heterogeneous group and not homogenous for pregnancy prospects. Apart from oocytes retrieved, age and ovarian reserve will also modulate the chance of pregnancy which is higher in women <35 years and those with adequate ovarian reserve. Poor responders still represent a therapeutic challenge to the clinician, and future studies should explore the most optimal treatment strategy for management of poor responders according to the POSEIDON stratification.
Keywords: Assisted reproductive technology outcome, ovarian reserve, patient-oriented strategies encompassing individualized oocyte number stratification, poor responders
|How to cite this article:|
Patil M, Patil M, Puchalapalli R. Assisted reproductive technology outcome in poor responders classified by patient-oriented strategies encompassing individualized oocyte number stratification. Onco Fertil J 2019;2:27-34
|How to cite this URL:|
Patil M, Patil M, Puchalapalli R. Assisted reproductive technology outcome in poor responders classified by patient-oriented strategies encompassing individualized oocyte number stratification. Onco Fertil J [serial online] 2019 [cited 2020 Jan 19];2:27-34. Available from: http://www.tofjonline.org/text.asp?2019/2/1/27/261257
| Introduction|| |
The management of patients with poor ovarian response (POR) remains controversial and complex and represents a therapeutic challenge to the clinician. Successful end point of any assisted reproductive technology (ART) treatment is live birth, which depends on various factors including adequate number of follicles being stimulated, adequate number of oocytes retrieved, and quality of oocytes, which in turn depends on ovarian response. Usually, success rate is low in women who respond poorly to controlled ovarian stimulation (COS). Bologna criteria have been used in the past to identify poor responders. Before 2011, number of oocytes retrieved was adopted as a criterion of POR in most trials, although the threshold number differed considerably among studies. To standardize the definition of POR, Ferraretti et al. proposed the “Bologna criteria,” based on three features (1) advanced maternal age (≥40 years) or any other risk factor for POR (2) a previous POR – ≤3 oocytes with a conventional stimulation protocol, and (3) an abnormal ovarian reserve test (ORT) (antral follicle count (AFC) <5–7 follicles or anti-Mullerian hormone (AMH) of 0.5–1.1 ng/ml). Two of these three criteria are required for diagnosis of POR. In addition, two cycles with POR after maximal stimulation in the absence of advanced maternal age or abnormal ORT are sufficient to classify a patient as a poor responder. Based on this, the poor responders could be divided into eight subgroups as shown in [Table 1].
Despite this broad classification, Bologna criteria were not ideal because of the heterogeneity of subgroups making it difficult to manage women with POR. Moreover, specific profiles of abnormal ovarian response such as hypo and suboptimal and the age-related embryo/blastocyst aneuploidy rate, which could dramatically change the prognosis in women that have the same oocyte yield were not included in Bologna criteria.
The Bologna criteria were found to be useful in predicting the outcome of in vitro fertilization (IVF) and for counseling patients. However, as the women who were grouped together using the Bologna criteria were significantly different in their biologic characteristics, this grouping was not useful in comparing different clinical trial. To reduce heterogeneity of the BOLOGNA criteria, researchers from 7 countries came together and proposed the Patient-Oriented Strategies Encompassing IndividualizeD Oocyte Number (POSIEDON) Stratification.
According to POSIEDON stratification, patients are subdivided into 4 groups [Figure 1] based on quantitative and qualitative parameters, namely age, AFC, AMH, and ovarian response if previous stimulation was performed. Apart from low ovarian reserve that results in POR, there could be suboptimal response despite adequate ovarian reserve or a hyporesponse with requirement of a higher gonadotropin dose, and these two group of patients were also included in the POSIEDON stratification. According to the POSEIDON Working Group, this new stratification will serve as a guide to personalize treatment for an optimal ART outcome.
|Figure 1: Low prognosis groups according to by patients-oriented strategies encompassing individualized oocyte number stratification|
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The main goal of this study was to evaluate the ART outcome among various subgroups of poor responders defined by the POSEIDON stratification. Apart from the ART outcome, this study also looked at other parameters such as total days and dose of gonadotropin stimulation, estradiol (E2) and progesterone on the day of ovulation trigger, and embryo quality on day 3 and 5.
| Materials and Methods|| |
In this retrospective cohort study at a tertiary infertility clinic, we reviewed the clinical and laboratory records, two-hundred and sixty women that were diagnosed as poor responder from January 2015 to December 2018. Patients were then classified into 4 groups according to POSIEDON stratification taking into consideration, age, AFC, and AMH values. The study was approved by the clinic's ethical committee.
The inclusion and exclusion criteria were as follows:
- Number of oocytes retrieved ≤9 at previous COS
- Gonadotropin-releasing hormone (GnRH) antagonist cycles.
- Male factor (azoospermia)
- Endometriosis (Grade 3 and Grade 4)
- Frozen embryo transfer cycle
- Premature ovarian failure
- >9 oocytes retrieved in past cycles.
Ovarian stimulation and embryo transfer
Baseline day 2 parameters which included AFC, AMH, follicle-stimulating hormone (FSH), luteinizing hormone (LH), and thyroid-stimulating hormone were assessed in the cycle before ART. In the treatment cycle on day 2 AFC, E2 and progesterone (P4) levels were evaluated. For COS, a combination of recombinant FSH and ultrapure human menopausal gonadotropin (HMG) was used in a GnRH antagonist cycle. Recombinant human chorionic gonadotropin (HCG) 250 mcg was administered subcutaneously for trigger when follicular diameter was 17 mm or more. Oocyte retrieval was performed 35 h after administration of HCG. Conventional IVF or intracytoplasmic sperm injection (ICSI) was performed as appropriate (70% ICSI and 30% IVF). The best embryos of good quality were selected for embryo transfer at blastocyst stage under ultrasound guidance. Intramuscular progesterone was given for luteal phase support. Serum β-HCG levels were done 10 days after embryo transfer. If the β-HCG was positive, luteal phase support was continued and β-HCG repeated after 7 days and a transvaginal ultrasound done for documentation of clinical pregnancy. The transvaginal ultrasound scan was repeated after 1 week for documentation of fetal cardiac activity. Luteal phase support was continued till 12 weeks of gestation.
Data collection and outcome parameters
Data were collected from the hospital records. Patient's data included maternal age, duration, and causes of infertility as well as clinical and laboratory characteristics of ART cycles. The primary outcome parameter was live birth, and the secondary outcome parameters were fertilization, cleavage, blastocyst formation, and implantation rates. We also looked at the days and total dose of stimulation, oocytes retrieved, quality of embryos on days 3 and 5, CPR, and miscarriage rate. Clinical pregnancy was considered as the presence of a gestational sac with fetal heart activity at 6 weeks of gestation. The implantation rate was the number of gestational sacs observed by transvaginal sonography divided by the number of embryos transferred. Fertilization rate was considered as 2 pronuclear or syngamy embryos divided by the total number of metaphase II (MII) oocytes.
All patients were categorized into 4 groups according to the POSEIDON stratification [Figure 1]. Outcome parameters were also compared between 4 groups and 2 subgroups in Groups 1 and 2.
The statistical analysis was performed by STATA 11.2 (College Station, StataCorp LP, TX, USA). Analysis of variance for variables that did not distribute normally was done by Krurskal–Wallis test. Chi-square test or Fisher's exact test was used to measure the association between the fertilization rate, cleavage rate, implantation rate, biochemical pregnancy rate, liver birth rate, and miscarriage rate and expressed as frequency and percentage. P < 0.05 was considered statistically significant.
| Results|| |
We stratified poor responder women into four groups according to the POSEIDON stratification. The number of patients were 174, 45, 22, and 19 in Group 1 to 4, respectively. The demographic features and cycle characteristics of the four groups are listed in [Table 2]. Age, AFC, AMH, total days, and dosage of gonadotropins used, E2 on the day of HCG, and number of cumulus oocyte complexes retrieved were significantly different between groups (P < 0.001). There was no difference in the fertilization and cleavage rate across the groups, but the blastocyst formation rate was higher in younger patients and reached statistical significance [Figure 2]. There was no difference in the quality of embryos on day 3 and 5 across the groups [Figure 3]. ART outcome is depicted in [Table 3]. When four subgroups of Groups 1 and 2 were compared to Groups 3 and 4, implantation rate was significantly higher in women <35 years (P < 0.001) that is 1b and 3. However, this increased implantation rate did not convert to CPR and live birth rate (LBR), which was significantly lower in Group 3. The implantation rate was significantly higher in Group 1 b as compared to 2b, which corresponds to higher implantation rate in women <35 years.
|Figure 2: Fertilization, cleavage and blastocyst formation rate in different groups|
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|Figure 3: Embryo quality on day 3 and day 5 of in vitro fertilization culture|
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CPR was statistically higher in Group 1b and Group 2b where ovarian reserve was adequate and more than 5 oocytes were retrieved irrespective of the age (P < 0.001). In those with low ovarian reserve, CPR was statistically higher in the women <35 years (P < 0.001). LBR was higher in women with adequate ovarian reserve and more than 5 oocytes were retrieved, that is, Group 1b and Group 2b irrespective of the age (P = 0.029). In patients with low ovarian reserve though LBR was more in women <35 years it did not reach statistical significance. Miscarriage rate was higher in women with low ovarian reserve but did not reach statistical significance (P = 0.931). With regard to LBR, there was no difference between the POSEIDON subgroup classification 1 and 2 when more than five oocytes were retrieved. There were no pregnancies in Groups 1 and 2 when less than five oocytes were retrieved [Table 4].
| Discussion|| |
In our study, we observed that LBR was significantly higher in POSEIDON Groups 1b and 2b compared with the other groups after COS in an antagonist protocol. Apart from ovarian reserve, age was also an important factor influencing the success of ART in our study and this is in coherence with other published data., A study published by Eftekhar et al. in 2018 showed that it was only the ovarian reserve that played an important role.
The POSEIDON stratification on the other hand introduced a new measure for successful ART outcome, namely, the ability to retrieve adequate number of oocytes needed for a specific patient to obtain at least one euploid embryo for transfer. Adequate ovarian reserve with more than five oocytes retrieved in Groups 1b and 2b led to better ART outcome as compared to those with low ovarian reserve and when less than five oocytes were retrieved.
Classifying patients into four groups according to POSIEDON stratification taking into consideration the age, AFC, and AMH values enable us to predict the ART outcome. There are publications which have proposed AFC and AMH levels to be good ovarian reserve markers for prediction of ovarian response to COS. However, ultimately the choice of marker used may depend on the organization, setting, availability of equipment, or patient-related conditions. AFC and AMH may have the best sensitivity and specificity but is associated with 10%–20% false-positive rate. AMH may be a better marker than AFC as it measures also the submerged part of the iceberg of follicles, i.e., the intrinsic, so-called “acyclic” ovarian activity. Assessment of serum AMH concentration especially in older patients more than 40 years may be able to predict oocytes numbers after COS at ART. If we need to use a single marker to predict response, AFC seems to be efficient, most used, and more readily available. It may be of value to use combination of ORTs – FSH, AMH, AFC, inhibin B, especially if the female age is more than 37 years or when there has been a previous poor response to COS.
At times in our clinical practice, we do observe that the response to COS may be poor despite good ovarian reserve. This could be due to suboptimal response to COS and may be related to FSH and LH receptor polymorphism or hyposensitivity to FSH. At times, it could also be related to the use of suboptimal drug quality. At this stage, calculating the follicular output rate (FORT) may be helpful in explaining the discrepancy between ovarian response to the stimulation and ovarian reserve and also could be considered as a good marker for individualized ovarian stimulation. The incidence of hyporesponse is about 15%. It reflects the hyposensitivity of granulosacells to standard FSH dose and is associated with higher FSH consumption, low FORT, unexpected poor response (i.e., <3 eggs retrieved), and lower pregnancy rates. If identified early (i.e., days 5–8 of COS), addition of r-human LH/HMG is effective in rescuing follicle/oocyte number (FORT) and improving the embryo competence with better ART outcome.
Therefore, we must not only consider decreased ovarian reserve patients as poor responders with low prognosis but also those patients with normal ovarian reserve who are hyporesponders as low prognosis group. The POSEIDON stratification was therefore introduced to decrease the heterogeneity of the Bologna criteria and to serve as a guide for personalized treatment protocols. Hyporesponders can be identified by looking at the response to previous stimulation and identifying gonadotropin and their receptor polymorphism. We can then individualize the COS protocols using different GnRH analog regimens, modifying the FSH starting dose, personalizing gonadotropin dose and type (i.e., FSH monotherapy or LH- containing drugs) and evaluating special regimens, like oocyte/embryo accumulation to maximize outcomes. Once identified, one could also offer them fertility preservation by ovarian cortical tissue cryopreservation, especially if she wants to delay conception, either after one live birth or due to social reasons. Individualized treatment protocols for poor responders should be based on women's age, accurate evaluation of ovarian reserve, prior response to COS, and FORT. Hence, to individualize COS protocols, we must determine the ideal number of oocytes required to maximize success rate and minimize adverse outcomes. One must also remember that it is not only the quantity but also the quality of the oocytes that is going to influence the success rate.
There were several studies that attempted to determine the ideal number of oocytes to achieve an optimal success rate with a high LBR.,,, The numbers varied from 10 to 18. In our study, Groups 1 and 2 had significantly higher MII oocytes with a mean of 6.13 and 5.56 compared to Groups 3 and 4 with 4.18 and 3.58, respectively. Although women in the high AMH had significantly more blastocysts available for transfer than women in the low AMH stratum, the probability that a MII oocyte developed to a blastocyst decreased significantly with increasing r-human FSH doses (P < 0.001) in the high AMH group (P < 0.001).
In our study, the LBR was similar and significantly higher in Groups 1b and 2b when more than 4 oocytes were retrieved. We did not have any live births in Group 1a and 2a, whereas in Groups 3 and 4, the LBR was significantly lower compared to Group 1b and 2b. This data signify that despite good ovarian reserve, it is the number of oocytes that determines the ART outcome. These results are comparable to that of Drakopouloset al., who had evaluated 1099 women undergoing their first IVF cycle with the single embryo transfer and had concluded that the LBR was significantly higher if 4 or more oocytes are retrieved.
Sunkaraet al. analyzed 12,4351 IVF pregnancies andfound anassociation between response to ovarian stimulation and miscarriage in ART pregnancies. The miscarriage rate was significantly higher (16.9%) in women where three or less oocytes were retrieved. In our study, the miscarriage rate was higher in women with low ovarian reserve and when three or less oocytes were retrieved (25% in group 3 compared to 18% and 16% in group 1b and 2b respectively) but did not reach statistical significance (P = 0.931).
The POSEIDON classification also emphasis on the embryos' euploidy, as a factor influencing the ART outcome. All of us are aware and agree that embryo aneuploidy rate is age dependent and is significantly higher in women more than 37 years, and this can influence the oocyte and embryo quality. It ranges from 25% to 30% in women younger than 35 to more than 90% in women older than 42 years.,, In our study too, the LBR was higher in Group 1b compared to 2b and in Group 3 compared to 4, but this did not reach statistical significance.
Apart from age, one must also look for FSH receptor polymorphism, which can decrease the follicular sensitivity to exogenous FSH and result in low follicular output rate (FORT).,,,, Therefore, investigating for FSH and LH receptor polymorphism in women who have had poor response in previous ART cycles could be a good option to identify this subgroup and offer different approach to COS. However, this may not be possible in Indian settings with low resources.
| Conclusions|| |
Use of POSEIDON stratification in patients with a reduced ovarian reserve or unexpected inappropriate ovarian response to exogenous gonadotropins, helps in identifying low prognosis patients and helps to improve the management protocols. In those patients undergoing ART, it allows the clinician to use a tailored approach to patient handling by personalizing gonadotropin type and doses (i.e., FSH monotherapy or LH-containing gonadotropins), choosing the right GnRH analog regimens, evaluating and adopting regimens such as oocyte/embryo accumulation. If feasible, one could also detect polymorphisms of gonadotropins and their receptors. Poor responders are heterogeneous group and not homogeneous for pregnancy prospects and thus represents a therapeutic challenge to the clinicians. Apart from the number of oocytes retrieved and number of MII oocytes, age is an important factor that modulates the chance of pregnancy. Adopting the POSEIDON criteria to individualize the therapy to obtain at least one euploid embryo will minimize the time to pregnancy with a higher successful outcome.
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Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2], [Table 3], [Table 4]