KnE Medicine | The 6th Congress of the Asia Pacific Initiative on Reproduction (ASPIRE 2016) | pages: 193-201

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1. Introduction

Management of poor responder patients is still a challenge for clinicians engaged in Asisted Reproductive Technology [1,2]. Various protocols have been given for improving outcomes for patients with poor responders, but the results are often disappointing, since any given protocol provides the end result with no significant different [2,3,4].

Poor response patient in the literature have diversity in terminology, characterized generally these patients respond minimal to the protocol of ovarian stimulation given, which is illustrated by the results of the low number of follicles, the low number of oocytes, the high failure cycle, in which will ultimately result in lower pregnancy success rates [1-7].

Poor response patient had a wide range of age [1,2]. Although associated with reduced ovarian reserve caused by aging process, poor responders can occur at a young age. Although egg donation is often suggested as an alternative, but different stimulation protocols should be done before it is offered in younger patients with poor response, since the optimal ovarian stimulation should be given first before proceed to the egg donation [1,2].

Various stimulation protocols offered for patients with poor response, such as by using high-dose gonadotrophin, estrogen, androgen administration, agents modulating androgen etc [3,4]. But there has been no RCTs or research can prove the success rate or superiority of one protocol among other in treatment of poor responder.

Infertility has become emerging problems in Indonesia, self-awareness for seeking help for fertility issues had increase in decade. Approximately 10% of population experiencing infertility issues [8]. Among those percentage, 9% - 24% are poor response patients [9]. There are limited basic data about the poor response patients in Indonesia. Likewise the best stimulation protocol or an additional protocol provided with the success rate.

2. Methods

Table 1

Demographic characteristics of patients.


Variables Median ± Standar Deviasi N (%)
Age 39 ± 5,406
Duration of infertility 8 ± 4,783
Additional etiology
Endometriosis 64 (22,8)
Endometrial polyps 39 (13,9)
Fibroid 17 (6)
Ovarian cyst 4 (1,4)
Bilateral tubal occlusion 9 (3,2)
Unilateral tubal occlusion 4 (1,4)
Bilateral non patent tube 9 (3,2)
Unilateral non patent tube 6 (2,1)
Adenomyosis 16 (5,7)
Hydrosalping 14 (5)
OAT 17 (6)
Azoosperm 10 (3,6)
Astenozoosperm 9 (3,2)
Oligozoosperm 12 (4,3)
Oligosperm 18 (6,4)
Hyperprolactin 5 (1,8)
Table 2

Distribution of therapy given and demographic data.


Variables LH GH LH+GH Control
Median ± SD N (%) Mean/ Median ± SD N (%) Median ± SD N (%) Median ± SD N (%)
Number of patients 118 28 47 88
Age 39 ± 4,623 39 ± 8,025 40 ± 4,186 39 ± 5,914
Duration of infertility 9 ± 4,679 9,86 8 ± 4,631 7 ± 4,837
Additional etiology
Endometriosis 29 (24,6) 6 (21,4) 6 (12,8) 23 (26,1)
Endometrial polyps 23 (19,5) 1 (3,6) 2 (4,3) 13 (14,8)
Fibroid 10 (8,5) 0 (0) 2 (4,3) 5 (5,7)
Ovarian cyst 1 (0,8) 0 (0) 0 (0) 3 (3,4)
Bilateral tubal occlusion 3 (2,5) 2 (7,1) 3 (6,4) 1 (1,1)
Unilateral tubal occlusion 2 (1,7) 0 (0) 0 (0) 2 (2,3)
Bilateral non patent tube 3 (2,5) 1 (3,6) 2 (4,3) 3 (3,4)
Unilateral non patent tube 4 (3,4) 1 (3,6) 0 (0) 1 (1,1)
Adenomyosis 10 (8,5) 0 (0) 1 (2,1) 5 (5,7)
Hydrosalping 9 (7,6) 1 (3,6) 1 (2,1) 3 (3,4)
OAT 14 (11,9) 1 (3,6) 0 (0) 2 (2,3)
Azoosperm 1 (0,8) 1 (3,6) 3 (6,4) 5 (5,7)
Astenozoosperm 2 (1,7) 4 (14,3) 2 (4,3) 1 (1,1)
Oligozoosperm 5 (4,2) 1 (3,6) 3 (6,4) 3 (3,4)
Oligosperm 9 (7,6) 1 (3,6) 6 (12,8) 2 (2,3)
Hyperprolactin 3 (2,5) 0 (0) 0 (0) 2 (2,3)
Table 3

Outcome data of research samples.


LH GH LH+GH Control
Number of patients 118 28 47 88
Follicles count 6 ± 4,015 8 ± 6,523 5 ± 4,621 3 ± 3,954
Oocyte count 4 ± 2,923 5 ± 4,634 4 ± 3,695 2 ± 2,406
Number of patients experienced degenerative oocyte 11 2 3 6
Mean of embryo transferred 2 ± 0,977 2,58 2 ± 0,984 1 ± 0,868
Table 4

Outcome data of statistic difference in number of mean follicles count.


P value
Kontrol LH Seizen LH+Seizen
Kontrol 0,000 0,006 0,016
LH 0,000 0,298 0,999
Seizen 0,006 0,298 0,404
LH+Seizen 0,016 0,999 0,404
Table 5

Outcome data of statistic difference in number of mean oocyte count.


P value
Kontrol LH Seizen LH+Seizen
Kontrol 0,001 0,012 0,005
LH 0,001 0,347 0,730
Seizen 0,012 0,347 0,806
LH+Seizen 0,005 0,730 0,806
Table 6

Comparison of cleavage rate between LH and control groups.


Cleavage rate Good Poor Total p
LH 27 80 107 0,004
Control 37 45 82
Total 64 125 189
RR 1,788 (CI 95% 1,194 – 2,679)
Table 7

Comparison of cleavage rate between GH and control groups.


Cleavage rate Good Poor Total p
GH 7 19 26 0,1
Control 37 45 82
Total 44 64 108
RR 1,676 (CI 95% 0,852 – 3,297)
Table 8

Comparison of cleavage rate between LH+GH and control groups.


Cleavage rate Good Poor Total p
LH+GH 26 18 44 0,649
Control 37 45 82
Total 63 63 126
RR 1,103 (CI 95% 0,719 – 1,692)
Table 9

Comparison of chemical pregnancy between LH and control groups.


Chemical pregnancy Yes No Total P
LH 52 46 98 0,112
Control 32 46 78
Total 84 92 176
RR 0,773 ( CI 95% 0,559 – 1,070)
Table 10

Comparison of chemical pregnancy between GH and control groups.


Chemical pregnancy Yes No Total P
GH 14 10 24 0,136
ontrol 32 46 78
Total 46 56 102
RR 0,703 (CI 95% 0,457 – 1,081)
Table 11

Comparison of chemical pregnancy between GH and control groups.


Chemical pregnancy Yes No Total P
LH+GH 21 21 42 0,345
Control 32 46 78
Total 53 67 120
RR 0,821 (CI 95% 0,548 – 1,228)

2.1. Population and Sample

This retrospective cohort study was performed on Yasmin Clinic, Jakarta. Target population of this research was poor response patients underwent assisted reproductive treatment in Yasmin Clinic, Jakarta. The accessible population was poor response patients who came in between January 2012 to January 2015 and underwent assisted reproductive treatment in Yasmin Clinic (RSCM). The study was approved by ethics committee.

2.2. Data Collection

Data were collected from medical record. Inclusion criteria used in this research are all infertile patients who meet the Bologna criteria (EHSRE) for poor response patients in Yasmin Clinic. Exclusion criteria from this study are patients which failed to continue the stimulation nor stop the protocol and the ones with incomplete or loss of medical record data. All medical records from Yasmin Clinic between January 2012 to January 2015 were collected. We collected patients' demographic data, etiology of infertility, selected treatment for infertility, cleavage rate and chemical pregnancy as the outcome.

Cycles were cancelled in the presence of <1 developing follicle. eggs retrieval was performed after administration of HCG. Insemination was performed by either conventional IVF or ICSI. Fertilization then assessed 16 hours after insemination and embryo's cleavage was evaluated at 24-hours interval by recording cell number and then classified as grade I – III (poor – good).

2.3. Data Analysis

Statistical analysis of obtained data was analyzed by means of Statistical Package for the Social Sciences (SPSS) for Windows version 11.0 software. Differences between each variables were analyzed using Chi-square to compare the chemical pregnancy rate between selected therapy and to asses the cleavage rate within them.

3. Result

From January 2012 to January 2015, there were 324 patients meet the criteria of poor response based on our inclusion criteria. From all 324, we were having 43 patients as the drop out due to incomplete medical report and cycle cancellation. Demographic and infertility characteristic of patients are summarized in Table 1.

Poor response patients were given several different therapies, used gonadotrophin only; we used this group as a control, several added Luteinizing hormones, Growth hormones and even combination between two. Table 2 showed distribution of therapy given to poor response patients. We also obtained data for follicles and oocyte numbers, number of patients experienced degeneratives oocyte and mean of embryo transferred, listed in Table 3.

We classified mean of follicle count in each group and calculated the difference between groups, we found the follicle count in LH groups shows significant higher compare with control group, Table 4. We also classified oocyte count in each groups and searched for the difference between groups, and once again LH groups showed significant higher number of oocyte counts than control groups, as listed in Table 5.

We calculated the cleavage rate of each groups and also the chemical pregnancy rate in each groups and find the most suitable therapy for poor response patients. The cleavage rate was statistically significant different between control group and LH group (p value 0,004), where control group give the positive correlation with cleavage rate, while we found no difference between other groups and also in chemical pregnancy we found no differences. Here are the data of the outcome results.

4. Discussion

Various protocols have been proposed to improve the outcome for patients, although no RCT can provide the evidence based of success rate of one protocol among others [1-4,17]. we did not differ our patients into young and old poor responders, since it is generally accepted that both groups have diminished number of follicle in the ovary [1].

Our study demonstrated the follicle count and the oocyte count were statistically significant difference between control group and LH group. Our findings was similar with previous study which stated that with LH pretreatment could increase the number of collected oocyte compare with control [2]. Our study showed supplementation with r-LH giving higher follicles count and oocyte count.

Our study demonstrated the cleavage rate were statistically significant difference between control group and LH group. However, other cleavage rate comparison between groups were statistically similar. The use of LH is suggested by several studies which reporting a higher embryo ploidy rate and a lightly higher pregnancy rate [12], although in our study we only found the correlation with chemical pregnancy.

The chemical pregnancy success rate between control group, LH group, GH group and LH+GH group showed no statistically different.

5. Conclusion

In this study we found that with adjuvant therapy with recombinant Luteinizing Hormones, produced higher follicles count, oocyte count and cleavage rate. A larger trial and comprehensive trial need to be prepared to assess contributing factors to increase the pregnancy rate in assisted technology reproductive methods.

6. Acknowledgments

Authors would like to thank our mentor, Dr. dr. Budi Wiweko, SpOG(K) for his expertise which guided us in doing this study, helping and supporting us in many ways while making this paper. This research also made possible with cooperation of Yasmin Clinic for giving us all the support and time needed to do the research.

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